Protocol

Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med 2013;368:2455-66. DOI: 10.1056/NEJMoa1304048

Wenzel S, et al. Dupilumab in Adults with Inadequately Controlled Asthma and Elevated Eosinophils

"This supplement contains the following items: 1. Original protocol, final protocol, summary of changes. 2. Statistical analysis plan, summary of changes prior to database lock"

CLINICAL TRIAL PROTOCOL TITLE: A randomized, double-blind, placebo-controlled, parallel group study to assess the efficacy, safety, and tolerability of SAR231893/REGN668 administered subcutaneously (SC) once weekly for 12 weeks in patients with persistent moderate to severe eosinophilic asthma who are partially controlled/uncontrolled by inhaled corticosteroid (ICS) plus long-acting beta2 agonist (LABA) therapy COMPOUND: SAR231893/REGN668 STUDY NUMBER: ACT11457

Version Number:

1

EudraCT and/or IND Number(s):

105,379

Date:

15-Nov-2010

Total number of pages:

105

Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of sanofi-aventis (or any of its affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written consent of sanofi-aventis (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date of communication or afterwards (i) controls directly or indirectly sanofi-aventis, (ii) is directly or indirectly controlled by sanofiaventis, with ‘control’ meaning direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity

According to template: QSD-002579 VERSION N°3.0 (11-JUN-2010)

Page 1

Clinical Trial Protocol ACT11457 - SAR231893/REGN668

15-Nov-2010 Version number: 1

NAMES AND ADDRESSES OF COORDINATING INVESTIGATOR

Name: Address:

Tel: Fax: E-mail:

MONITORING TEAM’S REPRESENTATIVE

Name: Address:

Tel: Fax: E-mail:

SPONSOR

Company: Address:

OTHER EMERGENCY TELEPHONE NUMBERS

Property of the sanofi-aventis group - strictly confidential

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CLINICAL TRIAL SUMMARY COMPOUND: SAR231893/REGN668 STUDY No : ACT11457 TITLE

A randomized, double-blind, placebo-controlled, parallel group study to assess the efficacy, safety, and tolerability of SAR231893/REGN668 administered subcutaneously (SC) once weekly for 12 weeks in patients with persistent moderate to severe eosinophilic asthma who are partially controlled/uncontrolled by inhaled corticosteroid (ICS) plus long-acting beta2 agonist (LABA) therapy

INVESTIGATOR/TRIAL LOCATION

USA

STUDY OBJECTIVE(S)

Primary Objective The primary objective of this study is to investigate the effects of SAR231893/REGN668 administered subcutaneously (SC) once weekly for 12 weeks as compared to placebo on reducing the incidence of asthma exacerbations in patients with persistent moderate to severe eosinophilic asthma. Secondary Objective(s)

STUDY DESIGN

•

To assess the safety and tolerability of SAR231893/REGN668 administered SC once weekly for 12 weeks in patients with persistent moderate to severe eosinophilic asthma

•

To assess SAR231893/REGN668 serum concentrations following once weekly SC dosing for 12 weeks in patients with persistent moderate to severe eosinophilic asthma

Randomized, double-blind, placebo-controlled, with parallel groups; 2 week screening and run-in, 4-week background therapy stable phase and 8-week background therapy withdrawal phase postrandomization; add-on therapy approach to ICS/LABA combination therapy with systematic ICS/LABA withdrawal during treatment; 6-week follow-up period: • •

Screening period (up to 14 days) Treatment (12 weeks) - Background therapy stable phase (4 weeks) - Background therapy withdrawal phase (8 weeks) • Follow-up (6 weeks) Patients who satisfy the inclusion and exclusion criteria will be randomized to one of the following treatments: •

300 mg SAR231893/REGN688 administered SC once weekly for 12 weeks • Placebo administered SC once weekly for 12 weeks Post-randomization visits during the 12-week treatment period will occur every week and will be followed by a 6 week follow-up period off investigational product to assess the safety of SAR231893/REGN668. Sentinel cohort: Prior to opening enrollment to the entire cohort of 100 patients, a sentinel cohort consisting of 20 patients (10 active, 10 placebo) will Property of the sanofi-aventis group - strictly confidential

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be enrolled and evaluated by an Independent Data Monitoring Committee (IDMC) for any safety issues. Blinded clinical safety data through Week 5 (Visit 7) will be reviewed by the IDMC. Based on this review, a decision will be made to enroll the remainder of patients, modify the protocol, or stop the study. During this safety evaluation the sentinel cohort will continue to receive investigational product for the scheduled 12 weeks. Algorithm for background therapy (ICS/LABA) withdrawal: •

At 4 weeks post-randomization (Visit 6) patients will be switched from their 250/50 µg BID or 500/50 µg BID fluticasone/salmeterol combination therapy (Advair®) to an equivalent ICS dose of fluticasone (220 µg BID or 440 µg BID) monotherapy. The LABA component (ie, salmeterol) will be discontinued. • At subsequent 2 week visits, beginning with Week 6, the fluticasone dose will be reduced by approximately 50% provided that the patient does not meet any of the criteria for an asthma exacerbation as defined below: - A 30% or greater reduction from baseline in morning peak expiratory flow (PEF) together with ≥6 additional reliever puffs of albuterol in a 24 hour period (compared to baseline) on 2 consecutive days - Deterioration of asthma, as determined by the Investigator, requiring: - Oral steroid treatment, or - An increase in ICS ≥4 times the baseline dose of ICS, or - Hospitalization If a patient meets the above criteria for an asthma exacerbation, he/she will be withdrawn from investigational product and treated by the investigator with appropriate medical therapy. The patient will be followed for safety for the subsequent 6 weeks per the study schedule. Post-Treatment Follow-up : Upon completing 12 weeks of treatment with the investigational product (or following early discontinuation of investigational product), patients will be placed on their original dose of fluticasone/salmeterol combination therapy (dose at study entry) and albuterol (as needed) to control their symptoms. Patients will continue to record daily their PEFs, asthma symptoms, and albuterol use in their electronic diaries for an additional 6 weeks off investigational product, and they will return to the study site at the end of the 6-week period for a safety evaluation. In addition, prior to the visit scheduled for Week 18, the patient will be contacted by telephone on Weeks 13, 14, and 16 (1, 2, and 4 weeks after the end-of-treatment assessment) to evaluate adverse events (AEs). Patients will be instructed to contact the Investigator during the 6-week follow-up period, if their asthma symptoms worsen, requiring medical attention. Stopping Rules for the administration of investigational product in an individual patient: Discontinuation of investigational product in an individual patient will be based upon the criteria set forth above for an asthma exacerbation.


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If a patient meets any of the criteria for asthma exacerbation, the Investigator will treat them according to standard medical practice and then place them on their pre-existing asthma medication (prior to study entry) and follow them for 6 weeks for safety per the study schedule. Treatment Discontinuation Follow-up : Patients who discontinue investigational product prior to 12 weeks of treatment will receive end of treatment assessments normally scheduled for Visit 14, receive follow-up telephone calls 1, 2, and 4 weeks after the end of treatment assessment, and return to the clinic 6 weeks after the end of treatment assessment for a safety evaluation. STUDY POPULATION

Inclusion Criteria:

Main selection criteria:

I 01. Patients with a physician diagnosis of moderate to severe persistent asthma for at least 12 months based on the Global Initiative for Asthma (GINA) 2009 Guidelines, whose airway inflammation is likely to be eosinophilic and whose asthma is partially controlled or uncontrolled on fluticasone/salmeterol combination therapy based on the following criteria: •

On a stable dose of either 250/50 µg BID or 500/50 µg BID fluticasone/salmeterol combination therapy for at least 3 months prior to screening • Blood eosinophils ≥350 cells /µL during the screening phase • ACQ score ≥1.5 and ≤2.5 at the screening visit • Forced expiratory volume (FEV1) ≥50% and ≤80% predicted normal during the screening phase (3 attempts maximum) and on the randomization day prior to the first dose of investigational product (3 attempts maximum) • Reversibility of at least 12% and 200 mL in FEV1 after 200 µg to 400 µg (2 to 4 inhalations) of albuterol during the screening phase (3 attempts maximum) I 02. Patients who have signed an Informed Consent Form and Health Insurance Portability and Accountability Act (HIPAA) Authorization Form Exclusion Criteria Patients who have met all the inclusion criteria will be screened for the following exclusion criteria: E 01. Patients less than 18 years or greater than 65 years of age (ie, have reached the age of 66 at the screening visit) E 02. Clinically relevant abnormal laboratory values suggesting an unknown disease and requiring further evaluation E 03. Chronic obstructive pulmonary disease (COPD) and/or other lung diseases impairing Pulmonary Function Tests E 04. Patients requiring beta-adrenergic receptor blockers for any reason E 05. Current smoker or cessation of smoking within the 6 months prior to screening


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E 06. Previous smoking with a smoking history >10 cigarette packyears E 07. In-patient hospitalization or emergency care visit due to asthma exacerbation in the 3 months prior to screening E 08. Plans to begin allergen immunotherapy within the study period E 09. Participation in another study within 6 months prior to screening if the study medication is an antibody or within 30 days prior to screening for all other study medications E 10. Previous enrollment into the current study E 11. Patient is the Investigator, his/her family member, or employee at the investigational site E 12. Known or suspected non-compliance, alcohol or drug abuse E 13. Inability to follow the procedures of the study (eg, due to language problems, psychological disorders) E 14. Reversal of sleep pattern (eg, night shift workers) E 15. Treatment with drugs known to prolong QTc interval E 16. Concomitant severe diseases or diseases for which the use of ICS (eg, active and inactive pulmonary tuberculosis) or longacting beta2 agonists (eg, diagnosis of a history of significant cardiovascular diseases, insulin-dependent diabetes mellitus, uncontrolled hypertension, hyperthyroidism, thyrotoxicosis, pheochromocytoma, hypokalemia, prolonged QTc interval [male >430 msec, female >450 msec] or tachyarrhythmia) are contraindicated E 17. Use of injectable glucocorticosteroids or oral systemic glucocorticosteroids within 2 months prior to screening or more than 3 courses within the 6 months prior to screening E 18. Pre-treatment with variable doses of ICS, either alone or in combination with a non-steroidal controller (other than fluticasone/salmeterol combination therapy) E 19. Patients receiving prohibited concomitant medications (see list Section 8.10) E 20. Known allergy to doxycycline or related compounds E 21. Pregnancy or intention to become pregnant during the course of the study, breast feeding, or unwillingness to use a highly effective method of contraception (oral contraception or intrauterine device) throughout the study in women of childbearing potential E22. Recent history of a parasitic infection or travel to a parasitic endemic area within 6 months prior to screening Total expected number of patients:

Approximately 100


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STUDY TREATMENT(s) Investigational Product(s)

SAR231893/REGN668 or Matching Placebo

Formulation

Sterile SAR231893 /REGN668 150 mg/mL solution for SC injection will be provided in a 5 mL glass vial. Each vial will contain a withdrawable volume of 2 mL. Sterile placebo will be provided in identically matched glass 5 mL vials.

Route(s) of administration:

Subcutaneous

Dose regimen:

SAR231893/REGN668 (300 mg) administered SC once weekly in the morning in the clinic for 12 weeks Placebo administered SC once weekly in the morning in the clinic for 12 weeks

Non Investigational Product(s)

Patients may administer albuterol hydrofluoroalkane pressurized metered-dose inhaler as rescue medication as needed throughout the study. Fluticasone/salmeterol combination therapy during background therapy stable phase (first 4 weeks) followed by fluticasone (monotherapy) during background therapy withdrawal phase (Week 4 to end of treatment).


Oral inhalation for albuterol, fluticasone/salmeterol combination therapy and fluticasone monotherapy

Dose regimen:

Albuterol: As needed Background therapy stable phase: Fluticasone/salmeterol combination therapy (250/50 µg BID or 500/50 µg BID) from screening/run-in to Week 4 Background therapy withdrawal phase: Fluticasone monotherapy 220 µg BID or 440 µg BID Week 4 to Week 6, then decreased by 50% every 2 weeks

PRIMARY AND SECONDARY ENDPOINT(S)

Primary Endpoint: Occurrence of an exacerbation of asthma as defined by any of the following: • A 30% or greater reduction from baseline in morning PEF together with ≥6 additional reliever puffs of albuterol in a 24 hour period (compared to baseline) on 2 consecutive days • Deterioration of asthma, as determined by the Investigator, requiring: - Oral steroid treatment, or - An increase in ICS ≥4 times the baseline dose of ICS, or -Hospitalization Secondary Endpoint(s): • Time to asthma exacerbation post-randomization • FEV1 change from baseline at Week 12 and change from baseline at each visit • Morning and evening PEF change from baseline at Week 12 and change from baseline at each visit • ACQ score change from baseline at Week 12 and change from


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baseline at each study visit • Change from baseline at Week 12 and change from baseline at each visit for asthma symptom scores in the morning and evening, and nocturnal awakenings • Change from baseline at Week 12 and change from baseline at each visit in number of inhalations/day of albuterol for symptom relief Safety Evaluation: • Adverse events (AE) • Vital signs • Physical exam • Electrocardiogram (ECG) • Clinical laboratory tests • Anti-drug antibodies Pharmacokinetic Evaluation: • Serum SAR231893/REGN668 concentrations and pharmacokinetic (PK) profile Pharmacodynamics: • Total IgE, antigen-specific IgE (Phadiatop®), eotaxin-3, YKL-40, thymus and activation-regulated chemokine (TARC), thymic stromal lymphopoietin (TSLP), carcinoembryonic antigen (CEA) • Serum samples for exploratory protein analysis • Whole blood samples for Ribonucleic acid (RNA) • Pharmacogenomic deoxyribonucleic acid (DNA) sample (optional) • Induced sputum for eosinophils and neutrophils and exploratory analyses (subset of sites) • Exhaled nitric oxide (eNO) levels (subset of sites) • Blood eosinophil count ASSESSMENT SCHEDULE

Screening/Run-in – Day -14 to Day -1 • Sign informed consent, demography, medical history, inclusion/exclusion criteria, FEV1 to assess reversibility, prior meds, physical exam, ACQ, spirometry, dispense electronic diary/peak flow meter, dispense albuterol as needed, assessment of AEs, vital signs, ECG, serum pregnancy test, blood collection for hematology (including eosinophil count for eligibility) and clinical chemistries, blood collection for total IgE, Phadiatop, eotaxin-3, TARC, YKL-40, TSLP, CEA, protein, and RNA Randomization –Within 2 weeks of the start of screening (Day 1) • Prior/concomitant meds, spirometry, randomization to 1 of 2 treatments and administration of SC dose of SAR231893/REGN668 or placebo, sputum collection for eosinophil and neutrophil counts (subset), eNO (subset), AEs, vital signs, urine pregnancy test, blood for PK and antiSAR231893/REGN668 antibody, blood for pharmacogenomics (optional), blood collection for total IgE, eotaxin-3, TARC, YKL-40, TSLP, CEA, protein, and RNA Treatment – post-randomization Day 1 to Week 12: Once weekly SC administration of investigational product at clinic on Days 1 to Week 11 • Background therapy stable phase – post-randomization Day 1 to Week 4


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Concomitant meds, ACQ, spirometry, discontinue fluticasone/salmeterol combination therapy and replace with equivalent dose of fluticasone on Week 4; evaluation of data from electronic diary/PEF meter, sputum collection for eosinophil and neutrophil counts (subset), eNO (subset), AEs, vital signs, ECG, blood for hematology (including eosinophil count) and clinical chemistries, blood for PK and anti-SAR231893/REGN668 antibody, blood collection for total IgE, eotaxin-3, TARC, YKL-40, TSLP, CEA, protein, and RNA • Background therapy withdrawal phase – post-Week 4 to Week 12 Concomitant meds, physical examination, ACQ, spirometry, reduce ICS dose by 50% every 2 weeks unless patient meets criteria for asthma exacerbation (patient withdrawn), evaluation of data from electronic diary/PEF meter, sputum collection for eosinophil and neutrophil counts (subset), eNO (subset), AEs, vital signs, ECG, urine pregnancy test, blood for hematology (including eosinophil count) and clinical chemistries, blood for PK and anti-SAR231893/REGN668 antibody, blood collection for total IgE, Phadiatop, eotaxin-3, TARC, YKL-40, TSLP, CEA, and protein Post-treatment Observations – Week 18 • Concomitant meds, ACQ; spirometry, AEs (including telephone contact at Week 13, 14, and 16 to evaluate AEs), vital signs, blood for PK and anti-SAR231893/REGN668 antibody STATISTICAL CONSIDERATIONS

Randomization: A total of 100 patients will be randomized in a 1:1 ratio into the 2 treatment groups. The randomization will be stratified by patient’s prior fluticasone/salmeterol combination therapy doses (250/50 µg BID or 500/50 µg BID). Primary Efficacy Endpoint: Asthma exacerbation during the treatment period including both the background therapy stable phase and the background therapy withdrawal phase. Sample Size: The sample size calculations are based on the Phase 2 study results for inhaled pitrakinra (IL-4R mutein), where an absolute reduction in the proportion of patients with an exacerbation of 37% (treatment rate of 13% versus placebo rate of 50%) was observed for this patient population. This study is designed to detect an absolute difference of 35% between treatment groups. To detect such a difference with 90% power (α=0.05, two-tailed test), 41 patients are required per treatment group (Fisher’s exact test). Accounting for an anticipated 15% dropout rate during the study, approximately 50 patients are required to be enrolled into each treatment group. Primary Analysis: For the primary analysis of proportion of patients experiencing an asthma exacerbation, a logistic regression model will be used to compare SAR231893/REGN668 group with placebo. The model will include terms for treatment, stratification factor (prior fluticasone/salmeterol combination therapy dose) and investigative


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center. The primary analysis will be performed based on modified intent-to-treat (mITT) population which includes all randomized patients who receive at least one dose of investigational product. A stratified chi-square test will also be used to corroborate the primary analysis. Safety variables including AEs, laboratory parameter, vital signs, ECG and physical examinations will be summarized using descriptive statistics. DURATION OF STUDY PERIOD (per patient)

Total 141 days (approximately 20 weeks) including 14 days screening/run-in, 85 days treatment period, and 42 days posttreatment observation period


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1

FLOW CHARTS

1.1

GRAPHICAL STUDY DESIGN


Screening/ run-in period

Post-treatment period

Treatment period 50 patients: SAR231893/REGN668 300 mg SC

weekly

50 patients: Placebo SC weekly Randomization

Day 29 Week 4 Background therapy stable phase

Day 43 Week 6

Day 57 Week 8

Day 71 Week 10

Day 85 Week 12

Day 127 Week 18

Background therapy withdrawal phase

Long-acting beta2 agonist Inhaled corticosteroid

Fluticasone/salmeterol 250/50 µg BID or 500/50 µg BID


Fluticasone 220 µg BID or 440 µg BID



Fluticasone 0 µg or 44 µg BID

Fluticasone/salmeterol 250/50 µg BID or 500/50 µg BID

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1.2


STUDY FLOWCHART

VISIT DAY

Screening/ Treatment (+/- 2 days) run-ina Background therapy stable phase Background therapy withdrawal phase V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14b D22 D29 D36 D43 D50 D57 D64 D71 D78 D85 D-14 to D-1 D1 D8 D15

WEEK

Informed consent Patient demography Previous medical & surgical history Inclusion/exclusion criteria Reversibility Prior & concomitant meds Physical examination ACQ Spirometrye

Week 1

Week 2

Week 3

Week 4

X

X

X

X

X

X

X

X

X

Xc

X X

X X

X X

X X

X X

X X

X X

X X

X

X

X

X

X

X

X

X

X

X

X

X

X

V15 D127

Week 10

Week 11

Week 12

Week 18

X

X

X

X

X X

X X

X X

X X

X X X X

X

X

X

X

X

X

X

X

X

X

X

X

X X X X Xc X X X Xc,d

Randomization Investigational product administration Dispense electronic diary/PEF meter and provide instructions for usef Download electronic diary/PEF meter

X

Dispense albuterol as neededg

X

Discontinue fluticasone/salmeterol combination & replace with equivalent dose of fluticasoneh

X X

X

Evaluation for ICS withdrawali Induced sputum for eosinophils & neutrophils (subset)j Exhaled nitric oxide (subset)j Adverse event observation period Vital Signs

Week 5 Week 6 Week 7 Week 8 Week 9

Posttreatment

X

X X


X

X

X

X

X

X

X

X

X

X

X X

X

X X

X

X X

X

X X

X

X X

X

X X

X

X X

X X Page 12


VISIT DAY

WEEK

Electrocardiogram


Screening/ Treatment (+/- 2 days) run-ina Background therapy stable phase Background therapy withdrawal phase V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14b D22 D29 D36 D43 D50 D57 D64 D71 D78 D85 D-14 to D-1 D1 D8 D15 Week 1

Pregnancy testk

X X

Clinical lab testingl

X

Blood eosinophil samplem

X

SAR231893/REGN668 samplingn Additional SAR231893/REGN668 samplingo Anti-SAR231893/REGN668 antibody sampling Phadiatop (antigen-specific IgE) serum sample IgE, eotaxin-3, TARC, YKL-40, TSLP, CEA serum sample Protein (serum) sample RNA (whole blood) samplen

Week 2

Week 3

Week 4


X

X X

X

X

X

X X

X X X

X X

X X

X

X

X

X

X X

X X

X X

X

X

Pharmacogenomic sampling (optional)p Discontinue fluticasone and resume pretreatment fluticasone/salmeterol combination

Week 12

X X X

X

Week 11

X X

X

Week 10

Posttreatment V15 D127

Week 18

X X X

X

X

X

--------------Xo-------------X X X X

X X

Safety telephone contactsq

Xq

ACQ = Asthma Control Questionnaire; CEA = carcinoembryonic antigen; ICS = inhaled corticosteroid; PEF = peak expiratory flow; TARC = thymus and activation-regulated chemokine; TSLP = thymic stromal lymphopoietin a The screening/run-in period must be at least 7 days in duration prior to randomization to allow for the collection of 7 days worth of baseline data on PEF, asthma symptom scores, nocturnal awakenings, and albuterol use. b End-of-treatment visit: Patients who discontinue prematurely from the study, should be assessed as soon as possible using the procedure normally planned for V14 and return to the study site 6 weeks later for the post-treatment evaluation of safety normally planned for V15. c Three attempts may be made during the screening period to meet the qualifying criteria for reversibility and spirometry. Patients must also meet the criteria for spirometry prior to randomization on Day 1. If a patient’s FEV1 does not qualify, then he/she will not be randomized on that day. He/she may return to the site on a subsequent day to attempt to meet the spirometry criteria (3 pre-randomization attempts maximum). d Following a 6 hour withhold of asthma medication and albuterol. e Spirometry performed between 6 and 10 AM after a 6 hour withhold of albuterol and prior to administration of investigational product. Property of the sanofi-aventis group - strictly confidential

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f Electronic diary/PEF meter to be used for daily recording of albuterol use, nocturnal awakenings, morning and evening asthma symptom scores and PEF. g Resupply as needed h Patients will be switched from 250/50 µg BID or 500/50 µg BID fluticasone/salmeterol combination therapy to an equivalent ICS dose of fluticasone monotherapy (220 µg or 440 µg BID) The LABA component will be discontinued. i Fluticasone dose to be reduced by 50% at V8, V10, and V12 provided that the patient does not meet the criteria for asthma exacerbation. j A subset of study sites will participate in an evaluation of exhaled nitric oxide and induced sputum. The goal is for approximately 50 patients to participate in this analysis. In addition sputum cell counts of leukocytes, soluble factors in sputum may also be examined if feasible (eg, IL-4, IL-13). k Serum pregnancy test at V1, and urine pregnancy tests at V2, V8, and V14. A negative result must be obtained at V1 and at V2 prior to randomization. l Hematology to include hemoglobin, hematocrit, platelet count, total white blood cell count, differential count, and total red blood cell count. Serum chemistry to include creatinine, blood urea nitrogen, glucose, uric acid, total cholesterol, total protein, albumin, bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, electrolytes (sodium, potassium, chloride), bicarbonate, and creatine phosphokinase. m Eosinophil counts at V1 and V14 will be derived from the sample drawn for clinical lab testing (differential count). At V6 and V10 only a hematology sample will be taken for eosinophil counts, as serum chemistry testing is not scheduled for these visits. n Serum pharmacoketic sample and RNA sample will be collected prior to administration of investigational product. o For the lead-in cohort of 20 patients additional pharmacokinetic samples to be collected after the final dose on Days 82, 92, 99, 106, and 113 p For patients who have signed the Pharmacogenomics informed consent form. The DNA sample should be collected at the baseline visit, but it can be collected at any visit during the study. q Telephone call to be made to the patients to evaluate AEs on Week 13, 14, and 16 (1, 2, and 4 weeks after the end-of-treatment visit).


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2


TABLE OF CONTENTS

CLINICAL TRIAL PROTOCOL.......................................................................................................................1 1

FLOW CHARTS.............................................................................................................................11

1.1

GRAPHICAL STUDY DESIGN ......................................................................................................11

1.2

STUDY FLOWCHART ...................................................................................................................12

2

TABLE OF CONTENTS ................................................................................................................15

3

LIST OF ABBREVIATIONS ..........................................................................................................21

4

INTRODUCTION AND RATIONALE.............................................................................................23

5

STUDY OBJECTIVES ...................................................................................................................25

5.1

PRIMARY.......................................................................................................................................25

5.2

SECONDARY ................................................................................................................................25

6

STUDY DESIGN ............................................................................................................................26

6.1

DESCRIPTION OF THE PROTOCOL ...........................................................................................26

6.2

DURATION OF STUDY PARTICIPATION ....................................................................................27

6.2.1

Duration of study participation for each patient .............................................................................27

6.2.2

Determination of end of clinical trial (all patients) ..........................................................................27

6.3

INTERIM ANALYSIS......................................................................................................................27

6.4

STUDY COMMITTEES ..................................................................................................................27

7

SELECTION OF PATIENTS..........................................................................................................28

7.1

NUMBER OF PATIENTS PLANNED.............................................................................................28

7.2

INCLUSION CRITERIA..................................................................................................................28

7.3

EXCLUSION CRITERIA ................................................................................................................28

7.3.1

Exclusion criteria related to study methodology ............................................................................28

7.3.2

Exclusion criteria related to the active comparator and/or mandatory background therapies.......29

7.3.3

Exclusion criteria related to the current knowledge of sanofi-aventis compound ..........................30

8

STUDY TREATMENTS .................................................................................................................31

8.1

INVESTIGATIONAL PRODUCT ....................................................................................................31


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8.2

NON INVESTIGATIONAL PRODUCTS.........................................................................................31

8.3

DESCRIPTION OF BLINDING METHODS ...................................................................................32

8.4

COMPENSATION FOR LACK OF BLINDING...............................................................................32

8.5

METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................32

8.6

PACKAGING AND LABELING ......................................................................................................33

8.7

STORAGE CONDITIONS AND SHELF LIFE ................................................................................33

8.8

RANDOMIZATION CODE BREAKING DURING THE STUDY .....................................................33

8.9

RESPONSIBILITIES ......................................................................................................................33

8.10

CONCOMITANT MEDICATION.....................................................................................................34

8.11

TREATMENT ACCOUNTABILITY AND COMPLIANCE ...............................................................34

8.12

RETURN AND/OR DESTRUCTION OF TREATMENTS ..............................................................35

9

ASSESSMENT OF INVESTIGATIONAL PRODUCT ...................................................................36

9.1

EFFICACY .....................................................................................................................................36

9.1.1

Primary endpoint ............................................................................................................................36

9.1.2

Secondary endpoints .....................................................................................................................36

9.1.3

Efficacy methods............................................................................................................................36

9.2

SAFETY .........................................................................................................................................38

9.3

PHARMACOKINETICS..................................................................................................................39

9.3.1

Sampling schedule.........................................................................................................................39

9.3.2

Sample handling procedure ...........................................................................................................39

9.4

PHARMACOGENOMIC SAMPLES ...............................................................................................39

9.5

PHARMACODYNAMIC MEASURES ............................................................................................41

9.6

MEASURES TO PROTECT BLINDING OF THIS TRIAL ..............................................................42

10

PATIENT SAFETY.........................................................................................................................43

10.1

SAFETY ENDPOINTS ASSESSED IN THIS TRIAL .....................................................................43

10.1.1

Medical history and prior and concomitant medication..................................................................43

10.1.2

Adverse events ..............................................................................................................................43

10.1.3

Vital signs .......................................................................................................................................43

10.1.4

Clinical laboratory tests ..................................................................................................................43

10.1.5

Electrocardiogram ..........................................................................................................................44


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10.1.6

Pregnancy test ...............................................................................................................................44

10.1.7

Physical examination .....................................................................................................................45

10.2

SAFETY INSTRUCTIONS .............................................................................................................45

10.3

ADVERSE EVENTS MONITORING ..............................................................................................45

10.4

DEFINITIONS OF ADVERSE EVENT (AE) AND SERIOUS ADVERSE EVENT (SAE)...............45

10.5

OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................46

10.5.1

Adverse Events ..............................................................................................................................46

10.5.2

Serious Adverse Events.................................................................................................................47

10.5.3

Safety Observations.......................................................................................................................47

10.5.4 Adverse events of special interest (AESI)......................................................................................48 10.5.4.1 AESI with immediate notification....................................................................................................48 10.5.4.2 AESI without immediate notification...............................................................................................49 10.5.5

Laboratory abnormalities with pre-specified monitoring ................................................................49

10.6

OBLIGATIONS OF THE SPONSOR .............................................................................................49

11

HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION ......................................51

11.1

TEMPORARY TREATMENT DISCONTINUATION WITH INVESTIGATIONAL PRODUCT(S).................................................................................................................................51

11.2

PERMANENT TREATMENT DISCONTINUATION WITH INVESTIGATIONAL PRODUCT(S).................................................................................................................................51

11.2.1

List of criteria for definitive treatment discontinuation....................................................................51

11.2.2

Handling of patients after permanent treatment discontinuation ...................................................52

11.3

PROCEDURE AND CONSEQUENCE FOR PATIENT WITHDRAWAL FROM STUDY ..............53

12

STUDY PROCEDURES ................................................................................................................54

12.1

VISIT SCHEDULE..........................................................................................................................54

12.1.1

Screening Period: Visit 1 (Day -14 to Day -1) ................................................................................54

12.1.2 12.1.2.1 12.1.2.2 12.1.2.3 12.1.2.4 12.1.2.5

Treatment period: Background therapy stable phase (Day 1 to Week 4 [Visits 2 to 6])................55 Randomization: Visit 2 (Day 1) ......................................................................................................55 Visit 3 (Week 1 +/- 2 days).............................................................................................................56 Visit 4 (Week 2 +/- 2 days).............................................................................................................56 Visit 5 (Week 3 +/- 2 days).............................................................................................................57 Visit 6 (Week 4 +/- 2 days).............................................................................................................57

12.1.3 12.1.3.1 12.1.3.2 12.1.3.3

Treatment period: Background therapy withdrawal phase (Visits 7 to 14) ....................................58 Visit 7 (Week 5 +/- 2 days).............................................................................................................58 Visit 8 (Week 6 +/- 2 days).............................................................................................................58 Visit 9 (Week 7 +/- 2 days).............................................................................................................59


Page 17


12.1.3.4 12.1.3.5 12.1.3.6 12.1.3.7 12.1.3.8


Visit 10 (Week 8 +/- 2 days)...........................................................................................................59 Visit 11 (Week 9 +/- 2 days)...........................................................................................................60 Visit 12 (Week 10 +/- 2 days).........................................................................................................60 Visit 13 (Week 11 +/- 2 days).........................................................................................................61 Visit 14 (Week 12 +/- 2 days) End of treatment visit......................................................................61

12.1.4 Post-treatment period.....................................................................................................................62 12.1.4.1 Visit 15 (Week 18 +/- 2 days).........................................................................................................62 12.1.5

All visits ..........................................................................................................................................62

12.2

DEFINITION OF SOURCE DATA..................................................................................................62

13

STATISTICAL CONSIDERATIONS ..............................................................................................64

13.1

DETERMINATION OF SAMPLE SIZE...........................................................................................64

13.2

ANALYSIS ENDPOINTS ...............................................................................................................64

13.2.1

Demographic and baseline characteristics ....................................................................................64

13.2.2 Efficacy endpoints ..........................................................................................................................65 13.2.2.1 Primary efficacy endpoint...............................................................................................................65 13.2.2.2 Secondary efficacy endpoint(s)......................................................................................................65 13.2.3 13.2.3.1 13.2.3.2 13.2.3.3 13.2.3.4 13.2.3.5 13.2.3.6

Safety endpoints ............................................................................................................................65 Adverse events ..............................................................................................................................65 Deaths ............................................................................................................................................66 Laboratory safety variables ............................................................................................................66 Vital signs .......................................................................................................................................66 ECG variables ................................................................................................................................66 Physical examination .....................................................................................................................66

13.2.4

Pharmacokinetic variables .............................................................................................................66

13.2.5

Pharmacodynamic/genomics variables .........................................................................................67

13.3

DISPOSITION OF PATIENTS .......................................................................................................67

13.4

ANALYSIS POPULATIONS...........................................................................................................67

13.4.1

Efficacy populations .......................................................................................................................67

13.4.2

Safety population ...........................................................................................................................68

13.5

STATISTICAL METHODS .............................................................................................................68

13.5.1


13.5.2

Prior or concomitant medications...................................................................................................68

13.5.3 Extent of study treatment exposure and compliance.....................................................................69 13.5.3.1 Extent of investigational product exposure ....................................................................................69 13.5.3.2 Compliance ....................................................................................................................................69 13.5.4 Analyses of efficacy endpoints.......................................................................................................69 13.5.4.1 Analysis of primary efficacy endpoint.............................................................................................69 13.5.4.2 Analyses of secondary efficacy endpoints .....................................................................................69


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13.5.4.3 Multiplicity Considerations .............................................................................................................70 13.5.5 13.5.5.1 13.5.5.2 13.5.5.3 13.5.5.4

Analyses of safety data ..................................................................................................................70 Analysis of adverse events ............................................................................................................70 Analysis of laboratory variables .....................................................................................................71 Analysis of vital signs variables .....................................................................................................72 Analysis of other safety variables ..................................................................................................72

13.5.6 Analyses of pharmacokinetic and pharmacodynamic variables ....................................................72 13.5.6.1 Pharmacokinetic parameters .........................................................................................................72 13.5.6.2 Pharmacokinetic/Pharmacodynamic parameters ..........................................................................72 13.5.7

Immunogenicity ..............................................................................................................................72

13.6

DATA HANDLING CONVENTIONS ..............................................................................................72

13.7


13.8

DATABASE LOCK .........................................................................................................................73

14

ETHICAL AND REGULATORY STANDARDS.............................................................................74

14.1

ETHICAL PRINCIPLES .................................................................................................................74

14.2

LAWS AND REGULATIONS .........................................................................................................74

14.3

INFORMED CONSENT .................................................................................................................74

14.4

INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) ..............75

15

STUDY MONITORING...................................................................................................................76

15.1

RESPONSIBILITIES OF THE INVESTIGATOR(S) .......................................................................76

15.2

RESPONSIBILITIES OF THE SPONSOR.....................................................................................76

15.3

SOURCE DOCUMENT REQUIREMENTS....................................................................................77

15.4

USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL REQUEST ......................................................................................................................................77

15.5

USE OF COMPUTERIZED SYSTEMS..........................................................................................77

16

ADMINISTRATIVE RULES ...........................................................................................................78

16.1

CURRICULUM VITAE....................................................................................................................78

16.2

RECORD RETENTION IN STUDY SITES (S) ..............................................................................78

17

CONFIDENTIALITY.......................................................................................................................79

18

PROPERTY RIGHTS.....................................................................................................................80

19

DATA PROTECTION.....................................................................................................................81


Page 19



20

INSURANCE COMPENSATION ...................................................................................................82

21

SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ................................83

22

PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF A SITE............................................................................................................................................84

22.1

DECIDED BY THE SPONSOR IN THE FOLLOWING CASES: ....................................................84

22.2

DECIDED BY THE INVESTIGATOR .............................................................................................84

23

CLINICAL TRIAL RESULTS.........................................................................................................85

24

PUBLICATIONS AND COMMUNICATIONS ................................................................................86

25

CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................87

26

BIBLIOGRAPHIC REFERENCES.................................................................................................88

27

APPENDICES................................................................................................................................89

APPENDIX A

DRUGS KNOWN TO PROLONG THE QTC INTERVAL ....................................................89

APPENDIX B

SPIROMETRY.....................................................................................................................90

APPENDIX C

JUNIPER ASTHMA CONTROL QUESTIONNAIRE ...........................................................92

APPENDIX D

SPUTUM INDUCTION PROCEDURE ................................................................................94

APPENDIX E GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY ABNORMALITIES BY SANOFI-AVENTIS .....................................................................................99 APPENDIX F

DNA SAMPLE COLLECTION ...........................................................................................104


Page 20


3


LIST OF ABBREVIATIONS

ACQ AE AESI ALT AM AST ATC ATS BID CEA CPK CRF DNA ECG e-CRF ELISA ERS FEV1 FVC GINA HIPAA HLT HLGT ICH ICS IDMC IEC IL-4 IL-4Rα IL-13 IRB IV IVRS IWRS LABA mITT MedDRA PCSA PEF PK PM PT

Asthma control questionnaire Adverse event Adverse event of special interest Alanine aminotransferase Morning Aspartate aminotransferase Anatomic Therapeutic Chemical Classification American Thoracic Society Twice-daily dosing Carcinoembryonic antigen Creatine phosphokinase Case report form Deoxyribonucleic acid Electrocardiogram Electronic case report form Enzyme-linked immunosorbent assay European Respiratory Society Forced expiratory volume in one second Forced vital capacity Global Initiative for Asthma Health Insurance Portability and Accountability Act High level term High level group term International Conference on Harmonization Inhaled corticosteroid Independent Data Monitoring Committee Independent Ethics Committee Interleukin-4 Interleukin-4 receptor alpha subunit Interleukin-13 Institutional Review Board Intravenous Interactive Voice Response System Interactive Web Response System Long-acting beta2-adrenergic agonist Modified Intent to treat Medical Dictionary for Regulatory Activities Potentially clinically significant abnormality Peak expiratory flow Pharmacokinetic Evening Preferred term


Page 21


RNA SAE SAP SC SD SOC SUSAR TARC TEAE TSLP ULN USA


Ribonucleic acid Serious adverse event Statistical Analysis Plan Subcutaneous Standard deviation System organ class Suspected unexpected adverse drug reaction Thymus and activation-regulated chemokine Treatment-emergent adverse event Thymic stromal lymphopoietin Upper limit of normal United States of America


Page 22


4


INTRODUCTION AND RATIONALE

Asthma is a chronic inflammatory disease of the airways characterized by airway hyperresponsiveness, acute and chronic bronchoconstriction, airway edema, and mucus plugging. The inflammation component of asthma is thought to involve many cell types including mast cells, eosinophils, T lymphocytes, neutrophils, and epithelial cells and their biological products. Patients with asthma most often present with symptoms of wheezing, shortness of breath, cough, and chest tightness. For most asthma patients a regimen of controller therapy and bronchodilator therapy provides adequate long-term control. Inhaled corticosteroids (ICS) are considered the “gold standard” in controlling asthma symptoms and inhaled beta2-agoists are the most effective bronchodilators currently available. Landmark studies by Greening et al (1) and Woolcock et al (2) demonstrated that combination therapy of an ICS with an inhaled long-acting beta2-agonist (LABA) provides better asthma control than high doses of ICS alone. Since then, combination therapy has been the recommended treatment for subjects who are not controlled on low doses of ICS alone. However, it is estimated that 5% to 10% of the population with asthma has symptomatic disease despite maximum recommended treatment with combinations of anti-inflammatory and bronchodilator drugs. Furthermore, this severe asthma population accounts for up to 50% of the total health cost through hospital admissions, use of emergency services, and unscheduled physician visits.(3) There is an unmet need for a new therapy in this severe asthma population as many of these patients are poorly responsive to ICS due to a number of cellular and molecular mechanisms. In addition, the long term adverse effects of systemic and inhaled corticosteroids on bone metabolism, adrenal function, and growth in children lead to attempts to minimize the amount of corticosteroid usage. In the severe, corticosteroid-refractory allergy-induced asthma population, the anti-IgE agent, omalizumab, has proven effective. Although a large portion of asthma patients are managed reasonably well with current treatments, patients with severe corticosteroid-refractory asthma have few therapeutic treatment options that can adequately control the disease.(4) The consequences of unresponsiveness to therapy or lack of compliance with therapy is loss of asthma control and ultimately asthma exacerbation. One of the reasons for the poor response to medication in some patients with severe asthma may be the heterogeneity of the disease. Interest is increasing in understanding these distinct phenotypes because targeted therapy is more likely to be successful in patients with similar underlying pathobiological features.(5) Recent therapeutic approaches in asthma have been focused on trying to control the T helper cell-2 response. Up-regulation of interleukin-4 (IL-4) and interleukin-13 (IL-13) has been implicated as an important inflammatory component of asthma disease progression. SAR231893/REGN668 is under development as a potential novel treatment for asthma. SAR231893/REGN668, a fully human monoclonal antibody, is directed against the IL-4 receptor alpha subunit (IL-4Rα), which is a component of IL-4 receptors Type I and Type II, as well as the IL-13 receptor system. The binding of SAR231893/REGN668 to IL4Rα results in a blockade of the function of both IL-4 and IL-13 signal transduction. Inhibition of this Th2 inflammatory pathway is currently or has previously been evaluated with other agents. There are currently two IL-4/IL-13 dual antagonists in clinical development. A subcutaneously administered fully human antibody with a similar mechanism of action, AMG317 (Amgen, Inc), Property of the sanofi-aventis group - strictly confidential

Page 23



and pitrakinra, an inhaled IL-4 mutein (Aerovance, Inc.), have been evaluated in Phase 2 clinical trials of moderately-severe asthma based on their ability to bind to IL-4Rα and block activation of IL-4 and IL-13 mediated signaling. The Aerovance study results indicated that a subpopulation of patients with eosinophilic asthma responded positively to the drug, while non-eosinophilic asthmatics did not have a significant reduction in asthma exacerbations.(6) The most frequently reported adverse events (AEs) in the AMG317 clinical trial were injection site reactions and headache/myalgia.(7, 8, 9) Similar AEs may be observed with SAR231893/REGN668. The first-in-human study (R668-AS-0907) to investigate safety and pharmacokinetics (PK) of a single intravenous (IV) infusion of 4 dose levels (1, 3, 8, and 12 mg/kg) and a single subcutaneous (SC) injection of 1 of 2 dose levels (150 and 300 mg) of SAR231893/REGN668 in normal healthy volunteers has been completed. Treatment with SAR231893/REGN668 was generally welltolerated. No treatment-emergent AEs led to cohort expansion for further elucidation of AEs, and dosing was escalated to the highest dose level in this healthy volunteer population. No serious adverse events (SAEs) assessed as related to the investigational product were reported. The most frequent AEs were blood creatine phosphokinase increased, blood pressure increased, and headache. (See the Investigator’s Brochure for further details). The objective of the current study is to investigate the effects of SAR231893/REGN668 (300 mg) administered SC once weekly for 12 weeks as compared to placebo on reducing the incidence of asthma exacerbations in patients with persistent moderate to severe eosinophilic asthma. In addition, the safety and tolerability of SAR231893/REGN668 and plasma concentrations following weekly dosing will be assessed. The dose of SAR231893/REGN668 (300 mg) that will be administered in this study is within the range of SC doses administered to healthy volunteers in the single-dose study described above. Because it is expected that the target IL-4 receptors are primarily located on the cell surface in tissue, it may be important to saturate the target-mediated pathway of elimination. The 300 mg dose was selected because a high dose may be required in patients with asthma who may exhibit higher IL-4Rα expression than healthy subjects, and because the target tissue can be difficult to reach.


Page 24


5

STUDY OBJECTIVES

5.1

PRIMARY


The primary objective of this study is to investigate the effects of SAR231893/REGN668 administered SC once weekly for 12 weeks as compared to placebo on reducing the incidence of asthma exacerbations in patients with persistent moderate to severe eosinophilic asthma. 5.2

SECONDARY

The secondary objectives are as follows: •


•



Page 25


6

STUDY DESIGN

6.1

DESCRIPTION OF THE PROTOCOL


This randomized, double-blind, placebo-controlled, study with parallel groups includes a 2-week screening/run-in, followed by a 12-week treatment period with an add-on therapy approach to background therapy (ICS/LABA combination therapy) and systematic background therapy withdrawal, and a 6-week follow-up period. This study consists of a 1 to 14-day screening/run-in period. To be eligible for this study, patients are required to be on a stable dose of fluticasone/salmeterol combination therapy (Advair® 250/50 µg BID or 500/50 µg BID) for at least 3 months prior to screening and will continue on their current fluticasone/salmeterol combination therapy dose for the duration of the screening period. Following screening, patients will be randomized 1:1 to receive either SAR231893/REGN668 or placebo in a 12-week, double-blind, parallel-group treatment period. The 12-week treatment period is divided into 2 phases: a 4-week background therapy stable phase and an 8-week background therapy withdrawal phase. During the background therapy stable phase patients will remain on their current dose of fluticasone/salmeterol combination therapy along with the randomized investigational product. At the start of the background therapy withdrawal phase (Week 4) patients will discontinue the LABA component of fluticasone/salmeterol combination therapy (ie, salmeterol) and switch to an equivalent ICS dose of fluticasone (220 µg BID or 440 µg BID). Day 29 marks the beginning of the 8-week background therapy withdrawal phase. Every 2 weeks for the next 8 weeks, patients will be evaluated for adjustment of their ICS dose. The fluticasone dose will be reduced by approximately 50% every 2 weeks provided that the patient does not meet the criteria for an asthma exacerbation (see Section 9.1.1). If a patient meets the criteria for an asthma exacerbation, he/she will be withdrawn from the study and treated by the Investigator with appropriate medical therapy. Upon completing 12 weeks of treatment with investigational product (or after early discontinuation), patients will be placed on their original dose of fluticasone/salmeterol (dose at study entry) and albuterol as-needed to control their symptoms for an additional 6 weeks off study medication before a final safety evaluation. Prior to opening enrollment to the entire cohort of 100 patients, a sentinel cohort consisting of 20 patients (10 active, 10 placebo) will be evaluated by an Independent Data Monitoring Committee (IDMC) for any safety issues. Blinded clinical safety data through Week 5 (Visit 7) will be reviewed by the IDMC. Based on this review, a decision will be made to enroll the remainder of patients, modify the protocol, or stop the study. During this safety evaluation the sentinel cohort will continue to receive investigational product for the scheduled 12 weeks.


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6.2


DURATION OF STUDY PARTICIPATION

6.2.1 Duration of study participation for each patient

The total duration of study participation for each subject is up to 141 days (approximately 20 weeks) including 14 days screening/run-in, 85 days treatment period, and 42 days post-treatment observation period. The total duration of exposure to investigational product is 12 weeks (12 weekly SC injections of investigational product). 6.2.2 Determination of end of clinical trial (all patients)

The end of the clinical trial will be defined as the last patient last visit/contact. 6.3

INTERIM ANALYSIS

No interim analysis of efficacy is planned. An IDMC will evaluate the blinded clinical safety data of a sentinel cohort consisting of 20 patients (10 active, 10 placebo) through Week 5 (Visit 7) for any safety issues. Based on this review, a decision will be made to enroll the remainder of patients, modify the protocol, or stop the study (for more details see Section 6.4). 6.4

STUDY COMMITTEES

An IDMC will be established, which is independent of the Sponsor and participating Investigators. The IDMC will be comprised of members with a high level of expertise and experience in clinical research and the interpretation of safety data and information. The IDMC will evaluate the blinded clinical safety data of a sentinel cohort consisting of 20 patients (10 active, 10 placebo) through Week 5 (Visit 7) for any safety issues. Based on this review, a decision will be made to enroll the remainder of patients, modify the protocol, or stop the study. In addition, the IDMC will continue to monitor the safety of patients throughout the trial. The review of the clinical data by the IDMC will be conducted at pre-determined times as specified by the IDMC and outlined in the IDMC charter. These data reviews shall not be construed as interim efficacy assessments for statistical purposes. The IDMC will have broad authority to make recommendations regarding the study conduct.


Page 27


7

SELECTION OF PATIENTS

7.1

NUMBER OF PATIENTS PLANNED


A total of approximately 100 subjects (approximately 50 subjects per treatment arm) are expected to be randomized and treated in up to approximately 40 study sites in the US. (See Section 13.1 Determination of sample size). 7.2

INCLUSION CRITERIA

I 01.

Patients with a physician diagnosis of moderate to severe persistent asthma for at least 12 months based on Global Initiative for Asthma (GINA) 2009 Guidelines,(4) whose airway inflammation is likely to be eosinophilic and whose asthma is partially controlled or uncontrolled on fluticasone/salmeterol combination therapy based on the following criteria:

•

On a stable dose of either 250/50 µg BID or 500/50 µg BID fluticasone/salmeterol combination therapy for at least 3 months prior to screening

•

Blood eosinophils ≥350 cells /µL during the screening phase

•

Juniper Asthma Control Questionnaire (ACQ) score ≥1.5 and ≤2.5 at the screening visit

•

Forced expiratory volume (FEV1) ≥50 and ≤80% predicted normal during the screening phase (3 attempts maximum) and on the randomization day prior to the first dose of investigational product (3 attempts maximum)

•

Reversibility of at least 12% and 200 mL in FEV1 after 200 µg to 400 µg (2 to 4 inhalations) of albuterol during the screening phase (3 attempts maximum)

I 02.

Patients who have signed an Informed Consent Form and Health Insurance Portability and Accountability Act (HIPAA) Authorization Form

7.3

EXCLUSION CRITERIA

Patients who have met all the above inclusion criteria listed in Section 7.2 will be screened for the following exclusion criteria which are sorted and numbered in the following 3 sub-sections: 7.3.1 Exclusion criteria related to study methodology

E 01. Patients less than 18 years or greater than 65 years of age (ie, have reached the age of 66 at the screening visit) E 02. Clinically relevant abnormal laboratory values suggesting an unknown disease and requiring further evaluation


Page 28



E 03. Chronic obstructive pulmonary disease and/or other lung diseases impairing Pulmonary Function Tests E 04. Patients requiring beta-adrenergic receptor blockers for any reason E 05. Current smoker or cessation of smoking within the 6 months prior to screening E 06. Previous smoking with a smoking history >10 cigarette pack-years E 07. In-patient hospitalization or emergency care visit due to asthma exacerbation in the 3 months prior to screening E 08. Plans to begin allergen immunotherapy within the study period E 09. Participation in another study within 6 months prior to screening if the study medication is an antibody or within 30 days prior to screening for all other study medications E 10. Previous enrollment into the current study E 11. Patient is the Investigator, his/her family member, or employee at the investigational site E 12. Known or suspected non-compliance, alcohol or drug abuse E 13. Inability to follow the procedures of the study (eg, due to language problems, psychological disorders) E 14. Reversal of sleep pattern (eg, night shift workers) 7.3.2 Exclusion criteria related to the active comparator and/or mandatory background therapies

E 15. Treatment with drugs known to prolong QTc interval (see Appendix A) E 16. Concomitant severe diseases or diseases for which the use of ICS (eg, active and inactive pulmonary tuberculosis) or LABA (eg, diagnosis of a history of significant cardiovascular diseases, insulin-dependent diabetes mellitus, uncontrolled hypertension, hyperthyroidism, thyrotoxicosis, pheochromocytoma, hypokalemia, prolonged QTc interval [male >430 msec, female >450 msec] or tachyarrhythmia) are contraindicated E 17. Use of injectable glucocorticosteroids or oral systemic glucocorticosteroids within 2 months prior to screening or more than 3 courses within the 6 months prior to screening E 18. Pre-treatment with variable doses of ICS, either alone or in combination with a nonsteroidal controller (other than fluticasone/salmeterol combination therapy) E 19. Patients receiving prohibited concomitant medications (see list Section 8.10)


Page 29



7.3.3 Exclusion criteria related to the current knowledge of sanofi-aventis compound

E 20. Known allergy to doxycycline or related compounds E 21. Pregnancy or intention to become pregnant during the course of the study, breast feeding, or unwillingness to use a highly effective method of contraception (oral contraception or intrauterine device) throughout the study in women of child-bearing potential E 22. Recent history of a parasitic infection or travel to a parasitic endemic area within 6 months prior to screening


Page 30


8

STUDY TREATMENTS

8.1

INVESTIGATIONAL PRODUCT


SAR231893/REGN668: Sterile SAR231893 /REGN668 150 mg/mL solution for SC injection will be provided in a 5 mL glass vial. Each vial will contain a withdrawable volume of 2 mL. A 300 mg dose will be administered at the study site once weekly in the morning for 12 weeks. Placebo: Sterile placebo for SAR231893/REGN668 for SC injection will be provided in a 5 mL glass vial. Each vial will contain a withdrawable volume of 2 mL. Placebo will be administered at the study site once weekly in the morning for 12 weeks. 8.2

NON INVESTIGATIONAL PRODUCTS

Albuterol: Patients will be administered albuterol hydrofluoroalkane pressurized metered-dose inhaler as rescue medication as needed throughout the study. Patients will record their daily albuterol use in their electronic diaries. ICS/LABA combination therapy: Patients must be on a stable dose of fluticasone/salmeterol combination therapy (Advair®, 250/50 µg BID or 500/50 µg BID) at study entry for at least 3 months. They will continue on this dose through the screening period and for the background therapy stable phase (first 4 weeks) of the treatment period. The last day of fluticasone/salmeterol combination therapy administration will be Day 28 (±2 days). ICS (monotherapy): At 4 weeks post-randomization (Visit 6) patients will be switched from fluticasone/salmeterol combination therapy to an equivalent ICS dose of fluticasone (220 µg BID or 440 µg BID) monotherapy, thereby discontinuing the LABA component of fluticasone/salmeterol combination therapy (ie, salmeterol). Every 2 weeks thereafter, beginning with Week 6, the fluticasone dose will be reduced by approximately 50% provided that the patient does not meet any of the criteria for an asthma exacerbation (see Section 9.1.1). If no asthma exacerbations occur, ICS withdrawal will proceed according to the following dosing schedule:


Page 31



Background therapy stable phase

Background therapy withdrawal phase Week 4

Week 6

Week 8

Week 10

Fluticasone/salmeterol 250/50 µg BID

Fluticasone: 220 µg BID

110 µg BID

44 µg BID

0

Fluticasone/salmeterol 500/50 µg BID

Fluticasone: 440 µg BID

220 µg BID

110 µg BID

44 BID

Albuterol, fluticasone/salmeterol combination therapy, and fluticasone will be provided as needed by the Investigator who will be reimbursed by the Sponsor. 8.3

DESCRIPTION OF BLINDING METHODS

SAR231893/REGN668 and placebo will be provided in identically matched glass 5 mL vials. To protect the blind, each treatment kit will be prepared such that the treatments are identical and indistinguishable and will be labeled with a treatment kit number. The randomized treatment kit number list will be generated by sanofi-aventis. In accordance with the double-blind design, study patients, Investigators, and study site personnel will remain blinded to study treatment and will not have access to the randomization (treatment codes) except under circumstances described in Section 8.8. 8.4

COMPENSATION FOR LACK OF BLINDING

Not applicable. 8.5

METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP

A randomized treatment kit number list will be generated centrally by sanofi-aventis. The investigational product (SAR231893/REGN668 or placebo) will be packaged in accordance with this list. The sanofi-aventis Clinical Supplies Project Demand Manager will provide the randomized treatment kit number list and the Study Biostatistician will provide the randomization scheme to the centralized treatment allocation system. This centralized treatment allocation system will generate the patient randomization list according to which it will allocate the treatments to the patients. Patients will be randomized to receive either SAR231893/REGN668 or placebo. The treatment kit numbers will be obtained by the Investigator at the time of patient randomization and subsequent patient scheduled visits via an Interactive Voice Response System/Interactive Web Response System (IVRS/IWRS) that will be available 24 hours a day. A randomized patient is defined as a patient who is registered and assigned with a treatment kit number from the centralized treatment allocation system, as documented from its log file. A patient cannot be randomized more than once in the study.


Page 32


8.6


PACKAGING AND LABELING

SAR231893/REGN668 and placebo will be supplied as a single vial packed in a box. Both vial and box will be labeled with a double-blind label. The content of the labeling is in accordance with the local regulatory specifications and requirements. 8.7

STORAGE CONDITIONS AND SHELF LIFE

All investigational product should be stored at a temperature between 2°C and 8°C in an appropriate locked room under the responsibility of the Investigator or other authorized persons (eg, pharmacists) in accordance with local regulations, policies and procedures. Control of investigational product storage conditions, especially control of temperature (eg, refrigerated storage) and information on in-use stability and instructions for handling the sanofiaventis compound should be managed according to the rules provided by the Sponsor. 8.8

RANDOMIZATION CODE BREAKING DURING THE STUDY

Please refer to Section 9.6 - Measures to protect blinding of this trial. In case of an AE, the code must be broken only in exceptional circumstances when knowledge of the investigational product is essential for treating the patient. If possible, a contact should be initiated with the Monitoring Team before breaking the code. Code breaking can be performed at any time by using the proper module of the IVRS/IWRS and/or by calling any other phone number provided by the Sponsor for that purpose. If the blind is broken, the Investigator should document the date, time of day, and reason for code breaking. If the blind is broken, the patient must be withdrawn from the treatment. They should return to the study site for their end of treatment assessment (normally scheduled for Visit 14) and return again 6 weeks later for the post-treatment safety assessment (normally scheduled for Visit 15). 8.9

RESPONSIBILITIES

The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense investigational product will be responsible for ensuring that the investigational product used in the clinical trial is securely maintained as specified by the Sponsor and in accordance with the applicable regulatory requirements. All investigational product shall be dispensed in accordance with the Investigator's prescription, and it is the Investigator's responsibility to ensure that an accurate record of investigational product issued and returned is maintained.


Page 33



Any quality issue noticed with the receipt or use of an investigational product (deficiency in condition, appearance, pertaining documentation, labeling, expiration date, etc.) should be promptly notified to the Sponsor. Some deficiencies may be recorded through a complaint procedure. A potential defect in the quality of investigational product may be subject to initiation of a recall procedure by the Sponsor. In this case, the Investigator will be responsible for promptly addressing any request made by the Sponsor, in order to recall investigational product and eliminate potential hazards. Under no circumstances will the Investigator supply investigational product to a third party, allow the investigational product to be used other than as directed by this Clinical Trial Protocol, or dispose of investigational product in any other manner. 8.10

CONCOMITANT MEDICATION

A concomitant medication is any treatment received by the patient concomitant with any investigational product. The following concomitant treatments are not permitted during the study from screening onwards: •

Any inhaled steroid other than fluticasone/salmeterol combination therapy or fluticasone administered per protocol

•

Systemic or ocular steroids (Intranasal steroids are permitted during the study, but patients must be on a stable dose for 30 days prior to screening and through the screening/run-in period)

•

LABAs other than the salmeterol component of fluticasone/salmeterol combination therapy administered per protocol

•

ICS/LABA combination products other than fluticasone/salmeterol combination therapy administered per protocol

•

Ipratropium bromide or other inhaled anti-cholinergic agents (eg, tiotropium)

•

Methylxanthines (theophylline, aminophyllines)

•

Leukotriene receptor antagonists or leukotriene synthesis inhibitors

•

Lipoxygenase inhibitors

•

Cromones

•

Anti-immunoglobuline E (IgE) therapy (Xolair®)

8.11

TREATMENT ACCOUNTABILITY AND COMPLIANCE

The administration and treatment kit number of the investigational product will be recorded on the appropriate page of the electronic Case Report Form (e-CRF) by the Investigator or his/her


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delegate. The Monitoring Team in charge of the study will check the e-CRF data by comparing them with the IVRS/IWRS treatment allocation. All drug accountability and compliance records must be kept current, including shipment receipts containing dates, quantities and identification numbers (or lot numbers) of investigational product received by the Investigator, shipment temperature records (if applicable), storage temperature logs, pharmacy dose preparation logs and IVRS/IWRS confirmation reports. The Investigator must be able to account for all used and unused investigational product. These records should contain the dates, quantity and investigational product returned to sanofi-aventis or its designee. All accountability and compliance records must be made available for inspection by sanofiaventis and regulatory agency inspectors and photocopies of all drug accountability and compliance records must be provided to sanofi-aventis at the conclusion of the study. 8.12

RETURN AND/OR DESTRUCTION OF TREATMENTS

Investigational product: All partially used or unused treatments will be retrieved by the Sponsor. A detailed treatment log of the returned investigational product will be established with the Investigator (or the pharmacist) and countersigned by the Investigator and the Monitoring Team. The Investigator will not destroy the unused investigational product. A potential defect in the quality of investigational product may be subject to initiation of a recall procedure by the Sponsor. In this case, the Investigator will be responsible for promptly addressing any request made by the Sponsor, in order to recall investigational product and eliminate potential hazards. Non-investigational product: For non-investigational product not provided by the Sponsor (ie, albuterol, fluticasone/salmeterol combination therapy, and fluticasone), tracking and reconciliation has to be achieved by the Investigator according to the system proposed by the Sponsor.


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9

ASSESSMENT OF INVESTIGATIONAL PRODUCT

9.1

EFFICACY

9.1.1 Primary endpoint

The primary endpoint of this study is the occurrence of an exacerbation of asthma as defined by any of the following: •

A 30% or greater reduction from baseline in morning peak expiratory flow (PEF) together with ≥6 additional reliever puffs of albuterol in a 24 hour period (compared to baseline) on 2 consecutive days

•

Deterioration of asthma, as determined by the Investigator, requiring: -

Oral steroid treatment, or

-

An increase in ICS ≥4 times the baseline dose of ICS, or

-

Hospitalization

9.1.2 Secondary endpoints

•

Time to asthma exacerbation post-randomization For patients who experience asthma exacerbation, based on the definition provided in Section 9.1.1, the time from randomization to asthma exacerbation will be determined.

•

FEV1 change from baseline at Week 12 and change from baseline at each visit

•

Morning and evening PEF change from baseline at Week 12 and change from baseline at each visit

•

ACQ score change from baseline at Week 12 and change from baseline at each study visit

•

Change from baseline at Week 12 and change from baseline at each visit for asthma symptom scores in the morning, evening, and nocturnal awakenings

•

Change from baseline at Week 12 and change from baseline at each visit in number of inhalations/day of albuterol for symptom relief

9.1.3 Efficacy methods

Peak expiratory flow: At screening (Visit 1), patients will be issued an electronic PEF meter for recording morning (AM) and evening (PM) PEF, daily albuterol use, morning and evening asthma symptom scores, and number of nighttime awakenings due to asthma symptoms that require rescue medications. Patients will be instructed on the use of the device, and written instructions on the use of the


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electronic PEF meter will be provided to the patients. In addition, the investigator will instruct the patients on how to record the following variables in the electronic PEF meter: •

AM PEF will be performed within 15 minutes after arising (between 6 am and 10 am) prior to taking any albuterol

•

PM PEF will be performed in the evening (between 6 pm and 10 pm) prior to taking any albuterol

•

Subjects should try to withhold albuterol for at least 6 hours prior to measuring their PEF

•

Three PEF efforts will be performed by the patient; all 3 values will be recorded by the electronic PEF meter, and the highest value will be used for evaluation

Baseline AM PEF will be the mean AM measurement recorded for the 7 days prior to the first dose of investigational product, and baseline PM PEF will be the mean PM measurement recorded for the 7 days prior to the first dose of investigational product. Information derived from the electronic PEF meter will be evaluated by the Investigator at the patient’s weekly visit to the study site. Patients with asthma exacerbation as defined Section 9.1.1 will be discontinued from the study. They are to be given the end-of-treatment assessments normally scheduled for Visit 14, and are to return 6 weeks later for a post treatment safety evaluation (normally scheduled for Visit 15). Forced expiratory flow in 1 second: A spirometer that meets the 2005 American Thoracic Society (ATS)/ European Respiratory Society (ERS) recommendations will be used. The ATS/ ERS Standardization of Spirometry should be used as a guideline.(10) Spirometry will be performed between 6 and 10 AM after an albuterol withhold of at least 6 hours. Pulmonary function tests will be measured in the sitting position, and the highest measure will be recorded for FEV1 (in liters). The predose spirometry on the postrandomization visits should be performed within one hour of the time it was performed on Visit 2 (Day 1). The same spirometer and standard spirometric techniques, including calibration, will be used to perform spirometry at all visits and whenever possible the same person should perform the measurements. An instruction manual describing further details (data processing, quality assurance) will be provided. Further details on spirometry are available in Appendix B. Juniper Asthma Control Questionnaire: The Juniper ACQ is a validated questionnaire to evaluate asthma control.(11) Patients will complete the ACQ questionnaire at screening and at their weekly visit to the clinic. A copy of the Juniper ACQ is provided in Appendix C.


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Asthma Symptom Score: Patients will record overall symptom scores twice a day prior to measuring PEF. The patient’s overall asthma symptoms experienced during the waking hours will be recorded in the evening (PM symptom score). Symptoms experienced during the night will be recorded upon arising (AM symptom score). Baseline symptom scores will be the mean AM and mean PM scores recorded for the 7 days prior to randomization. Patients will be instructed to record the severity of symptoms as follows: AM symptom score: -

0 = No asthma symptoms, slept through the night,

-

1 = Slept well, but some complaints in the morning. No nighttime awakenings,

-

2 = Woke up once because of asthma (including early awakening),

-

3 = Woke up several times because of asthma (including early awakening),

-

4 = Bad night, awake most of the night because of asthma,

PM symptom score: -

0 = Very well, no asthma symptoms,

-

1 = One episode of wheezing, cough, or breathlessness,

-

2 = More than one episode of wheezing, cough, or breathlessness without interference of normal activities,

-

3 = Wheezing, cough, or breathlessness most of the day, which interfered to some extent with normal activities,

-

4 = Asthma very bad. Unable to carry out daily activities as usual

Albuterol use for symptom relief: The number of albuterol inhalations will be recorded daily by the patients in their electronic diary/PEF meter. Each patient should be reminded that albuterol should be used only as needed for symptoms, not on a regular basis or prophylactically. The baseline number of albuterol inhalations/day will be based on the mean for the 7 days prior to randomization. 9.2

SAFETY

A secondary objective is to assess the safety of the SAR231893/REGN668. The study specific and general safety criteria are referenced in Section 10.1. To assure the continuing safety of patients, this study will use an IDMC and is designed with a lead in cohort of a subset of patients. Prior to opening enrollment to the entire population of 100 patients, a sentinel cohort consisting of 20 patients (10 active, 10 placebo) will be evaluated by the IDMC for any safety issues. Blinded clinical safety data through Week 5 (Visit 7) will be reviewed by the IDMC. Based on this review, a decision will be made to enroll the remainder of Property of the sanofi-aventis group - strictly confidential

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patients, modify the protocol, or stop the study. During this safety evaluation the sentinel cohort will continue to receive investigational product for the scheduled 12 weeks. The IDMC will continue to monitor safety of all patients throughout the study. Patients will be evaluated for asthma exacerbation at each visit. Patients with asthma exacerbation, as defined in Section 9.1.1 will be discontinued from the study. 9.3

PHARMACOKINETICS

SAR231893/REGN688 and anti-SAR231893/REGN688 antibody serum samples will be assayed using validated enzyme-linked immunosorbent assays (ELISA) under the responsibility of the Preclinical department of Regeneron (Sample Management, Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10592). 9.3.1 Sampling schedule

SAR231893/REGN668: Blood samples for the determination of serum SAR231893/REGN668 concentrations will be collected in all patients on Day 1 (Visit 2), Week 1 (Visit 3), Week 4 (Visit 6), Week 6 (Visit 8), Week 8 (Visit 10), Week 10 (Visit 12), Week 11 (Visit 13), Week 12 (Visit 14) and Week 18 (Visit 15) and as soon as possible in the event of early treatment discontinuation. For the lead-in cohort of 20 patients, additional blood samples will be collected after the final dose on Days 82, 92, 99, 106 and 113. Anti-SAR231893/REGN668 antibody: Blood samples for the determination of serum anti-SAR231893/REGN668 antibody will be collected on Day 1 (Visit 2), Week 4 (Visit 6), Week 6 (Visit 8), Week 8 (Visit 10), Week 10 (Visit 12) and Week 18 (Visit 15). Serum samples for pharmacokinetic analysis will be collected prior to the administration of investigational product. The procedure for SAR231893/REGN668 and anti-SAR231893 antibody sample handling is detailed in Section 9.3.2. 9.3.2 Sample handling procedure

All blood samples for measurement of SAR231893/REGN668 and anti-SAR231893 antibody will be processed by the central laboratory services vendor - Covance Laboratories. All special procedures for collection, storage and shipment of these samples are provided in the Study Procedure Manual supplied to the site by Covance Central Laboratory Services. 9.4

PHARMACOGENOMIC SAMPLES

Patients who meet all the inclusion/exclusion criteria for the study will have the option to consent to an additional blood draw on Day 1 for the purpose of pharmacogenomic testing. Patients who Property of the sanofi-aventis group - strictly confidential

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are willing to participate in pharmacogenomic testing must sign an additional informed consent prior to the blood sample collection. The data from genetic material can be used to determine if there is a relationship between genes and responses to treatment with SAR231893/REGN668, how the body processes SAR231893/REGN668 and possible side effects to SAR231893/REGN668. Analyses may include sequence determination and/or single nucleotide polymorphism studies of candidate genes. Genes that may be studied include those for the IL-4 receptor, IL-4, IL-13, and additional genes that may potentially be part of the IL-4/IL-13 signaling pathway or are potentially associated with asthma, atopy or other eosinophilic diseases. Participation in the pharmacogenomic substudy is optional and is not be required for a patient to participate in the main clinical trial. Patients who agree to participate in the pharmacogenomic substudy will be required to sign a separate Pharmacogenomic Informed Consent Form prior to collection of the blood sample. For those patients who sign the Pharmacogenomic Informed Consent Form, blood samples for deoxyribonucleic acid (DNA) pharmacogenomic analysis will be collected. A sample for ribonucleic acid (RNA) levels (non-genetic analysis) will be collected as part of the main protocol and will be addressed in the main protocol informed consent form. Additional RNA studies such as transcriptome sequencing (a type of genetic analysis) may be performed only if the patient has provided written informed consent to participate in the optional pharmacogenomics substudy. Pharmacogenomic samples will be stored for up to 15 years from the completion of the Clinical Study Report, after which time any remaining samples will be destroyed. The blood sample for DNA extraction should be collected on day 1/baseline (pre-dose) but may be collected at any study visit. Special procedures for storage and shipping of pharmacogenomic samples are summarized in Table 1 and are described in detail in Appendix F. Table 1 - Summary of handling procedures for pharmacogenomic samples Sample Type(s)

Pharmacogenomics

Blood Sample Volume

12 mL

Tube Type

2 x 6 mL Becton Dickinson K2 EDTA VACUTAINER™ Plus tubes with HEMOGARD™ closure (PN367863/4) sterile tubes (tube provided by Covance for DNA sample storage)

Anticoagulant

K2 EDTA

Blood Handling Procedures

Keep blood on ice or frozen at -20°C (or colder) within 30 min of sampling time. DO NOT CENTRIFUGE.

Storage Conditions

In collection tube at approximately -20°C (or colder)

The Sponsor has included safeguards for protecting patient confidentiality. The blood sample and DNA/RNA that is extracted will be assigned a second number, a Genetic ID (de-identification code) that is different from the Patient ID. This “double coding” is performed to separate a patient’s medical information and DNA data. The clinical study data (coded by Patient ID) will Property of the sanofi-aventis group - strictly confidential

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be stored in a distinct database at a different location from the database containing the genetic data (coded by Genetic ID). The key linking Patient ID and Genetic ID will be maintained by a third party, under appropriate access control. The matching of clinical data and pharmacogenomic data, for the purpose of data analysis, will be possible only by using this key, which will be under strict access control. All data will be reported only in coded form in order to maintain confidentiality. 9.5

PHARMACODYNAMIC MEASURES

Biomarkers: Pharmacodynamic effects of SAR231893/REGN668 will be assessed through measurement of the following biomarkers: total IgE, eotaxin-3, thymus and activation-regulated chemokine (TARC), YKL-40, thymic stromal lymphopoietin (TSLP), and carcinoembryonic antigen (CEA, also known as CEA cell adhesion molecule 5 [CEACAM5]). These markers are associated with asthma and in some cases may be associated with IL-4/IL-13 activity. Baseline levels of these biomarkers will be assessed for potential predictive value for treatment response. Post-treatment samples will be evaluated for pharmacodynamic effects of SAR231893/REGN668 on the biomarkers. Serum samples for biomarker analyses will be collected at screening and on Day 1 (Visit 2), Week 1 (Visit 3), Week 4 (Visit 6), Week 8 (Visit 10), and Week 12 (Visit 14) (or early termination visit). The Phadiatop test is an in vitro diagnostic screening tool used to detect antigen-specific IgE for common inhalants. Baseline results of the Phadiatop test will be assessed for potential predictive value for treatment response. Post-treatment samples will be evaluated for pharmacodynamic effects of SAR231893/REGN668 on the Phadiatop antigen panel. Blood samples for Phadiatop will be collected at screening (Visit 1) and Week 12 (Visit 14) or early termination. Serum protein and RNA analysis: Additional serum samples for exploratory serum analyses will be collected at screening (Visit 1), Day 1 (Visit 2), Week 1 (Visit 3), Week 4 (Visit 6), Week 8 (Visit 10), and Week 12 (Visit 14) or early termination. These serum samples may be used to study additional biomarkers related to SAR231893/REGN231893 response or activity, IL-4/IL-13 signaling, asthma, atopy, or eosinophilic diseases (eg, soluble IL-4Rα, IL-4, IL-13, and periostin). RNA research samples will be collected to determine RNA levels (non-genetic analysis). Additional RNA studies such as transcriptome sequencing (a type of genetic analysis) may be performed as part of the optional pharmacogenomics substudy for those patients who provide written informed consent to participate in the substudy, as described in Section 9.4. Induced sputum eosinophils and neutrophils: Induced sputum eosinophils and neutrophils are well-established direct markers of airway inflammation. A subset of study sites will participate in an evaluation of induced sputum. The goal is for approximately 50 patients to participate in this analysis. Sputum will be induced with inhalation of hypertonic saline solution. Sputum induction and processing of whole sputum will Property of the sanofi-aventis group - strictly confidential

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be performed essentially according to the ERS guidelines. Sputum cell counts of leukocytes (including eosinophils and neutrophils) will be performed. In addition, soluble factors in sputum may also be examined if feasible (eg, IL-4, IL-13). Further details on the sputum induction procedure and sample processing/examination are available in Appendix D, and instruction manuals describing additional details (data processing, quality assurance) for induced sputum will be provided. Induced sputum analysis will be performed on Day 1 (Visit 2) and Week 4 (Visit 6), Week 8 (Visit 10), and Week 12 (Visit 14) or early termination. Exhaled nitric oxide: A subset of study sites will participate in an evaluation of exhaled nitric oxide. The goal is for approximately 50 patients to participate in this analysis. Exhaled nitric oxide will be analyzed using a NIOX instrument (Aerocrine AB, Solna, Sweden). Further details on the procedure for measuring exhaled nitric oxide with NIOX will be provided in a separate instruction manual. Exhaled nitric oxide will be performed on Day 1 (Visit 2) and Week 4 (Visit 6), Week 8 (Visit 10), and Week 12 (Visit 14) or early termination. Blood eosinophil count: Blood eosinophil counts will be evaluated at screening (Visit 1) and at Week 4 (Visit 6), Week 8 (Visit 10), and Week 12 (Visit 14) or early termination. Eosinophil counts at screening and Week 12 (Visit 14) will be derived from the sample drawn for clinical lab testing (differential count). At Week 4 (Visit 6) and Week 8 (Visit 10) only a hematology sample will be taken for eosinophil counts, as serum chemistry testing is not scheduled for these visits. 9.6

MEASURES TO PROTECT BLINDING OF THIS TRIAL

The study will not be unblinded prior to database lock. The IDMC will review blinded safety data. However, at their request, the data can be unblinded. Results of individual pharmacokinetic assessments (SAR231893/REGN668 and anti-SAR231893 antibody) will not be provided to the Investigator or other study-site personnel when the study is ongoing. If emergency unblinding is required for an individual patient, the Investigator will follow the procedure described in Section 8.8. For safety, the treatment code will be unblinded by the Sponsor for reporting to the Health Authority of any Suspected Unexpected Adverse Drug Reaction (SUSAR) and reasonably associated with the use of the investigational product according to either the judgment of the Investigator and/or the Sponsor.


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10

PATIENT SAFETY

10.1

SAFETY ENDPOINTS ASSESSED IN THIS TRIAL

A secondary objective is to assess the safety of the SAR231893/REGN668. All analyses of safety variables will be based on the safety population defined in Section 13.4.2. Safety data will be analyzed on the basis of AEs, standard clinical laboratory findings, vital signs (blood pressure and heart rate), 12-lead electrocardiogram (ECG), and physical examination. 10.1.1 Medical history and prior and concomitant medication

Each patient will have a complete medical history at Visit 1 and details of prior and concomitant medication recorded at Visits 1 and 2. Medical conditions that have occurred within the past year or conditions that are ongoing (eg, headache, indigestion) are to be included. All corticosteroid and asthma medications taken within the 3 months and all non-asthma medication taken within 30 days prior to screening will be recorded, including the drug name, start and stop dates, and route of administration. The concomitant medication status will be reviewed at all visits during the treatment period. 10.1.2 Adverse events

Adverse events for each patient will be monitored and documented from the time the subject gives informed consent at the screening visit (Visit 1) until 6 weeks following the completion of the end-of-treatment visit. Adverse events and SAEs will be reported as described in Section 10.5.1 and Section 10.5.2, respectively. 10.1.3 Vital signs

Vital signs, including blood pressure (mmHg) and heart rate (beats per minute), will be measured at the screening and randomization visits (Visits 1 and 2) and every 2 weeks thereafter, including Week 2 (Visit 4), Week 4 (Visit 6), Week 6 (Visit 8), Week 8 (Visit 10), Week 10 (Visit 12), Week 12 (Visit 14), and Week 18 (Visit 15). Vital signs will be measured in the sitting position using the same arm at each visit, and will be measured prior to receiving investigational product at the clinic visits. 10.1.4 Clinical laboratory tests

At screening Visit 1 and at Week 2 (Visit 4), Week 6 (Visit 8), and Week 12 (Visit 14), approximately a 2 mL blood sample will be required for hematology testing, and approximately a 3 mL blood sample will be required for serum biochemistry testing. The eosinophil count obtained at screening and Week 12 will also be recorded as a pharmacodynamic variable. (In addition, a hematology sample will be collected at Week 4 and Week 8 for the purpose of obtaining eosinophil counts for pharmacodynamic testing).


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The clinical laboratory tests will be carried out according to Good Laboratory Practice and appropriate standard operating procedures by a validated central laboratory. After reviewing the laboratory report and evaluating any results that are outside the normal range, the Investigator must sign and date the laboratory report. Abnormal laboratory values that are considered to be clinically significant by the Investigator must be repeated as soon as possible after receiving the laboratory report to rule out laboratory error. Persistent abnormal laboratory values should be repeated until they return to normal or until an etiology of the persistent abnormality is determined. Details of the clinical laboratory parameters that will be measured in safety hematology and chemistry blood samples are listed below: Hematology: To include hemoglobin, hematocrit, platelet count, total white blood cell count, differential count, and total red blood cell count. Serum chemistry: To include creatinine, blood urea nitrogen, glucose, uric acid, total cholesterol, total protein, albumin, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, electrolytes (sodium, potassium, chloride), bicarbonate, and creatine phosphokinase (CPK). Decision trees for the management of certain laboratory abnormalities by sanofi-aventis are provided in Appendix E. 10.1.5 Electrocardiogram

One recording of a standard 12-lead ECG will be performed at screening (Visit 1), and at Week 2 (Visit 4), Week 6 (Visit 8), and Week 12 (Visit 14). At the post-randomization visits, ECGs will be performed prior to investigational product administration. All ECGs will be performed with the subject in a reclined position. A minimum of 3 complexes in an appropriate lead (lead II) will be averaged to determine the PR-interval, QT-interval, QRS-complex and heart rate will be measured for each ECG. The corrected QT interval (QTc) will be calculated using the Bazett and Fredericia formulas. All measurements will be made from a single lead: Lead II, or Lead I if Lead II is not possible, or lead V5 if Lead II and Lead I are not possible. 10.1.6 Pregnancy test

A serum pregnancy test (β-human chorionic gonadotrophin) will be performed at screening (Visit 1) in women of childbearing potential, and a urine pregnancy test will be performed at Visit 2 prior to randomization. A negative result must be obtained at Visit 1 and 2 prior to randomization. Additional urine pregnancy tests will be performed at Weeks 6 and 12 (Visits 8 and 14) or end-of-treatment visit.


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10.1.7 Physical examination

Physical examinations will include an assessment of general appearance, skin, eyes, ear/nose/throat, heart, chest, abdomen, reflexes, lymph nodes, spine, extremities, height (Visit 1 only), and weight. All deviations from normal will be recorded, including those attributable to the patient’s disease. Physical examinations will be performed at screening (Visit 1) and at Week 12 (Visit 14) or end-of-treatment visit. 10.2

SAFETY INSTRUCTIONS

Since low levels of doxycycline are used in the manufacturing process, patients allergic to doxycycline or related compounds should be excluded from this study. Emergency equipment and medication for the treatment of potential allergy/hypersensitivity reactions must be available for immediate use during study visits. This study uses an add-on therapy approach to background therapy (ICS/LABA combination) with systematic background therapy withdrawal during treatment. A 4-week background therapy stable phase will be followed by an 8-week background therapy withdrawal phase. Patients will enter the study having been on a stable dose of fluticasone/salmeterol combination therapy for 3 months. At Week 4 patients will be switched to an equivalent ICS dose of fluticasone monotherapy, thereby discontinuing the LABA component of fluticasone/salmeterol combination therapy. At subsequent 2 week visits, beginning with Week 6, the fluticasone dose will be reduced by approximately 50% provided that the patient does not meet any of the criteria for an asthma exacerbation as defined in Section 9.1.1. If a patient meets the criteria for an asthma exacerbation, he/she will be withdrawn from the study and treated by the Investigator with appropriate medical therapy. 10.3

ADVERSE EVENTS MONITORING

All events will be managed and reported in compliance with all applicable regulations, and included in the final clinical study report. 10.4

DEFINITIONS OF ADVERSE EVENT (AE) AND SERIOUS ADVERSE EVENT (SAE)

An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: •

Results in death or

•

Is life-threatening or Note: The term "life-threatening" in the definition of "serious" refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe.


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•

Requires inpatient hospitalization or prolongation of existing hospitalization or

•

Results in persistent or significant disability/incapacity or

•

Is a congenital anomaly/birth defect

•

Is a medically important event: Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention (ie, specific measures or corrective treatment) to prevent one of the other outcomes listed in the definition above.

Note: The following medical important events intend to serve as a guideline for determining which condition has to be considered as a medically important event. It is not intended to be exhaustive: •

Intensive treatment in an emergency room or at home for: -

allergic bronchospasm

-

blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, myelodysplasia, pancytopenia)

-

convulsions (seizures, epilepsy, epileptic fit, absence)

•

Development of drug dependency or drug abuse

•

ALT > 3 ULN + total bilirubin > 2 ULN or asymptomatic ALT increase > 10 ULN

•

Suicide attempt or any event suggestive of suicidality

•

Syncope, loss of consciousness (except if documented as a consequence of blood sampling)

•

Bullous cutaneous eruptions

•

Cancers diagnosed during the study or aggravated during the study

•

Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study

10.5

OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING

10.5.1 Adverse Events

All AEs regardless of seriousness or relationship to investigational product or non investigational product, spanning from the signature of the informed consent form, until the end of the study as defined by the protocol for that patient, are to be recorded on the corresponding page(s) or screen(s) included in the CRF. Since asthma exacerbation (as defined in Section 9.1.1) is the primary efficacy endpoint, it should not be reported as an AE unless it fulfills the criteria for an SAE.


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Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. The Investigator should specify the date of onset, intensity, action taken with respect to investigational product, corrective treatment/therapy given, additional investigations performed, outcome and his/her opinion as to whether there is a reasonable possibility that the AE was caused by the investigational product. Laboratory, vital signs, or ECG abnormalities are to be recorded as AEs only if: •

symptomatic and/or

•

requiring either corrective treatment or consultation, and/or

•

leading to investigational product discontinuation or modification of dosing, and/or

•

fulfilling a seriousness criterion, and/or

•

defined as an AE of special interest (AESI) with immediate notification (see Section 10.5.4).

10.5.2 Serious Adverse Events

In the case of occurrence of a SAE, the Investigator must immediately: •

ENTER (within 1 working day) the information related to the SAE in the appropriate screens of the e-CRF; the system will automatically send the notification to the Monitoring Team after approval of the Investigator within the e-CRF or after a standard delay.

•

SEND (preferably by fax or e-mail) the photocopy of all examinations carried out and the dates on which these examinations were performed, to the representative of the sanofiaventis Safety Group at 1-877-FAX-SAES [1-877-329-7237] or GV CRU [email protected]. Care should be taken to ensure that the patient's identity is protected and the patient's identifiers in the Clinical Trial are properly mentioned on any copy of source document provided to the Sponsor. For laboratory results, include the laboratory normal ranges

•

All further data updates should be recorded in the e-CRF as appropriate, and further documentation as well as additional information (for lab data, concomitant medication, patient status) should be sent (by fax or e-mail) to the Safety Group within 1 working day of knowledge. In addition, any effort should be made to further document each SAE that is fatal or life threatening within the week (7 days) following initial notification.

•

A back-up plan is used (using paper flow) when the e-CRF system does not work.

10.5.3 Safety Observations

•

The Investigator should take all appropriate measures to ensure the safety of the patients. Notably, he/she should follow up the outcome of SAEs /AESI until clinical recovery is complete and laboratory results have returned to normal or until progression has been stabilized or death. In all cases, this may imply that observations will continue beyond the last planned visit per protocol, and that additional investigations may be requested by the Sponsor.


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•

When treatment is prematurely discontinued, the patient’s observations will continue until the end of the study as defined by the protocol for that patient.

•

In case of any SAE/AESI with immediate notification brought to the attention of the Investigator at any time after the end of the study for the patient and considered by him/her to be caused by the investigational product with a reasonable possibility, this should be reported to the Sponsor.

10.5.4 Adverse events of special interest (AESI)

Adverse events of special interest are AEs (serious or non-serious) of scientific or medical concern for which ongoing monitoring and rapid communication may be important. These may include events that are either specific to the investigational product or events that, in general, may be of clinical significance with any medicinal product under development. As such, these need to be monitored, documented, and managed in a pre-specified manner described in the protocol. 10.5.4.1 AESI with immediate notification

For these AEs, the Sponsor will be informed immediately (ie, within 1 working day), per SAE notification described in Section 10.5.2, even if not fulfilling a seriousness criterion, using the corresponding pages in the CRF (to be sent) or screens in the e-CRF. •

•

•

ALT increase where: (see flowchart in Appendix E) -

ALT > 5 X the upper limit of normal (ULN) in patients with baseline ALT < ULN; or

-

ALT >3X baseline ALT in patients with baseline ALT ≥ ULN; or

-

ALT ≥3 ULN and ≤5 ULN plus total bilirubin >2 ULN in patients with baseline ALT < ULN; or

-

ALT ≥2X baseline ALT and ≤3X baseline ALT plus total bilirubin >2 ULN in patients with baseline ALT ≥ ULN.

Pregnancy -

Pregnancy occurring in a female patient included in the clinical trial. Pregnancy will be recorded as a pre-specified AE with immediate notification in all cases. It will be qualified as an SAE only if it fulfills the SAE criteria.

-

In the event of pregnancy, investigational product should be discontinued.

-

The follow-up of the pregnancy will be mandatory until the outcome has been determined.

Symptomatic overdose with investigational product An overdose (accidental or intentional) with the investigational product is an event suspected by the Investigator and defined as at least twice the dose during the planned intervals.

Adverse events and laboratory abnormalities requiring expedited reporting are summarized in Table 2. Property of the sanofi-aventis group - strictly confidential

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10.5.4.2 AESI without immediate notification

•

Asymptomatic overdose

•

ALT elevation where: -

ALT ≥3 ULN and ≤5 ULN plus total bilirubin ≤2 ULN in patients with baseline ALT < ULN; or

-

ALT ≥2X baseline ALT and ≤3X baseline ALT plus total bilirubin ≤2 ULN in patients with baseline ALT ≥ ULN Table 2 - Summary of Expedited Safety Reporting

Adverse event / laboratory abnormality Serious adverse event Pregnancy Overdose Symptomatic Asymptomatic ALT elevation Baseline < ULN ALT > 5 ULN 3 ULN ≤ ALT ≤ 5 ULN plus total bilirubin > 2 ULN Baseline ≥ ULN ALT > 3x baseline 2 x baseline ≤ ALT ≤ 3x baseline plus total bilirubin > 2 ULN

Reporting timeline Within 1 working day Within 1 working day Within 1 working day Routine Within 1 working day Within 1 working day Within 1 working day Within 1 working day

10.5.5 Laboratory abnormalities with pre-specified monitoring

Laboratory abnormalities should be monitored, documented, and managed according to the related flowchart in Appendix E. •

Increase in ALT

•

Neutropenia

•

Thrombocytopenia

•

Acute renal insufficiency

•

Suspicion of rhabdomyolysis

10.6

OBLIGATIONS OF THE SPONSOR

During the course of the study, the Sponsor will report in an expedited manner all SAEs that are both unexpected and at least reasonably related to the investigational product (SUSAR), to the Health Authorities, Independent Ethics Committees/Institutional Review Boards (IECs/IRBs) as appropriate and to the Investigators. In addition, the Sponsor will report in an expedited manner all SAEs that are expected and at least reasonably related to the investigational product to the Authorities, according to local regulations. In this study, some AEs are considered related to the underlying condition and thus will not be considered unexpected (please refer to the Investigator’s Brochure). Property of the sanofi-aventis group - strictly confidential

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Any other AE not listed as an expected event in the Investigator’s Brochure or in this protocol will be considered as unexpected. The Sponsor will report all safety observations made during the conduct of the trial in the clinical study report.


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11


HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION

The investigational product should be continued whenever possible. In case the investigational product is stopped, it should be determined if the stop can be made temporarily; permanent investigational product discontinuation should be a last resort. Any investigational product discontinuation should be fully documented in the e-CRF. In any case, the patient should remain in the study as long as possible. 11.1

TEMPORARY TREATMENT DISCONTINUATION WITH INVESTIGATIONAL PRODUCT(S)

Temporary treatment discontinuation may be considered by the Investigator because of suspected AEs. Reinitiation of treatment with the investigational product will be done under close and appropriate clinical/and or laboratory monitoring once the Investigator will have considered according to his/her best medical judgment that the responsibility of the investigational product(s) in the occurrence of the concerned event was unlikely and if the selection criteria for the study are still met (refer to Sections 7.2 and 7.3). All temporary treatment discontinuation and date of treatment re-initiation should be recorded by the Investigator in the appropriate pages when considered as confirmed. 11.2

PERMANENT TREATMENT DISCONTINUATION WITH INVESTIGATIONAL PRODUCT(S)

Permanent treatment discontinuation is any treatment discontinuation associated with the definitive decision from the Investigator or the patient not to re-expose the patient to the investigational product at any time. 11.2.1 List of criteria for definitive treatment discontinuation

The patients may withdraw from treatment with investigational product if they decide to do so, at any time and irrespective of the reason, or this may be the Investigator’s decision. All efforts should be made to document the reasons for treatment discontinuation, and this should be documented in the e-CRF. Patients must be withdrawn from the study (ie, from any further investigational product or study procedure) for the following reasons: •

At their own request or at the request of their legally authorized representative (Legally authorized representative means an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective patient to the patient’s participation in the procedure(s) involved in the research).


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•

If, in the Investigator’s opinion, continuation in the study would be detrimental to the patient’s well-being

•

At the specific request of the Sponsor

•

In the event of a protocol deviation, at the discretion of the Investigator or the Sponsor

•

Pregnancy

•

Asthma exacerbation: Patients will be instructed to contact the Investigator if a patient feels that his or her asthma is not adequately controlled (clinical exacerbation, intolerable or incapacitating symptoms, frequent nocturnal awakenings, frequent albuterol use). In addition, if a patient meets the criteria for an asthma exacerbation, he/she will be withdrawn from the study and treated by the Investigator with appropriate medical therapy. Exacerbation of asthma is defined by any of the following:

•

-

A 30% or greater reduction from baseline in morning PEF together with ≥6 additional reliever puffs of albuterol in a 24 hour period (compared to baseline) on 2 consecutive days

-

Deterioration of asthma, as determined by the Investigator, requiring: - Oral steroid treatment, or - An increase in ICS ≥4 times the baseline dose of ICS, or - Hospitalization

Any treatment unblinding by the Investigator will lead to permanent treatment discontinuation.

11.2.2 Handling of patients after permanent treatment discontinuation

Patients will be followed up according to the study procedures as specified in this protocol up to the scheduled date of study completion, or up to recovery or stabilization of any AE to be followed-up as specified in this protocol, whichever comes last. If possible, and after the permanent discontinuation of treatment, the patients will be assessed using the procedure normally planned for the end-of-treatment visit (including a PK sample) and followed-up 6 weeks later for a safety evaluation. If treatment with disallowed medication is indicated, every attempt should be made to complete the end-of-treatment visit evaluations prior to taking disallowed medications. If however, disallowed medications are taken prior to the end-of-treatment visit then the patient must be withdrawn from the study. Any urgent medical care will be left to the Investigator’s discretion. In all cases, the reason for and date of withdrawal must be recorded in the e-CRF and in the patient’s medical records. The patient must be followed up to establish whether the reason was an AE, and, if so, this must be reported in accordance with the procedures in Section 10.


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As far as possible, all examinations scheduled for the final study day must be performed on all patients who receive the investigational product but do not complete the study according to protocol. The Investigator must make every effort to contact patients lost to follow-up. Attempts to contact such patients must be documented in the patient’s records (eg, times and dates of attempted telephone contact, receipt for sending a registered letter). All permanent treatment discontinuation should be recorded by the Investigator in the appropriate pages when considered as confirmed. 11.3

PROCEDURE AND CONSEQUENCE FOR PATIENT WITHDRAWAL FROM STUDY

The patients may withdraw from the study, before study completion if they decide to do so, at any time and irrespective of the reason. If possible, the patients who discontinue early will be assessed using the procedure normally planned for the end-of-treatment visit (including a PK sample), and followed-up 6 weeks later for a safety evaluation. For patients who fail to return to the site, the Investigator should make the best effort to re-contact the patient (eg, contacting patient’s family or private physician, review available registries or health care database), and to determine his/her health status, including at least his/her vital status. Attempts to contact such patients must be documented in the patient’s records (eg, times and dates of attempted telephone contact, receipt for sending a registered letter). The statistical analysis plan will specify how these patients lost to follow-up for their primary endpoints will be considered. Patients who have withdrawn from the study cannot be re-randomized (treated) in the study. Their inclusion and treatment number must not be reused. Patients who withdraw from the study will not be replaced.


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12

STUDY PROCEDURES

12.1

VISIT SCHEDULE


This study consists of a screening period (Visit 1), a treatment period (Visits 2 through 14), and a post-treatment observation period (Visit 15). The treatment period includes a randomization visit (Visit 2) and is divided into a background therapy stable phase (Visits 2 to 6) and a background therapy withdrawal phase (Visits 7 to 14). Prior to opening enrollment to the entire cohort of 100 patients, a sentinel cohort consisting of 20 patients (10 active, 10 placebo) will be evaluated by the IDMC for any safety issues. Blinded clinical safety data through Week 5 (Visit 7) will be reviewed by the IDMC. Based on this review, a decision will be made to enroll the remainder of patients, modify the protocol, or stop the study. During this safety evaluation the sentinel cohort will continue to receive investigational product for the scheduled 12 weeks. This cohort will undergo additional PK sampling following investigational product discontinuation. 12.1.1 Screening Period: Visit 1 (Day -14 to Day -1)

At this visit the subject will be asked to sign an informed consent form in order to enter the study. The following procedures will then be performed: •

Collect demographic information (date of birth, sex, race, ethnicity)

•

Patient’s medical/surgical history (including asthma history)

•

Review inclusion and exclusion criteria

•

Evaluate reversibility (3 attempts may be made during the 14 day screening period to meet the entrance criterion of at least 12% and 200 mL in FEV1 after 200 µg to 400 µg [2 to 4 inhalations] of albuterol)

•

Prior and concomitant medication review

•

Physical examination

•

Administer ACQ

•

Spirometry following a 6 hour withhold of asthma medication and albuterol (3 attempts may be made during the 14 day screening period to meet the entrance criterion of FEV1 ≥50 and ≤80% predicted normal)

•

Dispense electronic diary/PEF meter, provide instructions for daily use, and remind patient to bring the device to Visit 2

•

Dispense albuterol for use as rescue medication and instruct patients to record usage in the electronic diary as needed. Instruct patients to withhold their last dose of albuterol 6 hours prior to Visit 2


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•

Commence AE reporting

•

Vital signs (sitting blood pressure and heart rate)

•

12-lead ECG

•

Blood samples for the following: -

Pregnancy test

-

Clinical laboratory testing (hematology and serum chemistry)

-

Eosinophil count (derived from clinical laboratory test)

-

Serum samples for total IgE, eotaxin-3, TARC, YKL-40, TSLP, CEA, and Phadiatop (antigen-specific IgE) analysis

-

Serum samples for protein analysis

-

Whole blood samples for RNA analysis

•

Instruct patients to continue dosing with current stable dose of fluticasone/salmeterol combination therapy, but to withhold dosing the morning of Visit 2

•

Remind patient to return to the clinic for Visit 2

12.1.2 Treatment period: Background therapy stable phase (Day 1 to Week 4 [Visits 2 to 6]) 12.1.2.1 Randomization: Visit 2 (Day 1)

•


•

Spirometry following a 6 hour withhold of asthma medication and albuterol. Patients must meet the entrance criterion of FEV1 ≥50 and ≤80% predicted normal on randomization day. If criterion not met, then patient will not be randomized on that day. He/she may return on a subsequent day to attempt to meet FEV1 criterion (3 attempts maximum).

•

Randomization via IVRS/IWRS

•

Download and review data from electronic diary/PEF meter

•

Induced sputum collection for eosinophils and neutrophils and exploratory analyses (subset of patients at particular sites)

•

Exhaled nitric oxide (subset of patients at particular sites)

•

AE reporting

•


•

Urine pregnancy test

•


Serum sample for PK analysis

-

Serum sample for anti-SAR231893/REGN668 antibody analysis


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-

Serum samples for total IgE, eotaxin-3, TARC, YKL-40, and TSLP, and CEA analysis

-


-


-

Optional pharmacogenomic sample (requires additional informed consent)

•

Administer investigational product

•


•


12.1.2.2 Visit 3 (Week 1 +/- 2 days)

•

Concomitant medication review

•

Administer ACQ

•

Spirometry following a 6 hour withhold of asthma medication and albuterol

•


•

AE reporting

•



-

Serum samples for total IgE, eotaxin-3, TARC, YKL-40, TSLP, and CEA analysis

-


-


•


•


•


12.1.2.3 Visit 4 (Week 2 +/- 2 days)

•


•

Administer ACQ

•


•


•

AE reporting

•


•

12-lead ECG


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•



Hematology and serum chemistry

•


•


•


12.1.2.4 Visit 5 (Week 3 +/- 2 days)

•


•

Administer ACQ

•


•


•

AE reporting

•


•


•


12.1.2.5 Visit 6 (Week 4 +/- 2 days)

•


•

Administer ACQ

•


•


•


•


•

AE reporting

•


•


Eosinophils

-


-


-



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-



•


•

Instruct patients to discontinue their fluticasone/salmeterol combination therapy and switch them to the equivalent dose of fluticasone monotherapy(according to Section 8.2), but to withhold dosing of fluticasone monotherapy the morning of Visit 7

•


12.1.3 Treatment period: Background therapy withdrawal phase (Visits 7 to 14) 12.1.3.1 Visit 7 (Week 5 +/- 2 days)

•


•

Administer ACQ

•


•


•

AE reporting

•


•

Instruct patients to continue dosing with current dose of fluticasone monotherapy, but to withhold dosing the morning of Visit 8

•


12.1.3.2 Visit 8 (Week 6 +/- 2 days)

•


•

Administer ACQ

•


•


•

Evaluate patient for ICS withdrawal, and reduce fluticasone dose by 50% provided the patient does not meet the criteria for asthma exacerbation

•

AE reporting

•


•

12-lead ECG

•


•



-



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-



•


•

Remind patient to withhold fluticasone dosing the morning of Visit 9

•


12.1.3.3 Visit 9 (Week 7 +/- 2 days)

•


•

Administer ACQ

•


•


•

AE reporting

•


•

Instruct patient to continue dosing with current dose of fluticasone monotherapy, but to withhold dosing the morning of Visit 10

•


12.1.3.4 Visit 10 (Week 8 +/- 2 days)

•


•

Administer ACQ

•


•


•


•


•


•

AE reporting

•


•


Eosinophils

-


-


-



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-



•


•


•


12.1.3.5 Visit 11 (Week 9 +/- 2 days)

•


•

Administer ACQ

•


•


•

AE reporting

•


•


•


12.1.3.6 Visit 12 (Week 10 +/- 2 days)

•


•

Administer ACQ

•


•


•


•

AE reporting

•


•



-


•


•


•



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12.1.3.7 Visit 13 (Week 11 +/- 2 days)

•


•

Administer ACQ

•


•


•

AE reporting

•



•


•


•


Additional visits for the sentinel cohort of 20 patients: Following the final dose of investigational product on Day 78 the sentinel cohort will return to the study site on Days 82, 92, 99, 106, and 113 for PK sampling. 12.1.3.8 Visit 14 (Week 12 +/- 2 days) End of treatment visit

•


•


•

Administer ACQ

•


•


•


•


•

AE reporting

•


•

12-lead ECG

•


•


Clinical laboratory test (hematology and serum chemistry)

-


-



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-

Serum samples for total IgE, eotaxin-3, TARC, YKL-40, TSLP, CEA, and Phadiatop (antigen-specific IgE) analysis

-


•

Instruct patient to discontinue fluticasone monotherapy and resume pre-treatment dose of fluticasone/salmeterol combination therapy, but to withhold dosing the morning of Visit 15

•

Remind patient to return to the clinic for final safety evaluation on Visit 15 and remind patients that they will be contacted by telephone at 1 week , 2 weeks, and 4 weeks after this visit to assess adverse events

12.1.4 Post-treatment period

Prior to the Visit scheduled for Week 18, contact the patient by telephone on Weeks 13, 14, and 16 (1, 2, and 4 weeks after the end-of-treatment assessment) to evaluate AEs 12.1.4.1 Visit 15 (Week 18 +/- 2 days)

•


•

Administer ACQ

•


•


•

AE reporting

•


•



-


12.1.5 All visits

The Investigator will make every attempt to assure maintenance of asthma control for each patient during this study. If a patient shows deterioration in asthma control during the treatment period, albuterol should be utilized as a rescue medication to control asthma symptoms. In case of clinical exacerbation of asthma where the Investigator considers that the patient’s asthma is deteriorating and requires treatment with a medication disallowed in the current study, the patient must be withdrawn from the study. 12.2

DEFINITION OF SOURCE DATA

Source data is all information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and Property of the sanofi-aventis group - strictly confidential

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evaluation of the trial. Source data are contained in source documents. Source documents are original documents, data and records such as hospital records, clinic and office charts, laboratory notes, memoranda, pharmacy dispensing records, recorded data from automated instruments, etc. All the data collected in the e-CRF should be transcribed directly from source documents. Data downloaded from the patients’ electronic diaries/PEF meters will be considered source data.


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13

STATISTICAL CONSIDERATIONS

13.1

DETERMINATION OF SAMPLE SIZE

The sample size calculations are based on the Phase 2 study results for inhaled pitrakinra (IL-4R mutein), where an absolute reduction in the proportion of patients with an asthma exacerbation of 37% (treatment rate of 13% versus placebo rate of 50%) was observed for this patient population. This study is designed to detect an absolute difference of 35% between treatment groups. To detect such a difference with 90% power (α=0.05, two-tailed test), 41 patients are required per treatment group (Fisher’s exact test). Accounting for an anticipated 15% dropout rate during the study, approximately 50 patients are required to be enrolled into each treatment group. 13.2

ANALYSIS ENDPOINTS

13.2.1 Demographic and baseline characteristics

The baseline value is generally defined as the last available value before randomization. The following demographic and baseline disease characteristics will be summarized by treatment group for the randomized population: •

Age (in years) to be derived as: (Date of informed consent - date of birth)/365.25

•

Gender (male, female)

•

Race (Caucasian/White, Black, Asian/Oriental, Other)

•

Ethnicity (Hispanic, Not Hispanic)

•

Height (cm)

•

Body weight (kg)

•

Duration of asthma = (Date of informed consent – date of diagnosis of asthma +1)/365.25

•

History of allergic rhinitis, eosinophilic esophagitis or atopic dermatitis

•

Current asthma therapy use

•

Other prior and concomitant medications

•

Physical examination and medical history will be described at baseline

•

The baseline efficacy data of FEV1 (including pre-dose FEV1, pre-dose FEV1 percent predicted, and FEV1 reversibility), PEF, and ACQ will be summarized. The baseline AM and PM PEF will be the mean AM measurements and mean PM measurements, respectively, recorded for the 7 days prior to the first dose


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13.2.2 Efficacy endpoints 13.2.2.1 Primary efficacy endpoint

The primary endpoint of this study is the occurrence of an exacerbation of asthma as defined by any of the following: •

A 30% or greater reduction from baseline in morning peak expiratory flow (PEF) together with ≥6 additional reliever puffs of albuterol in a 24 hour period (compared to baseline) on 2 consecutive days

•


Oral steroid treatment, or

-

An increase in ICS ≥4 times the baseline dose of ICS, or

-

Hospitalization

13.2.2.2 Secondary efficacy endpoint(s)

The key secondary efficacy endpoints include: •

Time to asthma exacerbation from randomization

•


•


•


•


•

Change from baseline at Week 12 and change from baseline at each visit in number of inhalations/day of albuterol for symptom relief

13.2.3 Safety endpoints

Safety will be assessed by the review of summaries of all safety variables including AEs, laboratory findings, vital signs, ECGs, and physical examinations. 13.2.3.1 Adverse events

An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.


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13.2.3.2 Deaths

Deaths are categorized per the following observation periods: •

Death on-study: deaths occurring after the start of treatment up to the end of the study (defined as last protocol planned visit [post-treatment safety follow-up visit] or the resolution/stabilization of all SAE)

•

Death on-treatment: deaths occurring during the treatment period

•

Death post-study: deaths occurring after the end of study

13.2.3.3 Laboratory safety variables

The clinical laboratory data consist of blood analysis (including hematology and clinical chemistry). Blood samples will be collected at screening (Visit 1) and at Week 2 (Visit 4), Week 6 (Visit 8), and Week 12 (Visit 14). Clinical laboratory values will be analyzed after conversion into standard international units. International units will be used in all listings and tables. 13.2.3.4 Vital signs

Vital sign parameters include sitting blood pressure (mmHg) and heart rate (bpm), which are collected at screening (Visit 1) and on Day 1 (Visit 2), Week 2 (Visit 4), Week 4 (Visit 6), Week 6 (Visit 8), Week 8 (Visit 10), Week 10 (Visit 12), Week 12 (Visit 14), and Week 18 (Visit 15). The following variables will be used for the analysis of vital signs: systolic and diastolic blood pressure, and heart rate. 13.2.3.5 ECG variables

A standard 12-lead ECG will be performed at screening (Visit 1), and at Week 2 (Visit 4), Week 6 (Visit 8), and Week 12 (Visit 14). A minimum of 3 complexes in an appropriate lead (lead II) will be averaged to determine the PR-interval, QT-interval, QRS-complex and heart rate will be measured for each ECG. The corrected QT interval (QTc) will be calculated using the Bazett and Fredericia formulas. 13.2.3.6 Physical examination

Physical examination will be performed at the screening visit and at the end-of-treatment visit. 13.2.4 Pharmacokinetic variables

Serum SAR231893/REGN668 concentrations will be measured in all patients on Day 1 (Visit 2), Week 1 (Visit 3), Week 4 (Visit 6), Week 6 (Visit 8), Week 8 (Visit 10), Week 10 (Visit 12), Week 11 (Visit 13), Week 12 (Visit 14) and Week 18 (Visit 15) and as soon as possible in the event of early treatment discontinuation. For the lead-in cohort of 20 patients, additional blood samples will be collected after the final dose on Days 82, 92, 99, 106 and 113. Serum PK


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parameters (Cmax, tmax, AUC0-τ, t1/2z, if feasible) in the lead-in cohort of 20 will be assessed as well as the extent of accumulation in all evaluable PK patients, if feasible. 13.2.5 Pharmacodynamic/genomics variables

•

Total IgE, antigen-specific IgE (Phadiatop), eotaxin-3, YKL-40, TARC, TLSP, and CEA

•

Serum samples for exploratory protein analysis

•

RNA (whole blood) samples

•

Pharmacogenomics (DNA) sample (optional – additional informed consent required)

•

Induced sputum for eosinophils and neutrophils and exploratory analyses (subset of patients at particular sites)

•

Exhaled nitric oxide levels (subset of patients at particular sites)

•

Blood eosinophil count

13.3

DISPOSITION OF PATIENTS

Screened patients are defined as any patient who met the inclusion criteria and signed the informed consent. Randomized patients consist of all screened patients with a treatment kit number allocated and recorded in the IVRS/IWRS database, regardless of whether the treatment kit was used or not. Patients treated without being randomized will not be considered as randomized and will not be included in any efficacy population. For any patient randomized more than once, only the data associated with the first randomization will be used in any analysis population. The safety experience associated with any later randomization will be assessed separately. The safety experience of patients treated and not randomized will be reported separately, and these patients will not be in the safety population. 13.4

ANALYSIS POPULATIONS

13.4.1 Efficacy populations

The primary efficacy analysis population for all efficacy variables will be the modified intent-totreat (mITT) population. This will include all randomized patients who receive at least one dose of investigational product. All efficacy analyses using the mITT population will be performed as randomized.


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13.4.2 Safety population

The safety or all treated population is comprised of all randomized patients who take at least one dose of investigational product. The safety analyses using the safety population will be analyzed as treated, that is, in the event a patient received treatment that differed from what he/she was randomized to, this patient will be classified under the actual treatment (as-treated) received, rather than his/her randomized treatment for the purposes of safety analyses and safety data presentation. Analyses of all PK variables will be also performed as treated using the safety population. In addition: •

Non-randomized but treated patients will not be part of the safety population, but their safety data will be presented separately.

•

Randomized patients for whom it is unclear whether they took the study medication will be included in the safety population as randomized.

13.5

STATISTICAL METHODS


All baseline measurements are to be collected prior to the first dose of investigational product. Measurements that were obtained after the first dose of investigational product are considered post-randomization values. If no measurement of a variable is obtained before the first dose of investigational product then the variable has missing , value. Parameters will be summarized on the all randomized population, analyzed in the treatment group to which they were randomized. Analyses for the safety population will be included in the appendices if the size of the safety population is different (>10%) from the size of that in the primary analysis population for any treatment group. Baseline values for the following efficacy endpoints will be calculated by taking the mean of the last 7 days (measurements) prior to randomization: AM and PM PEF, AM and PM symptom scores and nocturnal awakenings. 13.5.2 Prior or concomitant medications

The prior and concomitant medications will be presented on the randomized population. Medications will be summarized by treatment group according to the World Health Organization Drug Dictionary, considering the first digit of the Anatomic Therapeutic Chemical Classification (ATC) class (anatomic category) and the first three digits of the ATC class (therapeutic category). All ATC codes corresponding to a medication will be summarized, patients will be counted once in each ATC categories (anatomic or therapeutic) linked to the medication, therefore patients may be counted several time for the same medication. Property of the sanofi-aventis group - strictly confidential

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13.5.3 Extent of study treatment exposure and compliance

The extent of study treatment exposure will be assessed and summarized by actual treatment received within the safety population. 13.5.3.1 Extent of investigational product exposure

Duration of investigational product exposure is defined as: last dose date – first dose date + 1 day, regardless of unplanned intermittent discontinuations. 13.5.3.2 Compliance

A given administration will be considered as non compliant if the patient did not take the planned dose of treatment as required by the protocol. No imputation will be made for patients with missing or incomplete data. Treatment compliance, above-planned and under-planned dosing percentages will be summarized descriptively (N, Mean, standard deviation [SD], Median, Min, and Max). The percentage of patients with compliance < 80% will be summarized. 13.5.4 Analyses of efficacy endpoints 13.5.4.1 Analysis of primary efficacy endpoint

For the primary analysis of proportion of patients experiencing an asthma exacerbation, a logistic regression model will be used to compare SAR231893/REGN668 group with placebo. The model will include terms for treatment, stratification factor (prior fluticasone/salmeterol combination therapy dose) and investigative center. A stratified chi-square test will also be used to corroborate the primary analysis. 13.5.4.2 Analyses of secondary efficacy endpoints

Time to asthma exacerbation will be compared between treatment groups using a stratified (prior fluticasone/salmeterol combination therapy dose) log-rank test. The survival curves will be estimated using Kaplan-Meier estimates and the hazard ratio (and 95%confidence interval) will be provided using a Cox proportional hazards model. The secondary endpoints of FEV1 change from baseline, change from baseline in AM and PM PEF, change from baseline in ACQ score, change from baseline in AM and PM symptom scores and nocturnal awakenings will be analyzed using an analysis of covariance model including factors for treatment, stratification factor (prior fluticasone/salmeterol combination therapy and investigative center).


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13.5.4.3 Multiplicity Considerations

There is only one primary endpoint with only one primary analysis. As a result, no adjustment for multiplicity is necessary. Furthermore, all secondary endpoints are considered hypothesisgenerating and will be tested at 2-sided α=0.05 level after the primary endpoint has been analyzed. 13.5.5 Analyses of safety data 13.5.5.1 Analysis of adverse events

All AEs are to be coded to a “Preferred Term” (PT) and associated “High Level Group Term” (HLGT), “High Level Term” (HLT), and primary “System Organ Class” (SOC) using the version of MedDRA (Medical Dictionary for Regulatory Activities) currently in use at sanofi-aventis at the time of database lock before the randomization treatment code is broken. Adverse events will be summarized into 3 segments according to the time of occurrence: pre-treatment, on-treatment and post-treatment, and be reported using classification by SOC and/or MedDRA term. The pretreatment/screening period is defined as the time between when the subjects sign the informed consent form and the start of investigational product. The treatment period is defined as the time from first dose of investigational product to 7 days (±2 days) after the last dose of investigational product (end-of treatment visit). The post-treatment period is defined as the time starting after the end-of-treatment visit (7 days after the last dose of investigational product) until 6 weeks later. Pre-treatment AEs are defined as AEs that develop, worsen, or become serious during the pretreatment period. If the start date of an AE is undetermined due to incomplete or missing values and if the end date is prior to the date of first dose of double-blind study medication, the AE will be evaluated as pre-treatment. Treatment-emergent AEs (TEAEs) are defined as AEs that develop, worsen, or become serious during the treatment period. If the timing of an AE cannot be identified because of missing data, the AE will be considered as a TEAE. Details on handling missing data and partial dates will be provided in Statistical Analysis Plan (SAP). Post-treatment AEs are defined as AEs that develop, worsen, or become serious more than 7 days after the last dose of investigational product. The focus of AE reporting will be on TEAEs. Details of the presentation of frequency distributions of TEAEs will be provided in the SAP. Adverse event incidence tables will present by SOC (sorted by internationally agreed order), HLGT, HLT, and PT sorted in alphabetical order for each treatment group, the number (n) and percentage (%) of patients experiencing an AE. Multiple occurrences of the same event in the same patient will be counted only once in the tables within a treatment phase. The denominator for computation of percentages is the safety population within each treatment group.


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Deaths: The following deaths summaries will be generated: •

Number (%) of patients who died by study period (TEAE, on-study) and reasons for death if collected in death report form summarized on the safety population by treatment received

•

Death in non-randomized patients or randomized and not treated patients

•

All AEs leading to death (death as an outcome on the AE e-CRF page as reported by the Investigator), by primary SOC, HLGT, HLT and PT, showing number (%) of patients sorted by internationally agreed order of SOC and alphabetic order of HLGT, HLT, and PT

•

TEAE leading to death (death as an outcome on the AE e-CRF page as reported by the Investigator) by primary SOC , HLGT, HLT and PT showing number (%) of patients sorted by internationally agreed order of SOC and alphabetic order of HLGT, HLT, and PT.

13.5.5.2 Analysis of laboratory variables

The following approaches will be used to summarize laboratory data for the safety population: •

Summary statistics (number of subjects, mean, SD, median, minimum, maximum) of values at baseline (screening, Visit 1) and Week 2 (Visit 4), Week 6 (Visit 8), and Week 12 (Visit 14) or end-of-treatment visit, and of changes from baseline to each visit. Analyses of change from baseline to end of study will be conducted using the KruskalWallis test.

•

Number and frequency of subjects with low, normal or high values, with respect to the normal range for baseline and clinic visits (shift tables)

•

Number and frequency of subjects with predefined Potentially Clinically Significant Abnormality (PCSA). PCSA values are defined as abnormal values considered medically important by the Sponsor according to predefined criteria/thresholds based on literature review and defined by the Sponsor for clinical laboratory tests.

The following definitions will be applied to laboratory parameters, vital signs, and ECG. •

The PCSA values are defined as abnormal values considered medically important by the Sponsor according to predefined criteria/thresholds based on literature review and defined by the Sponsor for clinical laboratory tests, vital signs and ECG.

•

PCSA criteria will determine which patients had at least one PCSA during the ontreatment period, taking into account all evaluations performed during the on-treatment period, including non-scheduled or repeated evaluations. The number of all such patients will be the numerator for the on-treatment PCSA percentage.

Details on handling missing data, data abnormalities, re-tests, and unscheduled visits, will be provided in the SAP.


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13.5.5.3 Analysis of vital signs variables

Vital signs and weight data for the safety population will be summarized using primarily descriptive statistics (number of patients, mean, SD, SE, median, minimum, maximum) by treatment group for baseline (Day 1) and Week 2 (Visit 4), Week 4 (Visit 6), Week 6 (Visit 8), Week 8 (Visit 10), Week 10 (Visit 12), and Week 12 (Visit 14) or end-of-treatment visit. Analyses of change from baseline to end of study will be conducted using the Kruskal-Wallis test. 13.5.5.4 Analysis of other safety variables

Findings for physical examination data will be summarized. Shifts from normal to abnormal and vice versa will be presented in addition to summary statistics with patient count and percentage for each treatment group for physical examinations done at screening and end-of-treatment. 13.5.6 Analyses of pharmacokinetic and pharmacodynamic variables 13.5.6.1 Pharmacokinetic parameters

Serum concentrations of SAR231893/REGN688 and its PK parameters (Cmax, tmax, AUC0-τ, t1/2z, if feasible) will be summarized using arithmetic and geometric means, SD, standard error of the mean (SEM), coefficient of variation, minimum, median and maximum per sampling time. The trough serum concentrations will be further examined in an exploratory manner to see if the steady state condition has been established and to assess the extent of accumulation, if feasible. 13.5.6.2 Pharmacokinetic/Pharmacodynamic parameters

The relationship between efficacy, safety variables or other exploratory parameters and SAR231893/REGN668 serum concentrations may be explored using graphical and regression methods, if applicable. 13.5.7 Immunogenicity

Anti-SAR231893/REGN668 antibody assay results will be described categorically as negative (if below the assay cut-point or not drug specific) and positive (if drug specific signal is above the assay cut-point) by visit. 13.6

DATA HANDLING CONVENTIONS

In general, if a patient withdraws from the study prior to a scheduled visit, and no data are available for that visit, the data for that patient will be considered missing and will be excluded from the analysis. No baseline value will be carried forward to impute a missing post-baseline value.


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13.7


INTERIM ANALYSIS

No interim analysis of efficacy is planned. The IDMC will evaluate the blinded clinical safety data of a sentinel cohort consisting of 20 patients (10 active, 10 placebo) through Week 5 (Visit 7) for any safety issues. Based on this review, a decision will be made to enroll the remainder of patients, modify the protocol, or stop the study. 13.8

DATABASE LOCK

Database lock is planned for approximately 30 working days after Last Patient Last Visit.


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14

ETHICAL AND REGULATORY STANDARDS

14.1

ETHICAL PRINCIPLES

This Clinical Trial will be conducted in accordance with the principles laid down by the 18th World Medical Assembly (Helsinki, 1964) and all applicable amendments laid down by the World Medical Assemblies, and the International Conference on Harmonization (ICH) guidelines for Good Clinical Practice. In compliance with sanofi-aventis public disclosure commitments, this clinical trial will be recorded in the public registry website clinicaltrials.gov before the enrollment of the first patient. The registry will contain basic information about the trial sufficient to inform interested patients (and their healthcare practitioners) how to enroll in the trial. 14.2

LAWS AND REGULATIONS

This Clinical Trial will be conducted in compliance with all international guidelines, and national laws and regulations of the country(ies) in which the Clinical Trial is performed, as well as any applicable guidelines (see Section 15.1). 14.3

INFORMED CONSENT

The Investigator (according to applicable regulatory requirements), or a person designated by the Investigator, and under the Investigator's responsibility, should fully inform the patient of all pertinent aspects of the Clinical Trial including the written information giving approval/favorable opinion by the Ethics Committee (Institutional Review Board/Independent Ethics Committee [IRB/IEC]). All participants should be informed to the fullest extent possible about the study, in language and terms they are able to understand. Prior to a patient’s participation in the Clinical Trial, the written Informed Consent Form should be signed, name filled in and personally dated by the patient or by the patient’s legally acceptable representative, and by the person who conducted the informed consent discussion. A copy of the signed and dated written Informed Consent Form will be provided to the patient. The Informed Consent Form used by the Investigator for obtaining the patient's informed consent must be reviewed and approved by the Sponsor prior to submission to the appropriate Ethics Committee (IRB/IEC) for approval/favorable opinion. DNA and RNA sequence analysis is proposed as part of a pharmacogenomic substudy to the main clinical study. For patients wishing to participate in this substudy, a specific Pharmacogenomics Informed Consent Form must be signed, name filled and personally dated by the patient and by the person who conducted the consent discussion prior to DNA sample collection. There is no obligation for a patient who agrees to participate in the main clinical trial to participate in the


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pharmacogenomic substudy. This information will be clearly specified in the written informed consent form. A copy of the signed and dated written informed consent form will be provided to the patient. 14.4

INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC)

As required by local regulation, the Investigator or the Sponsor must submit this Clinical Trial Protocol to the appropriate Ethics Committee (IRB/IEC), and is required to forward to the respective other party a copy of the written and dated approval/favorable opinion signed by the Chairman with Ethics Committee (IRB/IEC) composition. The Clinical Trial (study number, Clinical Trial Protocol title and version number), the documents reviewed (Clinical Trial Protocol, Informed Consent Form, Investigator’s Brochure, Investigator’s curriculum vitae [CV], etc.) and the date of the review should be clearly stated on the written (IRB/IEC) approval/favorable opinion. Investigational product will not be released at the study site and the Investigator will not start the study before the written and dated approval/favorable opinion is received by the Investigator and the Sponsor. During the Clinical Trial, any amendment or modification to the Clinical Trial Protocol should be submitted to the Ethics Committee (IRB/IEC) before implementation, unless the change is necessary to eliminate an immediate hazard to the patients, in which case the IRB/IEC should be informed as soon as possible. It should also be informed of any event likely to affect the safety of patients or the continued conduct of the Clinical Trial, in particular any change in safety. All updates to the Investigator’s Brochure will be sent to the Ethics Committee (IRB/IEC). A progress report is sent to the Ethics Committee (IRB/IEC) at least annually and a summary of the Clinical Trial’s outcome at the end of the Clinical Trial.


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15

STUDY MONITORING

15.1

RESPONSIBILITIES OF THE INVESTIGATOR(S)

The Investigator(s) and delegated Investigator staff undertake(s) to perform the Clinical Trial in accordance with this Clinical Trial Protocol, International Conference on Harmonization (ICH) guidelines for Good Clinical Practice and the applicable regulatory requirements. The Investigator is required to ensure compliance with all procedures required by the Clinical Trial Protocol and with all study procedures provided by the Sponsor (including security rules). The Investigator agrees to provide reliable data and all information requested by the Clinical Trial Protocol (with the help of the e-CRF, Discrepancy Resolution Form or other appropriate instrument) in an accurate and legible manner according to the instructions provided and to ensure direct access to source documents by Sponsor representatives. If any circuit includes transfer of data particular attention should be paid to the confidentiality of the patient's data to be transferred. The Investigator may appoint such other individuals as he/she may deem appropriate as SubInvestigators to assist in the conduct of the Clinical Trial in accordance with the Clinical Trial Protocol. All Sub-Investigators shall be appointed and listed in a timely manner. The SubInvestigators will be supervised by and work under the responsibility of the Investigator. The Investigator will provide them with a copy of the Clinical Trial Protocol and all necessary information. 15.2

RESPONSIBILITIES OF THE SPONSOR

The Sponsor of this Clinical Trial is responsible to Health Authorities for taking all reasonable steps to ensure the proper conduct of the Clinical Trial Protocol as regards ethics, Clinical Trial Protocol compliance, and integrity and validity of the data recorded on the e-CRFs. Thus, the main duty of the Monitoring Team is to help the Investigator and the Sponsor maintain a high level of ethical, scientific, technical and regulatory quality in all aspects of the Clinical Trial. At regular intervals during the Clinical Trial, the site will be contacted, through monitoring visits, letters or telephone calls, by a representative of the Monitoring Team to review study progress, Investigator and patient compliance with Clinical Trial Protocol requirements and any emergent problems. These monitoring visits, will include but not be limited to review of the following aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and reporting, AESI documentation and reporting, AE documentation, investigational product allocation, patient compliance with the investigational product regimen, investigational product accountability, concomitant therapy use and quality of data.


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15.3


SOURCE DOCUMENT REQUIREMENTS

According to the ICH guidelines for Good Clinical Practice, the Monitoring Team must check the e-CRF entries against the source documents, except for the pre-identified source data directly recorded in the e-CRF. The Informed Consent Form will include a statement by which the patient allows the Sponsor’s duly authorized personnel, the Ethics Committee (IRB/IEC), and the regulatory authorities to have direct access to original medical records which support the data on the e-CRFs (eg, patient's medical file, appointment books, original laboratory records, etc). These personnel, bound by professional secrecy, must maintain the confidentiality of all personal identity or personal medical information (according to confidentiality and personal data protection rules). 15.4

USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL REQUEST

It is the responsibility of the Investigator to maintain adequate and accurate e-CRFs (according to the technology used) designed by the Sponsor to record (according to Sponsor instructions) all observations and other data pertinent to the clinical investigation in a timely manner. All e-CRFs should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of data. Should a correction be made, the corrected information will be entered in the e-CRF overwriting the initial information. An audit trail allows identifying the modification. Data are available within the system to the Sponsor as soon as they are entered in the e-CRF. The computerized handling of the data by the Sponsor when available in the e-CRF may generate additional requests (DRF) to which the Investigator is obliged to respond by confirming or modifying the data questioned. The requests with their responses will be managed through the eCRF. 15.5

USE OF COMPUTERIZED SYSTEMS

Computerized systems will be used to create, modify, maintain, archive, retrieve or transmit data. Computerized systems used during the different steps of the study are: • For screening and randomization activities, IVRS/IWRS • For data management activities, Oracle RDC • For pharmacokinetic activities, WinNonlin® • For statistical activities, SAS • For pharmacovigilance activities, AWARE • For investigational product ordering/tracking, SmartSupplies PMD • For monitoring activities, IMPACT, SmartSupplies RAR • For medical writing activities, DOMASYS


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16

ADMINISTRATIVE RULES

16.1

CURRICULUM VITAE


A current copy of the curriculum vitae describing the experience, qualification and training of each Investigator and Sub-Investigator will be signed, dated and provided to the Sponsor prior to the beginning of the Clinical Trial. 16.2

RECORD RETENTION IN STUDY SITES (S)

The Investigator must maintain confidential all study documentation, and take measures to prevent accidental or premature destruction of these documents. The Investigator should retain the study documents at least fifteen (15) years after the completion or discontinuation of the Clinical Trial. However, applicable regulatory requirements should be taken into account in the event that a longer period is required. The Investigator must notify the Sponsor prior to destroying any study essential documents following the Clinical Trial completion or discontinuation. If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, the Investigator shall inform the Sponsor and the relevant records shall be transferred to a mutually agreed upon designee.


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17


CONFIDENTIALITY

All information disclosed or provided by the Sponsor (or any company/institution acting on their behalf), or produced during the Clinical Trial, including, but not limited to, the Clinical Trial Protocol, the e-CRFs, the Investigator's Brochure and the results obtained during the course of the Clinical Trial, is confidential, prior to the publication of results. The Investigator and any person under his/her authority agree to undertake to keep confidential and not to disclose the information to any third party without the prior written approval of the Sponsor. However, the submission of this Clinical Trial Protocol and other necessary documentation to the Ethics Committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same obligation of confidentiality. The Sub-Investigators shall be bound by the same obligation as the Investigator. The Investigator shall inform the Sub-Investigators of the confidential nature of the Clinical Trial. The Investigator and the Sub-Investigators shall use the information solely for the purposes of the Clinical Trial, to the exclusion of any use for their own or for a third party's account. Furthermore, the Investigator and the Sponsor agree to adhere to the principles of personal data confidentiality in relation to the patients, Investigator and its collaborators involved in the study.


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18


PROPERTY RIGHTS

All information, documents and investigational product provided by the Sponsor or its designee are and remain the sole property of the Sponsor. The Investigator shall not mention any information or the Product in any application for a patent or for any other intellectual property rights. All the results, data, documents and inventions, which arise directly or indirectly from the Clinical Trial in any form, shall be the immediate and exclusive property of the Sponsor. The Sponsor may use or exploit all the results at its own discretion, without any limitation to its property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, develop, market or otherwise use the results of the Clinical Trial. As the case may be, the Investigator and/or the Sub-Investigators shall provide all assistance required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, including signature of legal documents.


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19


DATA PROTECTION •

The patient's personal data, which are included in the Sponsor database shall be treated in compliance with all applicable laws and regulations;

•

When archiving or processing personal data pertaining to the Investigator and/or to the patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to this data by any unauthorized third party.

•

The Sponsor also collects specific data regarding Investigator as well as personal data from any person involved in the study which may be included in the Sponsor’s databases, shall be treated by both the Sponsor and the Investigator in compliance with all applicable laws and regulations.


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20


INSURANCE COMPENSATION

The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials under its sponsorship. This insurance policy is in accordance with local laws and requirements. The insurance of the Sponsor does not relieve the Investigator and the collaborators from maintaining their own liability insurance policy. An insurance certificate will be provided to the Ethics committees/IRB or Health Authorities in countries requiring this document.


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21


SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES

For the purpose of ensuring compliance with the Clinical Trial Protocol, Good Clinical Practice and applicable regulatory requirements, the Investigator should permit auditing by or on the behalf of the Sponsor and inspection by regulatory authorities. The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study records for review, being understood that these personnel is bound by professional secrecy, and as such will not disclose any personal identity or personal medical information. The Investigator will make every effort to help with the performance of the audits and inspections, giving access to all necessary facilities, data, and documents. As soon as the Investigator is notified of a planned inspection by the authorities, he will inform the Sponsor and authorize the Sponsor to participate in this inspection. The confidentiality of the data verified and the protection of the patients should be respected during these inspections. Any result and information arising from the inspections by the regulatory authorities will be immediately communicated by the Investigator to the Sponsor. The Investigator shall take appropriate measures required by the Sponsor to take corrective actions for all problems found during the audit or inspections.


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22

PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF A SITE

22.1

DECIDED BY THE SPONSOR IN THE FOLLOWING CASES:

•

If the information on the product leads to doubt as to the benefit/risk ratio;

•

If the Investigator has received from the Sponsor all investigational product, means and information necessary to perform the Clinical Trial and has not included any patient after a reasonable period of time mutually agreed upon;

•

In the event of breach by the Investigator of a fundamental obligation under this agreement, including but not limited to breach of the Clinical Trial Protocol, breach of the applicable laws and regulations or breach of the ICH guidelines for Good Clinical Practice;

•

If the total number of patients are included earlier than expected;

In any case the Sponsor will notify the Investigator of its decision by written notice. 22.2

DECIDED BY THE INVESTIGATOR

The Investigator must notify (30 days' prior notice) the Sponsor of his/her decision and give the reason in writing. In all cases (decided by the Sponsor or by the Investigator), the appropriate Ethics Committee(s) (IRB/IEC) and Health Authorities should be informed according to applicable regulatory requirements.


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23


CLINICAL TRIAL RESULTS

The Sponsor will be responsible for preparing a Clinical Study Report and to provide a summary of study results to the Investigator.


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24


PUBLICATIONS AND COMMUNICATIONS

The Investigator undertakes not to make any publication or release pertaining to the Study and/or results of the Study prior to the Sponsor’s written consent, being understood that the Sponsor will not unreasonably withhold its approval. As the Study is being conducted at multiple sites, the Sponsor agrees that, consistent with scientific standards, first presentation or publication of the results of the Study shall be made only as part of a publication of the results obtained by all sites performing the Protocol. However, if no multicenter publication has occurred within 12 months of the completion of this Study at all sites, the Investigator shall have the right to publish or present independently the results of this Study to the review procedure set forth herein. The Investigator shall provide the Sponsor with a copy of any such presentation or publication derived from the Study for review and comment at least 30 days in advance of any presentation or submission for publication. In addition, if requested by the Sponsor, any presentation or submission for publication shall be delayed for a limited time, not to exceed 90 days, to allow for filing of a patent application or such other measures as the Sponsor deems appropriate to establish and preserve its proprietary rights. The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or promotional material or publication without the prior written consent of the Sponsor. The Sponsor shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional material or publication without having received his/her and/or their prior written consent(s). The Sponsor has the right at any time to publish the results of the study.


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25


CLINICAL TRIAL PROTOCOL AMENDMENTS

All appendices attached hereto and referred to herein are made part of this Clinical Trial Protocol. The Investigator should not implement any deviation from, or changes of the Clinical Trial Protocol without agreement by the Sponsor and prior review and documented approval/favorable opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to Clinical Trial Patients, or when the change(s) involves only logistical or administrative aspects of the trial. Any change agreed upon will be recorded in writing, the written amendment will be signed by the Investigator and by the Sponsor and the signed amendment will be filed with this Clinical Trial Protocol. Any amendment to the Clinical Trial Protocol requires written approval/favorable opinion by the Ethics Committee (IRB/IEC) prior to its implementation, unless there are overriding safety reasons. In some instances, an amendment may require a change to the Informed Consent Form. The Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised Informed Consent Form prior to implementation of the change and patient signature should be recollected if necessary.


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26


BIBLIOGRAPHIC REFERENCES

1. Greening AP, Wind P, Northfield M, Shaw G. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroids. Lancet 1994;344:219. 2. Woolcock A, Lundback BO, Ringdal N, Jacques LA. Comparison of addition to salmeterol to inhaled steroids with doubling of the does of inhaled steroids. Am J Respir Crit Care Med 1996;153:1481. 3. Godard P, Chanez P, Siraudin L, Nicoloyannis L, Duru G. Costs of asthma are corelated with severity: A 1 year prospaective study. Eur Respir J 2002; 19:61-67. 4. Global Initiative for Asthma (GINA). Global Stategy for Asthma management and Prevention. www.ginasthma.org 2009 5. Levine SJ Wenzel SE. Narrative review: The role of Th2 immune pathway modulation in the treatment of severe asthma and its phenotypes. Ann Intern Med. 2010;152:232-237. 6. Wenzel SE, Ind PW, Outlana BA, Bleeker ER, Kuna P, Yen YP. Inhaled pitrakinra, an IL4/IL-13 antagonist, reduced exacerbations in patients with eosinophilic asthma. Abstracts 18th ERS Annual Congress. Eur Resp J 2008;32 7. Banfield C, Vincent M, Kakkar T, Chia M, Thien F, Chiah TC, Gerson J, Wu Y. Multiple dose study of AMG 317 in adults with asthma: Pharmacokinetics and safety. J Allergy Clin Immunol. 2008; 121;S79. 8. Vincent M, Banfield C, Kakkar T, Shakib S, Schicchitano R, Chiah TC, Gerson J. Singledose, first-in-human study of AMG 317: Pharmacokinetics and safety in healthy and asthmatic adults. J Allergy Clin Immunol. 2008;121:S10. 9. Corren J, Busse, W, Meltzer EO, Mansfield L, Bensch G, Fahrenholz J, Wenzel SE, Chon Y, Dunn M, Weng HH, Lin S-L. A randomized, controlled, phase 2 study of AMG 317, an IL4R antagonist, in patients with asthma. Am J Respir Crit Care Med. 2010;181;788-796. 10. Standardization of the measurement of lung volumes. ATS/ERS Task Force: Standardization of Lung Function Testing. Edited by V. Brusasco, R. Crapo, and G. Viegi. Eur Resir J. 2005;26:511-552. 11. Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J. 1999;14:902-907. 12. Hankinson J et al. Spirometric reference values from a sample of the general US population. Am J Respir Crit Care Med. 1999;159:179-187


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27


APPENDICES

Appendix A

Drugs known to prolong the QTc interval Generic Name Chloroquine Sotalol Clarithromycin Quinidine Amiodarone Ibutilide Methadone Erythromycin Erythromycin Haloperidol Halofantrine Droperidol Thioridazine Methadone Domperidone Pentamidine Disopyramide Pimozide Levomethadyl Amiodarone Pentamidine Procainamide Procainamide Cisapride Quinidine Mesoridazine Chlorpromazine Dofetilide Arsenic trioxide Bepridil Sparfloxacin


Brand Name Aralen Betapace Biaxin Cardioquin Cordarone Corvert Dolophine E.E.S. Erythrocin Haldol Halfan Inapsine Mellaril Methadose Motilium NebuPent Norpace Orap Orlaam Pacerone Pentam Procan Pronestyl Propulsid Quiniglute Serentil Thorazine Tikosyn Trisenox Vascor Zagam

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Appendix B


Spirometry

Equipment The same spirometer and standard spirometric techniques including calibration will be used to perform pulmonary function tests at all visits. Spirometry will meet the specifications and performance criteria recommended in the ATS/ERS Task Force: Standardization of Lung Function Testing will be used (10). Preparing the patient Spirometry, an effort-dependent test, requires careful instruction and cooperation of the patient. It is important to ensure a good seal around the mouthpiece, and ensure that the patient’s posture is correct. Explain that maximum inspiration, followed by maximum forced expiration until no more can be exhaled (or for at least 6 seconds if possible) is required. Expiration must be rapid and complete. Maximum effort must be maintained during expiration. The results of spirometry should meet the following criteria for number of trials, acceptability, and reproducibility. The acceptability criteria should be applied before reproducibility is checked. Number of trials For screening spirometry and for pre-dose measurements at Visits 2 through 14, a minimum of 3 acceptable forced vital capacity (FVC) maneuvers should be performed. If a patient is unable to perform a single acceptable maneuver after 8 attempts, testing may be discontinued. However, after additional instruction and demonstration, more maneuvers may be performed depending on the patient's clinical condition and tolerance. Acceptability An acceptable maneuver has the following characteristics: •

No hesitation or false start;

•

A rapid start to rise time;

•

No cough, especially during the first second of the maneuver;

•

No early termination of exhalation (minimum exhalation time of 6 seconds is recommended, unless there is an obvious plateau of reasonable duration (ie, no volume change for 1 second) or the patient cannot continue to exhale further).


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Reproducibility The 2 largest FVC values from 3 acceptable maneuvers should not vary by more than 0.150 L, Recording of Data The highest FEV1 resulting from any of the acceptable curves are recorded. Post-Bronchodilator Spirometry Perform spirometry approximately 20-30 minutes after giving 200 µg or 400 µg of albuterol via a standard unit dose of albuterol nebulization to achieve 15% and 200ml reversibility. Each nebulizer treatment will require a set-up consisting of a compressor and single patient use attachment system including a nebulizing cup for medication, a mouthpiece and connecting tube. Apply the same performance and measurement criteria described above for post-bronchodilator spirometry. Predicted Normal NHANES predicted normal values will be used to determine FEV1 (L) predicted normal values in adolescents and adults (12).


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Appendix C


Juniper Asthma Control Questionnaire

Please answer Questions 1-6. Circle the number of the response that best describes how you have been during the past week. 1. On average, during the past week, how often were you woken by your asthma during the night? 0 Never 1 Hardly ever 2 A few times 3 Several times 4 Many times 5 A great many times 6 Unable to sleep because of asthma 2. On average, during the past week, how bad were your asthma symptoms when you woke up in the morning? 0 No symptoms 1 Very mild symptoms 2 Mild symptoms 3 Moderate symptoms 4 Quite severe symptoms 5 Severe symptoms 6 Very severe symptoms 3. In general, during the past week, how limited were you in your activities because of your asthma? 0 Not limited at all 1 Very slightly limited 2 Slightly limited 3 Moderately limited 4 Very limited 5 Extremely limited 6 Totally limited 4. In general, during the past week, how much shortness of breath did you experience because of your asthma? 0 None 1 A very little 2 A little Property of the sanofi-aventis group - strictly confidential

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3 A moderate amount 4 Quite a lot 5 A great deal 6 A very great deal 5. In general, during the past week, how much of the time did you wheeze? 0 Not at all 1 Hardly any of the time 2 A little of the time 3 A moderate amount of the time 4 A lot of the time 5 Most of the time 6 All the time 6. On average, during the past week, how many puffs of short-acting bronchodilator (e.g., Ventolin) have you used each day? 0 None 1 1-2 puffs most days 2 3-4 puffs most days 3 5-8 puffs most days 4 9-12 puffs most days 5 13-16 puffs most days 6 More than 16 puffs most days To be completed by a member of the clinic staff 7. FEV1 prebronchodilator _ _ _ _ _ _ FEV1 predicted _ _ _ _ _ _ FEV1 % predicted _ _ _ _ _ (Record actual valued on the dotted lines and score the FEV1 % predicted in the next column) 0 > 95% predicted 1 95-90% 2 89-80% 3 79-70% 4 69-60% 5 59-50% 6 < 50% predicted


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Appendix D


Sputum induction procedure

A subset of study sites will participate in an evaluation of induced sputum. The goal is for approximately 50 patients to participate in this analysis. The Test Sputum induction is a relatively non-invasive method to obtain sputum for cell or fluid phase inflammatory indices, culture or cytology. It is performed with an aerosol of normal or hypertonic saline generated by an ultrasonic nebulizer. As this aerosol is a potential bronchoconstrictive stimulus, it is made safe by pretreatment with salbutamol and inhalation in a dose response manner. Materials Needed Refrigerator for storing saline Saline solutions of 0.9%, 3%, 4% and 5% Alcohol swabs 10-ml. syringe with needle (20 gauge or yellow needle) Ultrasonic nebulizer, Universal III Spirometer Salbutamol or equivalent Stop watch or clock Sterile sputum collection jars Calculator and record sheet Equipment for cleaning apparatus (nebulizer and masks) Nose clips Glass of water Valved holding chamber (aerochamber or other spacing device) Box of tissues Protocol 1. Store saline in refrigerator at 4ºC until approximately 15 minutes before use. Once removed from the refrigerator, keep at room temperature (21 ºC) until use. Check the expiratory date on saline bottles. Saline is ordered from pharmacy. 2. Please read: Instructions to Patients about Sputum Induction to inform the patient of the purpose of the test, how it will be conducted, how to obtain sputum from the lungs and how to avoid the contamination of sputum with postnasal secretions. 3. Measure the baseline FEV1 and SVC as per ATS guidelines. Ensure expiratory FV curves are followed by maximum inspiratory FV curves at baseline. a. If the patient has taken the following medications, omit administration of salbutamol as mentioned in #4. i. SABA within 4 hours;


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ii. LABA within 6 hours; or iii. FEV1 is greater than 80% and the patient is not taking inhalers. 4. In all other instances, give salbutamol 2 puffs and measure FEV1 and SVC after 10 minutes, measurements done according to ATS guidelines. Ensure expiratory FV curves are followed by maximum inspiratory FV curves post salbutamol. •

Use the best post-salbutamol FEV1 value to calculate any later falls in FEV1. % fall = (Post best-salbutamol FEV1 – Post nebulization FEV1) x 100 Post best-salbutamol FEV1

5. If the best FEV1 post-bronchodilator is less than 1.0 L proceed cautiously (See: Other considerations.) If the FEV1 is 0.8L or less, do not proceed with test. Try to obtain a spontaneous sample or ask the physician requesting the procedure whether or not to proceed carefully with it. Starting concentrations: •

If the FEV1 > 70% (regardless of reversibility)

3% hypertonic saline

•

If the FEV1 < 70%

0.9% saline

6. Place 9 c.c. of the starting saline concentration into the well of the nebulizer. Place the mouthpiece onto the nebulizer. Adjust the regulating valve to “max” and depress the activator button to begin nebulization. •

Do not use nose plugs.

•

The clock/stop watch should be started at the beginning of each inhalation period and stopped as needed. (ie, if the patient needs to stop due to cough, dyspnea, etc.)

7. Instruct the patient to breathe normally by tidal breathing while inhaling the saline mist for 7 minutes. •

Some side effects, which may occur with hypertonic saline, are gagging, sore or burning throat but these rarely interfere with the test. These are usually not bothersome. Sometimes the patient may hyperventilate.

8. After the 7 minutes, stop the nebulizer and the timer. 9. Ask the patient to first blow their nose, and then rinse their mouth with water and swallow the water. Ask the patient to try to cough sputum from the chest into a sputum container. 10. Measure the FEV1 once, record on your worksheet and calculate any % fall. 11. If there has been 10%, see items #13 or #14


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12. Repeat steps 8-12 until: •

3 - 4 nebulization’s or a total time of 21 minutes has been completed, or

•

you have obtained an adequate sample (in total about half the size of a pea),

•

the FEV1 has dropped by 20% from baseline best post-bronchodilator value.

13. If the FEV1 falls between 10-20% (from the baseline best post-bronchodilator FEV1) after any nebulization, the concentration of saline must be kept the same for any further nebulizations. Carefully monitor the patient and repeat all induction steps until the three 7-minute inhalations (total of 21 minutes) have been completed, or until the FEV1 falls by >20%. 14. If the FEV1 falls by 200 ml and by 20 % or more (from the baseline best post-bronchodilator FEV1) at any time OR if bothersome symptoms occur, discontinue all inhalations of saline and treat with 2 puffs of salbutamol. •

Sputum induction should NOT be resumed.

•

As at baseline, conduct expiratory FV curves followed by maximum inspiratory FV curves.

•

Check the FEV1 10 minutes after salbutamol and monitor this until the FEV1 has returned to within 5% of baseline.

•

If the patient has not produced any sputum, have them rest with no coughing for another 10 minutes, and then ask them to try again to produce a sample.

15. You have now completed the sputum induction. •

If no sputum is obtained, have the patient try coughing again after 10 minutes.

16. Label the sputum cup with the patient’s name, physician, date and time of collection. Place the sputum cup in a biohazard bag and deliver for processing. If there is any delay, keep the specimen in the refrigerator. Cell counts are unchanged for up to 8 hours if kept in the refrigerator. Instructions to patients about sputum induction •

You will inhale a salty mist to try to loosen up some secretions from the chest so that you can cough them into a specimen jar.

•

You will inhale the mist for up to 7 minutes each time for a total of 3-4 times (21-28 minutes total).

•

Place your lips around the mouthpiece; breathe normally through your mouth.

•

If you experience any chest discomfort during the test please let me know and we will stop and check your breathing. You will be given a bronchodilator before starting so that this is less likely to happen.

•

If at any time you can cough up some phlegm from your chest, just come off the nebulizer and spit into the jar.


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•

Be careful not to sniff back from your nose – you must cough from your chest.

•

At the end of each 7 minute period, I’ll ask you to blow your nose, take a sip of water and try to cough from your chest and spit into the jar.

Other considerations •

If the FEV1 is less than 1.0 liter from the baseline best post-salbutamol FEV1, caution must be exercised with the inhalations. Monitor the patient’s FEV1 at the 3.5 minute interval during the initial 0.9% saline nebulization.

•

If the patient wishes to cough during any of the inhalation periods, turn off the nebulizer and clock and obtain the specimen. Then continue the same nebulization and restart the clock.

•

If the patient states he does not have any secretions and sounds very dry at early inhalations, encourage a deep breath and cough but only one or two times and continue to the next inhalation so as not to tire the patient or cause throat soreness. If the patient does not cough spontaneously, you can let the patient sit for 1-2 minutes and then try to cough.

•

Remind the patient to clear secretions from the throat forward by using the muscles at the side of the throat. It is important to instruct them to deliberately not swallow the sputum.

•

Listen to the patient to ensure that the sample is truly from the lungs and not postnasal secretions.

Spontaneous sputum – obtaining a good sample 1. Blow the nose to avoid contamination of sputum with nasal secretions. 2. Rinse the mouth with water and swallow it. 3. Do not sniff back before coughing out the sputum. 4. Cough deeply to ensure that the sputum is coming from the chest. 5. Cough out the sputum into a sterile container. 6. Label the container with the patient’s name, doctor, date and collection time. Equipment Cleaning Careful cleaning and thorough drying are essential for good hygienic maintenance of this equipment. With the Universal nebulizer, care must be taken of the metal plate (transducer) in the medication well when cleaning or adding hypertonic saline. Do not immerse the nebulizer unit in any solution. After each use, remove the hard plastic mouthpiece and place in dirty core container for cleaning. Rinse the well of the nebulizer and pour a small amount of isopropyl alcohol into the well. Allow the alcohol to sit a few minutes, empty, air dry and then rinse with water and allow to air dry (according to manufacturers directions). Remove blue circle and baffle at top of nebulizer and rinse with water. Wipe outside of nebulizer with alcohol prep.


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Personal Safety When the patient is coughing, maintain a minimum of one-meter distance according to Infection Control protocol. Have the patient face straight ahead and not towards you. Clean the workspace after each patient.


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Appendix E


General Guidance for the follow-up of laboratory abnormalities by sanofi-aventis


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Page 100



NOTE: IN ADDITION, AS SOON AS A SERIOUSNESS CRITERION IS MET, THE EVENT SHOULD BE NOTIFIED WITHIN 1 WORKING DAY TO THE MONITORING TEAM.


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Page 102




Page 103


Appendix F


DNA sample collection

1. PROCEDURE FOR COLLECTION, HANDLING, AND SHIPMENT OF DNA PHARMACOGENOMIC SPECIMENS •

Collection schedule: per protocol.

•

Labeling of samples -

Each sample tube should have attached to it the label provided by Covance. DNA Subject ID:XXX-001-YYY Study Number / Compound (pre-printed) Bar Code (preprinted) Accession Number (pre-printed)

•

•

Procedure -

Using a waterproof pen, write Subject ID Number on label in space provided.

-

Collect 12 mL of blood, using two 6 mL Vacutainer (Becton Dickinson; K2 EDTA with HEMOGARD Closure) tubes provided, and gently invert tube at least 8 times permitting the specimen to mix with the anticoagulant.

-

Under no circumstances should the tube be centrifuged.

-

Ensure the sample tube is clearly and appropriately labeled as described above and in detail in the Covance Laboratory Manual.

-

Immediately freeze and maintain the blood in an upright position at -20°C or colder for storage. Samples must be stored on dry ice if a freezer is not immediately available.

-

Complete the Laboratory Requisition Form (provided by Covance) for each sample.

Storage -

•

In the event of damage or loss of the provided labels, a new label should be immediately requested from Covance.

Samples must be kept at -20 ºC or colder, organized in a rack in numeric order according to the Subject ID, until ready for packaging and shipping.

Packaging and shipment -

Samples and accompanying documents should be packaged according to the detailed instructions in the Covance Laboratory Manual provided at the initiation of the study.

-

Samples must be packaged according to IATA Dangerous Goods Regulations, Packing Instructions 650, using the packing materials provided by contracted company.

-

In the event that the packaging materials or instructions are lost, please contact the study Sponsor.

-

Ship samples on dry ice to Covance as described in the Global Study Schedule, using the shipping materials provided.


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•

2.


Note: Additional detailed information can be found in the Covance Laboratory Manual, provided at the beginning of the study. This includes additional details regarding: -

Sample collection kits

-

Sample collection procedures

-

Documentation procedures

-

Packing and shipping instructions

-

Sample kit resupply

-

How to get help

SHIPMENT CONTACT NAMES AND ADDRESSES

For DNA Pharmacogenomic Samples: Use for the Americas: USA and Canada, as well as Latin America and the Islands (Dominican Republic, etc): Covance CLS Indianapolis 8211 SciCor Drive Indianapolis, IN 46214-2985 USA Tel. +1 (317) 271-1200 (local calls) Tel: +1 800-462-8885 Fax: (317) 273-4030


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AMENDED CLINICAL TRIAL PROTOCOL 5

COMPOUND: SAR231893/REGN668 A randomized, double-blind, placebo-controlled, parallel group study to assess the efficacy, safety, and tolerability of SAR231893/REGN668 administered subcutaneously (SC) once weekly for 12 weeks in patients with persistent moderate to severe eosinophilic asthma who are partially controlled/uncontrolled by inhaled corticosteroid (ICS) plus long-acting beta2 agonist (LABA) therapy STUDY NUMBER: ACT11457 VERSION DATE / STATUS: 12-Apr-2012/Approved CLINICAL STUDY DIRECTOR: Michael Tillinger, MD Protocol Amendment 5

Version number: 1 (electronic 1.0)

Date: 12 April 2012

Amended Clinical Trial Protocol 4


Date: 30 November 2011

Protocol Amendment 4


Date : 30 November 2011



Date : 12 September 2011



Date : 12 September 2011



Date : 23 May 2011



Date : 23 May 2011



Date : 17 January 2011



Date : 17 January 2011

Clinical Trial Protocol


Date : 15 November 2010

EudraCT or IND number : 105,379

Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of sanofi-aventis (or any of its affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written consent of sanofi-aventis (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date of communication or afterwards (i) controls directly or indirectly sanofi-aventis, (ii) is directly or indirectly controlled by sanofiaventis, with ‘control’ meaning direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity According to template: QSD-002579 VERSION N°3.0 (11-JUN-2010)

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Amended Clinical Trial Protocol 5 SAR231893/REGN668 - ACT11457

12-Apr-2012 Version number: 1

NAMES AND ADDRESSES OF COORDINATING INVESTIGATOR

Name: Address:

Tel: Fax: E-mail:

MONITORING TEAM’S REPRESENTATIVE

Name: Address:

Tel: Fax: E-mail:

SPONSOR

Company: Address:

OTHER EMERGENCY TELEPHONE NUMBERS


Name: Address:

Tel: Fax: E-Mail:

Name: Address: Tel: Fax: E-mail:

Company: Address:

Telephone Numbers:

Page 2



CLINICAL TRIAL SUMMARY COMPOUND: SAR231893/REGN668 STUDY No: ACT11457 TITLE

A randomized, double-blind, placebo-controlled, parallel group study to assess the efficacy, safety, and tolerability of SAR231893/REGN668 administered subcutaneously (SC) once weekly for 12 weeks in patients with persistent moderate to severe eosinophilic asthma who are partially controlled/uncontrolled by inhaled corticosteroid (ICS) plus long-acting beta2 agonist (LABA) therapy

INVESTIGATOR/TRIAL LOCATION

USA

STUDY OBJECTIVE(S)

Primary Objective The primary objective of this study is to investigate the effects of SAR231893/REGN668 administered subcutaneously (SC) once weekly for 12 weeks as compared to placebo on reducing the incidence of asthma exacerbations in patients with persistent moderate to severe eosinophilic asthma. Secondary Objective(s)

STUDY DESIGN

•


•


Randomized, double-blind, placebo-controlled, with parallel groups; 2 week screening and run-in, 4-week background therapy stable phase and 8-week background therapy withdrawal phase postrandomization; add-on therapy approach to ICS/LABA combination therapy with systematic ICS/LABA withdrawal during treatment; 8-week follow-up period: • •

Screening period (up to 14 days) Treatment (12 weeks) - Background therapy stable phase (4 weeks) - Background therapy withdrawal phase (8 weeks) • Follow-up (8 weeks) Prior to screening, patients must be on a stable dose of any of the following doses and formulations of ICS/LABA combination therapy for at least 1 month: •

• •


Fluticasone/salmeterol combination therapy - Advair® Diskus – dry powder inhaler (DPI): 250/50 µg BID or 500/50 µg BID, or - Advair® HFA – metered dose inhaler (MDI): 230/42 µg BID or 460/42 µg BID, or Budesonide/formoterol combination therapy (Symbicort® 160/9 µg BID or 320/9 µg BID), or Mometasone/formoterol combination therapy (Dulera® 200/10 µg BID or 400/10 µg BID)

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Patients who have been on budesonide/formoterol or mometasone/formoterol will be switched to an equivalent dose of fluticasone/salmeterol at randomization (Day 1), and patients who have been on fluticasone/salmeterol will remain on their current treatment as background therapy. Patients who satisfy the inclusion and exclusion criteria will be randomized to one of the following treatments: •

300 mg SAR231893/REGN688 administered SC once weekly for 12 weeks • Placebo administered SC once weekly for 12 weeks Post-randomization visits during the 12-week treatment period will occur every week and will be followed by an 8 week follow-up period off investigational product to assess the safety of SAR231893/REGN668. Sentinel cohort: Prior to opening enrollment to the entire cohort of up tp approximately 130 patients, a sentinel cohort consisting of approximately 20 patients (approximately 10 active and 10 placebo) will be enrolled. Data from this sentinel cohort will be evaluated by an Independent Data Monitoring Committee (IDMC) for any safety issues. After the 20th or so patient has been randomized, screening will be suspended for at least 2 weeks. Unblinded clinical safety data through at least 4 weeks of treatment will be reviewed by the IDMC. Based on this review, a decision will be made to continue treatment beyond 4 weeks for the currently enrolled patients. Additionally, based on the IDMC’s review, a decision may be made to modify the protocol or to stop the study. During this safety evaluation the sentinel cohort will continue to receive investigational product for the scheduled 12 weeks. Algorithm for background therapy (ICS/LABA) withdrawal: •

At 4 weeks post-randomization (Visit 6) patients will be switched from their BID fluticasone/salmeterol combination therapy to an equivalent ICS dose of fluticasone monotherapy - Flovent® Diskus (DPI formulation): 250 µg or 500 µg BID, or - Flovent® HFA (MDI formulation): 220 µg or 440 µg BID The LABA component (ie, salmeterol) will be discontinued.

•

At subsequent weekly visits, beginning with Week 6, the fluticasone dose will be reduced by approximately 50% provided that the patient does not meet any of the criteria for an asthma exacerbation as defined below: - A 30% or greater reduction from baseline in morning peak expiratory flow (PEF) on 2 consecutive days, or - ≥6 additional reliever puffs of albuterol or levalbuterol in a 24 hour period (compared to baseline) on 2 consecutive days, or - Deterioration of asthma, as determined by the Investigator, requiring: - Systemic (oral and/or parenteral) steroid treatment, or - An increase in ICS ≥4 times the last dose received prior to discontinuation from the study, or - Hospitalization


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If a patient meets the above criteria for an asthma exacerbation, he/she will be withdrawn from investigational product and treated by the investigator with appropriate medical therapy. The patient will be followed for safety for the subsequent 8 weeks per the study schedule. Post-Treatment Follow-up : Upon completing 12 weeks of treatment with the investigational product (or following early discontinuation of investigational product), patients will be placed on their original dose of ICS/LABA combination therapy (fluticasone/salmeterol, budesonide/formoterol, or mometasone/formoterol dose at study entry) and albuterol or levalbuterol (as needed) and any other medications deemed necessary to control their symptoms. Patients will return to the study site at 6 weeks and 8 weeks of the post-treatment period for a safety evaluation. In addition, prior to the visit scheduled for Week 18, the patient will be contacted by telephone on Weeks 13, 14, and 16 (1, 2, and 4 weeks after the end-of-treatment assessment) to evaluate adverse events (AEs). Patients will be instructed to contact the Investigator during the 8-week follow-up period, if their asthma symptoms worsen, requiring medical attention. Stopping Rules for the administration of investigational product in an individual patient: Discontinuation of investigational product in an individual patient will be based upon the criteria set forth above for an asthma exacerbation. If a patient meets any of the criteria for asthma exacerbation, the Investigator will treat them according to standard medical practice and then place them on their pre-existing asthma medication (prior to study entry) and follow them for 8 weeks for safety per the study schedule. Treatment Discontinuation Follow-up : Patients who discontinue investigational product prior to 12 weeks of treatment will receive end of treatment assessments normally scheduled for Visit 14, receive follow-up telephone calls 1, 2, and 4 weeks after the end of treatment assessment, and return to the clinic 6 weeks after the end of treatment assessment for a safety evaluation. STUDY POPULATION

Inclusion Criteria:

Main selection criteria:

I 01. Patients with a physician diagnosis of persistent asthma for at least 12 months based on the Global Initiative for Asthma (GINA) 2009 Guidelines, whose airway inflammation is likely to be eosinophilic and whose asthma is partially controlled or uncontrolled on ICS/LABA combination therapy based on the following criteria: •


On a stable dose of either fluticasone/salmeterol combination therapy (DPI formulation: 250/50 µg BID or 500/50 µg BID or MDI formulation: 230/42 µg BID or 460/42 µg BID) or budesonide/formoterol combination therapy (160/9 µg BID or 320/9 µg BID) or mometasone/formoterol combination therapy (200/10 µg BID or 400/10 µg BID) for at least 1 month prior to

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•

• •

•

•

screening Blood eosinophils ≥300 cells/µL or sputum eosinophils ≥3% during the screening phase (Patients whose initial screening blood eosinophil count is 200 to 299 cells/µL may have 1 additional hematology assessment to attempt to meet the minimum eosinophil criterion of 300 cells/µL). This can be performed during the current screening period if time permits OR they can be screen failed and rescreened as a new patient at a later time as long as all other inclusion/exclusion criteria can still be met and blood eosinophils in the range 200 to 299 cells/µL were only drawn once) Juniper Asthma Control Questionnaire (5-question version, ACQ) score ≥1.5 and ≤3.0 at screening Forced expiratory volume (FEV1) ≥50% predicted normal during the screening phase (3 attempts maximum) and on the randomization day prior to the first dose of investigational product (3 attempts maximum) Reversibility of at least 12% and 200 mL in FEV1 after 200 µg to 400 µg (2 to 4 inhalations) of albuterol during the screening phase (3 attempts maximum), or documented history of a reversibility test that meets this criteria within 12 months prior to screening, or documented history of bronchial hyperreactivity from a positive methacholine challenge (PD20 methacholine ≤ 8 mg) within 12 months prior to screening Has had within the 2 years prior to screening defined by any of the following events: - Treatment with 1 or more systemic (oral and/or parenteral) steroid bursts for worsening asthma - In-patient hospitalization or an emergency care visit for worsening asthma

I 02. Patients who have signed an Informed Consent Form and Health Insurance Portability and Accountability Act (HIPAA) Authorization Form Exclusion Criteria Patients who have met all the inclusion criteria will be screened for the following exclusion criteria: E 01. Patients less than 18 years or greater than 65 years of age (ie, have reached the age of 66 at the screening visit) E 02. Clinically relevant abnormal laboratory values suggesting an unknown disease and requiring further evaluation E 03. Chronic obstructive pulmonary disease (COPD) and/or other lung diseases impairing Pulmonary Function Tests E 04. Patients requiring beta-adrenergic receptor blockers for any reason E 05. Current smoker or cessation of smoking within the 6 months prior to screening E 06. Previous smoking with a smoking history >10 cigarette packyears E 07. In-patient hospitalization or emergency care visit due to


Page 6



asthma exacerbation in the 2 months prior to screening E 08. Plans to begin allergen immunotherapy within the study period E 09. Exposure to another investigative antibody within a time period prior to screening that is less than 5-half-lives of the antibody (if known). In case the half-life is not known, then the minimum interval since exposure to a prior investigative antibody is 6 months. The minimum interval since exposure to any other (non-antibody) investigative study medication is 30 days prior to screening E 10. Previous enrollment into the current study E 11. Patient is the Investigator, his/her family member, or employee at the investigational site E 12. Known or suspected non-compliance, alcohol or drug abuse E 13. Inability to follow the procedures of the study (eg, due to language problems, psychological disorders) E 14. Reversal of sleep pattern (eg, night shift workers) E 15. Treatment with drugs known to prolong QTc interval E 16. Concomitant severe diseases or diseases for which the use of ICS (eg, active and inactive pulmonary tuberculosis) or longacting beta2 agonists (eg, diagnosis of a history of significant cardiovascular diseases, insulin-dependent diabetes mellitus, uncontrolled hypertension, hyperthyroidism, thyrotoxicosis, pheochromocytoma, hypokalemia, prolonged QTc interval [male >450 msec, female >470 msec] or tachyarrhythmia) are contraindicated E 17. Use of injectable glucocorticosteroids or oral systemic glucocorticosteroids within 2 months prior to screening or more than 3 courses within the 6 months prior to screening E 18. Pre-treatment with variable doses of ICS, either alone or in combination with a non-steroidal controller (other than fluticasone/salmeterol combination therapy, budesonide/formoterol combination therapy, or mometasone/formoterol combination therapy) E 19. Patients receiving prohibited concomitant medications (see list Section 8.10) E 20. Known allergy to doxycycline or related compounds E 21. Pregnancy or intention to become pregnant during the course of the study, breast feeding, or unwillingness to use a highly effective method of contraception (bilateral tubal ligation, oral or implantable hormonal therapies stable for 2 cycles prior to study entry ["mini"- progesterone only pill excluded], vasectomy in male partner, or "double barrier" methods [ie, intrauterine device or diaphragm with spermicide jelly/foam + condom containing spermicide in male partner]) throughout the study in women of child-bearing potential E22. Recent history of a parasitic infection or travel to a parasitic endemic area within 6 months prior to screening Total expected number of patients:

Up to approximately 130


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STUDY TREATMENT(s) Investigational Product(s)

SAR231893/REGN668 or Matching Placebo

Formulation

Sterile SAR231893 /REGN668 150 mg/mL solution for SC injection will be provided in a 5 mL glass vial. Each vial will contain a withdrawable volume of 2 mL. Sterile placebo will be provided in identically matched glass 5 mL vials.


Subcutaneous

Dose regimen:

SAR231893/REGN668 (300 mg) administered SC once weekly in the morning in the clinic for 12 weeks Placebo administered SC once weekly in the morning in the clinic for 12 weeks

Non Investigational Product(s)

Patients may administer albuterol hydrofluoroalkane pressurized MDI or levalbuterol hydrofluoroalkane pressurized MDI as rescue medication as needed throughout the study. Fluticasone/salmeterol combination therapy during background therapy stable phase (first 4 weeks) followed by fluticasone (monotherapy) during background therapy withdrawal phase (Week 4 to end of treatment).


Oral inhalation for albuterol, levalbuterol, fluticasone/salmeterol combination therapy, and fluticasone monotherapy

Dose regimen:

Albuterol or levalbuterol: As needed Background therapy stable phase: Fluticasone/salmeterol combination therapy (DPI formulation: 250/50 µg BID or 500/50 µg BID or MDI formulation: 230/42 µg BID or 460/42 µg BID) from randomization day to Week 4 Background therapy withdrawal phase: Fluticasone monotherapy (DPI formulation: 250 µg BID or 500 µg BID or MDI formulation: 220 µg BID or 440 µg BID) Week 4 to Week 6, then decreased by approximately 50% weekly

PRIMARY AND SECONDARY ENDPOINT(S)

Primary Endpoint: Proportion of patients with an exacerbation of asthma as defined by any of the following: • A 30% or greater reduction from baseline in morning PEF on 2 consecutive days, or • ≥6 additional reliever puffs of albuterol or levalbuterol in a 24 hour period (compared to baseline) on 2 consecutive days, or • Deterioration of asthma, as determined by the Investigator, requiring: - Systemic (oral and/or parenteral) steroid treatment, or - An increase in ICS ≥4 times the last dose received prior to discontinuation from the study, or Hospitalization Secondary Endpoint(s): • •


Time to asthma exacerbation post-randomization Proportion of patients with a composite asthma event defined Page 8



by a 30% or greater reduction from baseline in morning PEF on 2 consecutive days together with ≥6 additional reliever puffs of albuterol or levalbuterol in a 24 hour period (compared to baseline) on 2 consecutive days • FEV1 change from baseline at Week 12 and change from baseline at each visit • Morning and evening PEF change from baseline at Week 12 and change from baseline at each visit • ACQ score change from baseline at Week 12 and change from baseline at each study visit • 22-item Sinonasal Outcome Test (SNOT-22) score change from baseline at Week 12 • Change from baseline at Week 12 and change from baseline at each visit for asthma symptom scores in the morning and evening, and nocturnal awakenings • Change from baseline at Week 12 and change from baseline at each visit in number of inhalations/day of albuterol or levalbuterol for symptom relief Safety Evaluation: • Adverse events (AE) • Vital signs • Physical exam • Electrocardiogram (ECG) • Clinical laboratory tests • Anti-drug antibodies Pharmacokinetic Evaluation: •

Serum SAR231893/REGN668 concentrations and pharmacokinetic (PK) profile Pharmacodynamics: • • • • • • • ASSESSMENT SCHEDULE

Total IgE, antigen-specific IgE (Phadiatop®), eotaxin-3, YKL40, thymus and activation-regulated chemokine (TARC), thymic stromal lymphopoietin (TSLP), carcinoembryonic antigen (CEA) Serum samples for exploratory protein analysis Whole blood samples for Ribonucleic acid (RNA) Pharmacogenomic deoxyribonucleic acid (DNA) sample (optional) Induced sputum for eosinophils and neutrophils and exploratory analyses (optional for patients at a subset of sites) Exhaled nitric oxide levels Blood eosinophil count

Screening/Run-in – Day -14 to Day -7 •


Sign informed consent, demography, medical history, inclusion/exclusion criteria, FEV1 to assess reversibility, prior meds, physical exam, ACQ, spirometry, dispense electronic diary/peak flow meter, dispense albuterol or levalbuterol as needed, sputum collection for eosinophil and neutrophil counts (subset), exhaled nitric oxide, assessment of AEs, vital signs, ECG, serum pregnancy test, blood collection for hematology (including eosinophil count for eligibility) and clinical chemistries, blood collection for total IgE, Phadiatop, eotaxin-3, TARC, YKL-40, TSLP, CEA, protein biomarker sample, and RNA

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Randomization –Within 2 weeks of the start of screening (Day 1) •

Prior/concomitant meds (patients who entered the study on budesonide/formoterol mometasone/formoterol will be switched on Day 1 to an equivalent dose of fluticasone/salmeterol), spirometry, randomization to 1 of 2 treatments and administration of SC dose of SAR231893/REGN668 or placebo, SNOT-22, AEs, vital signs, urine pregnancy test, blood for PK and anti-SAR231893/REGN668 antibody, blood for pharmacogenomics (optional), blood collection for total IgE, eotaxin-3, TARC, YKL-40, TSLP, CEA, protein biomarker sample, and RNA Treatment – post-randomization Day 1 to Week 12: Once weekly SC administration of investigational product at clinic on Days 1 to Week 11 •

Background therapy stable phase – post-randomization Day 1 to Week 4 Concomitant meds, ACQ, spirometry, discontinue fluticasone/salmeterol combination therapy and replace with equivalent dose of fluticasone on Week 4; evaluation of data from electronic diary/PEF meter, sputum collection for eosinophil and neutrophil counts (subset), exhaled nitric oxide, AEs, vital signs, ECG, blood for hematology (including eosinophil count) and clinical chemistries, blood for PK and antiSAR231893/REGN668 antibody, blood collection for total IgE, eotaxin-3, TARC, YKL-40, TSLP, CEA, protein biomarker sample, and RNA

•

Background therapy withdrawal phase – post-Week 4 to Week 12 Concomitant meds, physical examination, ACQ, spirometry, reduce ICS dose by 50% at Weeks 6, 7, 8 for patients who started on medium dose ICS and at Weeks 6, 7, 8, and 9 for patients who started on high dose ICS unless patient meets criteria for asthma exacerbation (patient withdrawn), evaluation of data from electronic diary/PEF meter, sputum collection for eosinophil and neutrophil counts (subset), exhaled nitric oxide, SNOT-22, AEs, vital signs, ECG, urine pregnancy test, blood for hematology (including eosinophil count) and clinical chemistries, blood for PK and anti-SAR231893/REGN668 antibody, blood collection for total IgE, Phadiatop, eotaxin-3, TARC, YKL-40, TSLP, CEA, and protein biomarker sample

Post-treatment Observations – Week 18 and Week 20 •


Concomitant meds, spirometry, AEs (including telephone contact at Week 13, 14, and 16 to evaluate AEs), vital signs, blood for PK and anti-SAR231893/REGN668 antibody

Randomization: Up to approximately 130 patients will be randomized in a 1:1 ratio into the 2 treatment groups. The randomization will be stratified by patient’s prior ICS/LABA combination therapy dose (high or medium). Primary Efficacy Endpoint: Asthma exacerbation during the treatment period including both the background therapy stable phase and the background therapy


Page 10



withdrawal phase. Sample Size: The sample size calculations are based on the Phase 2 study results for inhaled pitrakinra (IL-4R mutein), where an absolute reduction in the proportion of patients with an exacerbation of 37% (treatment rate of 13% versus placebo rate of 50%) was observed for this patient population. This study is designed to detect an absolute difference of 30% between treatment groups. To detect such a difference with 80% power (α=0.05, two-tailed test), 44 patients are required per treatment group (Fisher’s exact test). Accounting for an anticipated 10% dropout rate during the study, up to approximately 50 patients are required to be enrolled into each treatment group. The sample size for the protocol originally was to achieve 80% power to detect an absolute difference of 30% or a relative reduction of 60% assuming the placebo rate of exacerbations of 50%. It was expected that the overall rate of asthma exacerbations would be around 35% (assuming placebo rate of 50% and a SAR rate of 20%). The observed rate of asthma exacerbations based on a blinded review of the entire study population as of March 2012 is around 28%. In order to maintain a statistical power of 80% to detect a relative reduction of 60% difference as described above, a possible increase of sample size from 100 to up to approximately 130 (an increase of up to 15 patients for a possible total of 65 patients per treatment group) may be implemented. With 65 patients per treatment group, the study will have 80% power (2-sided alpha=0.05) to detect a relative reduction of 60%, assuming that the placebo rate of exacerbations is around 40%, i.e. placebo rate of 40% vs. a SAR rate of 16% with an overall exacerbation rate of 28%. Primary Analysis: For the primary analysis of proportion of patients experiencing an asthma exacerbation, a logistic regression model will be used to compare SAR231893/REGN668 group with placebo. The model will include terms for treatment, stratification factor (prior ICS/LABA combination therapy dose), and investigative center. The primary analysis will be performed based on modified intent-to-treat (mITT) population which includes all randomized patients who receive at least one dose of investigational product. A stratified chi-square test will also be used to corroborate the primary analysis. Safety variables including AEs, laboratory parameter, vital signs, ECG and physical examinations will be summarized using descriptive statistics. Interim Analyses: The IDMC will review the safety data periodically. The first safety review will occur after approximately 20 patients have received at least 4 weeks of treatment to allow for further enrollment in the study. An early analysis of efficacy will be performed after approximately 66 patients have completed 12 weeks of treatment. Although there is no intent to terminate or modify the trial based on this early efficacy look, a Haybittle-Peto type alpha-spending function is used for this interim analysis of efficacy. An external consulting group will perform the unblinding and all the unblinded analyses for the IDMC reviews and also the interim efficacy analysis. The Property of the sanofi-aventis group - strictly confidential

Page 11



Sponsor personnel will remain blinded to the results of the periodic safety review and will only receive grouped summary results for the interim efficacy analysis. DURATION OF STUDY PERIOD (per patient)

Total 155 days (approximately 22 weeks) including 14 days screening/run-in, 85 days treatment period, and 56 days posttreatment observation period


Page 12


1

FLOW CHARTS

1.1

GRAPHICAL STUDY DESIGN


Screening/ run-in period

Treatment period


Up to approximately 65 patients: SAR231893/REGN668 300 mg SC weekly Up to approximately 65 patients: Placebo SC weekly

Randomization

Day 29 Week 4

Day 43 Week 6


Day 50 Week 7

Day 57 Week 8

Day 64 Week 9

Day 71 Week 10

Day 78 Week 11

Day 85 Week 12

Day 127 Week 18

Day 141 Week 20



Fluticasone/salmeterol DPI: 250/50 µg BID 500/50 µg BID

Fluticasone 250 µg BID 500 µg BID

100 µg BID 250 µg BID



0 µg BID

Fluticasone/salmeterol 250/50 µg BID 500/50 µg BID

MDI: 230/42 µg BID 460/42 µg BID





0 µg BID

230/42 µg BID 460/42 µg BID

Budesonide/formoterol 160/9 µg BID or 320/9 µg BID OR Mometasone/formoterol 200/10 µg BID or 400/10 µg BID


BID = twice daily doing; DPI = dry powder inhalation; MDI = metered dose inhalation; SC = subcutaneous Property of the sanofi-aventis group - strictly confidential

Page 13


1.2


STUDY FLOWCHART Posttreatment

Screening/ Treatment (+/- 2 days) run-ina Background therapy stable phase Background therapy withdrawal phase VISIT DAY WEEK

Informed consent Patient demography Previous medical & surgical history Inclusion/exclusion criteria Reversibility

V1

V2

D-14 to D-7 X X X X Xd


X

ACQe

X

Spirometryf Randomization

Xg

Dispense albuterol or levalbuterol as neededj Discontinue fluticasone/salmeterol combination & replace with equivalent dose of fluticasonek Evaluation for ICS withdrawall Induced sputum for eosinophils & neutrophils (subset)m Exhaled nitric oxiden SNOT-22

V4 D15

V5 D22

V6 D29

Week 1

Week 2

Week 3

Week 4

Xd

X

X

X

X

V7 D36

V8 D43

V9 D50

V10 D57

V11 D64


V12 D71

V13 D78

V14b D85

V15 D127

V16 D141

Week 10

Week 11

Week 12

Week 18

Week 20

X

X

X

X

X

Xc

Prior & concomitant meds

Investigational product administrationh Dispense electronic diary/PEF meter and provide instructions for usei Download electronic diary/PEF meter

D1

V3 D8

X

X

X

X

X

X X

X

X

X

X

X

X

X

X

X

X

X

Xg X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X X

X X

X

X

X

X

X

X

X

X


X

X Page 14



Posttreatment

Screening/ Treatment (+/- 2 days) run-ina Background therapy stable phase Background therapy withdrawal phase VISIT DAY

V1

V2

D-14 to D-7 X

D1 X

Vital Signs

X

X

Electrocardiogram

X

Pregnancy testo

X

Clinical lab testingp

X

Blood eosinophil sampleq

X

WEEK

Adverse event observation period

SAR231893/REGN668 samplingr

V4 D15

V5 D22

V6 D29

Week 1

Week 2

Week 3

Week 4

X

X

X

X

X

X

X X X

V7 D36

V8 D43

V9 D50

V10 D57

V11 D64

X

X

X

X

X


X

X

X

X X

X

V12 D71

V13 D78

V14b D85

Week 11

Week 12

Week 18

Week 20

X

X

X

X

X

X

X

X

X

--------------Xs-------------X

X

X

X

X

X

X X

X

X X

X X X

X

X

Phadiatop (antigen-specific IgE) serum sample

X

Serum sample for IgE, TARC, YKL-40, TSLP, CEA and plasma sample for eotaxin-3 Protein biomarker (serum) sample

X

X

X

X

X

X

X

X

X

X

X

X

RNA (whole blood) sampler

X

X

X

Pharmacogenomic sampling (optional)t Discontinue fluticasone and resume pre-study ICS/LABA combinationu Safety telephone contactsv

V16 D141

X

X

X

V15 D127

Week 10

X

X X

Additional SAR231893/REGN668 samplings Anti-SAR231893/REGN668 antibody sampling

V3 D8

X

X X Xv

ACQ = Asthma Control Questionnaire; CEA = carcinoembryonic antigen; ICS = inhaled corticosteroid; LABA = long-acting beta2 agonist; PEF = peak expiratory flow; SNOT-22 = Sinonasal Outcome Test; TARC = thymus and activation-regulated chemokine; TSLP = thymic stromal lymphopoietin a The screening/run-in period must be at least 7 days in duration prior to randomization to allow for the collection of 7 days worth of baseline data on PEF, asthma symptom scores, nocturnal awakenings, and albuterol or levalbuterol use. b End-of-treatment visit: Patients who discontinue prematurely from the study, should be assessed as soon as possible using the procedure normally planned for V14 and return to the study site 6 and 8 weeks later for the post-treatment evaluation of safety normally planned for V15 and V16.


Page 15



c Reversibility test to be conducted only in patients for whom there is no documented history of reversibility meeting the entry criteria within 12 months prior to screening and no documented history of bronchial hyperreactivity from a positive methacholine challenge (PD20 methacholine ≤ 8 mg) within 12 months prior to screening. For patients requiring a reversibility test, 3 attempts may be made during the screening period to meet the qualifying criteria for reversibility. d Prior to screening, patients must be on a stable dose of either fluticasone/salmeterol combination therapy (DPI formulation: 250/50 µg BID or 500/50 µg BID or MDI formulation: 230/42 µg BID or 460/42 µg BID), or budesonide/formoterol combination therapy (160/9 µg BID or 320/9 µg BID), or mometasone/formoterol combination therapy (200/10 µg BID or 400/10 µg BID) for at least 1 month. Patients who have been on budesonide/formoterol or mometasone/formoterol will be switched on Day 1 to an equivalent dose of fluticasone/salmeterol only after they meet all screening entry criteria, and patients who have been on fluticasone/salmeterol will remain on their current treatment as background therapy. e 5-question version of the ACQ. The ACQ is to be completed in the patient’s electronic diary during clinic visits. f Spirometry performed between 6 and 10 AM after a 6 hour withhold of albuterol or levalbuterol and prior to administration of investigational product. g Three attempts may be made during the screening period to meet the qualifying criteria for spirometry. Patients must also meet the criteria for spirometry prior to randomization on Day 1. If a patient’s FEV1 does not qualify, then he/she will not be randomized on that day. He/she may return to the site on a subsequent day to attempt to meet the spirometry criteria (3 pre-randomization attempts maximum). Spirometry performed following a 6 hour withhold of asthma medication and albuterol or levalbuterol. h Weekly investigational product administrations must be separated by at least 5 days. i Electronic diary/PEF meter to be used for daily recording of albuterol or levalbuterol use, nocturnal awakenings, morning and evening asthma symptom scores and PEF. j Resupply as needed k Patients will be switched from fluticasone/salmeterol combination therapy (DPI formulation: 250/50 µg BID or 500/50 µg BID or MDI formulation: 230/42 µg BID or 460/42 µg BID) to an equivalent ICS dose of fluticasone monotherapy ((DPI formulation: 250 µg BID or 500 µg BID or MDI formulation: 220 µg BID or 440 µg BID) The LABA component will be discontinued. l Fluticasone dose to be reduced by 50% at Weeks 6, 7, 8, and 9 provided that the patient does not meet the criteria for asthma exacerbation. m A subset of study sites will be selected to perform evaluations of induced sputum, and patients at these selected sites will have the option to participate in this assessment. The goal is for approximately 50 patients to participate in this analysis. The first sputum sample from each site will be evaluated by an independent reader to assess the quality of the sample. If the quality is inadequate, additional training will be conducted at the site prior to collecting sputum samples from subsequent patients, and the sample from the first patient will be discarded and recollected prior to randomization. In addition sputum cell counts of leukocytes, soluble factors in sputum may also be examined if feasible (eg, IL-4, IL-13). n Exhaled nitric oxide assessment to be conducted prior to spirometry and following a fast of at least 1 hour. o Serum pregnancy test at V1, and urine pregnancy tests at V2, V8, and V14. A negative result must be obtained at V1 and at V2 prior to randomization. p Hematology to include hemoglobin, hematocrit, platelet count, total white blood cell count, differential count, and total red blood cell count. Serum chemistry to include creatinine, blood urea nitrogen, glucose, uric acid, total cholesterol, total protein, albumin, bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, electrolytes (sodium, potassium, chloride), bicarbonate, and creatine phosphokinase. q Eosinophil counts at V1 and V14 will be derived from the sample drawn for clinical lab testing (differential count). Patients whose initial V1 eosinophil count is 200 to 299 cells/µL may have 1 additional hematology assessment to attempt to meet the minimum eosinophil criterion of 300 cells/µL). This can be performed during the current screening period if time permits or subject may be re-screened as a new patient at a later time as long as all other inclusion/exclusion can still be met and blood eosinophils in the range of 200 to 299 cells/µL were only drawn once prior). At V6 and V10 only a hematology sample will be taken for eosinophil counts, as serum chemistry testing is not scheduled for these visits. r Serum pharmacoketic sample and RNA sample will be collected prior to administration of investigational product. s For the lead-in cohort of approximately 20 patients additional pharmacokinetic samples to be collected after the final dose on Days 82, 92, 99, 106, and 113 t For patients who have signed the Pharmacogenomics informed consent form. The DNA sample should be collected at the baseline visit, but it can be collected at any visit during the study. u Patients to resume taking their original dose of ICS/LABA combination therapy (fluticasone/salmeterol, budesonide/formoterol, or mometasone/formoterol, dose at study entry) v Telephone call to be made to the patients to evaluate AEs on Week 13, 14, and 16 (1, 2, and 4 weeks after the end-of-treatment visit).


Page 16


2


TABLE OF CONTENTS

1

FLOW CHARTS.............................................................................................................................13

1.1

GRAPHICAL STUDY DESIGN ......................................................................................................13

1.2

STUDY FLOWCHART ...................................................................................................................14

2

TABLE OF CONTENTS ................................................................................................................17

3

LIST OF ABBREVIATIONS ..........................................................................................................23

4

INTRODUCTION AND RATIONALE.............................................................................................25

5

STUDY OBJECTIVES ...................................................................................................................27

5.1

PRIMARY.......................................................................................................................................27

5.2

SECONDARY ................................................................................................................................27

6

STUDY DESIGN ............................................................................................................................28

6.1

DESCRIPTION OF THE PROTOCOL ...........................................................................................28

6.2

DURATION OF STUDY PARTICIPATION ....................................................................................29

6.2.1

Duration of study participation for each patient .............................................................................29

6.2.2

Determination of end of clinical trial (all patients) ..........................................................................29

6.3


6.4

STUDY COMMITTEES ..................................................................................................................29

7

SELECTION OF PATIENTS..........................................................................................................31

7.1

NUMBER OF PATIENTS PLANNED.............................................................................................31

7.2

INCLUSION CRITERIA..................................................................................................................31

7.3

EXCLUSION CRITERIA ................................................................................................................32

7.3.1

Exclusion criteria related to study methodology ............................................................................32

7.3.2

Exclusion criteria related to the active comparator and/or mandatory background therapies.......33

7.3.3

Exclusion criteria related to the current knowledge of sanofi-aventis compound..........................33

8

STUDY TREATMENTS .................................................................................................................34

8.1

INVESTIGATIONAL PRODUCT ....................................................................................................34

8.2

NON INVESTIGATIONAL PRODUCTS.........................................................................................34


Page 17



8.3

DESCRIPTION OF BLINDING METHODS ...................................................................................35

8.4

COMPENSATION FOR LACK OF BLINDING...............................................................................35

8.5

METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................35

8.6

PACKAGING AND LABELING ......................................................................................................36

8.7

STORAGE CONDITIONS AND SHELF LIFE ................................................................................36

8.8

RANDOMIZATION CODE BREAKING DURING THE STUDY .....................................................36

8.9

RESPONSIBILITIES ......................................................................................................................37

8.10

CONCOMITANT MEDICATION.....................................................................................................37

8.11

TREATMENT ACCOUNTABILITY AND COMPLIANCE ...............................................................38

8.12

RETURN AND/OR DESTRUCTION OF TREATMENTS ..............................................................38

9

ASSESSMENT OF INVESTIGATIONAL PRODUCT ...................................................................40

9.1

EFFICACY .....................................................................................................................................40

9.1.1

Primary endpoint ............................................................................................................................40

9.1.2

Secondary endpoints .....................................................................................................................40

9.1.3

Efficacy methods............................................................................................................................41

9.2

SAFETY .........................................................................................................................................43

9.3

PHARMACOKINETICS..................................................................................................................43

9.3.1

Sampling schedule.........................................................................................................................43

9.3.2

Sample handling procedure ...........................................................................................................44

9.4

PHARMACOGENOMIC SAMPLES ...............................................................................................44

9.5

PHARMACODYNAMIC MEASURES ............................................................................................45

9.6

MEASURES TO PROTECT BLINDING OF THIS TRIAL ..............................................................47

10

PATIENT SAFETY.........................................................................................................................48

10.1

SAFETY ENDPOINTS ASSESSED IN THIS TRIAL .....................................................................48

10.1.1

Medical history and prior and concomitant medication..................................................................48

10.1.2

Adverse events ..............................................................................................................................48

10.1.3

Vital signs .......................................................................................................................................48

10.1.4

Clinical laboratory tests ..................................................................................................................48

10.1.5

Electrocardiogram ..........................................................................................................................49

10.1.6

Pregnancy test ...............................................................................................................................49


Page 18



10.1.7

Physical examination .....................................................................................................................50

10.2

SAFETY INSTRUCTIONS .............................................................................................................50

10.3

ADVERSE EVENTS MONITORING ..............................................................................................50

10.4

DEFINITIONS OF ADVERSE EVENT (AE) AND SERIOUS ADVERSE EVENT (SAE)...............50

10.5

OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................51

10.5.1

Adverse Events ..............................................................................................................................51

10.5.2

Serious Adverse Events.................................................................................................................52

10.5.3

Safety Observations.......................................................................................................................52

10.5.4 Adverse events of special interest (AESI)......................................................................................53 10.5.4.1 AESI with immediate notification....................................................................................................53 10.5.4.2 AESI without immediate notification...............................................................................................54 10.5.5

Laboratory abnormalities with pre-specified monitoring ................................................................54

10.6

OBLIGATIONS OF THE SPONSOR .............................................................................................54

11

HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION ......................................56

11.1

TEMPORARY TREATMENT DISCONTINUATION WITH INVESTIGATIONAL PRODUCT(S).................................................................................................................................56

11.2

PERMANENT TREATMENT DISCONTINUATION WITH INVESTIGATIONAL PRODUCT(S).................................................................................................................................56

11.2.1

List of criteria for definitive treatment discontinuation....................................................................56

11.2.2

Handling of patients after permanent treatment discontinuation ...................................................57

11.3

PROCEDURE AND CONSEQUENCE FOR PATIENT WITHDRAWAL FROM STUDY ..............58

12

STUDY PROCEDURES ................................................................................................................59

12.1

VISIT SCHEDULE..........................................................................................................................59

12.1.1

Screening Period: Visit 1 (Day -14 to Day -7) ................................................................................59

12.1.2 12.1.2.1 12.1.2.2 12.1.2.3 12.1.2.4 12.1.2.5

Treatment period: Background therapy stable phase (Day 1 to Week 4 [Visits 2 to 6])................60 Randomization: Visit 2 (Day 1) ......................................................................................................60 Visit 3 (Week 1 +/- 2 days).............................................................................................................61 Visit 4 (Week 2 +/- 2 days).............................................................................................................62 Visit 5 (Week 3 +/- 2 days).............................................................................................................62 Visit 6 (Week 4 +/- 2 days).............................................................................................................63

12.1.3 12.1.3.1 12.1.3.2 12.1.3.3 12.1.3.4 12.1.3.5

Treatment period: Background therapy withdrawal phase (Visits 7 to 14) ....................................63 Visit 7 (Week 5 +/- 2 days).............................................................................................................63 Visit 8 (Week 6 +/- 2 days).............................................................................................................64 Visit 9 (Week 7 +/- 2 days).............................................................................................................64 Visit 10 (Week 8 +/- 2 days)...........................................................................................................65 Visit 11 (Week 9 +/- 2 days)...........................................................................................................65


Page 19



12.1.3.6 Visit 12 (Week 10 +/- 2 days).........................................................................................................66 12.1.3.7 Visit 13 (Week 11 +/- 2 days).........................................................................................................66 12.1.3.8 Visit 14 (Week 12 +/- 2 days) End of treatment visit......................................................................67 12.1.4 Post-treatment period.....................................................................................................................67 12.1.4.1 Visit 15 (Week 18 +/- 2 days).........................................................................................................68 12.1.4.2 Visit 16 (Week 20 +/- 2 days).........................................................................................................68 12.1.5

All visits ..........................................................................................................................................68

12.2

DEFINITION OF SOURCE DATA..................................................................................................68

13

STATISTICAL CONSIDERATIONS ..............................................................................................69

13.1

DETERMINATION OF SAMPLE SIZE...........................................................................................69

13.2

ANALYSIS ENDPOINTS ...............................................................................................................69

13.2.1


13.2.2 Efficacy endpoints ..........................................................................................................................70 13.2.2.1 Primary efficacy endpoint...............................................................................................................70 13.2.2.2 Secondary efficacy endpoint(s)......................................................................................................70 13.2.3 13.2.3.1 13.2.3.2 13.2.3.3 13.2.3.4 13.2.3.5 13.2.3.6

Safety endpoints ............................................................................................................................71 Adverse events ..............................................................................................................................71 Deaths ............................................................................................................................................71 Laboratory safety variables ............................................................................................................71 Vital signs .......................................................................................................................................71 ECG variables ................................................................................................................................72 Physical examination .....................................................................................................................72

13.2.4


13.2.5

Pharmacodynamic/genomics variables .........................................................................................72

13.3


13.4

ANALYSIS POPULATIONS...........................................................................................................73

13.4.1

Efficacy populations .......................................................................................................................73

13.4.2

Safety population ...........................................................................................................................73

13.5


13.5.1


13.5.2


13.5.3 Extent of study treatment exposure and compliance.....................................................................74 13.5.3.1 Extent of investigational product exposure ....................................................................................74 13.5.3.2 Compliance ....................................................................................................................................74 13.5.4 13.5.4.1 13.5.4.2 13.5.4.3

Analyses of efficacy endpoints.......................................................................................................74 Analysis of primary efficacy endpoint.............................................................................................74 Analyses of secondary efficacy endpoints .....................................................................................75 Multiplicity Considerations .............................................................................................................75


Page 20


13.5.5 13.5.5.1 13.5.5.2 13.5.5.3 13.5.5.4


Analyses of safety data ..................................................................................................................75 Analysis of adverse events ............................................................................................................75 Analysis of laboratory variables .....................................................................................................76 Analysis of vital signs variables .....................................................................................................77 Analysis of other safety variables ..................................................................................................77

13.5.6 Analyses of pharmacokinetic and pharmacodynamic variables ....................................................77 13.5.6.1 Pharmacokinetic parameters .........................................................................................................77 13.5.6.2 Pharmacokinetic/Pharmacodynamic parameters ..........................................................................77 13.5.7

Immunogenicity ..............................................................................................................................78

13.6

DATA HANDLING CONVENTIONS ..............................................................................................78

13.7


13.8

DATABASE LOCK .........................................................................................................................79

14

ETHICAL AND REGULATORY STANDARDS.............................................................................80

14.1

ETHICAL PRINCIPLES .................................................................................................................80

14.2

LAWS AND REGULATIONS .........................................................................................................80

14.3

INFORMED CONSENT .................................................................................................................80

14.4

INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) ..............81

15

STUDY MONITORING...................................................................................................................82

15.1

RESPONSIBILITIES OF THE INVESTIGATOR(S) .......................................................................82

15.2

RESPONSIBILITIES OF THE SPONSOR.....................................................................................82

15.3

SOURCE DOCUMENT REQUIREMENTS....................................................................................83

15.4

USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL REQUEST ......................................................................................................................................83

15.5

USE OF COMPUTERIZED SYSTEMS..........................................................................................83

16

ADMINISTRATIVE RULES ...........................................................................................................84

16.1

CURRICULUM VITAE....................................................................................................................84

16.2

RECORD RETENTION IN STUDY SITES (S) ..............................................................................84

17

CONFIDENTIALITY.......................................................................................................................85

18

PROPERTY RIGHTS.....................................................................................................................86

19

DATA PROTECTION.....................................................................................................................87

20

INSURANCE COMPENSATION ...................................................................................................88


Page 21



21

SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ................................89

22

PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF A SITE............................................................................................................................................90

22.1

DECIDED BY THE SPONSOR IN THE FOLLOWING CASES: ....................................................90

22.2

DECIDED BY THE INVESTIGATOR .............................................................................................90

23

CLINICAL TRIAL RESULTS.........................................................................................................91

24

PUBLICATIONS AND COMMUNICATIONS ................................................................................92

25

CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................93

26

BIBLIOGRAPHIC REFERENCES.................................................................................................94

27

APPENDICES................................................................................................................................96

APPENDIX A

DRUGS KNOWN TO PROLONG THE QTC INTERVAL ....................................................97

APPENDIX B ELECTRONIC PEAK EXPIRATORY FLOW METER/DIARY SCREEN INSTRUCTIONS ............................................................................................................................98 APPENDIX C

SPIROMETRY...................................................................................................................101

APPENDIX D

JUNIPER ASTHMA CONTROL QUESTIONNAIRE .........................................................103

APPENDIX E

22-ITEM SINONASAL OUTCOME TEST .........................................................................105

APPENDIX F

SPUTUM INDUCTION PROCEDURE ..............................................................................106

APPENDIX G GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY ABNORMALITIES BY SANOFI-AVENTIS ...................................................................................111 APPENDIX H

DNA SAMPLE COLLECTION ...........................................................................................116


Page 22


3


LIST OF ABBREVIATIONS

ACQ AE AESI ALT AM AST ATC ATS BID CEA CPK CRF DNA DPI ECG e-CRF ELISA ERS FEV1 FVC GINA HIPAA HLT HLGT ICH ICS IDMC IEC IL-4 IL-4Rα IL-13 IRB IV IVRS IWRS LABA MDI mITT MedDRA PCSA PEF PK PM

Asthma control questionnaire (5-question version) Adverse event Adverse event of special interest Alanine aminotransferase Morning Aspartate aminotransferase Anatomic Therapeutic Chemical Classification American Thoracic Society Twice-daily dosing Carcinoembryonic antigen Creatine phosphokinase Case report form Deoxyribonucleic acid Dry powder inhaler Electrocardiogram Electronic case report form Enzyme-linked immunosorbent assay European Respiratory Society Forced expiratory volume in one second Forced vital capacity Global Initiative for Asthma Health Insurance Portability and Accountability Act High level term High level group term International Conference on Harmonization Inhaled corticosteroid Independent Data Monitoring Committee Independent Ethics Committee Interleukin-4 Interleukin-4 receptor alpha subunit Interleukin-13 Institutional Review Board Intravenous Interactive Voice Response System Interactive Web Response System Long-acting beta2-adrenergic agonist Metered dose inhaler Modified Intent to treat Medical Dictionary for Regulatory Activities Potentially clinically significant abnormality Peak expiratory flow Pharmacokinetic Evening


Page 23


ppb PT RNA SAE SAP SC SD SNOT-22 SOC SUSAR TARC TEAE TSLP ULN USA


Parts per billion Preferred term Ribonucleic acid Serious adverse event Statistical Analysis Plan Subcutaneous Standard deviation Sinonasal Outcome Test System organ class Suspected unexpected adverse drug reaction Thymus and activation-regulated chemokine Treatment-emergent adverse event Thymic stromal lymphopoietin Upper limit of normal United States of America


Page 24


4


INTRODUCTION AND RATIONALE

Asthma is a chronic inflammatory disease of the airways characterized by airway hyperresponsiveness, acute and chronic bronchoconstriction, airway edema, and mucus plugging. The inflammation component of asthma is thought to involve many cell types including mast cells, eosinophils, T lymphocytes, neutrophils, and epithelial cells and their biological products. Patients with asthma most often present with symptoms of wheezing, shortness of breath, cough, and chest tightness. For most asthma patients a regimen of controller therapy and bronchodilator therapy provides adequate long-term control. Inhaled corticosteroids (ICS) are considered the “gold standard” in controlling asthma symptoms and inhaled beta2-agoists are the most effective bronchodilators currently available. Landmark studies by Greening et al (1) and Woolcock et al (2) demonstrated that combination therapy of an ICS with an inhaled long-acting beta2-agonist (LABA) provides better asthma control than high doses of ICS alone. Since then, combination therapy has been the recommended treatment for subjects who are not controlled on low doses of ICS alone. However, it is estimated that 5% to 10% of the population with asthma has symptomatic disease despite maximum recommended treatment with combinations of anti-inflammatory and bronchodilator drugs. Furthermore, this severe asthma population accounts for up to 50% of the total health cost through hospital admissions, use of emergency services, and unscheduled physician visits.(3) There is an unmet need for a new therapy in this severe asthma population as many of these patients are poorly responsive to ICS due to a number of cellular and molecular mechanisms. In addition, the long term adverse effects of systemic and inhaled corticosteroids on bone metabolism, adrenal function, and growth in children lead to attempts to minimize the amount of corticosteroid usage. In the severe, corticosteroid-refractory allergy-induced asthma population, the anti-IgE agent, omalizumab, has proven effective. Although a large portion of asthma patients are managed reasonably well with current treatments, patients with severe corticosteroid-refractory asthma have few therapeutic treatment options that can adequately control the disease.(4) The consequences of unresponsiveness to therapy or lack of compliance with therapy is loss of asthma control and ultimately asthma exacerbation. One of the reasons for the poor response to medication in some patients with severe asthma may be the heterogeneity of the disease. Interest is increasing in understanding these distinct phenotypes because targeted therapy is more likely to be successful in patients with similar underlying pathobiological features.(5) Recent therapeutic approaches in asthma have been focused on trying to control the T helper cell-2 response. Up-regulation of interleukin-4 (IL-4) and interleukin-13 (IL-13) has been implicated as an important inflammatory component of asthma disease progression. SAR231893/REGN668 is under development as a potential novel treatment for asthma. SAR231893/REGN668, a fully human monoclonal antibody, is directed against the IL-4 receptor alpha subunit (IL-4Rα), which is a component of IL-4 receptors Type I and Type II, as well as the IL-13 receptor system. The binding of SAR231893/REGN668 to IL4Rα results in a blockade of the function of both IL-4 and IL-13 signal transduction. Inhibition of this Th2 inflammatory pathway is currently or has previously been evaluated with other agents. There are currently two IL-4/IL-13 dual antagonists in clinical development. A subcutaneously administered fully human antibody with a similar mechanism of action, AMG317 (Amgen, Inc), Property of the sanofi-aventis group - strictly confidential

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and pitrakinra, an inhaled IL-4 mutein (Aerovance, Inc.), have been evaluated in Phase 2 clinical trials of moderately-severe asthma based on their ability to bind to IL-4Rα and block activation of IL-4 and IL-13 mediated signaling. The Aerovance study results indicated that a subpopulation of patients with eosinophilic asthma responded positively to the drug, while non-eosinophilic asthmatics did not have a significant reduction in asthma exacerbations.(6) The most frequently reported adverse events (AEs) in the AMG317 clinical trial were injection site reactions and headache/myalgia.(7, 8, 9) Similar AEs may be observed with SAR231893/REGN668. The first-in-human study (R668-AS-0907) to investigate safety and pharmacokinetics (PK) of a single intravenous (IV) infusion of 4 dose levels (1, 3, 8, and 12 mg/kg) and a single subcutaneous (SC) injection of 1 of 2 dose levels (150 and 300 mg) of SAR231893/REGN668 in normal healthy volunteers has been completed. Treatment with SAR231893/REGN668 was generally welltolerated. No treatment-emergent AEs led to cohort expansion for further elucidation of AEs, and dosing was escalated to the highest dose level in this healthy volunteer population. No serious adverse events (SAEs) assessed as related to the investigational product were reported. The most frequent AEs were blood creatine phosphokinase increased, blood pressure increased, and headache. (See the Investigator’s Brochure for further details). The objective of the current study is to investigate the effects of SAR231893/REGN668 (300 mg) administered SC once weekly for 12 weeks as compared to placebo on reducing the incidence of asthma exacerbations in patients with persistent moderate to severe eosinophilic asthma. In addition, the safety and tolerability of SAR231893/REGN668 and plasma concentrations following weekly dosing will be assessed. The dose of SAR231893/REGN668 (300 mg) that will be administered in this study is within the range of SC doses administered to healthy volunteers in the single-dose study described above. Because it is expected that the target IL-4 receptors are primarily located on the cell surface in tissue, it may be important to saturate the target-mediated pathway of elimination. The 300 mg dose was selected because a high dose may be required in patients with asthma who may exhibit higher IL-4Rα expression than healthy subjects, and because the target tissue can be difficult to reach.


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5

STUDY OBJECTIVES

5.1

PRIMARY


The primary objective of this study is to investigate the effects of SAR231893/REGN668 administered SC once weekly for 12 weeks as compared to placebo on reducing the incidence of asthma exacerbations in patients with persistent moderate to severe eosinophilic asthma. 5.2

SECONDARY

The secondary objectives are as follows: •


•



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6

STUDY DESIGN

6.1

DESCRIPTION OF THE PROTOCOL


This randomized, double-blind, placebo-controlled, study with parallel groups includes a 2-week screening/run-in, followed by a 12-week treatment period with an add-on therapy approach to background therapy (ICS/LABA combination therapy) and systematic background therapy withdrawal, and an 8-week follow-up period. This study consists of a 7 to 14-day screening/run-in period. To be eligible for this study, patients are required to be on a stable dose of any of the following doses and formulations of ICS/LABA combination therapy for at least 1 month: •

Fluticasone/salmeterol combination therapy: -

Advair® Diskus – dry powder inhaler (DPI): 250/50 µg BID or 500/50 µg BID or

-

Advair® HFA – metered dose inhaler (MDI): 230/42 µg BID or 460/42 µg BID or

•

Budesonide/formoterol combination therapy (Symbicort® 160/9 µg BID or 320/9 µg BID) or

•

Mometasone/formoterol combination therapy (Dulera® 200/10 µg BID or 400/10 µg BID)

Patients who have been on budesonide/formoterol or mometasone/formoterol will be switched to an equivalent dose of fluticasone/salmeterol at randomization (Day 1), and patients who have been on fluticasone/salmeterol will remain on their current treatment as background therapy. Following screening, patients will be randomized 1:1 to receive either SAR231893/REGN668 or placebo in a 12-week, double-blind, parallel-group treatment period. The 12-week treatment period is divided into 2 phases: a 4-week background therapy stable phase and an 8-week background therapy withdrawal phase. During the background therapy stable phase patients will remain on their current dose of fluticasone/salmeterol combination therapy along with the randomized investigational product. At the start of the background therapy withdrawal phase (Week 4) patients will discontinue the LABA component of fluticasone/salmeterol combination therapy (ie, salmeterol) and switch to an equivalent ICS dose of fluticasone: •

Flovent® Diskus [DPI formulation]: 250 µg BID or 500 µg BID or

•

Flovent® HFA [MDI formulation]: 220 µg BID 440 µg BID

Day 29 (Week 4) marks the beginning of the 8-week background therapy withdrawal phase. At Weeks 6, 7, 8, and 9, patients will be evaluated for adjustment of their ICS dose. At these visits, the fluticasone dose will be reduced by approximately 50% provided that the patient does not meet the criteria for an asthma exacerbation (see Section 9.1.1). If a patient meets the criteria for an asthma exacerbation at any visit, he/she will be withdrawn from the study and treated by the Investigator with appropriate medical therapy. Upon completing 12 weeks of treatment with investigational product (or after early discontinuation), patients will be placed on their original dose of fluticasone/salmeterol, budesonide/formoterol, or mometasone/formoterol (dose at study Property of the sanofi-aventis group - strictly confidential

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entry) and albuterol or levalbuterol as-needed to control their symptoms for an additional 8 weeks off study medication before a final safety evaluation. Prior to opening enrollment to the entire cohort of up to approximately 130 patients, a sentinel cohort consisting of approximately 20 patients (approximately 10 active and 10 placebo) will be enrolled. Data from this sentinel cohort will be evaluated by an Independent Data Monitoring Committee (IDMC) for any safety issues. After the 20th or so patient has been randomized, screening will be suspended for at least 2 weeks. Unblinded clinical safety data through at least 4 weeks of treatment will be reviewed by the IDMC. By the time the IDMC has completed their review (approximately 8 weeks after the final patient in the sentinel cohort is randomized), the patients who were randomized immediately after the pause in screening will be approaching their fourth week of treatment. Based on this review, a decision will be made to continue treatment beyond 4 weeks for the currently enrolled patients. Additionally, based on the IDMC’s review, a decision may be made to modify the protocol or stop the study. During this safety evaluation the sentinel cohort will continue to receive investigational product for the scheduled 12 weeks. 6.2

DURATION OF STUDY PARTICIPATION

6.2.1 Duration of study participation for each patient

The total duration of study participation for each subject is up to 155 days (approximately 22 weeks) including 14 days screening/run-in, 85 days treatment period, and 56 days post-treatment observation period. The total duration of exposure to investigational product is 12 weeks (12 weekly SC injections of investigational product). 6.2.2 Determination of end of clinical trial (all patients)

The end of the clinical trial will be defined as the last patient last visit/contact. 6.3

INTERIM ANALYSIS

An early analysis of efficacy is planned when approximately 66 patients complete 12 weeks of treatment (Visit 14). This early analysis of efficacy is only for the purpose of an early administrative look to help prepare for further development of the compound. The statistical operating characteristics such as alpha-spending function are described in the statistical considerations section (Section 13.7). 6.4

STUDY COMMITTEES

An IDMC will be established, which is independent of the Sponsor and participating Investigators. The IDMC will be comprised of external independent members with a high level of expertise and experience in clinical research and the interpretation of safety data and information. The IDMC will evaluate the unblinded clinical safety data of a sentinel cohort consisting of approximately 20 patients (approximately 10 active and 10 placebo) through at least 4 weeks of


Page 29



treatment for any safety issues. The IDMC will continue to monitor the safety of patients throughout the study with periodic review of the unblinded safety data. The review of the clinical safety data by the IDMC will be conducted at pre-determined times as specified by the IDMC and outlined in the IDMC charter. After each review meeting, the IDMC will advise sponsor representatives regarding patient safety as well as the course of action regarding the conduct of the trial. These data reviews shall not be construed as interim efficacy assessments for statistical purposes. The IDMC will have broad authority to make recommendations regarding the study conduct.


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7

SELECTION OF PATIENTS

7.1

NUMBER OF PATIENTS PLANNED


A total of up to approximately 130 subjects (up to approximately 65 subjects per treatment arm) are expected to be randomized and treated in up to approximately 50 study sites in the US. (See Section 13.1 Determination of sample size). 7.2

INCLUSION CRITERIA

I 01.

Patients with a physician diagnosis of persistent asthma for at least 12 months based on Global Initiative for Asthma (GINA) 2009 Guidelines,(4) whose airway inflammation is likely to be eosinophilic and whose asthma is partially controlled or uncontrolled on ICS/LABA combination therapy based on the following criteria:

•

On a stable dose of either fluticasone/salmeterol combination therapy (DPI formulation: 250/50 µg BID or 500/50 µg BID or MDI formulation: 230/42 µg BID or 460/42 µg BID), or budesonide/formoterol combination therapy (160/9 µg BID or 320/9 µg BID), or mometasone/formoterol combination therapy (200/10 µg BID or 400/10 µg BID) for at least 1 month prior to screening

•

Blood eosinophils ≥300 cells /µL or sputum eosinophils ≥3% during the screening phase (Patients whose initial screening blood eosinophil count is 200 to 299 cells/µL may have 1 additional hematology assessment to attempt to meet the minimum eosinophil criterion of 300 cells/µL). This can be performed during the current screening period if time permits or they can be screen failed and re-screened as a new patient at a later time as long as all other inclusion/exclusion criteria can still be met and blood eosinophils in the range 200 to 299 cells/µL were only drawn once)

•

Juniper Asthma Control Questionnaire (5-question version, ACQ) score ≥1.5 and ≤3.0 at screening

•

Forced expiratory volume (FEV1) ≥50% predicted normal during the screening phase (3 attempts maximum) and on the randomization day prior to the first dose of investigational product (3 attempts maximum)

•

Reversibility of at least 12% and 200 mL in FEV1 after 200 µg to 400 µg (2 to 4 inhalations) of albuterol during the screening phase (3 attempts maximum), or documented history of a reversibility test that meets this criteria within 12 months prior to screening, or documented history of bronchial hyperreactivity from a positive methacholine challenge (PD20 methacholine ≤ 8 mg) within 12 months prior to screening

•

Has had within the 2 years prior to screening at least 1 asthma exacerbation defined by any of the following events: -

Treatment with 1 or more systemic (oral and/or parenteral) steroid bursts for worsening asthma


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-


In-patient hospitalization or an emergency care visit for worsening asthma

I 02.

Patients who have signed an Informed Consent Form and Health Insurance Portability and Accountability Act (HIPAA) Authorization Form

7.3

EXCLUSION CRITERIA

Patients who have met all the above inclusion criteria listed in Section 7.2 will be screened for the following exclusion criteria which are sorted and numbered in the following 3 sub-sections: 7.3.1 Exclusion criteria related to study methodology

E 01. Patients less than 18 years or greater than 65 years of age (ie, have reached the age of 66 at the screening visit) E 02. Clinically relevant abnormal laboratory values suggesting an unknown disease and requiring further evaluation E 03. Chronic obstructive pulmonary disease and/or other lung diseases impairing Pulmonary Function Tests E 04. Patients requiring beta-adrenergic receptor blockers for any reason E 05. Current smoker or cessation of smoking within the 6 months prior to screening E 06. Previous smoking with a smoking history >10 cigarette pack-years E 07. In-patient hospitalization or emergency care visit due to asthma exacerbation in the 2 months prior to screening E 08. Plans to begin allergen immunotherapy within the study period E 09. Exposure to another investigative antibody within a time period prior to screening that is less than 5 half-lives of the antibody (if known). In case the half-life is not known, then the minimum interval since exposure to a prior investigative antibody is 6 months. The minimum interval since exposure to any other (non-antibody) investigative study medication is 30 days prior to screening E 10. Previous enrollment into the current study E 11. Patient is the Investigator, his/her family member, or employee at the investigational site E 12. Known or suspected non-compliance, alcohol or drug abuse E 13. Inability to follow the procedures of the study (eg, due to language problems, psychological disorders)


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E 14. Reversal of sleep pattern (eg, night shift workers) 7.3.2 Exclusion criteria related to the active comparator and/or mandatory background therapies

E 15. Treatment with drugs known to prolong QTc interval (see Appendix A) E 16. Concomitant severe diseases or diseases for which the use of ICS (eg, active and inactive pulmonary tuberculosis) or LABA (eg, diagnosis of a history of significant cardiovascular diseases, insulin-dependent diabetes mellitus, uncontrolled hypertension, hyperthyroidism, thyrotoxicosis, pheochromocytoma, hypokalemia, prolonged QTc interval [male >450 msec, female >470 msec] or tachyarrhythmia) are contraindicated E 17. Use of injectable glucocorticosteroids or oral systemic glucocorticosteroids within 2 months prior to screening or more than 3 courses within the 6 months prior to screening E 18. Pre-treatment with variable doses of ICS, either alone or in combination with a nonsteroidal controller (other than fluticasone/salmeterol combination therapy, budesonide/formoterol combination therapy, or mometasone/formoterol combination therapy) E 19. Patients receiving prohibited concomitant medications (see list Section 8.10) 7.3.3 Exclusion criteria related to the current knowledge of sanofi-aventis compound

E 20. Known allergy to doxycycline or related compounds E 21. Pregnancy or intention to become pregnant during the course of the study, breast feeding, or unwillingness to use a highly effective method of contraception (bilateral tubal ligation, oral or implantable hormonal therapies stable for 2 cycles prior to study entry ["mini"progesterone only pill excluded], vasectomy in male partner, or "double barrier" methods [ie, intrauterine device or diaphragm with spermicide jelly/foam + condom containing spermicide in male partner]) throughout the study in women of child-bearing potential E 22. Recent history of a parasitic infection or travel to a parasitic endemic area within 6 months prior to screening


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8

STUDY TREATMENTS

8.1

INVESTIGATIONAL PRODUCT


SAR231893/REGN668: Sterile SAR231893 /REGN668 150 mg/mL solution for SC injection will be provided in a 5 mL glass vial. Each vial will contain a withdrawable volume of 2 mL. A 300 mg dose will be administered at the study site once weekly in the morning for 12 weeks. Patients should remain in the clinic for at least 30 minutes after investigational product administration so site staff can observe for any adverse reactions. Placebo: Sterile placebo for SAR231893/REGN668 for SC injection will be provided in a 5 mL glass vial. Each vial will contain a withdrawable volume of 2 mL. Placebo will be administered at the study site once weekly in the morning for 12 weeks. Weekly doses of investigational product must be separated by at least 5 days. In case scheduled study visits occur less than 5 days apart, all study visit procedures are to be performed as scheduled with the exception of investigational product administration. In these cases, the patient must return to the study site for the weekly administration of investigational product (at least 5 days after the most recent administration. 8.2

NON INVESTIGATIONAL PRODUCTS

Albuterol or levalbuterol: Patients will be administered albuterol hydrofluoroalkane pressurized MDI or levalbuterol hydrofluoroalkane pressurized MDI as rescue medication as needed throughout the study. Patients will record their daily albuterol or levalbuterol use in their electronic diaries. ICS/LABA combination therapy: Patients must be on a stable dose of ICS/LABA combination therapy (fluticasone/salmeterol: DPI formulation - 250/50 µg BID or 500/50 µg BID or MDI formulation - 230/42 µg BID or 460/42 µg BID, or budesonide/formoterol: 160/9 µg BID or 320/9 µg BID, or mometasone/formoterol: 200/10 µg BID or 400/10 µg BID) at study entry for at least 1 month prior to screening. Patients who have been on budesonide/formoterol or mometasone/formoterol will be switched on Day 1 to an equivalent dose of fluticasone/salmeterol only after they meet all screening entry criteria, and patients who have been on fluticasone/salmeterol will remain on their current treatment for the background therapy stable phase (first 4 weeks) of the treatment period. The last day of fluticasone/salmeterol combination therapy administration will be Day 28 (±2 days). ICS (monotherapy): At 4 weeks post-randomization (Visit 6) patients will be switched from fluticasone/salmeterol combination therapy to an equivalent ICS dose of fluticasone (DPI formulation: 250 µg BID or Property of the sanofi-aventis group - strictly confidential

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500 µg BID or MDI formulation: 220 µg BID or 440 µg BID) monotherapy, thereby discontinuing the LABA component of fluticasone/salmeterol combination therapy (ie, salmeterol). At Weeks 6, 7, 8, and 9, the fluticasone dose will be reduced by approximately 50% according to the schedule in the table below, provided that the patient does not meet any of the criteria for an asthma exacerbation (see Section 9.1.1). If no asthma exacerbations occur, ICS withdrawal will proceed according to the following dosing schedule: Background therapy stable phase

Background therapy withdrawal phase Week 4

Week 6

Week 7

Week 8

Week 9

Fluticasone/salmeterol (DPI): 250/50 µg BID

Fluticasone (DPI): 250 µg BID

100 µg BID

50 µg BID

0 µg BID

0 µg BID

Fluticasone/salmeterol (DPI): 500/50 µg BID

Fluticasone (DPI): 500 µg BID

250 µg BID

100 µg BID

50 µg BID

0 µg BID

Fluticasone/salmeterol (MDI): 230/42 µg BID

Fluticasone (MDI): 220 µg BID

110 µg BID

44 µg BID

0 µg BID

0 µg BID

Fluticasone/salmeterol (MDI): 460/42 µg BID

Fluticasone (MDI): 440 µg BID

220 µg BID

110 µg BID

44 µg BID

0 µg BID

Albuterol, levalbuterol, fluticasone/salmeterol combination therapy, and fluticasone will be provided as needed by the Investigator who will be reimbursed by the Sponsor. 8.3

DESCRIPTION OF BLINDING METHODS

SAR231893/REGN668 and placebo will be provided in identically matched glass 5 mL vials. To protect the blind, each treatment kit will be prepared such that the treatments are identical and indistinguishable and will be labeled with a treatment kit number. The randomized treatment kit number list will be generated by sanofi-aventis. In accordance with the double-blind design, study patients, Investigators, and study site personnel will remain blinded to study treatment and will not have access to the randomization (treatment codes) except under circumstances described in Section 8.8. 8.4

COMPENSATION FOR LACK OF BLINDING

Not applicable. 8.5

METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP

A randomized treatment kit number list will be generated centrally by sanofi-aventis. The investigational product (SAR231893/REGN668 or placebo) will be packaged in accordance with this list. The sanofi-aventis Clinical Supplies Project Demand Manager will provide the randomized treatment kit number list and the Study Biostatistician will provide the randomization scheme to Property of the sanofi-aventis group - strictly confidential

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the centralized treatment allocation system. This centralized treatment allocation system will generate the patient randomization list according to which it will allocate the treatments to the patients. Patients who meet the entry criteria will be randomized to receive either SAR231893/REGN668 or placebo. Patients who fail to meet the entry criteria can be re-screened once more at a later date for any reason (with the exception of patients who fail 2 attempts to meet the eosinophil minimum or patients who have failed to meet the entry criterion for sputum eosinophils). The treatment kit numbers will be obtained by the Investigator at the time of patient randomization and subsequent patient scheduled visits via an Interactive Voice Response System/Interactive Web Response System (IVRS/IWRS) that will be available 24 hours a day. A randomized patient is defined as a patient who is registered and assigned with a treatment kit number from the centralized treatment allocation system, as documented from its log file. A patient cannot be randomized more than once in the study. 8.6

PACKAGING AND LABELING

SAR231893/REGN668 and placebo will be supplied as a single vial packed in a box. Both vial and box will be labeled with a double-blind label. The content of the labeling is in accordance with the local regulatory specifications and requirements. 8.7

STORAGE CONDITIONS AND SHELF LIFE

All investigational product should be stored at a temperature between 2°C and 8°C in an appropriate locked room under the responsibility of the Investigator or other authorized persons (eg, pharmacists) in accordance with local regulations, policies and procedures. Control of investigational product storage conditions, especially control of temperature (eg, refrigerated storage) and information on in-use stability and instructions for handling the sanofiaventis compound should be managed according to the rules provided by the Sponsor. 8.8

RANDOMIZATION CODE BREAKING DURING THE STUDY

Please refer to Section 9.6 - Measures to protect blinding of this trial. In case of an AE, the code must be broken only in exceptional circumstances when knowledge of the investigational product is essential for treating the patient. If possible, a contact should be initiated with the Monitoring Team before breaking the code. Code breaking can be performed at any time by using the proper module of the IVRS/IWRS and/or by calling any other phone number provided by the Sponsor for that purpose. If the blind is broken, the Investigator should document the date, time of day, and reason for code breaking.


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If the blind is broken, the patient must be withdrawn from the treatment. They should return to the study site for their end of treatment assessment (normally scheduled for Visit 14) and return again 6 and 8 weeks later for the post-treatment safety assessment (normally scheduled for Visit 15 and Visit 16). 8.9

RESPONSIBILITIES

The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense investigational product will be responsible for ensuring that the investigational product used in the clinical trial is securely maintained as specified by the Sponsor and in accordance with the applicable regulatory requirements. All investigational product shall be dispensed in accordance with the Investigator's prescription, and it is the Investigator's responsibility to ensure that an accurate record of investigational product issued and returned is maintained. Any quality issue noticed with the receipt or use of an investigational product (deficiency in condition, appearance, pertaining documentation, labeling, expiration date, etc.) should be promptly notified to the Sponsor. Some deficiencies may be recorded through a complaint procedure. A potential defect in the quality of investigational product may be subject to initiation of a recall procedure by the Sponsor. In this case, the Investigator will be responsible for promptly addressing any request made by the Sponsor, in order to recall investigational product and eliminate potential hazards. Under no circumstances will the Investigator supply investigational product to a third party, allow the investigational product to be used other than as directed by this Clinical Trial Protocol, or dispose of investigational product in any other manner. 8.10

CONCOMITANT MEDICATION

A concomitant medication is any treatment received by the patient concomitant with any investigational product. The following concomitant treatments are not permitted during the study from the screening visit until the end of the treatment period: •

Any inhaled steroid other than fluticasone/salmeterol combination therapy or fluticasone administered per protocol (or budesonide/formoterol or mometasone/formoterol during the screening period)

•

Systemic or ocular steroids (Intranasal steroids are permitted during the study, but patients must be on a stable dose for 30 days prior to screening and through the screening/run-in period)


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•

LABAs other than the salmeterol component of fluticasone/salmeterol combination therapy administered per protocol

•

ICS/LABA combination products other than fluticasone/salmeterol combination therapy administered per protocol (or budesonide/formoterol or mometasone/formoterol during the screening period)

•

Ipratropium bromide or other inhaled anti-cholinergic agents (eg, tiotropium)

•

Methylxanthines (theophylline, aminophyllines)

•

Leukotriene receptor antagonists or leukotriene synthesis inhibitors

•

Lipoxygenase inhibitors

•

Cromones

•

Anti-immunoglobuline E (IgE) therapy (Xolair®)

8.11

TREATMENT ACCOUNTABILITY AND COMPLIANCE

The administration and treatment kit number of the investigational product will be recorded on the appropriate page of the electronic Case Report Form (e-CRF) by the Investigator or his/her delegate. The Monitoring Team in charge of the study will check the e-CRF data by comparing them with the IVRS/IWRS treatment allocation. All drug accountability and compliance records must be kept current, including shipment receipts containing dates, quantities and identification numbers (or lot numbers) of investigational product received by the Investigator, shipment temperature records (if applicable), storage temperature logs, pharmacy dose preparation logs and IVRS/IWRS confirmation reports. The Investigator must be able to account for all used and unused investigational product. These records should contain the dates, quantity and investigational product returned to sanofi-aventis or its designee. All accountability and compliance records must be made available for inspection by sanofiaventis and regulatory agency inspectors and photocopies of all drug accountability and compliance records must be provided to sanofi-aventis at the conclusion of the study. 8.12

RETURN AND/OR DESTRUCTION OF TREATMENTS

Investigational product: All partially used or unused treatments will be retrieved by the Sponsor. A detailed treatment log of the returned investigational product will be established with the Investigator (or the pharmacist) and countersigned by the Investigator and the Monitoring Team. The Investigator will not destroy the unused investigational product. A potential defect in the quality of investigational product may be subject to initiation of a recall procedure by the Sponsor. In this case, the Investigator will be responsible for promptly Property of the sanofi-aventis group - strictly confidential

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addressing any request made by the Sponsor, in order to recall investigational product and eliminate potential hazards. Non-investigational product: For non-investigational product not provided by the Sponsor (ie, albuterol, levalbuterol, fluticasone/salmeterol combination therapy, and fluticasone), tracking and reconciliation has to be achieved by the Investigator according to the system proposed by the Sponsor.


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9

ASSESSMENT OF INVESTIGATIONAL PRODUCT

9.1

EFFICACY

9.1.1 Primary endpoint

The primary endpoint of this study is the proportion of patients with an exacerbation of asthma as defined by any of the following: •

A 30% or greater reduction from baseline in morning peak expiratory flow (PEF) on 2 consecutive days, or

•

≥6 additional reliever puffs of albuterol or levoalbuterol in a 24 hour period (compared to baseline) on 2 consecutive days, or

•


Systemic (oral and/or parenteral) steroid treatment, or

-

An increase in ICS ≥4 times the last dose received prior to discontinuation from the study, or

-

Hospitalization

9.1.2 Secondary endpoints

•

Time to asthma exacerbation post-randomization For patients who experience asthma exacerbation, based on the definition provided in Section 9.1.1, the time from randomization to asthma exacerbation will be determined.

•

Proportion of patients with a composite asthma event defined by a 30% or greater reduction from baseline in morning PEF on 2 consecutive days together with ≥6 additional reliever puffs of albuterol or levalbuterol in a 24 hour period (compared to baseline) on 2 consecutive days

•


•


•


•

22-item Sinonasal Outcome Test (SNOT-22) score change from baseline at Week 12

•


•

Change from baseline at Week 12 and change from baseline at each visit in number of inhalations/day of albuterol or levalbuterol for symptom relief


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9.1.3 Efficacy methods

Peak expiratory flow: At screening (Visit 1), patients will be issued an electronic PEF meter for recording morning (AM) and evening (PM) PEF, daily albuterol or levalbuterol use, morning and evening asthma symptom scores, and number of nighttime awakenings due to asthma symptoms that require rescue medications. Patients will be instructed on the use of the device, and written instructions on the use of the electronic PEF meter will be provided to the patients. The instructions that appear on the LogPad screen of the electronic PEF/diary are provided in Appendix B. In addition, the investigator will instruct the patients on how to record the following variables in the electronic PEF meter: •

AM PEF will be performed within 15 minutes after arising (between 6 am and 10 am) prior to taking any albuterol or levalbuterol

•

PM PEF will be performed in the evening (between 6 pm and 10 pm) prior to taking any albuterol or levalbuterol

•

Patients should try to withhold albuterol or levalbuterol for at least 6 hours prior to measuring their PEF

•


Baseline AM PEF will be the mean AM measurement recorded for the 7 days prior to the first dose of investigational product, and baseline PM PEF will be the mean PM measurement recorded for the 7 days prior to the first dose of investigational product. Information derived from the electronic PEF meter will be evaluated by the Investigator at the patient’s weekly visit to the study site. Patients with asthma exacerbation as defined Section 9.1.1 will be discontinued from the study. They are to be given the end-of-treatment assessments normally scheduled for Visit 14, and are to return 6 weeks and 8 weeks later for a post treatment safety evaluation (normally scheduled for Visit 15 and Visit 16). Forced expiratory flow in 1 second: A spirometer that meets the 2005 American Thoracic Society (ATS)/ European Respiratory Society (ERS) recommendations will be used. The ATS/ ERS Standardization of Spirometry should be used as a guideline. (10) Spirometry will be performed between 6 and 10 AM after an albuterol or levalbuterol withhold of at least 6 hours. Pulmonary function tests will be measured in the sitting position, and the highest measure will be recorded for FEV1 (in liters). The predose spirometry on the postrandomization visits should be performed within one hour of the time it was performed on Visit 2 (Day 1). The same spirometer and standard spirometric techniques, including calibration, will be used to perform spirometry at all visits and whenever possible the same person should perform the measurements. Property of the sanofi-aventis group - strictly confidential

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An instruction manual describing further details (data processing, quality assurance) will be provided. Further details on spirometry are available in Appendix C. Juniper Asthma Control Questionnaire: The 5-question version of the Juniper ACQ is a validated questionnaire to evaluate asthma control. (11, 12) The 5-question version of the ACQ differs from the full ACQ (7-question version) in that the question about short-acting bronchodilator use and FEV1 score are excluded. (These 2 variables are being collected separately as secondary efficacy endpoints). Patients will complete the ACQ questionnaire within their electronic diaries at screening and at their weekly visit to the clinic. A copy of the Juniper ACQ is provided in Appendix D. 22-item Sinonasal Outcome Test: The SNOT-22 is a validated questionnaire to assess the impact of chronic rhinosinusitis on quality of life. (13) Patients will complete the SNOT-22 questionnaire at randomization and at Week 12. A copy of the SNOT-22 questionnaire is provided in Appendix E. Asthma Symptom Score: Patients will record overall symptom scores twice a day prior to measuring PEF. The patient’s overall asthma symptoms experienced during the waking hours will be recorded in the evening (PM symptom score). Symptoms experienced during the night will be recorded upon arising (AM symptom score). Baseline symptom scores will be the mean AM and mean PM scores recorded for the 7 days prior to randomization (see Appendix B). Patients will be instructed to record the severity of symptoms as follows: AM symptom score: -


-


-


-


-


PM symptom score: -


-


-


-


-



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Albuterol or levalbuterol use for symptom relief: The number of albuterol or levalbuterol inhalations will be recorded daily by the patients in their electronic diary/PEF meter. Each patient should be reminded that albuterol or levalbuterol should be used only as needed for symptoms, not on a regular basis or prophylactically. The baseline number of albuterol or levalbuterol inhalations/day will be based on the mean for the 7 days prior to randomization. 9.2

SAFETY

A secondary objective is to assess the safety of the SAR231893/REGN668. The study specific and general safety criteria are referenced in Section 10.1. To assure the continuing safety of patients, this study will use an IDMC and is designed with a lead in cohort of a subset of patients. Prior to opening enrollment to the entire population of up to approximately 130 patients, a sentinel cohort consisting of approximately 20 patients (approximately 10 active and 10 placebo) will be enrolled. Data from this sentinel cohort will be evaluated by the IDMC for any safety issues. Unblinded clinical safety data through at least 4 weeks of treatment will be reviewed by the IDMC. Based on this review, a decision will be made to continue treatment beyond 4 weeks for the currently enrolled patients. Additionally, based on the IDMC’s review, a decision may be made to modify the protocol or stop the study. During this safety evaluation the sentinel cohort will continue to receive investigational product for the scheduled 12 weeks. The IDMC will continue to monitor safety of all patients throughout the study. Patients will be evaluated for asthma exacerbation at each visit. Patients with asthma exacerbation, as defined in Section 9.1.1 will be discontinued from the study. 9.3

PHARMACOKINETICS

SAR231893/REGN688 and anti-SAR231893/REGN688 antibody serum samples will be assayed using validated enzyme-linked immunosorbent assays (ELISA) under the responsibility of the Preclinical department of Regeneron (Sample Management, Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10592). 9.3.1 Sampling schedule

SAR231893/REGN668: Blood samples for the determination of serum SAR231893/REGN668 concentrations will be collected in all patients on Day 1 (Visit 2), Week 1 (Visit 3), Week 4 (Visit 6), Week 6 (Visit 8), Week 8 (Visit 10), Week 10 (Visit 12), Week 11 (Visit 13), Week 12 (Visit 14), Week 18 (Visit 15), Week 20 (Visit 16) and as soon as possible in the event of early treatment discontinuation. For the lead-in cohort of approximately 20 patients, additional blood samples will be collected after the final dose on Days 82, 92, 99, 106 and 113.


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Anti-SAR231893/REGN668 antibody: Blood samples for the determination of serum anti-SAR231893/REGN668 antibody will be collected on Day 1 (Visit 2), Week 4 (Visit 6), Week 6 (Visit 8), Week 8 (Visit 10), Week 10 (Visit 12), Week 18 (Visit 15) and Week 20 (Visit 16). Serum samples for pharmacokinetic analysis will be collected prior to the administration of investigational product. The procedure for SAR231893/REGN668 and anti-SAR231893 antibody sample handling is detailed in Section 9.3.2. 9.3.2 Sample handling procedure

All blood samples for measurement of SAR231893/REGN668 and anti-SAR231893 antibody will be processed by the central laboratory services vendor - Covance Laboratories. All special procedures for collection, storage and shipment of these samples are provided in the Study Procedure Manual supplied to the site by Covance Central Laboratory Services. 9.4

PHARMACOGENOMIC SAMPLES

Patients who meet all the inclusion/exclusion criteria for the study will have the option to consent to an additional blood draw on Day 1 for the purpose of pharmacogenomic testing. Patients who are willing to participate in pharmacogenomic testing must sign an additional informed consent prior to the blood sample collection. The data from genetic material can be used to determine if there is a relationship between genes and responses to treatment with SAR231893/REGN668, how the body processes SAR231893/REGN668 and possible side effects to SAR231893/REGN668. Analyses may include sequence determination and/or single nucleotide polymorphism studies of candidate genes. Genes that may be studied include those for the IL-4 receptor, IL-4, IL-13, and additional genes that may potentially be part of the IL-4/IL-13 signaling pathway or are potentially associated with asthma, atopy or other eosinophilic diseases. Participation in the pharmacogenomic substudy is optional and is not be required for a patient to participate in the main clinical trial. Patients who agree to participate in the pharmacogenomic substudy will be required to sign a separate Pharmacogenomic Informed Consent Form prior to collection of the blood sample. For those patients who sign the Pharmacogenomic Informed Consent Form, blood samples for deoxyribonucleic acid (DNA) pharmacogenomic analysis will be collected. A sample for ribonucleic acid (RNA) levels (non-genetic analysis) will be collected as part of the main protocol and will be addressed in the main protocol informed consent form. Additional RNA studies such as transcriptome sequencing (a type of genetic analysis) may be performed only if the patient has provided written informed consent to participate in the optional pharmacogenomics substudy. Pharmacogenomic samples will be stored for up to 15 years from the completion of the Clinical Study Report, after which time any remaining samples will be destroyed.


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The blood sample for DNA extraction should be collected on day 1/baseline (pre-dose) but may be collected at any study visit. Special procedures for storage and shipping of pharmacogenomic samples are summarized in Table 1 and are described in detail in Appendix H. Table 1 - Summary of handling procedures for pharmacogenomic samples Sample Type(s) Blood Sample Volume Tube Type Anticoagulant Blood Handling Procedures Storage Conditions

Pharmacogenomics 12 mL 2 x 6 mL Becton Dickinson K2 EDTA VACUTAINER™ Plus tubes with HEMOGARD™ closure (PN367863/4) sterile tubes (tube provided by Covance for DNA sample storage) K2 EDTA Keep blood on ice or frozen at -20°C (or colder) within 30 min of sampling time. DO NOT CENTRIFUGE. In collection tube at approximately -20°C (or colder)

The Sponsor has included safeguards for protecting patient confidentiality. The blood sample and DNA/RNA that is extracted will be assigned a second number, a Genetic ID (de-identification code) that is different from the Patient ID. This “double coding” is performed to separate a patient’s medical information and DNA data. The clinical study data (coded by Patient ID) will be stored in a distinct database at a different location from the database containing the genetic data (coded by Genetic ID). The key linking Patient ID and Genetic ID will be maintained by a third party, under appropriate access control. The matching of clinical data and pharmacogenomic data, for the purpose of data analysis, will be possible only by using this key, which will be under strict access control. All data will be reported only in coded form in order to maintain confidentiality. 9.5

PHARMACODYNAMIC MEASURES

Biomarkers: Pharmacodynamic effects of SAR231893/REGN668 will be assessed through measurement of the following biomarkers: total IgE, thymus and activation-regulated chemokine (TARC), YKL-40, thymic stromal lymphopoietin (TSLP), and carcinoembryonic antigen (CEA, also known as CEA cell adhesion molecule 5 [CEACAM5]) in serum and eotaxin-3 in plasma. These markers are associated with asthma and in some cases may be associated with IL-4/IL-13 activity. Baseline levels of these biomarkers will be assessed for potential predictive value for treatment response. Post-treatment samples will be evaluated for pharmacodynamic effects of SAR231893/REGN668 on the biomarkers. Serum samples for biomarker analyses will be collected at screening and on Day 1 (Visit 2), Week 1 (Visit 3), Week 4 (Visit 6), Week 8 (Visit 10), and Week 12 (Visit 14) (or early termination visit). The Phadiatop test is an in vitro diagnostic screening tool used to detect antigen-specific IgE for common inhalants. Baseline results of the Phadiatop test will be assessed for potential predictive value for treatment response. Post-treatment samples will be evaluated for pharmacodynamic Property of the sanofi-aventis group - strictly confidential

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effects of SAR231893/REGN668 on the Phadiatop antigen panel. Blood samples for Phadiatop will be collected at screening (Visit 1) and Week 12 (Visit 14) or early termination. Serum protein and RNA analysis: Additional serum samples for exploratory serum analyses will be collected at screening (Visit 1), Day 1 (Visit 2), Week 1 (Visit 3), Week 4 (Visit 6), Week 8 (Visit 10), and Week 12 (Visit 14) or early termination. These serum samples may be used to study additional protein biomarkers related to SAR231893/REGN231893 response or activity, IL-4/IL-13 signaling, asthma, atopy, or eosinophilic diseases (eg, soluble IL-4Rα, IL-4, IL-13, and periostin). RNA research samples will be collected to determine RNA levels (non-genetic analysis). Additional RNA studies such as transcriptome sequencing (a type of genetic analysis) may be performed as part of the optional pharmacogenomics substudy for those patients who provide written informed consent to participate in the substudy, as described in Section 9.4. Induced sputum eosinophils and neutrophils: Induced sputum eosinophils and neutrophils are well-established direct markers of airway inflammation. A subset of study sites will be selected to perform evaluations of induced sputum, and patients at these selected sites will have the option to participate in this assessment. The first sputum sample from each site will be evaluated by an independent reader to assess the quality of the sample. If the quality is inadequate, additional training will be conducted at the site prior to collecting sputum samples from subsequent patients, and the sample from the first patient will be discarded and recollected prior to randomization. The goal is for approximately 50 patients to participate in this analysis. Sputum will be induced with inhalation of hypertonic saline solution. Sputum induction and processing of whole sputum will be performed essentially according to the ERS guidelines. Sputum cell counts of leukocytes (including eosinophils and neutrophils) will be performed. In addition, soluble factors in sputum may also be examined if feasible (eg, IL-4, IL13). Further details on the sputum induction procedure and sample processing/examination are available in Appendix F, and instruction manuals describing additional details (data processing, quality assurance) for induced sputum will be provided. Induced sputum analysis will be performed on Day -14 to -7 (Visit 1), Week 4 (Visit 6), Week 8 (Visit 10), and Week 12 (Visit 14) or early termination. Exhaled nitric oxide: Exhaled nitric oxide will be analyzed using a NIOX instrument (Aerocrine AB, Solna, Sweden). This assessment should be conducted prior to spirometry and following a fast of at least 1 hour. Further details on the procedure for measuring exhaled nitric oxide with NIOX will be provided in a separate instruction manual. Exhaled nitric oxide will be performed on Day -14 to -7 (Visit 1), Week 4 (Visit 6), Week 8 (Visit 10), and Week 12 (Visit 14) or early termination.


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Blood eosinophil count: Blood eosinophil counts will be evaluated at screening (Visit 1) and at Week 4 (Visit 6), Week 8 (Visit 10), and Week 12 (Visit 14) or early termination. Eosinophil counts at screening and Week 12 (Visit 14) will be derived from the sample drawn for clinical lab testing (differential count). Patients whose initial screening eosinophil count is 200 to 299 cells/µL may have 1 additional screening hematology assessment to attempt to meet the minimum eosinophil criterion of 300 cells/µL. At Week 4 (Visit 6) and Week 8 (Visit 10) only a hematology sample will be taken for eosinophil counts, as serum chemistry testing is not scheduled for these visits. 9.6

MEASURES TO PROTECT BLINDING OF THIS TRIAL

The study will not be unblinded prior to database lock. The IDMC will review blinded safety data. However, at their request, the data can be unblinded. Results of individual pharmacokinetic assessments (SAR231893/REGN668 and anti-SAR231893 antibody) will not be provided to the Investigator or other study-site personnel when the study is ongoing. If emergency unblinding is required for an individual patient, the Investigator will follow the procedure described in Section 8.8. For safety, the treatment code will be unblinded by the Sponsor for reporting to the Health Authority of any Suspected Unexpected Adverse Drug Reaction (SUSAR) and reasonably associated with the use of the investigational product according to either the judgment of the Investigator and/or the Sponsor.


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10

PATIENT SAFETY

10.1

SAFETY ENDPOINTS ASSESSED IN THIS TRIAL

A secondary objective is to assess the safety of the SAR231893/REGN668. All analyses of safety variables will be based on the safety population defined in Section 13.4.2. Safety data will be analyzed on the basis of AEs, standard clinical laboratory findings, vital signs (blood pressure and heart rate), 12-lead electrocardiogram (ECG), and physical examination. 10.1.1 Medical history and prior and concomitant medication

Each patient will have a complete medical history at Visit 1 and details of prior and concomitant medication recorded at Visits 1 and 2. Medical conditions that have occurred within the past year or conditions that are ongoing (eg, headache, indigestion) are to be included. All corticosteroid and asthma medications taken within the 3 months and all non-asthma medication taken within 30 days prior to screening will be recorded, including the drug name, start and stop dates, and route of administration. The concomitant medication status will be reviewed at all visits during the treatment period. 10.1.2 Adverse events

Adverse events for each patient will be monitored and documented from the time the subject gives informed consent at the screening visit (Visit 1) until 8 weeks following the completion of the end-of-treatment visit. Adverse events and SAEs will be reported as described in Section 10.5.1 and Section 10.5.2, respectively. 10.1.3 Vital signs

Vital signs, including blood pressure (mmHg) and heart rate (beats per minute), and body weight data will be measured at the screening and randomization visits (Visits 1 and 2) and every 2 weeks thereafter, including Week 2 (Visit 4), Week 4 (Visit 6), Week 6 (Visit 8), Week 8 (Visit 10), Week 10 (Visit 12), Week 12 (Visit 14), Week 18 (Visit 15) and Week 20 (Visit 16). Height will be measured at screening (Visit 1) only. Vital signs will be measured in the sitting position using the same arm at each visit, and will be measured prior to receiving investigational product at the clinic visits. 10.1.4 Clinical laboratory tests

At screening Visit 1 and at Week 2 (Visit 4), Week 6 (Visit 8), and Week 12 (Visit 14), approximately a 2 mL blood sample will be required for hematology testing, and approximately a 3 mL blood sample will be required for serum biochemistry testing. The eosinophil count obtained at screening and Week 12 will also be recorded as a pharmacodynamic variable. (In


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addition, a hematology sample will be collected at Week 4 and Week 8 for the purpose of obtaining eosinophil counts for pharmacodynamic testing). The clinical laboratory tests will be carried out according to Good Laboratory Practice and appropriate standard operating procedures by a validated central laboratory. After reviewing the laboratory report and evaluating any results that are outside the normal range, the Investigator must sign and date the laboratory report. Abnormal laboratory values that are considered to be clinically significant by the Investigator must be repeated as soon as possible after receiving the laboratory report to rule out laboratory error. Persistent abnormal laboratory values should be repeated until they return to normal or until an etiology of the persistent abnormality is determined. Details of the clinical laboratory parameters that will be measured in safety hematology and chemistry blood samples are listed below: Hematology: To include hemoglobin, hematocrit, platelet count, total white blood cell count, differential count, and total red blood cell count. Serum chemistry: To include creatinine, blood urea nitrogen, glucose, uric acid, total cholesterol, total protein, albumin, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, electrolytes (sodium, potassium, chloride), bicarbonate, and creatine phosphokinase (CPK). Decision trees for the management of certain laboratory abnormalities by sanofi-aventis are provided in Appendix G. 10.1.5 Electrocardiogram

One recording of a standard 12-lead ECG will be performed at screening (Visit 1), and at Week 2 (Visit 4), Week 6 (Visit 8), and Week 12 (Visit 14). At the post-randomization visits, ECGs will be performed prior to investigational product administration. All ECGs will be performed with the subject in a reclined position. A minimum of 3 complexes in an appropriate lead (lead II) will be averaged to determine the PR-interval, QT/QTc-interval, QRS-complex and heart rate will be measured for each ECG. All measurements will be made from a single lead: Lead II, or Lead I if Lead II is not possible, or lead V5 if Lead II and Lead I are not possible. 10.1.6 Pregnancy test

A serum pregnancy test (β-human chorionic gonadotrophin) will be performed at screening (Visit 1) in women of childbearing potential, and a urine pregnancy test will be performed at Visit 2 prior to randomization. A negative result must be obtained at Visit 1 and 2 prior to randomization. Additional urine pregnancy tests will be performed at Weeks 6 and 12 (Visits 8 and 14) or end-of-treatment visit.


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10.1.7 Physical examination

Physical examinations will include an assessment of general appearance, skin, eyes, ear/nose/throat, heart, chest, abdomen, reflexes, lymph nodes, spine, and extremities. All deviations from normal will be recorded, including those attributable to the patient’s disease. Physical examinations will be performed at screening (Visit 1) and at Week 12 (Visit 14) or endof-treatment visit. 10.2

SAFETY INSTRUCTIONS

Since low levels of doxycycline are used in the manufacturing process, patients allergic to doxycycline or related compounds should be excluded from this study. Emergency equipment and medication for the treatment of potential allergy/hypersensitivity reactions must be available for immediate use during study visits. This study uses an add-on therapy approach to background therapy (ICS/LABA combination) with systematic background therapy withdrawal during treatment. A 4-week background therapy stable phase will be followed by an 8-week background therapy withdrawal phase. Patients will enter the study having been on a stable dose of ICS/LABA combination therapy for at least 1 month. At Week 4 patients will be switched to an equivalent dose of ICS monotherapy, thereby discontinuing the LABA component of ICS/LABA combination therapy. At Week 6 and at subsequent weekly visits, the ICS dose will be reduced by approximately 50% provided that the patient does not meet any of the criteria for an asthma exacerbation as defined in Section 9.1.1. If a patient meets the criteria for an asthma exacerbation, he/she will be withdrawn from the study and treated by the Investigator with appropriate medical therapy. 10.3

ADVERSE EVENTS MONITORING

All events will be managed and reported in compliance with all applicable regulations, and included in the final clinical study report. 10.4

DEFINITIONS OF ADVERSE EVENT (AE) AND SERIOUS ADVERSE EVENT (SAE)

An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: •

Results in death or

•

Is life-threatening or Note: The term "life-threatening" in the definition of "serious" refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe.

•

Requires inpatient hospitalization or prolongation of existing hospitalization or


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•

Results in persistent or significant disability/incapacity or

•

Is a congenital anomaly/birth defect

•

Is a medically important event: Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or may require intervention (ie, specific measures or corrective treatment) to prevent one of the other outcomes listed in the definition above.

Note: The following medical important events intend to serve as a guideline for determining which condition has to be considered as a medically important event. It is not intended to be exhaustive: •

Intensive treatment in an emergency room or at home for: -

allergic bronchospasm

-

blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, myelodysplasia, pancytopenia)

-

convulsions (seizures, epilepsy, epileptic fit, absence)

•

Development of drug dependency or drug abuse

•

ALT > 3 ULN + total bilirubin > 2 ULN or asymptomatic ALT increase > 10 ULN

•

Suicide attempt or any event suggestive of suicidality

•

Syncope, loss of consciousness (except if documented as a consequence of blood sampling)

•

Bullous cutaneous eruptions

•

Cancers diagnosed during the study or aggravated during the study

•

Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study

10.5

OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING

10.5.1 Adverse Events

All AEs regardless of seriousness or relationship to investigational product or non investigational product, spanning from the signature of the informed consent form, until the end of the study as defined by the protocol for that patient, are to be recorded on the corresponding page(s) or screen(s) included in the CRF. Since asthma exacerbation (as defined in Section 9.1.1) is the primary efficacy endpoint, it should not be reported as an AE unless it fulfills the criteria for an SAE. Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. The Investigator should specify the date of onset, intensity, action taken with respect to investigational Property of the sanofi-aventis group - strictly confidential

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product, corrective treatment/therapy given, additional investigations performed, outcome and his/her opinion as to whether there is a reasonable possibility that the AE was caused by the investigational product. Laboratory, vital signs, or ECG abnormalities are to be recorded as AEs only if: •

symptomatic and/or

•

requiring either corrective treatment or consultation, and/or

•

leading to investigational product discontinuation or modification of dosing, and/or

•

fulfilling a seriousness criterion, and/or

•

defined as an AE of special interest (AESI) with immediate notification (see Section 10.5.4).

10.5.2 Serious Adverse Events

In the case of occurrence of a SAE, the Investigator must immediately: •

ENTER (within 1 working day) the information related to the SAE in the appropriate screens of the e-CRF; the system will automatically send the notification to the Monitoring Team after approval of the Investigator within the e-CRF or after a standard delay.

•

SEND (preferably by fax or e-mail) the photocopy of all examinations carried out and the dates on which these examinations were performed, to the representative of the sanofiaventis Safety Group at 1-877-FAX-SAES [1-877-329-7237] or [email protected]. Care should be taken to ensure that the patient's identity is protected and the patient's identifiers in the Clinical Trial are properly mentioned on any copy of source document provided to the Sponsor. For laboratory results, include the laboratory normal ranges

•

All further data updates should be recorded in the e-CRF as appropriate, and further documentation as well as additional information (for lab data, concomitant medication, patient status) should be sent (by fax or e-mail) to the Safety Group within 1 working day of knowledge. In addition, any effort should be made to further document each SAE that is fatal or life threatening within the week (7 days) following initial notification.

•

A back-up plan is used (using paper flow) when the e-CRF system does not work.

10.5.3 Safety Observations •

The Investigator should take all appropriate measures to ensure the safety of the patients. Notably, he/she should follow up the outcome of SAEs /AESI until clinical recovery is complete and laboratory results have returned to normal or until progression has been stabilized or death. In all cases, this may imply that observations will continue beyond the last planned visit per protocol, and that additional investigations may be requested by the Sponsor.

•

When treatment is prematurely discontinued, the patient’s observations will continue until the end of the study as defined by the protocol for that patient.


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•


In case of any SAE/AESI with immediate notification brought to the attention of the Investigator at any time after the end of the study for the patient and considered by him/her to be caused by the investigational product with a reasonable possibility, this should be reported to the Sponsor.

10.5.4 Adverse events of special interest (AESI)

Adverse events of special interest are AEs (serious or non-serious) of scientific or medical concern for which ongoing monitoring and rapid communication may be important. These may include events that are either specific to the investigational product or events that, in general, may be of clinical significance with any medicinal product under development. As such, these need to be monitored, documented, and managed in a pre-specified manner described in the protocol. 10.5.4.1 AESI with immediate notification

For these AEs, the Sponsor will be informed immediately (ie, within 1 working day), per SAE notification described in Section 10.5.2, even if not fulfilling a seriousness criterion, using the corresponding pages in the CRF (to be sent) or screens in the e-CRF. •

ALT increase where: (see flowchart in Appendix G) -

ALT > 5 X the upper limit of normal (ULN) in patients with baseline ALT < ULN; or

-

ALT >3X baseline ALT in patients with baseline ALT ≥ ULN; or

-

ALT ≥3 ULN and ≤5 ULN plus total bilirubin >2 ULN in patients with baseline ALT < ULN; or

-

ALT ≥2X baseline ALT and ≤3X baseline ALT plus total bilirubin >2 ULN in patients with baseline ALT ≥ ULN.

•

Anaphylactic reactions or acute allergic reactions that require immediate treatment

•

Severe injection site reactions that last longer than 24 hours

•

Severe infections including parasitic infections

•

Pregnancy

•

-

Pregnancy occurring in a female patient included in the clinical trial. Pregnancy will be recorded as a pre-specified AE with immediate notification in all cases. It will be qualified as an SAE only if it fulfills the SAE criteria.

-

In the event of pregnancy, investigational product should be discontinued.

-


Symptomatic overdose with investigational product An overdose (accidental or intentional) with the investigational product is an event suspected by the Investigator and defined as at least twice the dose during the planned intervals.


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Adverse events and laboratory abnormalities requiring expedited reporting are summarized in Table 2. 10.5.4.2 AESI without immediate notification

•


•


ALT ≥3 ULN and ≤5 ULN plus total bilirubin ≤2 ULN in patients with baseline ALT < ULN; or

-

ALT ≥2X baseline ALT and ≤3X baseline ALT plus total bilirubin ≤2 ULN in patients with baseline ALT ≥ ULN Table 2 - Summary of Expedited Safety Reporting

Adverse event / laboratory abnormality Serious adverse event Pregnancy Overdose Symptomatic Asymptomatic ALT elevation Baseline < ULN ALT > 5 ULN 3 ULN ≤ ALT ≤ 5 ULN plus total bilirubin > 2 ULN Baseline ≥ ULN ALT > 3x baseline 2 x baseline ≤ ALT ≤ 3x baseline plus total bilirubin > 2 ULN Anaphylactic reactions or acute allergic reactions that require immediate treatment Severe injection site reactions that last longer than 24 hours Severe infections including parasitic infections

Reporting timeline Within 1 working day Within 1 working day Within 1 working day Routine Within 1 working day Within 1 working day Within 1 working day Within 1 working day Within 1 working day Within 1 working day Within 1 working day

10.5.5 Laboratory abnormalities with pre-specified monitoring

Laboratory abnormalities should be monitored, documented, and managed according to the related flowchart in Appendix G. •

Increase in ALT

•

Neutropenia

•

Thrombocytopenia

•

Acute renal insufficiency

•

Suspicion of rhabdomyolysis

10.6

OBLIGATIONS OF THE SPONSOR

During the course of the study, the Sponsor will report in an expedited manner all SAEs that are both unexpected and at least reasonably related to the investigational product (SUSAR), to the Health Authorities, Independent Ethics Committees/Institutional Review Boards (IECs/IRBs) as appropriate and to the Investigators. Property of the sanofi-aventis group - strictly confidential

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In addition, the Sponsor will report in an expedited manner all SAEs that are expected and at least reasonably related to the investigational product to the Authorities, according to local regulations. In this study, some AEs are considered related to the underlying condition and thus will not be considered unexpected (please refer to the Investigator’s Brochure). Any other AE not listed as an expected event in the Investigator’s Brochure or in this protocol will be considered as unexpected. The Sponsor will report all safety observations made during the conduct of the trial in the clinical study report.


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11


HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION

The investigational product should be continued whenever possible. In case the investigational product is stopped, it should be determined if the stop can be made temporarily; permanent investigational product discontinuation should be a last resort. Any investigational product discontinuation should be fully documented in the e-CRF. In any case, the patient should remain in the study as long as possible. 11.1

TEMPORARY TREATMENT DISCONTINUATION WITH INVESTIGATIONAL PRODUCT(S)

Temporary treatment discontinuation may be considered by the Investigator because of suspected AEs. Reinitiation of treatment with the investigational product will be done under close and appropriate clinical/and or laboratory monitoring once the Investigator will have considered according to his/her best medical judgment that the responsibility of the investigational product(s) in the occurrence of the concerned event was unlikely and if the selection criteria for the study are still met (refer to Sections 7.2 and 7.3). All temporary treatment discontinuation and date of treatment re-initiation should be recorded by the Investigator in the appropriate pages when considered as confirmed. 11.2

PERMANENT TREATMENT DISCONTINUATION WITH INVESTIGATIONAL PRODUCT(S)

Permanent treatment discontinuation is any treatment discontinuation associated with the definitive decision from the Investigator or the patient not to re-expose the patient to the investigational product at any time. 11.2.1 List of criteria for definitive treatment discontinuation

The patients may withdraw from treatment with investigational product if they decide to do so, at any time and irrespective of the reason, or this may be the Investigator’s decision. All efforts should be made to document the reasons for treatment discontinuation, and this should be documented in the e-CRF. Patients must be withdrawn from the study (ie, from any further investigational product or study procedure) for the following reasons: •

At their own request or at the request of their legally authorized representative (Legally authorized representative means an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective patient to the patient’s participation in the procedure(s) involved in the research).


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•

If, in the Investigator’s opinion, continuation in the study would be detrimental to the patient’s well-being

•

At the specific request of the Sponsor

•

In the event of a protocol deviation, at the discretion of the Investigator or the Sponsor

•

Pregnancy

•

Asthma exacerbation: Patients will be instructed to contact the Investigator if a patient feels that his or her asthma is not adequately controlled (clinical exacerbation, intolerable or incapacitating symptoms, frequent nocturnal awakenings, frequent albuterol or levalbuterol use). In addition, if a patient meets the criteria for an asthma exacerbation, he/she will be withdrawn from the study and treated by the Investigator with appropriate medical therapy. Exacerbation of asthma is defined by any of the following:

•

-

A 30% or greater reduction from baseline in morning PEF on 2 consecutive days, or

-

≥6 additional reliever puffs of albuterol or levalbuterol in a 24 hour period (compared to baseline) on 2 consecutive days, or

-

Deterioration of asthma, as determined by the Investigator, requiring: - Systemic (oral and/or parenteral) steroid treatment, or - An increase in ICS ≥4 times the last dose received prior to discontinuation from the study, or - Hospitalization

Any treatment unblinding by the Investigator will lead to permanent treatment discontinuation.

11.2.2 Handling of patients after permanent treatment discontinuation

Patients will be followed up according to the study procedures as specified in this protocol up to the scheduled date of study completion, or up to recovery or stabilization of any AE to be followed-up as specified in this protocol, whichever comes last. If possible, and after the permanent discontinuation of treatment, the patients will be assessed using the procedure normally planned for the end-of-treatment visit (including a PK sample) and followed-up 8 weeks later for a safety evaluation. If treatment with disallowed medication is indicated, every attempt should be made to complete the end-of-treatment visit evaluations prior to taking disallowed medications. If however, disallowed medications are taken prior to the end-of-treatment visit then the patient must be withdrawn from the study. At the time of discontinuation, patients should be instructed to resume the ICS/LABA they were taking prior to screening. Any urgent medical care will be left to the Investigator’s discretion.


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In all cases, the reason for and date of withdrawal must be recorded in the e-CRF and in the patient’s medical records. The patient must be followed up to establish whether the reason was an AE, and, if so, this must be reported in accordance with the procedures in Section 10. As far as possible, all examinations scheduled for the final study day must be performed on all patients who receive the investigational product but do not complete the study according to protocol. The Investigator must make every effort to contact patients lost to follow-up. Attempts to contact such patients must be documented in the patient’s records (eg, times and dates of attempted telephone contact, receipt for sending a registered letter). All permanent treatment discontinuation should be recorded by the Investigator in the appropriate pages when considered as confirmed. 11.3

PROCEDURE AND CONSEQUENCE FOR PATIENT WITHDRAWAL FROM STUDY

The patients may withdraw from the study, before study completion if they decide to do so, at any time and irrespective of the reason. If possible, the patients who discontinue early will be assessed using the procedure normally planned for the end-of-treatment visit (including a PK sample), and followed-up 6 weeks and 8 weeks later for a safety evaluation. For patients who fail to return to the site, the Investigator should make the best effort to re-contact the patient (eg, contacting patient’s family or private physician, review available registries or health care database), and to determine his/her health status, including at least his/her vital status. Attempts to contact such patients must be documented in the patient’s records (eg, times and dates of attempted telephone contact, receipt for sending a registered letter). The statistical analysis plan will specify how these patients lost to follow-up for their primary endpoints will be considered. Patients who have withdrawn from the study cannot be re-randomized (treated) in the study. Their inclusion and treatment number must not be reused. Patients who withdraw from the study will not be replaced.


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12

STUDY PROCEDURES

12.1

VISIT SCHEDULE


This study consists of a screening period (Visit 1), a treatment period (Visits 2 through 14), and a post-treatment observation period (Visit 15 and Visit 16). The treatment period includes a randomization visit (Visit 2) and is divided into a background therapy stable phase (Visits 2 to 6) and a background therapy withdrawal phase (Visits 7 to 14). Prior to opening enrollment to the entire cohort of up to approximately 130 patients, a sentinel cohort consisting of approximately 20 patients (approximately 10 active and 10 placebo) will be enrolled. Data from this sentinel cohort will be evaluated by the IDMC for any safety issues. Unblinded clinical safety data through at least 4 weeks of treatment will be reviewed by the IDMC. Based on this review, a decision will be made to continue treatment beyond 4 weeks for the currently enrolled patients. Additionally, based on the IDMC’s review, a decision may be made to modify the protocol or stop the study. During this safety evaluation the sentinel cohort will continue to receive investigational product for the scheduled 12 weeks. This cohort will undergo additional PK sampling following investigational product discontinuation. 12.1.1 Screening Period: Visit 1 (Day -14 to Day -7)

At this visit the subject will be asked to sign an informed consent form in order to enter the study. The following procedures will then be performed: •

Collect demographic information (date of birth, sex, race, ethnicity)

•

Patient’s medical/surgical history (including asthma history)

•

Review inclusion and exclusion criteria

•

Reversibility test to be conducted only in patients for whom there is no documented history of reversibility meeting the entry criteria (at least 12% and 200 mL in FEV1 after 200 µg to 400 µg [2 to 4 inhalations] of albuterol) within the 12 months prior to screening and no documented history of bronchial hyperreactivity from a positive methacholine challenge (PD20 methacholine ≤ 8 mg) within the 12 months prior to screening. For patients requiring a reversibility test, 3 attempts may be made during the 14 day screening period to meet the entry criteria

•


•


•

Administer ACQ

•

Spirometry following a 6 hour withhold of asthma medication and albuterol or levalbuterol (3 attempts may be made during the 14 day screening period to meet the entrance criterion of FEV1 ≥50% predicted normal)


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•

Dispense electronic diary/PEF meter, provide instructions for daily use, and remind patient to bring the device to Visit 2

•

Dispense albuterol or levalbuterol for use as rescue medication and instruct patients to record usage in the electronic diary as needed. Instruct patients to withhold their last dose of albuterol or levalbuterol 6 hours prior to Visit 2

•

Induced sputum collection for eosinophils and neutrophils and exploratory analyses (optional for patients at particular sites)

•

Exhaled nitric oxide (to be conducted prior to spirometry and following a fast of at least 1 hour)

•

Commence AE reporting

•

Vital signs (sitting blood pressure and heart rate), height, and weight

•

12-lead ECG

•


Pregnancy test

-

Clinical laboratory testing (hematology and serum chemistry)

-

Eosinophil count (derived from clinical laboratory test). Patients whose initial screening eosinophil count is 200 to 299 cells/µL may have 1 additional screening hematology assessment to attempt to meet the minimum eosinophil criterion of 300 cells/µL. This can be performed during the current screening period if time permits or they can be screen failed and re-screened as a new patient at a later time as long as all other inclusion/exclusion can still be met and blood eosinophils in the range 200 to 299 cells/µL were only drawn once)

-

Serum samples for total IgE, TARC, YKL-40, TSLP, CEA, and Phadiatop (antigenspecific IgE) analysis

-

Plasma sample for eotaxin-3

-


-


•

Instruct patients to continue dosing with ICS/LABA combination therapy (fluticasone/salmeterol, budesonide/formoterol, or mometasone/formoterol) through the screening period

•

Remind patients to withhold dosing the morning of Visit 2

•


12.1.2 Treatment period: Background therapy stable phase (Day 1 to Week 4 [Visits 2 to 6]) 12.1.2.1 Randomization: Visit 2 (Day 1)

•



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•

Spirometry following a 6 hour withhold of asthma medication and albuterol or levalbuterol. Patients must meet the entrance criterion of FEV1 ≥50% predicted normal on randomization day. If criterion is not met, then patient will not be randomized on that day. He/she may return on a subsequent day to attempt to meet FEV1 criterion (3 attempts maximum).

•

Randomization via IVRS/IWRS

•


•

Administer SNOT-22 questionnaire

•

AE reporting

•

Vital signs (sitting blood pressure and heart rate) and weight

•


•



-


-

Serum samples for total IgE, TARC, YKL-40, and TSLP, and CEA analysis

-


-


-


-

Optional pharmacogenomic sample (requires additional informed consent)

•


•

Instruct patients to continue dosing ICS/LABA combination therapy as follows: -

Patients who entered the study on budesonide/formoterol or mometasone/formoterol will be switched to an equivalent dose of fluticasone/salmeterol

-

Patients who entered the study on fluticasone/salmeterol will remain on their current treatment

Remind patients to withhold dosing with ICS/LABA the morning of Visit 3 •


12.1.2.2 Visit 3 (Week 1 +/- 2 days)

•


•

Administer ACQ

•

Spirometry following a 6 hour withhold of asthma medication and albuterol or levalbuterol

•


•

AE reporting


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•




-

Serum samples for total IgE, TARC, YKL-40, TSLP, and CEA analysis

-


-


-


•


•


•


12.1.2.3 Visit 4 (Week 2 +/- 2 days)

•


•

Administer ACQ

•


•


•

AE reporting

•


•

12-lead ECG

•



•


•


•


12.1.2.4 Visit 5 (Week 3 +/- 2 days)

•


•

Administer ACQ

•


•


•

AE reporting

•



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•


•


12.1.2.5 Visit 6 (Week 4 +/- 2 days)

•


•

Administer ACQ

•


•


•


•


•

AE reporting

•


•


Eosinophils

-


-


-


-


-


•


•

Instruct patients to discontinue their fluticasone/salmeterol combination therapy and switch them to the equivalent dose of fluticasone monotherapy(according to Section 8.2), but to withhold dosing of fluticasone monotherapy the morning of Visit 7

•


12.1.3 Treatment period: Background therapy withdrawal phase (Visits 7 to 14) 12.1.3.1 Visit 7 (Week 5 +/- 2 days)

•


•

Administer ACQ

•



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•


•

AE reporting

•


•

Instruct patients to continue dosing with current dose of fluticasone monotherapy, but to withhold dosing the morning of Visit 8

•


12.1.3.2 Visit 8 (Week 6 +/- 2 days)

•


•

Administer ACQ

•


•


•


•

AE reporting

•


•

12-lead ECG

•


•



-


-


•


•


•


12.1.3.3 Visit 9 (Week 7 +/- 2 days)

•


•

Administer ACQ

•


•


•



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•

AE reporting

•


•


•


12.1.3.4 Visit 10 (Week 8 +/- 2 days)

•


•

Administer ACQ

•


•


•


•

Induced sputum collection for eosinophils and neutrophils and exploratory analyses (optional for at particular sites)

•


•

AE reporting

•


•


Eosinophils

-


-


-


-


-


•


•


•


12.1.3.5 Visit 11 (Week 9 +/- 2 days)

•


•

Administer ACQ

•



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•


•


•

AE reporting

•


•


12.1.3.6 Visit 12 (Week 10 +/- 2 days)

•


•

Administer ACQ

•


•


•

AE reporting

•


•



-


•


•


12.1.3.7 Visit 13 (Week 11 +/- 2 days)

•


•

Administer ACQ

•


•


•

AE reporting

•



•


•


Additional visits for the sentinel cohort of approximately 20 patients: Following the final dose of investigational product on Day 78 the sentinel cohort will return to the study site on Days 82, 92, 99, 106, and 113 for PK sampling. Property of the sanofi-aventis group - strictly confidential

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12.1.3.8 Visit 14 (Week 12 +/- 2 days) End of treatment visit

•


•


•

Administer ACQ

•


•

Download and review data from electronic diary/PEF meter and collect the electronic diary/PEF meter from the patient

•


•


•

Administer SNOT-22 questionnaire

•

AE reporting

•


•

12-lead ECG

•


•


Clinical laboratory test (hematology and serum chemistry)

-


-


-

Serum samples for total IgE, TARC, YKL-40, TSLP, CEA, and Phadiatop (antigenspecific IgE) analysis

-


-


•

Instruct patient to discontinue fluticasone monotherapy and resume pre-study dose of fluticasone/salmeterol combination therapy, budesonide/formoterol combination therapy, or mometasone/formoterol combination therapy, but to withhold dosing the morning of Visit 15

•

Remind patient to return to the clinic for final safety evaluation on Visit 15 and remind patients that they will be contacted by telephone at 1 week , 2 weeks, and 4 weeks after this visit to assess adverse events

12.1.4 Post-treatment period

Prior to the Visit scheduled for Week 18, contact the patient by telephone on Weeks 13, 14, and 16 (1, 2, and 4 weeks after the end-of-treatment assessment) to evaluate AEs Property of the sanofi-aventis group - strictly confidential

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12.1.4.1 Visit 15 (Week 18 +/- 2 days)

•


•


•

AE reporting

•


•



-


12.1.4.2 Visit 16 (Week 20 +/- 2 days)

•


•

AE reporting

•


•



-


12.1.5 All visits

The Investigator will make every attempt to assure maintenance of asthma control for each patient during this study. If a patient shows deterioration in asthma control during the treatment period, albuterol or levalbuterol should be utilized as a rescue medication to control asthma symptoms. In case of clinical exacerbation of asthma where the Investigator considers that the patient’s asthma is deteriorating and requires treatment with a medication disallowed in the current study, the patient must be withdrawn from the study. 12.2

DEFINITION OF SOURCE DATA

Source data is all information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents. Source documents are original documents, data and records such as hospital records, clinic and office charts, laboratory notes, memoranda, pharmacy dispensing records, recorded data from automated instruments, etc. All the data collected in the e-CRF should be transcribed directly from source documents. Data downloaded from the patients’ electronic diaries/PEF meters will be considered source data. Property of the sanofi-aventis group - strictly confidential

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13


13.1


The sample size calculations are based on the Phase 2 study results for inhaled pitrakinra (IL-4R mutein), where an absolute reduction in the proportion of patients with an asthma exacerbation of 37% (treatment rate of 13% versus placebo rate of 50%) was observed for this patient population. This study is designed to detect an absolute difference of 30% between treatment groups. To detect such a difference with 80% power (α=0.05, two-tailed test), 44 patients are required per treatment group (Fisher’s exact test). Accounting for an anticipated 10% dropout rate during the study, approximately 50 patients are required to be enrolled into each treatment group. The sample size for the protocol originally was to achieve 80% power to detect an absolute difference of 30% or a relative reduction of 60% assuming the placebo rate of exacerbations of 50%. It was expected that the overall rate of asthma exacerbations would be around 35% (assuming placebo rate of 50% and a SAR rate of 20%). However, the observed rate of asthma exacerbations based on a blinded review of the entire study population as of March 2012 is around 28%. In order to maintain a statistical power of 80% to detect a relative reduction of 60% difference as described above, a possible increase of sample size from 100 to up to approximately 130 (an increase of up to 15 patients for a possible total of 65 patients per treatment group) may be implemented. With 65 patients per treatment group, the study will have 80% power (2-sided alpha=0.05) to detect a relative reduction of 60%, assuming that the placebo rate of exacerbations is around 40%, i.e. placebo rate of 40% vs. a SAR rate of 16% with an overall exacerbation rate of 28%. 13.2

ANALYSIS ENDPOINTS




•


•


•


•

Height (cm)

•

Body weight (kg)

•



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•


•


•


•


•

The baseline efficacy data of FEV1 (including pre-dose FEV1, pre-dose FEV1 percent predicted, and FEV1 reversibility), PEF, and ACQ will be summarized. The baseline AM and PM PEF will be the mean AM measurements and mean PM measurements, respectively, recorded during the 7 days prior to the first dose. A minimum of 4 AM and 4 PM PEF measurements must be included in the means.



A 30% or greater reduction from baseline in morning peak expiratory flow (PEF) on 2 consecutive days, or

•


•



-


-

Hospitalization

13.2.2.2 Secondary efficacy endpoint(s)



•

Proportion of patients with a composite asthma event defined by a 30% or greater reduction from baseline in morning PEF on 2 consecutive days together with ≥6 additional reliever puffs of albuterol or levalbuterol in a 24 hour period (compared to baseline) on 2 consecutive days, or

•


•


•



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•

SNOT-22 score change from baseline at Week 12

•


•


13.2.3 Safety endpoints

Safety will be assessed by the review of summaries of all safety variables including AEs, laboratory findings, vital signs, ECGs, and physical examinations. 13.2.3.1 Adverse events

An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. 13.2.3.2 Deaths

Deaths are categorized per the following observation periods: •

Death on-study: deaths occurring after the start of treatment up to the end of the study (defined as last protocol planned visit [post-treatment safety follow-up visit] or the resolution/stabilization of all SAE)

•

Death on-treatment: deaths occurring during the treatment period

•

Death post-study: deaths occurring after the end of study

13.2.3.3 Laboratory safety variables

The clinical laboratory data consist of blood analysis (including hematology and clinical chemistry). Blood samples will be collected at screening (Visit 1) and at Week 2 (Visit 4), Week 6 (Visit 8), and Week 12 (Visit 14). Clinical laboratory values will be analyzed after conversion into standard international units. International units will be used in all listings and tables. 13.2.3.4 Vital signs

Vital sign parameters, including sitting blood pressure (mmHg) and heart rate (bpm), and body weight data will be collected at screening (Visit 1) and on Day 1 (Visit 2), Week 2 (Visit 4), Week 4 (Visit 6), Week 6 (Visit 8), Week 8 (Visit 10), Week 10 (Visit 12), Week 12 (Visit 14), Week 18 (Visit 15) and Week 20 (Visit 16).


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13.2.3.5 ECG variables

A standard 12-lead ECG will be performed at screening (Visit 1), and at Week 2 (Visit 4), Week 6 (Visit 8), and Week 12 (Visit 14). A minimum of 3 complexes in an appropriate lead (lead II) will be averaged to determine the PR-interval, QT/QTc-interval, QRS-complex and heart rate will be measured for each ECG. 13.2.3.6 Physical examination

Physical examination will be performed at the screening visit and at the end-of-treatment visit. 13.2.4 Pharmacokinetic variables

Serum SAR231893/REGN668 concentrations will be measured in all patients on Day 1 (Visit 2), Week 1 (Visit 3), Week 4 (Visit 6), Week 6 (Visit 8), Week 8 (Visit 10), Week 10 (Visit 12), Week 11 (Visit 13), Week 12 (Visit 14), Week 18 (Visit 15), and Week 20 (Visit 16) and as soon as possible in the event of early treatment discontinuation. For the lead-in cohort of approximately 20 patients, additional blood samples will be collected after the final dose on Days 82, 92, 99, 106 and 113. Serum PK parameters (Cmax, tmax, AUC0-τ, t1/2z, if feasible) in the lead-in cohort of approximately 20 will be assessed as well as the extent of accumulation in all evaluable PK patients, if feasible. 13.2.5 Pharmacodynamic/genomics variables

•

Total IgE, antigen-specific IgE (Phadiatop), eotaxin-3, YKL-40, TARC, TLSP, and CEA

•

Serum samples for exploratory protein analysis

•

RNA (whole blood) samples

•

Pharmacogenomics (DNA) sample (optional – additional informed consent required)

•

Induced sputum for eosinophils and neutrophils and exploratory analyses (optional for patients at particular sites)

•

Exhaled nitric oxide

•

Blood eosinophil count

13.3

DISPOSITION OF PATIENTS

Screened patients are defined as any patient who met the inclusion criteria and signed the informed consent. Randomized patients consist of all screened patients with a treatment kit number allocated and recorded in the IVRS/IWRS database, regardless of whether the treatment kit was used or not. Patients treated without being randomized will not be considered as randomized and will not be included in any efficacy population. Property of the sanofi-aventis group - strictly confidential

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For any patient randomized more than once, only the data associated with the first randomization will be used in any analysis population. The safety experience associated with any later randomization will be assessed separately. The safety experience of patients treated and not randomized will be reported separately, and these patients will not be in the safety population. 13.4

ANALYSIS POPULATIONS

13.4.1 Efficacy populations

The primary efficacy analysis population for all efficacy variables will be the modified intent-totreat (mITT) population. This will include all randomized patients who receive at least one dose of investigational product. All efficacy analyses using the mITT population will be performed as randomized. 13.4.2 Safety population

The safety for all treated population is comprised of all randomized patients who take at least one dose of investigational product. The safety analyses using the safety population will be analyzed as treated, that is, in the event a patient received treatment that differed from what he/she was randomized to, this patient will be classified under the actual treatment (as-treated) received, rather than his/her randomized treatment for the purposes of safety analyses and safety data presentation. Analyses of all PK variables will be also performed as treated using the safety population. In addition: •

Non-randomized but treated patients will not be part of the safety population, but their safety data will be presented separately.

•

Randomized patients for whom it is unclear whether they took the study medication will be included in the safety population as randomized.

13.5

STATISTICAL METHODS


All baseline measurements are to be collected prior to the first dose of investigational product. Measurements that were obtained after the first dose of investigational product are considered post-randomization values. If no measurement of a variable is obtained before the first dose of investigational product then the variable has missing , value. Parameters will be summarized on the all randomized population, analyzed in the treatment group to which they were randomized. Analyses for the safety population will be included in the Property of the sanofi-aventis group - strictly confidential

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appendices if the size of the safety population is different (>10%) from the size of that in the primary analysis population for any treatment group. Baseline values for the following efficacy endpoints will be calculated by taking the mean of the last 7 days (measurements) prior to randomization: AM and PM PEF, AM and PM symptom scores and nocturnal awakenings. 13.5.2 Prior or concomitant medications

The prior and concomitant medications will be presented on the randomized population. Medications will be summarized by treatment group according to the World Health Organization Drug Dictionary, considering the first digit of the Anatomic Therapeutic Chemical Classification (ATC) class (anatomic category) and the first three digits of the ATC class (therapeutic category). All ATC codes corresponding to a medication will be summarized, patients will be counted once in each ATC categories (anatomic or therapeutic) linked to the medication, therefore patients may be counted several time for the same medication. 13.5.3 Extent of study treatment exposure and compliance

The extent of study treatment exposure will be assessed and summarized by actual treatment received within the safety population. 13.5.3.1 Extent of investigational product exposure

Duration of investigational product exposure is defined as: last dose date – first dose date + 1 day, regardless of unplanned intermittent discontinuations. 13.5.3.2 Compliance

A given administration will be considered as non compliant if the patient did not take the planned dose of treatment as required by the protocol. No imputation will be made for patients with missing or incomplete data. Treatment compliance, above-planned and under-planned dosing percentages will be summarized descriptively (N, Mean, standard deviation [SD], Median, Min, and Max). The percentage of patients with compliance < 80% will be summarized. 13.5.4 Analyses of efficacy endpoints 13.5.4.1 Analysis of primary efficacy endpoint

For the primary analysis of proportion of patients experiencing an asthma exacerbation, a logistic regression model will be used to compare SAR231893/REGN668 group with placebo. The model will include terms for treatment, stratification factor (prior ICS/LABA combination therapy dose), and investigative center. Property of the sanofi-aventis group - strictly confidential

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A stratified chi-square test will also be used to corroborate the primary analysis. 13.5.4.2 Analyses of secondary efficacy endpoints

The proportion of patients with a composite asthma event as defined in Section 13.2.2.2 will be analyzed in a manner similar to the primary endpoint. Time to asthma exacerbation will be compared between treatment groups using a log-rank test. The survival curves will be estimated using Kaplan-Meier estimates and the hazard ratio (and 95%confidence interval) will be provided using a Cox proportional hazards model. The secondary endpoints of FEV1 change from baseline, change from baseline in AM and PM PEF, change from baseline in ACQ score, change from baseline in SNOT-22 score, change from baseline in AM and PM symptom scores, daily albuterol or levalbuterol use, and nocturnal awakenings will be analyzed using an analysis of covariance model including factors for treatment and investigative center. 13.5.4.3 Multiplicity Considerations

There is only one primary endpoint with only one primary analysis. As a result, no adjustment for multiplicity is necessary. Furthermore, all secondary endpoints are considered hypothesisgenerating and will be tested at 2-sided α=0.05 level after the primary endpoint has been analyzed. 13.5.5 Analyses of safety data 13.5.5.1 Analysis of adverse events

All AEs are to be coded to a “Preferred Term” (PT) and associated “High Level Group Term” (HLGT), “High Level Term” (HLT), and primary “System Organ Class” (SOC) using the version of MedDRA (Medical Dictionary for Regulatory Activities) currently in use at sanofi-aventis at the time of database lock before the randomization treatment code is broken. Adverse events will be summarized into 3 segments according to the time of occurrence: pre-treatment, on-treatment and post-treatment, and be reported using classification by SOC and/or MedDRA term. The pretreatment/screening period is defined as the time between when the patients sign the informed consent form and the start of investigational product. The treatment period is defined as the time from first dose of investigational product up to the end of the follow-up period (ie, up to 7 weeks after the last dose of investigational product). The post-treatment period is defined as the time starting after the end of the follow-up visit. Pre-treatment AEs are defined as AEs that develop, worsen, or become serious during the pretreatment period. If the start date of an AE is undetermined due to incomplete or missing values and if the end date is prior to the date of first dose of double-blind study medication, the AE will be evaluated as pre-treatment. Treatment-emergent AEs (TEAEs) are defined as AEs that develop, worsen, or become serious during the treatment period. If the timing of an AE cannot be identified because of missing data,


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the AE will be considered as a TEAE. Details on handling missing data and partial dates will be provided in Statistical Analysis Plan (SAP). Post-treatment AEs are defined as AEs that develop, worsen, or become serious after the end of the follow-up visit. The focus of AE reporting will be on TEAEs. Details of the presentation of frequency distributions of TEAEs will be provided in the SAP. Adverse event incidence tables will present by SOC (sorted by internationally agreed order), HLGT, HLT, and PT sorted in alphabetical order for each treatment group, the number (n) and percentage (%) of patients experiencing an AE. Multiple occurrences of the same event in the same patient will be counted only once in the tables within a treatment phase. The denominator for computation of percentages is the safety population within each treatment group. Deaths: The following deaths summaries will be generated: •

Number (%) of patients who died by study period (TEAE, on-study) and reasons for death if collected in death report form summarized on the safety population by treatment received

•

Death in non-randomized patients or randomized and not treated patients

•

All AEs leading to death (death as an outcome on the AE e-CRF page as reported by the Investigator), by primary SOC, HLGT, HLT and PT, showing number (%) of patients sorted by internationally agreed order of SOC and alphabetic order of HLGT, HLT, and PT

•

TEAE leading to death (death as an outcome on the AE e-CRF page as reported by the Investigator) by primary SOC , HLGT, HLT and PT showing number (%) of patients sorted by internationally agreed order of SOC and alphabetic order of HLGT, HLT, and PT.

13.5.5.2 Analysis of laboratory variables

The following approaches will be used to summarize laboratory data for the safety population: •

Summary statistics (number of subjects, mean, SD, median, minimum, maximum) of values at baseline (screening, Visit 1) and Week 2 (Visit 4), Week 6 (Visit 8), and Week 12 (Visit 14) or end-of-treatment visit, and of changes from baseline to each visit. Analyses of change from baseline to end of study will be conducted using the KruskalWallis test.

•

Number and frequency of subjects with low, normal or high values, with respect to the normal range for baseline and clinic visits (shift tables)

•

Number and frequency of subjects with predefined Potentially Clinically Significant Abnormality (PCSA). PCSA values are defined as abnormal values considered medically important by the Sponsor according to predefined criteria/thresholds based on literature review and defined by the Sponsor for clinical laboratory tests.


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The following definitions will be applied to laboratory parameters, vital signs, and ECG. •

The PCSA values are defined as abnormal values considered medically important by the Sponsor according to predefined criteria/thresholds based on literature review and defined by the Sponsor for clinical laboratory tests, vital signs and ECG.

•

PCSA criteria will determine which patients had at least one PCSA during the ontreatment period, taking into account all evaluations performed during the on-treatment period, including non-scheduled or repeated evaluations. The number of all such patients will be the numerator for the on-treatment PCSA percentage.

Details on handling missing data, data abnormalities, re-tests, and unscheduled visits, will be provided in the SAP. 13.5.5.3 Analysis of vital signs variables

Vital signs and weight data for the safety population will be summarized using primarily descriptive statistics (number of patients, mean, SD, SE, median, minimum, maximum) by treatment group for each visit or study assessment (baseline, each post baseline time point, and endpoint). Analyses of change from baseline to end of study will be conducted using the KruskalWallis test. 13.5.5.4 Analysis of other safety variables

Findings for physical examination data will be summarized. Shifts from normal to abnormal and vice versa will be presented in addition to summary statistics with patient count and percentage for each treatment group for physical examinations done at screening and end-of-treatment. 13.5.6 Analyses of pharmacokinetic and pharmacodynamic variables 13.5.6.1 Pharmacokinetic parameters

Serum concentrations of SAR231893/REGN688 and its PK parameters (Cmax, tmax, AUC0-τ, t1/2z, if feasible) will be summarized using arithmetic and geometric means, SD, standard error of the mean (SEM), coefficient of variation, minimum, median and maximum per sampling time. The trough serum concentrations will be further examined in an exploratory manner to see if the steady state condition has been established and to assess the extent of accumulation, if feasible. 13.5.6.2 Pharmacokinetic/Pharmacodynamic parameters

The relationship between efficacy, safety variables or other exploratory parameters and SAR231893/REGN668 serum concentrations may be explored using graphical and regression methods, if applicable.


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13.5.7 Immunogenicity

Anti-SAR231893/REGN668 antibody assay results will be described categorically as negative (if below the assay cut-point or not drug specific) and positive (if drug specific signal is above the assay cut-point) by visit. 13.6


For the primary efficacy endpoint, if a patient withdraws from treatment prior to the Background Therapy Withdrawal Phase (Week 5), the patient will be considered missing for the primary endpoint. After Week 5, if the patient withdraws from treatment, the patient will be included in the analysis of the primary efficacy endpoint if the patient withdraws due to an asthma exacerbation but will be excluded from analysis if the patient withdraws for reasons not related to study or treatment. Details on handling of missing data will be provided in the Statistical Analysis Plan. 13.7

INTERIM ANALYSIS

The IDMC will evaluate the unblinded clinical safety data of a sentinel cohort consisting of approximately 20 patients (approximately 10 active and 10 placebo) through at least 4 weeks of treatment for any safety issues. A group external to the study Sponsor will prepare the analyses for the IDMC and the study team will remain completely blinded to the unblinded results. Based on this IDMC safety review, the IDMC may recommend to continue treatment beyond 4 weeks for the currently enrolled patients and continue to enroll the remaining patients in the study as planned. Conversely, based on this safety review, the IDMC may recommend to modify the protocol or to terminate the study. There will be periodic safety reviews at approximately equal intervals of information (ie, number of patients enrolled) in the study. An early analysis of efficacy is planned when approximately 66 patients complete 12 weeks of treatment (Visit 14). This early analysis of efficacy is only for the purpose of an early administrative look to help prepare for further development of the compound. There is no intention on the part of the sponsor to terminate the study or modify the protocol based on this early administrative look. However, since an interim analysis of efficacy will be performed, it is planned to use a Haybittle-Peto type alpha-spending function that will have a nominal significance level of 0.0005 at the interim analysis.(14, 15) This approach will provide for a 2side significance level of 0.0500 for the final analysis with all patients. The consulting group external to the study Sponsor preparing the safety results for the IDMC will be utilized to perform this unblinded early efficacy analysis in order to keep the study team blinded. Only summary results will be presented to a limited team of Sponsor personnel, and all Sponsor personnel and the study team will remain blinded to the treatment assignment of individual patients.


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13.8


DATABASE LOCK



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14

ETHICAL AND REGULATORY STANDARDS

14.1

ETHICAL PRINCIPLES

This Clinical Trial will be conducted in accordance with the principles laid down by the 18th World Medical Assembly (Helsinki, 1964) and all applicable amendments laid down by the World Medical Assemblies, and the International Conference on Harmonization (ICH) guidelines for Good Clinical Practice. In compliance with sanofi-aventis public disclosure commitments, this clinical trial will be recorded in the public registry website clinicaltrials.gov before the enrollment of the first patient. The registry will contain basic information about the trial sufficient to inform interested patients (and their healthcare practitioners) how to enroll in the trial. 14.2

LAWS AND REGULATIONS

This Clinical Trial will be conducted in compliance with all international guidelines, and national laws and regulations of the country(ies) in which the Clinical Trial is performed, as well as any applicable guidelines (see Section 15.1). 14.3

INFORMED CONSENT

The Investigator (according to applicable regulatory requirements), or a person designated by the Investigator, and under the Investigator's responsibility, should fully inform the patient of all pertinent aspects of the Clinical Trial including the written information giving approval/favorable opinion by the Ethics Committee (Institutional Review Board/Independent Ethics Committee [IRB/IEC]). All participants should be informed to the fullest extent possible about the study, in language and terms they are able to understand. Prior to a patient’s participation in the Clinical Trial, the written Informed Consent Form should be signed, name filled in and personally dated by the patient or by the patient’s legally acceptable representative, and by the person who conducted the informed consent discussion. A copy of the signed and dated written Informed Consent Form will be provided to the patient. The Informed Consent Form used by the Investigator for obtaining the patient's informed consent must be reviewed and approved by the Sponsor prior to submission to the appropriate Ethics Committee (IRB/IEC) for approval/favorable opinion. DNA and RNA sequence analysis is proposed as part of a pharmacogenomic substudy to the main clinical study. For patients wishing to participate in this substudy, a specific Pharmacogenomics Informed Consent Form must be signed, name filled and personally dated by the patient and by the person who conducted the consent discussion prior to DNA sample collection. There is no obligation for a patient who agrees to participate in the main clinical trial to participate in the Property of the sanofi-aventis group - strictly confidential

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pharmacogenomic substudy. This information will be clearly specified in the written informed consent form. A copy of the signed and dated written informed consent form will be provided to the patient. 14.4

INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC)

As required by local regulation, the Investigator or the Sponsor must submit this Clinical Trial Protocol to the appropriate Ethics Committee (IRB/IEC), and is required to forward to the respective other party a copy of the written and dated approval/favorable opinion signed by the Chairman with Ethics Committee (IRB/IEC) composition. The Clinical Trial (study number, Clinical Trial Protocol title and version number), the documents reviewed (Clinical Trial Protocol, Informed Consent Form, Investigator’s Brochure, Investigator’s curriculum vitae [CV], etc.) and the date of the review should be clearly stated on the written (IRB/IEC) approval/favorable opinion. Investigational product will not be released at the study site and the Investigator will not start the study before the written and dated approval/favorable opinion is received by the Investigator and the Sponsor. During the Clinical Trial, any amendment or modification to the Clinical Trial Protocol should be submitted to the Ethics Committee (IRB/IEC) before implementation, unless the change is necessary to eliminate an immediate hazard to the patients, in which case the IRB/IEC should be informed as soon as possible. It should also be informed of any event likely to affect the safety of patients or the continued conduct of the Clinical Trial, in particular any change in safety. All updates to the Investigator’s Brochure will be sent to the Ethics Committee (IRB/IEC). A progress report is sent to the Ethics Committee (IRB/IEC) at least annually and a summary of the Clinical Trial’s outcome at the end of the Clinical Trial.


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15

STUDY MONITORING

15.1

RESPONSIBILITIES OF THE INVESTIGATOR(S)

The Investigator(s) and delegated Investigator staff undertake(s) to perform the Clinical Trial in accordance with this Clinical Trial Protocol, International Conference on Harmonization (ICH) guidelines for Good Clinical Practice and the applicable regulatory requirements. The Investigator is required to ensure compliance with all procedures required by the Clinical Trial Protocol and with all study procedures provided by the Sponsor (including security rules). The Investigator agrees to provide reliable data and all information requested by the Clinical Trial Protocol (with the help of the e-CRF, Discrepancy Resolution Form or other appropriate instrument) in an accurate and legible manner according to the instructions provided and to ensure direct access to source documents by Sponsor representatives. If any circuit includes transfer of data particular attention should be paid to the confidentiality of the patient's data to be transferred. The Investigator may appoint such other individuals as he/she may deem appropriate as SubInvestigators to assist in the conduct of the Clinical Trial in accordance with the Clinical Trial Protocol. All Sub-Investigators shall be appointed and listed in a timely manner. The SubInvestigators will be supervised by and work under the responsibility of the Investigator. The Investigator will provide them with a copy of the Clinical Trial Protocol and all necessary information. 15.2

RESPONSIBILITIES OF THE SPONSOR

The Sponsor of this Clinical Trial is responsible to Health Authorities for taking all reasonable steps to ensure the proper conduct of the Clinical Trial Protocol as regards ethics, Clinical Trial Protocol compliance, and integrity and validity of the data recorded on the e-CRFs. Thus, the main duty of the Monitoring Team is to help the Investigator and the Sponsor maintain a high level of ethical, scientific, technical and regulatory quality in all aspects of the Clinical Trial. At regular intervals during the Clinical Trial, the site will be contacted, through monitoring visits, letters or telephone calls, by a representative of the Monitoring Team to review study progress, Investigator and patient compliance with Clinical Trial Protocol requirements and any emergent problems. These monitoring visits, will include but not be limited to review of the following aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and reporting, AESI documentation and reporting, AE documentation, investigational product allocation, patient compliance with the investigational product regimen, investigational product accountability, concomitant therapy use and quality of data.


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15.3


SOURCE DOCUMENT REQUIREMENTS

According to the ICH guidelines for Good Clinical Practice, the Monitoring Team must check the e-CRF entries against the source documents, except for the pre-identified source data directly recorded in the e-CRF. The Informed Consent Form will include a statement by which the patient allows the Sponsor’s duly authorized personnel, the Ethics Committee (IRB/IEC), and the regulatory authorities to have direct access to original medical records which support the data on the e-CRFs (eg, patient's medical file, appointment books, original laboratory records, etc). These personnel, bound by professional secrecy, must maintain the confidentiality of all personal identity or personal medical information (according to confidentiality and personal data protection rules). 15.4

USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL REQUEST

It is the responsibility of the Investigator to maintain adequate and accurate e-CRFs (according to the technology used) designed by the Sponsor to record (according to Sponsor instructions) all observations and other data pertinent to the clinical investigation in a timely manner. All e-CRFs should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of data. Should a correction be made, the corrected information will be entered in the e-CRF overwriting the initial information. An audit trail allows identifying the modification. Data are available within the system to the Sponsor as soon as they are entered in the e-CRF. The computerized handling of the data by the Sponsor when available in the e-CRF may generate additional requests (DRF) to which the Investigator is obliged to respond by confirming or modifying the data questioned. The requests with their responses will be managed through the eCRF. 15.5

USE OF COMPUTERIZED SYSTEMS

Computerized systems will be used to create, modify, maintain, archive, retrieve or transmit data. Computerized systems used during the different steps of the study are: • For screening and randomization activities, IVRS/IWRS • For data management activities, Oracle RDC • For pharmacokinetic activities, WinNonlin® • For statistical activities, SAS • For pharmacovigilance activities, AWARE • For investigational product ordering/tracking, SmartSupplies PMD • For monitoring activities, IMPACT, SmartSupplies RAR • For medical writing activities, DOMASYS


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16

ADMINISTRATIVE RULES

16.1

CURRICULUM VITAE


A current copy of the curriculum vitae describing the experience, qualification and training of each Investigator and Sub-Investigator will be signed, dated and provided to the Sponsor prior to the beginning of the Clinical Trial. 16.2

RECORD RETENTION IN STUDY SITES (S)

The Investigator must maintain confidential all study documentation, and take measures to prevent accidental or premature destruction of these documents. The Investigator should retain the study documents at least fifteen (15) years after the completion or discontinuation of the Clinical Trial. However, applicable regulatory requirements should be taken into account in the event that a longer period is required. The Investigator must notify the Sponsor prior to destroying any study essential documents following the Clinical Trial completion or discontinuation. If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, the Investigator shall inform the Sponsor and the relevant records shall be transferred to a mutually agreed upon designee.


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17


CONFIDENTIALITY

All information disclosed or provided by the Sponsor (or any company/institution acting on their behalf), or produced during the Clinical Trial, including, but not limited to, the Clinical Trial Protocol, the e-CRFs, the Investigator's Brochure and the results obtained during the course of the Clinical Trial, is confidential, prior to the publication of results. The Investigator and any person under his/her authority agree to undertake to keep confidential and not to disclose the information to any third party without the prior written approval of the Sponsor. However, the submission of this Clinical Trial Protocol and other necessary documentation to the Ethics Committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same obligation of confidentiality. The Sub-Investigators shall be bound by the same obligation as the Investigator. The Investigator shall inform the Sub-Investigators of the confidential nature of the Clinical Trial. The Investigator and the Sub-Investigators shall use the information solely for the purposes of the Clinical Trial, to the exclusion of any use for their own or for a third party's account. Furthermore, the Investigator and the Sponsor agree to adhere to the principles of personal data confidentiality in relation to the patients, Investigator and its collaborators involved in the study.


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18


PROPERTY RIGHTS

All information, documents and investigational product provided by the Sponsor or its designee are and remain the sole property of the Sponsor. The Investigator shall not mention any information or the Product in any application for a patent or for any other intellectual property rights. All the results, data, documents and inventions, which arise directly or indirectly from the Clinical Trial in any form, shall be the immediate and exclusive property of the Sponsor. The Sponsor may use or exploit all the results at its own discretion, without any limitation to its property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, develop, market or otherwise use the results of the Clinical Trial. As the case may be, the Investigator and/or the Sub-Investigators shall provide all assistance required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, including signature of legal documents.


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19


DATA PROTECTION •

The patient's personal data, which are included in the Sponsor database shall be treated in compliance with all applicable laws and regulations;

•

When archiving or processing personal data pertaining to the Investigator and/or to the patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to this data by any unauthorized third party.

•

The Sponsor also collects specific data regarding Investigator as well as personal data from any person involved in the study which may be included in the Sponsor’s databases, shall be treated by both the Sponsor and the Investigator in compliance with all applicable laws and regulations.


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20


INSURANCE COMPENSATION

The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials under its sponsorship. This insurance policy is in accordance with local laws and requirements. The insurance of the Sponsor does not relieve the Investigator and the collaborators from maintaining their own liability insurance policy. An insurance certificate will be provided to the Ethics committees/IRB or Health Authorities in countries requiring this document.


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21


SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES

For the purpose of ensuring compliance with the Clinical Trial Protocol, Good Clinical Practice and applicable regulatory requirements, the Investigator should permit auditing by or on the behalf of the Sponsor and inspection by regulatory authorities. The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study records for review, being understood that these personnel is bound by professional secrecy, and as such will not disclose any personal identity or personal medical information. The Investigator will make every effort to help with the performance of the audits and inspections, giving access to all necessary facilities, data, and documents. As soon as the Investigator is notified of a planned inspection by the authorities, he will inform the Sponsor and authorize the Sponsor to participate in this inspection. The confidentiality of the data verified and the protection of the patients should be respected during these inspections. Any result and information arising from the inspections by the regulatory authorities will be immediately communicated by the Investigator to the Sponsor. The Investigator shall take appropriate measures required by the Sponsor to take corrective actions for all problems found during the audit or inspections.


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22

PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF A SITE

22.1

DECIDED BY THE SPONSOR IN THE FOLLOWING CASES:

•

If the information on the product leads to doubt as to the benefit/risk ratio;

•

If the Investigator has received from the Sponsor all investigational product, means and information necessary to perform the Clinical Trial and has not included any patient after a reasonable period of time mutually agreed upon;

•

In the event of breach by the Investigator of a fundamental obligation under this agreement, including but not limited to breach of the Clinical Trial Protocol, breach of the applicable laws and regulations or breach of the ICH guidelines for Good Clinical Practice;

•

If the total number of patients are included earlier than expected;

In any case the Sponsor will notify the Investigator of its decision by written notice. 22.2

DECIDED BY THE INVESTIGATOR

The Investigator must notify (30 days' prior notice) the Sponsor of his/her decision and give the reason in writing. In all cases (decided by the Sponsor or by the Investigator), the appropriate Ethics Committee(s) (IRB/IEC) and Health Authorities should be informed according to applicable regulatory requirements.


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23


CLINICAL TRIAL RESULTS

The Sponsor will be responsible for preparing a Clinical Study Report and to provide a summary of study results to the Investigator.


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24


PUBLICATIONS AND COMMUNICATIONS

The Investigator undertakes not to make any publication or release pertaining to the Study and/or results of the Study prior to the Sponsor’s written consent, being understood that the Sponsor will not unreasonably withhold its approval. As the Study is being conducted at multiple sites, the Sponsor agrees that, consistent with scientific standards, first presentation or publication of the results of the Study shall be made only as part of a publication of the results obtained by all sites performing the Protocol. However, if no multicenter publication has occurred within 12 months of the completion of this Study at all sites, the Investigator shall have the right to publish or present independently the results of this Study to the review procedure set forth herein. The Investigator shall provide the Sponsor with a copy of any such presentation or publication derived from the Study for review and comment at least 30 days in advance of any presentation or submission for publication. In addition, if requested by the Sponsor, any presentation or submission for publication shall be delayed for a limited time, not to exceed 90 days, to allow for filing of a patent application or such other measures as the Sponsor deems appropriate to establish and preserve its proprietary rights. The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or promotional material or publication without the prior written consent of the Sponsor. The Sponsor shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional material or publication without having received his/her and/or their prior written consent(s). The Sponsor has the right at any time to publish the results of the study.


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25


CLINICAL TRIAL PROTOCOL AMENDMENTS

All appendices attached hereto and referred to herein are made part of this Clinical Trial Protocol. The Investigator should not implement any deviation from, or changes of the Clinical Trial Protocol without agreement by the Sponsor and prior review and documented approval/favorable opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to Clinical Trial Patients, or when the change(s) involves only logistical or administrative aspects of the trial. Any change agreed upon will be recorded in writing, the written amendment will be signed by the Investigator and by the Sponsor and the signed amendment will be filed with this Clinical Trial Protocol. Any amendment to the Clinical Trial Protocol requires written approval/favorable opinion by the Ethics Committee (IRB/IEC) prior to its implementation, unless there are overriding safety reasons. In some instances, an amendment may require a change to the Informed Consent Form. The Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised Informed Consent Form prior to implementation of the change and patient signature should be recollected if necessary.


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26


BIBLIOGRAPHIC REFERENCES

1. Greening AP, Wind P, Northfield M, Shaw G. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroids. Lancet 1994;344:219. 2. Woolcock A, Lundback BO, Ringdal N, Jacques LA. Comparison of addition to salmeterol to inhaled steroids with doubling of the does of inhaled steroids. Am J Respir Crit Care Med 1996;153:1481. 3. Godard P, Chanez P, Siraudin L, Nicoloyannis L, Duru G. Costs of asthma are corelated with severity: A 1 year prospaective study. Eur Respir J 2002; 19:61-67. 4. Global Initiative for Asthma (GINA). Global Stategy for Asthma management and Prevention. www.ginasthma.org 2009 5. Levine SJ Wenzel SE. Narrative review: The role of Th2 immune pathway modulation in the treatment of severe asthma and its phenotypes. Ann Intern Med. 2010;152:232-237. 6. Wenzel SE, Ind PW, Outlana BA, Bleeker ER, Kuna P, Yen YP. Inhaled pitrakinra, an IL4/IL-13 antagonist, reduced exacerbations in patients with eosinophilic asthma. Abstracts 18th ERS Annual Congress. Eur Resp J 2008;32 7. Banfield C, Vincent M, Kakkar T, Chia M, Thien F, Chiah TC, Gerson J, Wu Y. Multiple dose study of AMG 317 in adults with asthma: Pharmacokinetics and safety. J Allergy Clin Immunol. 2008; 121;S79. 8. Vincent M, Banfield C, Kakkar T, Shakib S, Schicchitano R, Chiah TC, Gerson J. Singledose, first-in-human study of AMG 317: Pharmacokinetics and safety in healthy and asthmatic adults. J Allergy Clin Immunol. 2008;121:S10. 9. Corren J, Busse, W, Meltzer EO, Mansfield L, Bensch G, Fahrenholz J, Wenzel SE, Chon Y, Dunn M, Weng HH, Lin S-L. A randomized, controlled, phase 2 study of AMG 317, an IL4R antagonist, in patients with asthma. Am J Respir Crit Care Med. 2010;181;788-796. 10. Standardization of the measurement of lung volumes. ATS/ERS Task Force: Standardization of Lung Function Testing. Edited by V. Brusasco, R. Crapo, and G. Viegi. Eur Resir J. 2005;26:511-552. 11. Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J. 1999;14:902-907. 12. Juniper EF, Svensson K, Mork AC, Stahl E. Measurement properties and interpretation of three shortened versions of the asthma control questionnaire. Respir Med. 2005;99:553-558.


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13. Hopkins C, Gillett S, Slack R, Lund VJ, Browne JP. Pshycometric validity of the 22-item Sinonasal Outcome Test. Clin Otolar. 2009;34:447-454. 14. Haybittle JL. Repeated assessments of results in clinical trials of cancer treatment. Brit J Radiol. 1971;44:793–797. 15. Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design. Brit J Cancer. 1976;34:585– 612. 16. Hankinson J et al. Spirometric reference values from a sample of the general US population. Am J Respir Crit Care Med. 1999;159:179-187


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27


APPENDICES


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Appendix A


Drugs known to prolong the QTc interval Generic Name Chloroquine Sotalol Clarithromycin Quinidine Amiodarone Ibutilide Methadone Erythromycin Erythromycin Haloperidol Halofantrine Droperidol Thioridazine Methadone Domperidone Pentamidine Disopyramide Pimozide Levomethadyl Amiodarone Pentamidine Procainamide Procainamide Cisapride Quinidine Mesoridazine Chlorpromazine Dofetilide Arsenic trioxide Bepridil Sparfloxacin


Brand Name Aralen Betapace Biaxin Cardioquin Cordarone Corvert Dolophine E.E.S. Erythrocin Haldol Halfan Inapsine Mellaril Methadose Motilium NebuPent Norpace Orap Orlaam Pacerone Pentam Procan Pronestyl Propulsid Quiniglute Serentil Thorazine Tikosyn Trisenox Vascor Zagam

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Appendix B


Electronic Peak Expiratory Flow Meter/Diary Screen Instructions

Morning Diary Screen Text Screen

Text

1

Please rate your asthma symptoms since last night. - No asthma symptoms, slept through the night - Slept well, but some complaints in the morning. No nighttime awakenings - Woke up once because of asthma (including early awakening) - Woke up several times because of asthma (including early wakening) - Bad night, awake most of the night because of asthma

2

How many puffs of albuterol did you take since last night? (label should be puffs) (range from 0 – 12)

3

How many times were you woken by your asthma symptoms, requiring the use of rescue medication? (range from 0 – 10)

4

You must perform 3 blows into the AM1+. Before each blow please press

Once done, please tap the forward arrow.

5

On your AM1+ repeatedly press

until it displays


6

Communicating with AM1+ ...

7

Unable to communicate with the AM1+. Please make sure the AM1+ is within 3 meters and displays Would you like to:


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7.1


Try again Skip communication "Warning, use this option only if you lost or damaged your AM1+ Any other reason will result in loss of valuable information from your Diary."

8

The LogPad only received %i measurement(s) from the AM1+. Please perform %j additional blow(s). Before each blow please press


9

Thank you for your measurements. Your highest value was: PEF: %s L/min

Evening Diary Screen Text Screen

Text

1

Please rate your asthma symptoms since this morning. - Very well, no asthma symptoms - One episode of wheezing, cough, or breathlessness - More than one episode of wheezing, cough, or breathlessness without interference of normal activities - Wheezing, cough, or breathlessness most of the day, which interfered to some extent with normal activities - Asthma very bad. Unable to carry out daily activities as usual

2

How many puffs of albuterol did you take since this morning? (label should be puffs) (range from 0 – 12)

3

You must perform 3 blows into the AM1+. Before each blow please press



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4


On your AM1+ repeatedly press

until it displays


5

Communicating with AM1+ ...

6

Unable to communicate with the AM1+. Please make sure the AM1+ is within 3 meters and displays Would you like to:

6.1

Try again Skip communication "Warning, use this option only if you lost or damaged your AM1+ Any other reason will result in loss of valuable information from your Diary."

7

The LogPad only received %i measurement(s) from the AM1+. Please perform %j additional blow(s). Before each blow please press


8

Thank you for your measurements. Your highest value was: PEF: %s L/min


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Appendix C


Spirometry

Equipment The same spirometer and standard spirometric techniques including calibration will be used to perform pulmonary function tests at all visits. Spirometry will meet the specifications and performance criteria recommended in the ATS/ERS Task Force: Standardization of Lung Function Testing will be used (10). Preparing the patient Spirometry, an effort-dependent test, requires careful instruction and cooperation of the patient. It is important to ensure a good seal around the mouthpiece, and ensure that the patient’s posture is correct. Explain that maximum inspiration, followed by maximum forced expiration until no more can be exhaled (or for at least 6 seconds if possible) is required. Expiration must be rapid and complete. Maximum effort must be maintained during expiration. The results of spirometry should meet the following criteria for number of trials, acceptability, and reproducibility. The acceptability criteria should be applied before reproducibility is checked. Number of trials For screening spirometry and for pre-dose measurements at Visits 2 through 14, a minimum of 3 acceptable forced vital capacity (FVC) maneuvers should be performed. If a patient is unable to perform a single acceptable maneuver after 8 attempts, testing may be discontinued. However, after additional instruction and demonstration, more maneuvers may be performed depending on the patient's clinical condition and tolerance. Acceptability An acceptable maneuver has the following characteristics: •


•


•


•



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Reproducibility The 2 largest FVC values from 3 acceptable maneuvers should not vary by more than 0.150 L, Recording of Data The highest FEV1 resulting from any of the acceptable curves are recorded. Post-Bronchodilator Spirometry Perform spirometry approximately 20-30 minutes after giving 200 µg or 400 µg of albuterol via a standard unit dose of albuterol nebulization to achieve 12% and 200ml reversibility. Each nebulizer treatment will require a set-up consisting of a compressor and single patient use attachment system including a nebulizing cup for medication, a mouthpiece and connecting tube. Apply the same performance and measurement criteria described above for post-bronchodilator spirometry. Predicted Normal NHANES predicted normal values will be used to determine FEV1 (L) predicted normal values in adolescents and adults (16).


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Appendix D



Please answer Questions 1-5. Circle the number of the response that best describes how you have been during the past week. 1. On average, during the past week, how often were you woken by your asthma during the night? 0 Never 1 Hardly ever 2 A few times 3 Several times 4 Many times 5 A great many times 6 Unable to sleep because of asthma 2. On average, during the past week, how bad were your asthma symptoms when you woke up in the morning? 0 No symptoms 1 Very mild symptoms 2 Mild symptoms 3 Moderate symptoms 4 Quite severe symptoms 5 Severe symptoms 6 Very severe symptoms 3. In general, during the past week, how limited were you in your activities because of your asthma? 0 Not limited at all 1 Very slightly limited 2 Slightly limited 3 Moderately limited 4 Very limited 5 Extremely limited 6 Totally limited 4. In general, during the past week, how much shortness of breath did you experience because of your asthma? 0 None 1 A very little 2 A little Property of the sanofi-aventis group - strictly confidential

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3 A moderate amount 4 Quite a lot 5 A great deal 6 A very great deal 5. In general, during the past week, how much of the time did you wheeze? 0 Not at all 1 Hardly any of the time 2 A little of the time 3 A moderate amount of the time 4 A lot of the time 5 Most of the time 6 All the time


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Appendix E


22-item Sinonasal Outcome Test

Below you will find a list of symptoms and social/emotional consequences of your nasal rhinosinusitis. We would like to know more about these problems and would appreciate your answering the following question to the best of your ability. There are no right or wrong answers, and only you can provide us with this information. Please rate your problems, as they have been over the past two weeks. Thank you for your participation. Do not hesitate to ask for assistance if necessary. 1: Considering how severe the problem is when you experience it and how frequently it happens, please rate each item below on how ‘bad’ it is by circling the number that corresponds with how you feel using this scale Î

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12 13. 14. 15. 16. 17. 18. 19. 10. 21. 22.

Need to blow nose Nasal blockage Sneezing Runny nose Cough Post nasal discharge Thick nasal discharge Ear fullness Dizziness Ear pain Facial pain/pressure Decreased sense of smell/taste Difficulty falling asleep Waking up at night Lack of a good night’s sleep Waking up tired Fatigue Reduced productivity Reduced concentration Frustrated/restless/ irritable Sad Embarrassed

No Very problem mild problem

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

Mild or slight problem

Moderate problem

Severe problem

Problem as bad as it can be

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4

5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5

Most 5 important items

2. Please mark the most important items affecting your health (maximum of 5 items) ___________________________________


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Appendix F


Sputum induction procedure

A subset of study sites will be selected to perform evaluations of induced sputum, and patients at these selected sites will have the option to participate in this assessment. The first sputum sample from each site will be evaluated by an independent reader to assess the quality of the sample. If the quality is inadequate, additional training will be conducted at the site prior to collecting sputum samples from subsequent patients, and the sample from the first patient will be discarded and recollected prior to randomization. The goal is for approximately 50 patients to participate in this analysis. The Test Sputum induction is a relatively non-invasive method to obtain sputum for cell or fluid phase inflammatory indices, culture or cytology. It is performed with an aerosol of normal or hypertonic saline generated by an ultrasonic nebulizer. As this aerosol is a potential bronchoconstrictive stimulus, it is made safe by pretreatment with salbutamol and inhalation in a dose response manner. Materials Needed Refrigerator for storing saline Saline solutions of 0.9%, 3%, 4% and 5% Alcohol swabs 10-ml. syringe with needle (20 gauge or yellow needle) Ultrasonic nebulizer, Universal III Spirometer Salbutamol or equivalent Stop watch or clock Sterile sputum collection jars Calculator and record sheet Equipment for cleaning apparatus (nebulizer and masks) Nose clips Glass of water Valved holding chamber (aerochamber or other spacing device) Box of tissues Protocol 1. Store saline in refrigerator at 4ºC until approximately 15 minutes before use. Once removed from the refrigerator, keep at room temperature (21 ºC) until use. Check the expiratory date on saline bottles. Saline is ordered from pharmacy. 2. Please read: Instructions to Patients about Sputum Induction to inform the patient of the purpose of the test, how it will be conducted, how to obtain sputum from the lungs and how to avoid the contamination of sputum with postnasal secretions.


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3. Measure the baseline FEV1 and SVC as per ATS guidelines. Ensure expiratory FV curves are followed by maximum inspiratory FV curves at baseline. a. If the patient has taken the following medications, omit administration of salbutamol as mentioned in #4. i. SABA within 4 hours; ii. LABA within 6 hours; or iii. FEV1 is greater than 80% and the patient is not taking inhalers. 4. In all other instances, give salbutamol 2 puffs and measure FEV1 and SVC after 10 minutes, measurements done according to ATS guidelines. Ensure expiratory FV curves are followed by maximum inspiratory FV curves post salbutamol. •

Use the best post-salbutamol FEV1 value to calculate any later falls in FEV1. % fall = (Post best-salbutamol FEV1 – Post nebulization FEV1) x 100 Post best-salbutamol FEV1

5. If the best FEV1 post-bronchodilator is less than 1.0 L proceed cautiously (See: Other considerations.) If the FEV1 is 0.8L or less, do not proceed with test. Try to obtain a spontaneous sample or ask the physician requesting the procedure whether or not to proceed carefully with it. Starting concentrations: •

If the FEV1 > 70% (regardless of reversibility)

3% hypertonic saline

•

If the FEV1 < 70%

0.9% saline

6. Place 9 c.c. of the starting saline concentration into the well of the nebulizer. Place the mouthpiece onto the nebulizer. Adjust the regulating valve to “max” and depress the activator button to begin nebulization. •

Do not use nose plugs.

•

The clock/stop watch should be started at the beginning of each inhalation period and stopped as needed. (ie, if the patient needs to stop due to cough, dyspnea, etc.)

7. Instruct the patient to breathe normally by tidal breathing while inhaling the saline mist for 7 minutes. •

Some side effects, which may occur with hypertonic saline, are gagging, sore or burning throat but these rarely interfere with the test. These are usually not bothersome. Sometimes the patient may hyperventilate.

8. After the 7 minutes, stop the nebulizer and the timer. 9. Ask the patient to first blow their nose, and then rinse their mouth with water and swallow the water. Ask the patient to try to cough sputum from the chest into a sputum container. 10. Measure the FEV1 once, record on your worksheet and calculate any % fall. Property of the sanofi-aventis group - strictly confidential

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11. If there has been 10%, see items #13 or #14

12. Repeat steps 8-12 until: •

3 - 4 nebulization’s or a total time of 21 minutes has been completed, or

•

you have obtained an adequate sample (in total about half the size of a pea),

•

the FEV1 has dropped by 20% from baseline best post-bronchodilator value.

13. If the FEV1 falls between 10-20% (from the baseline best post-bronchodilator FEV1) after any nebulization, the concentration of saline must be kept the same for any further nebulizations. Carefully monitor the patient and repeat all induction steps until the three 7-minute inhalations (total of 21 minutes) have been completed, or until the FEV1 falls by >20%. 14. If the FEV1 falls by 200 ml and by 20 % or more (from the baseline best post-bronchodilator FEV1) at any time OR if bothersome symptoms occur, discontinue all inhalations of saline and treat with 2 puffs of salbutamol. •

Sputum induction should NOT be resumed.

•

As at baseline, conduct expiratory FV curves followed by maximum inspiratory FV curves.

•

Check the FEV1 10 minutes after salbutamol and monitor this until the FEV1 has returned to within 5% of baseline.

•

If the patient has not produced any sputum, have them rest with no coughing for another 10 minutes, and then ask them to try again to produce a sample.

15. You have now completed the sputum induction. •

If no sputum is obtained, have the patient try coughing again after 10 minutes.

16. Label the sputum cup with the patient’s name, physician, date and time of collection. Place the sputum cup in a biohazard bag and deliver for processing. If there is any delay, keep the specimen in the refrigerator. Cell counts are unchanged for up to 8 hours if kept in the refrigerator. Instructions to patients about sputum induction •

You will inhale a salty mist to try to loosen up some secretions from the chest so that you can cough them into a specimen jar.

•

You will inhale the mist for up to 7 minutes each time for a total of 3-4 times (21-28 minutes total).

•

Place your lips around the mouthpiece; breathe normally through your mouth.


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•

If you experience any chest discomfort during the test please let me know and we will stop and check your breathing. You will be given a bronchodilator before starting so that this is less likely to happen.

•

If at any time you can cough up some phlegm from your chest, just come off the nebulizer and spit into the jar.

•

Be careful not to sniff back from your nose – you must cough from your chest.

•

At the end of each 7 minute period, I’ll ask you to blow your nose, take a sip of water and try to cough from your chest and spit into the jar.

Other considerations •

If the FEV1 is less than 1.0 liter from the baseline best post-salbutamol FEV1, caution must be exercised with the inhalations. Monitor the patient’s FEV1 at the 3.5 minute interval during the initial 0.9% saline nebulization.

•

If the patient wishes to cough during any of the inhalation periods, turn off the nebulizer and clock and obtain the specimen. Then continue the same nebulization and restart the clock.

•

If the patient states he does not have any secretions and sounds very dry at early inhalations, encourage a deep breath and cough but only one or two times and continue to the next inhalation so as not to tire the patient or cause throat soreness. If the patient does not cough spontaneously, you can let the patient sit for 1-2 minutes and then try to cough.

•

Remind the patient to clear secretions from the throat forward by using the muscles at the side of the throat. It is important to instruct them to deliberately not swallow the sputum.

•

Listen to the patient to ensure that the sample is truly from the lungs and not postnasal secretions.

Spontaneous sputum – obtaining a good sample 1. Blow the nose to avoid contamination of sputum with nasal secretions. 2. Rinse the mouth with water and swallow it. 3. Do not sniff back before coughing out the sputum. 4. Cough deeply to ensure that the sputum is coming from the chest. 5. Cough out the sputum into a sterile container. 6. Label the container with the patient’s name, doctor, date and collection time. Equipment Cleaning Careful cleaning and thorough drying are essential for good hygienic maintenance of this equipment. With the Universal nebulizer, care must be taken of the metal plate (transducer) in the medication well when cleaning or adding hypertonic saline. Do not immerse the nebulizer unit in any solution. After each use, remove the hard plastic mouthpiece and place in dirty core container for cleaning. Rinse the well of the nebulizer and pour a small amount of isopropyl alcohol into


Page 109



the well. Allow the alcohol to sit a few minutes, empty, air dry and then rinse with water and allow to air dry (according to manufacturers directions). Remove blue circle and baffle at top of nebulizer and rinse with water. Wipe outside of nebulizer with alcohol prep. Personal Safety When the patient is coughing, maintain a minimum of one-meter distance according to Infection Control protocol. Have the patient face straight ahead and not towards you. Clean the workspace after each patient.


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Appendix G




Page 111




Page 112





Page 113




Page 114




Page 115


Appendix H


DNA sample collection

1. PROCEDURE FOR COLLECTION, HANDLING, AND SHIPMENT OF DNA PHARMACOGENOMIC SPECIMENS •

Collection schedule: per protocol.

•

Labeling of samples -

Each sample tube should have attached to it the label provided by Covance. DNA Subject ID:XXX-001-YYY Study Number / Compound (pre-printed) Bar Code (preprinted) Accession Number (pre-printed)

•

•

Procedure -

Using a waterproof pen, write Subject ID Number on label in space provided.

-

Collect 12 mL of blood, using two 6 mL Vacutainer (Becton Dickinson; K2 EDTA with HEMOGARD Closure) tubes provided, and gently invert tube at least 8 times permitting the specimen to mix with the anticoagulant.

-

Under no circumstances should the tube be centrifuged.

-

Ensure the sample tube is clearly and appropriately labeled as described above and in detail in the Covance Laboratory Manual.

-

Immediately freeze and maintain the blood in an upright position at -20°C or colder for storage. Samples must be stored on dry ice if a freezer is not immediately available.

-

Complete the Laboratory Requisition Form (provided by Covance) for each sample.

Storage -

•

In the event of damage or loss of the provided labels, a new label should be immediately requested from Covance.

Samples must be kept at -20 ºC or colder, organized in a rack in numeric order according to the Subject ID, until ready for packaging and shipping.

Packaging and shipment -

Samples and accompanying documents should be packaged according to the detailed instructions in the Covance Laboratory Manual provided at the initiation of the study.

-

Samples must be packaged according to IATA Dangerous Goods Regulations, Packing Instructions 650, using the packing materials provided by contracted company.

-

In the event that the packaging materials or instructions are lost, please contact the study Sponsor.

-

Ship samples on dry ice to Covance as described in the Global Study Schedule, using the shipping materials provided.


Page 116


•

2.


Note: Additional detailed information can be found in the Covance Laboratory Manual, provided at the beginning of the study. This includes additional details regarding: -

Sample collection kits

-

Sample collection procedures

-

Documentation procedures

-

Packing and shipping instructions

-

Sample kit resupply

-

How to get help

SHIPMENT CONTACT NAMES AND ADDRESSES

For DNA Pharmacogenomic Samples: Use for the Americas: USA and Canada, as well as Latin America and the Islands (Dominican Republic, etc): Covance CLS Indianapolis 8211 SciCor Drive Indianapolis, IN 46214-2985 USA Tel. +1 (317) 271-1200 (local calls) Tel: +1 800-462-8885 Fax: (317) 273-4030


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Clinical Study Report SAR231893-ACT11457 -

20-Mar-2013 Version number: 1

1.1.1 Changes in the conduct of the study

The protocol was amended 5 times during the study; amendment 1 was implemented prior to enrollment of the first patient in the study. The changes introduced by amendments 2-5 are summarized below. Table - Summary of protocol amendments No.

Date

Changes

2

23 May 2011

3

12 September 2011

4

30 November 2011

5

12 April 2012

• Changed inclusion criteria: - Include only patients using high dose ICS/LABA combination therapy prior to screening; - Reduce minimum duration of stable dose ICS/LABA prior to screening from 3 months to 1 month; - Allow re-screening of patients with blood eosinophil level 250-349 cells/μL; - Allow patients to qualify with either blood eosinophils > 350 cells/μL or sputum eosinophils > 3%; - Increase maximum ACQ-5 score from 2.5 to 3.0; - Decrease minimum FEV1 from 60% PV to 50% PV; • Changed timing of switch from budesonide/formoterol to fluticasone/salmeterol as background therapy from screening visit to randomization visit. • Changed inclusion criteria: - Lower minimum blood eosinophil level from 350 cells/μL to 300 cells/μL; lower range at which rescreening is allowed from 250-349 cells/μL to 200-299 cells/μL; - Added criterion of > 1 asthma exacerbation within the 2 years prior to screening; • Changed exclusion criteria: - Reduce minimum time since prior in-patient hospitalization or emergency care visit for exacerbation from 3 months to 2 months. • Broadened primary endpoint from asthma events requiring treatment with oral corticosteroids to asthma events requiring treatment with systemic (including oral and/or parenteral) corticosteroids ; clarified primary endpoint to specify that both “> 30% reduction from baseline in morning PEF” and “≥ 6 additional reliever puffs of albuterol in a 24 hour period on 2 consecutive days” must occur on 2 consecutive days; • Added secondary endpoint to analyze “> 30% reduction from baseline in morning PEF on 2 consecutive days” and “≥ 6 additional reliever puffs of albuterol in a 24 hour period on 2 consecutive days” as individually qualifying asthma exacerbation events • At the suggestion of the independent data monitoring committee, added the following additional adverse events of special interest: anaphylactic reactions or acute allergic reactions that required immediate treatment, severe injection site reactions that lasted longer than 24 hours, and any severe infection including parasitic infection. • Changed inclusion criteria: - Increase minimum ACQ-5 score from 1.0 to ≥1.5; - Revert to include patients on medium dose (> fluticasone 250μg bid or equivalent) ICS/LABA combination therapy; - Include patients using mometasone/formoterol combination therapy prior to screening • Modified definition of primary endpoint to separate the requirement that “> 30% reduction from baseline in morning PEF on 2 consecutive days” must occur with “≥ 6 additional reliever puffs of albuterol in a 24 hour period on 2 consecutive days”, as blinded evaluation of available data revealed that no patients met the criteria when linked together; the composite endpoint was then considered a secondary endpoint; • Increased pace of background therapy withdrawal from every 2 weeks to weekly between Weeks 6-9; • Added levalbuterol HFA as permitted reliever medication. • Increased sample size from 100 patients to approximately 130 patients, as blinded evaluation of available data revealed that the rate of asthma exacerbations was lower than expected (note: the study stopped recruitment when 104 patients were randomized, as an interim analysis of asthma exacerbations showed a significant treatment group difference); • Added a post-treatment visit at Week 20 to collect PK and ADA samples at a later time-point after the final study treatment, as, based on interim data, the PK half-life was longer than anticipated.

Property of Sanofi - strictly confidential

Page 1

STATISTICAL ANALYSIS PLAN A randomized, double-blind, placebo-controlled, parallel group study to assess the efficacy, safety, and tolerability of SAR231893/REGN668 administered subcutaneously (SC) once weekly for 12 weeks in patients with persistent moderate to severe eosinophilic asthma who are partially controlled/uncontrolled by inhaled corticosteroid (ICS) plus long-acting beta2 agonist (LABA) therapy SAR231893/REGN668 ACT11457 STUDY BIOSTATISTICIAN: Lu Xu BIOSTATISTICS DPE: Sudeep Kundu DATE OF ISSUE: 13-JAN-2012

Total number of pages:

Property of the sanofi-aventis group - strictly confidential According to template: QSD-002643 VERSION 2.0 (21-OCT-2009)

62

Page 1

Statistical Analysis Plan SAR231893/ACT11457

13-Jan-2012 Version number: 1.0

TABLE OF CONTENTS TABLE OF CONTENTS..................................................................................................................................2 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..........................................................................5 1

OVERVIEW AND INVESTIGATIONAL PLAN.................................................................................6

1.1

STUDY DESIGN AND RANDOMIZATION ......................................................................................6

1.2

OBJECTIVES...................................................................................................................................7

1.2.1

Primary objectives ............................................................................................................................7

1.2.2

Secondary objectives .......................................................................................................................7

1.3

DETERMINATION OF SAMPLE SIZE.............................................................................................7

1.4

STUDY PLAN...................................................................................................................................8

1.4.1

Graphical study design.....................................................................................................................8

1.4.2

Study flowchart.................................................................................................................................9

1.5

MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL................................12

1.6

STATISTICAL MODIFICATIONS MADE IN THE SAP ..................................................................13

2

STATISTICAL AND ANALYTICAL PROCEDURES .....................................................................14

2.1

ANALYSIS ENDPOINTS................................................................................................................14

2.1.1


2.1.2 2.1.2.1 2.1.2.2 2.1.2.3 2.1.2.4

Efficacy endpoints ..........................................................................................................................14 Primary efficacy endpoint ...............................................................................................................14 Secondary efficacy endpoints ........................................................................................................15 Exploratory efficacy endpoints .......................................................................................................15 Efficacy methods............................................................................................................................16

2.1.3 2.1.3.1 2.1.3.2 2.1.3.3 2.1.3.4 2.1.3.5 2.1.3.6

Safety endpoints.............................................................................................................................18 Adverse events variables ...............................................................................................................19 Deaths ............................................................................................................................................20 Laboratory safety variables ............................................................................................................20 Vital signs variables........................................................................................................................21 ECG variables ................................................................................................................................21 Physical examination......................................................................................................................21

2.1.4


2.1.5

Pharmacodynamic/genomics endpoints ........................................................................................21

2.2


2.2.1

Randomization and drug dispensing irregularities .........................................................................23


Page 2



2.3

ANALYSIS POPULATIONS ...........................................................................................................24

2.3.1

Efficacy population .........................................................................................................................24

2.3.2

Safety population............................................................................................................................24

2.3.3

Pharmacokinetics (PK) population .................................................................................................25

2.4


2.4.1

Demographics and baseline characteristics ..................................................................................25

2.4.2


2.4.3 2.4.3.1 2.4.3.2

Extent of investigational medicinal product exposure and compliance..........................................26 Extent of investigational medicinal product exposure ....................................................................26 Compliance ....................................................................................................................................27

2.4.4 2.4.4.1 2.4.4.2 2.4.4.3

Analyses of efficacy endpoints .......................................................................................................27 Analysis of primary efficacy endpoint(s).........................................................................................27 Analyses of secondary efficacy endpoints .....................................................................................29 Multiplicity issues............................................................................................................................30

2.4.5 2.4.5.1 2.4.5.2 2.4.5.3 2.4.5.4 2.4.5.5 2.4.5.6

Analyses of safety data ..................................................................................................................30 Analyses of adverse events ...........................................................................................................31 Deaths ............................................................................................................................................33 Analyses of laboratory variables ....................................................................................................33 Analyses of vital sign variables ......................................................................................................35 Analyses of ECG variables.............................................................................................................35 Analyses of other safety endpoints ................................................................................................35

2.4.6

Analyses of pharmacokinetic and pharmacodynamic variables ....................................................35

2.4.7

Immunogenicity variables...............................................................................................................36

2.4.8

DNA/RNA .......................................................................................................................................36

2.5

DATA HANDLING CONVENTIONS...............................................................................................36

2.5.1

General conventions ......................................................................................................................36

2.5.2

Data handling conventions for secondary efficacy variables..........................................................37

2.5.3

Missing data ...................................................................................................................................37

2.5.4

Windows for time points.................................................................................................................39

2.5.5

Unscheduled visits .........................................................................................................................39

2.5.6

Pooling of centers for statistical analyses ......................................................................................39

2.5.7

Statistical technical issues .............................................................................................................39

3

INTERIM ANALYSIS .....................................................................................................................40

4

DATABASE LOCK ........................................................................................................................41

5

SOFTWARE DOCUMENTATION..................................................................................................42

6

REFERENCES...............................................................................................................................43

7

LIST OF APPENDICES .................................................................................................................44


Page 3



APPENDIX A

SUMMARY OF STATISTICAL ANALYSES ........................................................................45

APPENDIX B

SPIROMETRY.....................................................................................................................49

APPENDIX C

JUNIPER ASTHMA CONTROL QUESTIONNAIRE ...........................................................51

APPENDIX D

22-ITEM SINONASAL OUTCOME TEST ...........................................................................53

APPENDIX E GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY ABNORMALITIES BY SANOFI-AVENTIS .....................................................................................54 APPENDIX F

POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES (PCSA) CRITERIA..........59


Page 4



LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ACQ AE AESI ALT AM AST ATC ATS BID CEA CPK CRF DNA ECG e-CRF ELISA ERS FEV1 FVC GINA HIPAA HLT HLGT ICH ICS IDMC IEC IL-4 IL-4Rá IL-13 IRB IV IVRS IWRS LABA mITT MedDRA MMRM PCSA PEF PK PM ppb SC SEM ULN

Asthma control questionnaire (5-question version) Adverse event Adverse event of special interest Alanine aminotransferase Morning Aspartate aminotransferase Anatomic Therapeutic Chemical Classification American Thoracic Society Twice-daily dosing Carcinoembryonic antigen Creatine phosphokinase Case report form Deoxyribonucleic acid Electrocardiogram Electronic case report form Enzyme-linked immunosorbent assay European Respiratory Society Forced expiratory volume in one second Forced vital capacity Global Initiative for Asthma Health Insurance Portability and Accountability Act High level term High level group term International Conference on Harmonization Inhaled corticosteroid Independent Data Monitoring Committee Independent Ethics Committee Interleukin-4 Interleukin-4 receptor alpha subunit Interleukin-13 Institutional Review Board Intravenous Interactive Voice Response System Interactive Web Response System Long-acting beta2-adrenergic agonist Modified Intent to treat Medical Dictionary for Regulatory Activities Mixed model repeated measures Potentially clinically significant abnormality Peak expiratory flow Pharmacokinetic Evening Parts per billion Subcutaneous Standard error of the mean Upper limit of normal


Page 5



1

OVERVIEW AND INVESTIGATIONAL PLAN

1.1

STUDY DESIGN AND RANDOMIZATION

This randomized, double-blind, placebo-controlled, study with parallel groups includes a 2-week screening/run-in, followed by a 12-week treatment period with an add-on therapy approach to background therapy (ICS/LABA combination therapy) and systematic background therapy withdrawal, and a 6-week follow-up period. This study consists of a 7 to 14-day screening/run-in period. To be eligible for this study, patients are required to be on a stable dose of any of the following doses and formulations of ICS/LABA combination therapy for at least 1 month: •

Fluticasone/salmeterol combination therapy: -

Advair® Diskus – dry powder inhaler (DPI): 250/50 µg BID or 500/50 µg BID or

-

Advair® HFA – metered dose inhaler (MDI): 230/42 µg BID or 460/42 µg BID or

•

Budesonide/formoterol combination therapy (Symbicort® 160/9 µg BID or 320/9 µg BID) or

•

Mometasone/formoterol combination therapy (Dulera® 200/10 µg BID or 400/10 µg BID)

Patients who have been on budesonide/formoterol or mometasone/formoterol will be switched to an equivalent dose of fluticasone/salmeterol at randomization (Day 1), and patients who have been on fluticasone/salmeterol will remain on their current treatment as background therapy. Following screening, patients will be randomized 1:1 to receive either SAR231893/REGN668 or placebo in a 12-week, double-blind, parallel-group treatment period. The 12-week treatment period is divided into 2 phases: a 4-week background therapy stable phase and an 8-week background therapy withdrawal phase. During the background therapy stable phase patients will remain on their current dose of fluticasone/salmeterol combination therapy along with the randomized investigational medicinal product (IMP). At the start of the background therapy withdrawal phase (Week 4) patients will discontinue the LABA component of fluticasone/salmeterol combination therapy (ie, salmeterol) and switch to an equivalent ICS dose of fluticasone: •

Flovent® Diskus [DPI formulation]: 250 µg BID or 500 µg BID or

•

Flovent® HFA [MDI formulation]: 220 µg BID 440 µg BID

Day 29 (Week 4) marks the beginning of the 8-week background therapy withdrawal phase. At Weeks 6, 7, 8, and 9, patients will be evaluated for adjustment of their ICS dose. At these visits, the fluticasone dose will be reduced by approximately 50% provided that the patient does not meet the criteria for an asthma exacerbation. If a patient meets the criteria for an asthma exacerbation at any visit, he/she will be withdrawn from the study and treated by the Investigator with appropriate medical therapy. Upon completing 12 weeks of treatment with IMP(or after early discontinuation), patients will be placed on their original dose of fluticasone/salmeterol, Property of the sanofi-aventis group - strictly confidential

Page 6



budesonide/formoterol, or mometasone/formoterol (dose at study entry) and albuterol or levalbuterol as needed to control their symptoms for an additional 6 weeks off study medication before a final safety evaluation. Prior to opening enrollment to the entire cohort of 100 patients, a sentinel cohort consisting of approximately 20 patients (approximately 10 active and 10 placebo) will be enrolled. Data from this sentinel cohort will be evaluated by an Independent Data Monitoring Committee (IDMC) for any safety issues. After the 20th or so patient has been randomized, screening will be suspended for at least 2 weeks. Unblinded clinical safety data through at least 4 weeks of treatment will be reviewed by the IDMC. By the time the IDMC has completed their review (approximately 8 weeks after the final patient in the sentinel cohort is randomized), the patients who were randomized immediately after the pause in screening will be approaching their fourth week of treatment. Based on this review, a decision will be made to continue treatment beyond 4 weeks for the currently enrolled patients. Additionally, based on the IDMC’s review, a decision may be made to modify the protocol or stop the study. During this safety evaluation the sentinel cohort will continue to receive IMP for the scheduled 12 weeks. 1.2

OBJECTIVES

1.2.1 Primary objectives

The primary objective of this study is to investigate the effects of SAR231893/REGN668 administered SC once weekly for 12 weeks as compared to placebo on reducing the incidence of asthma exacerbations in patients with persistent moderate to severe eosinophilic asthma. 1.2.2 Secondary objectives

The secondary objectives are:

1.3

•


•



The sample size calculations are based on the Phase 2 study results for inhaled pitrakinra (IL-4R mutein), where an absolute reduction in the proportion of patients with an asthma exacerbation of 37% (treatment rate of 13% versus placebo rate of 50%) was observed for this patient population. This study is designed to detect an absolute difference of 30% between treatment groups. To detect such a difference with 80% power (α=0.05, 2-tailed test), 44 patients are required per treatment group (Fisher’s exact test). Accounting for an anticipated 10% dropout rate during the study, approximately 50 patients are required to be enrolled into each treatment group.


Page 7


1.4


STUDY PLAN

1.4.1 Graphical study design Screening/ run-in period

Treatment period

50 patients: SAR231893/REGN668 300 mg SC


weekly

50 patients: Placebo SC weekly

Randomization

Day 29 Week 4

Day 43 Week 6


Day 50 Week 7

Day 57 Week 8

Day 64 Week 9

Day 71 Week 10

Day 78 Week 11

Day 85 Week 12

Day 127 Week 18



Fluticasone/salmeterol DPI: 250/50 µg BID 500/50 µg BID

Fluticasone 250 µg BID 500 µg BID




0 µg BID

Fluticasone/salmeterol 250/50 µg BID 500/50 µg BID

MDI: 230/42 µg BID 460/42 µg BID





0 µg BID

230/42 µg BID 460/42 µg BID


BID = twice daily doing; DPI = dry powder inhalation; MDI = metered dose inhalation; SC = subcutaneous



Page 8



1.4.2 Study flowchart

VISIT DAY


WEEK

Informed consent Patient demography Previous medical & surgical history Inclusion/exclusion criteria Reversibility Prior & concomitant meds Physical examination ACQe Spirometryf Randomization IMPt administrationh Dispense electronic diary/PEF meter and provide instructions for usei Download electronic diary/PEF meter Dispense albuterol or levalbuterol as neededj Discontinue fluticasone/salmeterol combination & replace with equivalent dose of fluticasonek Evaluation for ICS withdrawall Induced sputum for eosinophils & neutrophils (subset)m Exhaled nitric oxiden SNOT-22 Adverse event observation period Vital Signs Electrocardiogram

X X X X Xc Xd X X Xg

Week 1

Week 2

Week 3

Week 4


Xd

X

X

X

X

X

X

X

X

Xg

X X

X X

X X

X X

X X

X X

X X

X X

X

X

X

X

X

X

X

X

X

X

X

X

Posttreatment V15 D127

Week 10

Week 11

Week 12

Week 18

X

X

X

X

X X

X X

X X

X X

X X X X

X

X

X

X

X

X

X

X

X

X

X

X

X

X X

X

X X

X

X

X X

X X

X X X X X


X X X

X

X X X

X

X X

X

X X X

X

X X

X

X

X X

X

X X X X X

X X

Page 9


VISIT DAY



WEEK

Pregnancy testo Clinical lab testingp Blood eosinophil sampleq SAR231893/REGN668 samplingr Additional SAR231893/REGN668 samplings Anti-SAR231893/REGN668 antibody sampling Phadiatop (antigen-specific IgE) serum sample Serum sample for IgE, TARC, YKL-40, TSLP, CEA and plasma sample for eotaxin-3 Protein biomarker (serum) sample RNA (whole blood) sampler Pharmacogenomic sampling (optional)t Discontinue fluticasone and resume pre-study ICS/LABA combinationu Safety telephone contactsu

Week 1

X X X

X

X

X X

Week 3

Week 4


Week 10

X X

X X

X X

Week 2

X X X

X

X X

X

X

X

X

X

X

X

X

X

X X X

X X

X

X

Week 11

Week 12

Posttreatment V15 D127 Week 18

X X X X X X s --------------X -------------X X X X

X Xu

ACQ = Asthma Control Questionnaire; CEA = carcinoembryonic antigen; ICS = inhaled corticosteroid; IMP=investigational medicinal product; LABA = long-acting beta2 agonist; PEF = peak expiratory flow; SNOT-22 = Sinonasal Outcome Test; TARC = thymus and activation-regulated chemokine; TSLP = thymic stromal lymphopoietin a The screening/run-in period must be at least 7 days in duration prior to randomization to allow for the collection of 7 days worth of baseline data on PEF, asthma symptom scores, nocturnal awakenings, and albuterol or levalbuterol use. b End-of-treatment visit: Patients who discontinue prematurely from the study, should be assessed as soon as possible using the procedure normally planned for V14 and return to the study site 6 weeks later for the post-treatment evaluation of safety normally planned for V15. c Reversibility test to be conducted only in patients for whom there is no documented history of reversibility meeting the entry criteria within 12 months prior to screening and no documented history of bronchial hyperreactivity from a positive methacholine challenge (PD20 methacholine ≤ 8 mg) within 12 months prior to screening. For patients requiring a reversibility test, 3 attempts may be made during the screening period to meet the qualifying criteria for reversibility. d Prior to screening, patients must be on a stable dose of either fluticasone/salmeterol combination therapy (DPI formulation: 250/50 µg BID or 500/50 µg BID or MDI formulation: 230/42 µg BID or 460/42 µg BID), or budesonide/formoterol combination therapy (160/9 µg BID or 320/9 µg BID), or mometasone/formoterol combination therapy (200/10 µg BID or 400/10 µg BID) for at least 1 month. Patients who have been on budesonide/formoterol or mometasone/formoterol will be switched on Day 1 to an equivalent dose of fluticasone/salmeterol only after they meet all screening entry criteria, and patients who have been on fluticasone/salmeterol will remain on their current treatment as background therapy. e 5-question version of the ACQ. The ACQ is to be completed in the patient’s electronic diary during clinic visits. Property of the sanofi-aventis group - strictly confidential

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f Spirometry performed between 6 and 10 AM after a 6 hour withhold of albuterol or levalbuterol and prior to administration of IMP. g Three attempts may be made during the screening period to meet the qualifying criteria for spirometry. Patients must also meet the criteria for spirometry prior to randomization on Day 1. If a patient’s FEV1 does not qualify, then he/she will not be randomized on that day. He/she may return to the site on a subsequent day to attempt to meet the spirometry criteria (3 pre-randomization attempts maximum). Spirometry performed following a 6 hour withhold of asthma medication and albuterol or levalbuterol. h Weekly IMP administrations must be separated by at least 5 days. i Electronic diary/PEF meter to be used for daily recording of albuterol or levalbuterol use, nocturnal awakenings, morning and evening asthma symptom scores and PEF. j Resupply as needed k Patients will be switched from fluticasone/salmeterol combination therapy (DPI formulation: 250/50 µg BID or 500/50 µg BID or MDI formulation: 230/42 µg BID or 460/42 µg BID) to an equivalent ICS dose of fluticasone monotherapy ((DPI formulation: 250 µg BID or 500 µg BID or MDI formulation: 220 µg BID or 440 µg BID) The LABA component will be discontinued. l Fluticasone dose to be reduced by 50% at Weeks 6, 7, 8, and 9 provided that the patient does not meet the criteria for asthma exacerbation. m A subset of study sites will be selected to perform evaluations of induced sputum, and patients at these selected sites will have the option to participate in this assessment. The goal is for approximately 50 patients to participate in this analysis. The first sputum sample from each site will be evaluated by an independent reader to assess the quality of the sample. If the quality is inadequate, additional training will be conducted at the site prior to collecting sputum samples from subsequent patients, and the sample from the first patient will be discarded and recollected prior to randomization. In addition sputum cell counts of leukocytes, soluble factors in sputum may also be examined if feasible (eg, IL-4, IL-13). n Exhaled nitric oxide assessment to be conducted prior to spirometry and following a fast of at least 1 hour. o Serum pregnancy test at V1, and urine pregnancy tests at V2, V8, and V14. A negative result must be obtained at V1 and at V2 prior to randomization. p Hematology to include hemoglobin, hematocrit, platelet count, total white blood cell count, differential count, and total red blood cell count. Serum chemistry to include creatinine, blood urea nitrogen, glucose, uric acid, total cholesterol, total protein, albumin, bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, electrolytes (sodium, potassium, chloride), bicarbonate, and creatine phosphokinase. q Eosinophil counts at V1 and V14 will be derived from the sample drawn for clinical lab testing (differential count). Patients whose initial V1 eosinophil count is 200 to 299 cells/µL may have 1 additional hematology assessment to attempt to meet the minimum eosinophil criterion of 300 cells/µL). This can be performed during the current screening period if time permits or subject may be re-screened as a new patient at a later time as long as all other inclusion/exclusion can still be met and blood eosinophils in the range of 200 to 299 cells/µL were only drawn once prior). At V6 and V10 only a hematology sample will be taken for eosinophil counts, as serum chemistry testing is not scheduled for these visits. r Serum pharmacoketic sample and RNA sample will be collected prior to administration of IMP. s For the lead-in cohort of approximately 20 patients additional pharmacokinetic samples to be collected after the final dose on Days 82, 92, 99, 106, and 113 t For patients who have signed the Pharmacogenomics informed consent form. The DNA sample should be collected at the baseline visit, but it can be collected at any visit during the study. u Patients to resume taking their original dose of ICS/LABA combination therapy (fluticasone/salmeterol, budesonide/formoterol, or mometasone/formoterol, dose at study entry) v Telephone call to be made to the patients to evaluate AEs on Week 13, 14, and 16 (1, 2, and 4 weeks after the end-of-treatment visit).


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1.5


MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL

A few modifications are made to the statistical section of the protocol in the statistical analysis plan.

Table 1 Modifications to the statistical section of the protocol in the SAP

1

2

Text in the protocol The following description on the exposure definition: Duration of investigational product exposure is defined as: last dose date – first dose date + 1 day, regardless of unplanned intermittent discontinuations.

Text in the SAP Is changed in the SAP to: Duration of IMP exposure is defined as: last dose date – first dose date + 7 days, regardless of unplanned intermittent discontinuations

The following description on analyses of secondary efficacy endpoints: Time to asthma exacerbation will be compared between treatment groups using a log-rank test. The survival curves will be estimated using Kaplan-Meier estimates and the hazard ratio (and 95%confidence interval) will be provided using a Cox proportional hazards model. The secondary endpoints of FEV1 change from baseline, change from baseline in AM and PM PEF, change from baseline in ACQ score, change from baseline in SNOT-22 score, change from baseline in AM and PM symptom scores, daily albuterol or levalbuterol use, and nocturnal awakenings will be analyzed using an analysis of covariance model including factors for treatment and investigative center.

Is changed in the SAP to: Time to asthma exacerbation endpoint Time to asthma exacerbation (measured in days since the date of randomization) will be analyzed using a log-rank test for the mITT population. The log-rank test statistics from SAS PROC LIFETEST will be used to compare survival distributions for the treatment groups. The survival curves will be estimated using Kaplan-Meier estimates. Asthma endpoints The proportion of patients with a composite asthma event as defined in Section 2.1.2.2 will be analyzed in a manner similar to the primary endpoint. For endpoints FEV1, AM PEF, PM PEF, ACQ score, AM and PM asthma symptom scores, daily albuterol/levalbuterol use, and nocturnal awakenings, change from baseline at week 12 and at each visit will be analyzed with a mixed model repeated measures (MMRM) using SAS PROC MIXED. The repeated-measures analysis will be based on the restricted maximum likelihood method assuming an unstructured covariance structure to model the within-subject errors. A Kenward-Roger approximation will be used for the denominator degrees of freedom. The model, includes treatment, stratification factor (prior ICS/LABA combination therapy dose), and pooled investigative center, visit and treatment-by-visit interaction as fixed effects and baseline as a covariate, will be used to compare the least-squares means for the difference between SAR231893 (REG668) versus placebo in the change from baseline for the endpoints above at Week 12 and at each visit. Descriptive statistics including number of subjects, mean, standard error and least-square means (LS means) will be provided for the observed data and for the corresponding change from baseline. In addition, difference in LS means, the corresponding 95% CI and the p-value will be provided for comparisons of SAR231893


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(REG668) against placebo in the change from baseline for each endpoint above at each visit. A review of the residuals will be done to determine whether the model assumptions are met. If not, an MMRM with rank transformation will be done to corroborate the MMRM result. For each endpoint, LOCF procedure will be used to impute any missing data at Week 12 for the analyses of change from baseline. An analysis of covariance (ANCOVA) model including factors for baseline, treatment, stratification factor (prior ICS/LABA combination therapy dose), and pooled investigative center will be used for analysis. For treatment comparison, a two-sided 95% confidence interval will be constructed for the difference in least-squares means from the ANCOVA model. SNOT-22 score endpoint For SNOT-22 score, tables of descriptive statistics for the observed data and for the corresponding change from baseline will be provided using the mITT population at baseline and week 12. An ANCOVA model including factors for baseline, treatment, stratification factor (prior ICS/LABA combination therapy dose) and pooled investigative center will be used for the analysis of change from baseline at week 12 for this endpoint with mITT population. For treatment comparison, a two-sided 95% confidence interval will be constructed for the difference in least-squares means from the ANCOVA model. The patient will be excluded from analysis if the data for SNOT-22 at week 12 is missing.

1.6

STATISTICAL MODIFICATIONS MADE IN THE SAP

None.


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2

STATISTICAL AND ANALYTICAL PROCEDURES

2.1

ANALYSIS ENDPOINTS




•


•


•


•

Height (cm)

•

Body weight (kg)

•


•


•


•


•


•

The baseline efficacy data of forced expiratory volume in 1 second (FEV1) (including predose FEV1, predose FEV1 percent predicted, and FEV1 reversibility), AM and PM peak expiratory flow (PEF), AM and PM symptom scores and nocturnal awakenings, and asthma control questionnaire (ACQ) will be summarized. The baseline AM and PM PEF symptom scores and nocturnal awakenings will be the mean AM measurements and mean PM measurements, respectively, recorded during the 7 days prior to the first dose. A minimum of 4 AM and 4 PM PEF measurements must be included in the means.



A 30% or greater reduction from baseline in morning PEF on 2 consecutive days, or


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•


•



-


-

Hospitalization

2.1.2.2 Secondary efficacy endpoints


Time to asthma exacerbation postrandomization For patients who experience asthma exacerbation, based on the definition provided in Section 2.1.2.1, the time from randomization to asthma exacerbation will be determined.

•

Proportion of patients with a composite asthma event defined by a 30% or greater reduction from baseline in morning PEF on 2 consecutive days together with ≥6 additional reliever puffs of albuterol or levalbuterol in a 24 hour period (compared to baseline) on 2 consecutive days

•


•


•


•

22-item Sinonasal Outcome Test (SNOT-22) score change from baseline at Week 12

•


•


2.1.2.3 Exploratory efficacy endpoints

Additional exploratory efficacy endpoints include: •

Proportion of patients with a composite asthma event defined by a 30% or greater reduction from baseline in morning PEF on 2 consecutive days together with ≥6 additional reliever puffs of albuterol or levalbuterol in a 24-hour period (compared to baseline) on 2 consecutive days or

•




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-


-

Hospitalization

2.1.2.4 Efficacy methods

Peak expiratory flow: At screening (Visit 1), patients will be issued an electronic PEF meter for recording morning (AM) and evening (PM) PEF, daily albuterol or levalbuterol use, morning and evening asthma symptom scores, and number of nighttime awakenings due to asthma symptoms that require rescue medications. Patients will be instructed on the use of the device, and written instructions on the use of the electronic PEF meter will be provided to the patients. In addition, the investigator will instruct the patients on how to record the following variables in the electronic PEF meter: •

AM PEF will be performed within 15 minutes after arising (between 6 AM and 10 AM) prior to taking any albuterol or levalbuterol

•

PM PEF will be performed in the evening (between 6 PM and 10 PM) prior to taking any albuterol or levalbuterol

•

Patients should try to withhold albuterol or levalbuterol for at least 6 hours prior to measuring their PEF

•


Baseline AM PEF will be the mean AM PEF Maximum measurement from the most recent 7 (minimum of 4) morning diaries with an AM PEF Max completed prior to the first dose of IMP including the Morning Diary on the first dosing day in the calculation, and baseline PM PEF will be the mean PM PEF Maximum measurement from the most recent 7 (minimum of 4) evening diaries with an PM PEF Max completed prior to the first dose of IMP. Information derived from the electronic PEF meter will be evaluated by the Investigator at the patient’s weekly visit to the study site. Patients with asthma exacerbation will be discontinued from the study. They are to be given the end-of-treatment assessments normally scheduled for Visit 14, and are to return 6 weeks later for a posttreatment safety evaluation (normally scheduled for Visit 15). Forced expiratory flow in 1 second: A spirometer that meets the 2005 American Thoracic Society (ATS)/ European Respiratory Society (ERS) recommendations will be used. The ATS/ ERS Standardization of Spirometry should be used as a guideline. Spirometry will be performed between 6 and 10 AM after an albuterol or levalbuterol withhold of at least 6 hours. Pulmonary function tests will be measured in


Page 16



the sitting position, and the highest measure will be recorded for the forced expiratory volume in 1 second (FEV1, in liters). The predose spirometry on the postrandomization visits should be performed within one hour of the time it was performed on Visit 2 (Day 1). The same spirometer and standard spirometric techniques, including calibration, will be used to perform spirometry at all visits and whenever possible the same person should perform the measurements. An instruction manual describing further details (data processing, quality assurance) will be provided. Further details on spirometry are available in Appendix B. Juniper Asthma Control Questionnaire: The 5-question version of the Juniper ACQ is a validated questionnaire to evaluate asthma control. The 5-question version of the ACQ differs from the full ACQ (7-question version) in that the question about short-acting bronchodilator use and FEV1 score are excluded. (These 2 variables are being collected separately as secondary efficacy endpoints). Patients will complete the ACQ questionnaire within their electronic diaries at screening and at their weekly visit to the clinic. A copy of the Juniper ACQ is provided in Appendix C. 22-item Sinonasal Outcome Test: The SNOT-22 is a validated questionnaire to assess the impact of chronic rhinosinusitis on quality of life. Patients will complete the SNOT-22 questionnaire at randomization and at Week 12. A copy of the SNOT-22 questionnaire is provided in Appendix D. Asthma Symptom Score: Patients will record overall symptom scores twice a day prior to measuring PEF. The patient’s overall asthma symptoms experienced during the waking hours will be recorded in the evening (PM symptom score). Symptoms experienced during the night will be recorded upon arising (AM symptom score). Baseline symptom scores will be the mean AM and PM scores recorded from the most recent 7 days with valid measurements prior to randomization. Patients will be instructed to record the severity of symptoms as follows: AM symptom score: -


-


-


-


-



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PM symptom score: -


-


-


-


-


Albuterol or levalbuterol use for symptom relief: The number of albuterol or levalbuterol inhalations will be recorded daily by the patients in their electronic diary/PEF meter. Each patient should be reminded that albuterol or levalbuterol should be used only as needed for symptoms, not on a regular basis or prophylactically. The baseline number of albuterol or levalbuterol inhalations/day will be based on the mean for the 7 days prior to randomization. A valid albuterol or levalbuterol puff day is defined as a day with the presence of AM albuterol or levalbuterol puffs and PM albuterol or levalbuterol puffs (from previous day) and it is recorded under the date the AM albuterol or levalbuterol puff comes from. The baseline number of albuterol or levalbuterol inhalations/day will be based on the mean for the most recent 7 (minimum of 4) valid albuterol or levalbuterol puff days prior to randomization. 2.1.3 Safety endpoints

Safety will be assessed by the review of summaries of all safety variables including AEs, laboratory findings, vital signs, ECGs, and physical examinations. Observation period The observation period is divided into 3 segments: pretreatment, on-treatment and posttreatment. •

The pretreatment period is defined as the time between when the subjects sign the informed consent form and the start of IMP.

•

The treatment period is defined as the time from first dose of IMP up to the end of the follow-up period. (That is, up to 7 weeks after the last dose of IMP).

•

The posttreatment period is defined as the time starting after the end of follow-up visit.


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2.1.3.1 Adverse events variables

Pretreatment AEs, TEAEs and posttreatment AEs: •

Pretreatment AEs are AEs that developed or worsened or became serious from the signed informed consent date up to first dose of IMP;

•

Treatment-emergent AEs (TEAEs) are AEs that developed or worsened or became serious during the treatment period;

•

Posttreatment AEs are AEs that developed or worsened or became serious after the end of follow-up visit.

All adverse events (AEs) (including SAEs, AEs of special interest [AESI] and AEs with prespecified monitoring [AEPM]) will be coded to a “Lower Level Term (LLT)”, “Preferred Term (PT)”, “High Level term (HLT)”, “High Level Group Term (HLGT)” and associated primary “System Organ Class (SOC)” using the version of MedDRA currently in effect at sanofi-aventis at the time of database lock. The occurrence of AEs (including SAEs, AESIs and AEPMs) is recorded from the time of signed informed consent until the end of the study. Adverse events of special interest AESI with immediate notification includes the following items: •

ALT increase where: -

ALT > 5 X the upper limit of normal (ULN) in patients with baseline ALT 3X baseline ALT in patients with baseline ALT ≥ULN; or

-

ALT ≥3 ULN and ≤5 ULN plus total bilirubin >2 ULN in patients with baseline ALT 2 ULN in patients with baseline ALT ≥ULN.

•

Anaphylactic reactions or acute allergic reactions that require immediate treatment

•

Severe injection site reactions that last longer than 24 hours

•

Severe infections including parasitic infections

•

Pregnancy -

Pregnancy occurring in a female patient included in the clinical trial. Pregnancy will be recorded as a prespecified AE with immediate notification in all cases. It will be qualified as an SAE only if it fulfills the SAE criteria.

-

In the event of pregnancy, IMP should be discontinued.


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•



Symptomatic overdose with IMP -

An overdose (accidental or intentional) with the IMP is an event suspected by the Investigator and defined as at least twice the dose during the planned intervals.

AESI without immediate notification includes the following items: •


•


ALT ≥3 ULN and ≤5 ULN plus total bilirubin ≤2 ULN in patients with baseline ALT 10%) from the size of that in the primary analysis population for any treatment group. Parameters described in Section 2.1.1 will be summarized by treatment group and overall using descriptive statistics. Previous medical and surgical history will be summarized. P-values on demographic and baseline characteristic data will not be calculated. No specific description of the safety parameters will be provided at baseline. If relevant, the baseline values will be described along with each safety analysis. Baseline values for the following efficacy endpoints will be calculated by taking the mean of the last 7 days (measurements) prior to randomization: AM and PM PEF, AM and PM symptom scores and nocturnal awakenings.


Page 25



All baseline measurements are to be collected prior to the first dose of IMP. Measurements that were obtained after the first dose of IMP are considered postrandomization values. If no measurement of a variable is obtained before the first dose of IMP then the variable has missing value at baseline. 2.4.2 Prior or concomitant medications

The prior and concomitant medications will be presented on the randomized population. Medications will be summarized by treatment group according to the WHO-DD dictionary, considering the first digit of the ATC class (anatomic category) and the first 3 digits of the ATC class (therapeutic category). All ATC codes corresponding to a medication will be summarized. Patients will be counted once in each ATC categories (anatomic or therapeutic) linked to the medication, therefore patients may be counted several times for the same medication. The table for prior medications will be sorted by decreasing frequency of anatomic category followed by all other therapeutic classes based on the overall incidence across treatment groups. In case of equal frequency regarding anatomic categories (respectively therapeutic categories), alphabetical order will be used. The tables for concomitant medications will be sorted by decreasing frequency of anatomic category followed by all other therapeutic classes based on the incidence of SAR231893 group. In case of equal frequency regarding anatomic categories (respectively therapeutic categories), alphabetical order will be used. 2.4.3 Extent of investigational medicinal product exposure and compliance

The extent of IMP exposure will be assessed and summarized by actual treatment within the safety population (see Section 2.3.2). 2.4.3.1 Extent of investigational medicinal product exposure

The extent of IMP exposure will be assessed by the duration of IMP exposure. Duration of IMP exposure is defined as: last dose date – first dose date + 7 days, regardless of unplanned intermittent discontinuations (see Section 2.5.3 for calculation in case of missing or incomplete data). Duration of IMP exposure will be summarized descriptively as a quantitative variable (Number, Mean, SD, Median, Min, and Max). In addition, duration of treatment exposure will also be summarized categorically by counts and percentages for each of the following categories and cumulatively according to these categories: -

2 ULN which ever comes first) will be analyzed using Kaplan-Meier estimates, using the midpoint of the time interval between the first assessment showing the elevation and the previous assessment, presented by treatment group. A graph of distribution of peak values of ALT versus peak values of total bilirubin will also be presented. Note that the ALT and Total bilirubin values are presented on a logarithmic scale. The graph will be divided into 4 quadrants with a vertical line corresponding to 3xULN for ALT and a horizontal line corresponding to 2xULN for total bilirubin. Summarize the normalization by parameter (to ≤1 ULN or return to baseline) of elevated liver function tests by categories of elevation (3x, 5x, 10x, 20x ULN for ALT and AST, 1.5x ULN for Alkaline phosphatase, and 1.5x and 2x ULN for total bilirubin), with following categories of normalization: never normalized, normalized despite treatment continuation of IMP or normalized after IMP discontinuation. Note that a patient will be counted only under the maximum elevation category. Summarize the incidence of liver related AEs by treatment group. The selection of preferred terms will be based on standardized MedDRA query (SMQ) Hepatic disorder.


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2.4.5.4 Analyses of vital sign variables

The summary statistics (including number, mean, median, standard deviation, minimum and maximum) of all vital signs variables (vital signs values and changes from baseline) will be calculated for each visit or study assessment (baseline, each post baseline time point, and endpoint) by treatment group. Analyses of change from baseline to end of study will be conducted using the Kruskal-Wallis test. The incidence of PCSAs at any time during the TEAE period will be summarized by treatment group whatever the baseline level and/or according to the following baseline status categories: •

Normal/Missing

•

Abnormal according to PCSA criterion or criteria

Listings will be provided with flags indicating the PCSA values. 2.4.5.5 Analyses of ECG variables

The summary statistics (including number, mean, median, standard deviation, minimum and maximum) of all ECG variables (ECG values and changes from baseline) will be calculated for each visit or study assessment (baseline, each post baseline time point, and endpoint) by treatment group. The incidence of PCSAs at any time during the TEAE period will be summarized by treatment group whatever the baseline level and/or according to the following baseline status categories: •

Normal/Missing

•

Abnormal according to PCSA criterion or criteria

Listings will be provided with flags indicating the PCSA values. 2.4.5.6 Analyses of other safety endpoints

Findings for physical examination data will be summarized. Shifts from normal to abnormal and vice versa will be presented in addition to summary statistics with patient count and percentage for each treatment group for physical examinations done at screening and end-of-treatment. 2.4.6 Analyses of pharmacokinetic and pharmacodynamic variables

Serum concentrations of SAR231893 (REGN668) and its PK parameters (Cmax, tmax, AUC0-τ, t1/2z, if feasible) will be summarized using arithmetic and geometric means, SD, standard error of the mean (SEM), coefficient of variation, minimum, median and maximum per sampling time. If date and/or time of the drug intake and/or sampling is missing then the concentration will not be taken into account. Where concentration values are below the lower limit of quantification (LLOQ),


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one-half of the LLOQ will be used. Values will be expressed in the tables with no more than three significant figures. The relationship between efficacy, safety variables or other exploratory parameters and SAR231893 (REGN668) serum concentrations may be explored using graphical and regression methods, if applicable. For drug-treated patients, where concentration values are below the lower limit of quantification (LLOQ), one-half of the LLOQ will be used. Patients in the placebo group will be taken into account with a plasma concentration considered equal to 0. 2.4.7 Immunogenicity variables

Anti-SAR231893 antibody assay results will be described categorically as negative (if below the assay cut-point or not drug specific) or positive (if drug specific signal above the assay cut-point). The incidences of positive and negative will be summarized by treatment group for each visit as appropriate. 2.4.8 DNA/RNA

The DNA test is optional and patients need to sign a separate informed consent for DNA testing. Exploratory analysis of DNA/RNA will be addressed in a separate document. 2.5


2.5.1 General conventions

The following formulas will be used for computations of parameters. Demographic formulas: Age is calculated as following: Age = (informed consent date – birth date)/365.25 BMI is calculated as following: BMI = Weight in kg / (height2 in meters) Renal function formulas: Creatinine clearance (CrCl) value will be derived using the equation of Cockcroft and Gault: CrCL (ml/min) = (140 - age) * weight (kg) * (1 - 0.15*sex (0-M, 1-F)) /(0.814*creatinine (µmol/l)) CLcr will be calculated using weight assessed at the same visit that creatinine was assessed and the age when lab samples were taken. Property of the sanofi-aventis group - strictly confidential

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2.5.2 Data handling conventions for secondary efficacy variables

Calculation of Total Daily Albuterol/Levalbuterol Use: Daily albuterol/levalbuterol use will be the sum of AM and PM (from previous day) Albuterol/Levalbuterol use. Any missing AM or PM values of albuterol/levalbuterol use will be imputed by 0s. Mean of Asthma Diary Endpoints at Each Visit: For the asthma diary endpoints, AM and PM PEF, ACQ score, AM and PM asthma symptom scores, daily albuterol/levalbuterol use, and nocturnal awakenings, the means at each visit will be the average values from all days between last visit and this visit. 2.5.3 Missing data

For categorical variables, patients with missing data are not included in calculations of percentages unless otherwise specified. When relevant, the number of patients with missing data is presented. Handling of computation of treatment duration if investigational medicinal product end of treatment date is missing For the calculation of the treatment duration, the date of the last dose of IMP is equal to the date of last administration reported on the dosing CRF page. If this date is missing, the exposure duration should be kept as missing. The last dose intake should be clearly identified in the CRF and should not be approximated by the last returned package date. Handling of medication missing/partial dates No imputation of medication start/end dates or times will be performed. If a medication date or time is missing or partially missing, so it can not be determined whether it was taken prior to or concomitantly, it will be considered as both a prior and concomitant medication. Handling of AEs with missing or partial date/time of onset Missing or partial missing AE onset dates and times will be imputed so that if the partial AE onset date/time information does not indicate that the AE started prior to treatment or after the TEAE period, the AE will be classified as treatment-emergent. No imputation of AE end dates/times will be performed. These data imputations are for categorization purpose only and will not be used in listings. No imputation is planned for date/time of AE resolution.


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Handling of AE when date and time of first investigational medicinal product date is missing When the date and time of the first IMP is missing all AEs that occurred after or on the day of randomization should be considered as TEAEs. The exposure duration should be kept as missing. Handling of missing relationship to investigational medicinal product of AEs If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be assumed and the AE considered as such in the frequency tables of possibly related AEs, but no imputation should be done at the data level. Handling of missing severity of AEs If the severity is missing for one of the treatment emergent occurrences of an AE, the maximal severity on the remaining occurrences will be considered. If the severity is missing for all the occurrences a “missing” category will be added in summary table. Handling of PCSA If a patient has a missing baseline he/she will be grouped in the category “normal /missing at baseline”. For PCSA with 2 conditions, one based on a change from baseline value or a normal range and the other one on a threshold value, the first condition being missing, the PCSA will be based only on the second condition. For PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this threshold if the normal range is missing. For example, for eosinophils the PCSA is >0.5 GIGA/L or >ULN if ULN ≥0.5 GIGA/L. When ULN is missing the value 0.5 should be used. Measurements flagged as invalid by the laboratory will not be summarized nor be taken into account in the computation of PCSA values.


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2.5.4 Windows for time points

The screening/run-in period should be at least 7 days (minimum 4 days) in duration prior to randomization to allow for the collection of 7 days worth of baseline data on PEF, asthma symptom scores, nocturnal awakenings, and albuterol/levalbuterol use. Patients who discontinue prematurely from the study, should be assessed as soon as possible using the procedure normally planned for Visit 14 (End-of-treatment visit) and return to the study site 6 weeks later for the posttreatment evaluation of safety normally planned for Visit 15. 2.5.5 Unscheduled visits

Unscheduled visit measurements of laboratory data, vital signs, ECG will not be included in the by-visit summaries but will be used for computation of baseline and PCSA. 2.5.6 Pooling of centers for statistical analyses

A total of 45 investigative centers participated in this study. Centers from this study will be pooled for the purpose of statistical analysis. Centers without at least 3 patients per treatment group (randomized treatment) in the primary efficacy analysis mITT population will be incorporated into pooled centers, as follows: •

All such centers will be ordered from lowest to highest in terms of number of primary efficacy analysis, mITT population patients. In case of ties, the ordering for tied centers will be determined according to the center ID number (from smallest to largest). Centers will be combined beginning at the smallest until the resulting pooled center contains at least 3 primary efficacy analysis, mITT population patients per treatment group. The centers pooled in this way will be considered as a single center in statistical analyses. The process described above will resume for the remaining centers not meeting the criterion of at least three mITT patients in each treatment group. If the final set of pooled centers does not meet the criterion of at least 3 mITT patients per treatment group, the final set will be pooled with the preceding pooled center.

2.5.7 Statistical technical issues

None.


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3


INTERIM ANALYSIS

The IDMC will evaluate the unblinded clinical safety data of a sentinel cohort consisting of approximately 20 patients (approximately 10 active and 10 placebo) through Week 4 (Visit 6) for any safety issues. A group external to the study team will prepare the analyses for the IDMC and the study team will remain completely blinded to the unblinded results. At the time of the finalization of the SAP, this review was complete and the recommendation of the IDMC was to continue the study without any modifications. An early analysis of efficacy is planned when approximately 66 patients complete 12 weeks of treatment (Visit 14). This early analysis of efficacy is only for the purpose of an early administrative look to help prepare for further development of the compound. The study will not be terminated based on this early administrative look and as a result no α-spending function needs to be specified. The group preparing the safety results for the IDMC may be utilized to perform this early efficacy analysis in order to keep the study team blinded. Only summary results will be presented to a limited team of Sponsor personnel, and all Sponsor personnel and the study team will remain blinded to the treatment assignment of individual patients. A separate Interim Analysis Plan document will be prepared to detail the logistics of the interim analysis.


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4


DATABASE LOCK



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5


SOFTWARE DOCUMENTATION

All summaries and statistical analyses will be generated using SAS version 8.2 or higher.


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6


REFERENCES

1. Standardization of the measurement of lung volumes. ATS/ERS Task Force: Standardization of Lung Function Testing. Edited by V. Brusasco, R. Crapo, and G. Viegi. Eur Resir J. 2005;26:511-552. 2. Hankinson J et al. Spirometric reference values from a sample of the general US population. Am J Respir Crit Care Med. 1999;159:179-187


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7


LIST OF APPENDICES

Appendix A

Summary of statistical analyses

Appendix B

Spirometry

Appendix C


Appendix D


Appendix E


Appendix F

Potential clinically significant abnormalities (PCSA) criteria


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Appendix A Summary of statistical analyses EFFICACY ANALYSIS: Analysis Endpoint

Supportive

Subgroup

Other

Population

Primary Analysis

Analysis*

Analysis*

Analyses*

mITT

A logistic regression model will be used to compare SAR231893 (REGN668) group with placebo. The model will include terms for treatment, stratification factor (prior ICS/LABA combination therapy dose), and pooled investigative center.

Two-sided Chisquare test Descriptive statistics; cumulative plot.

Yes Subgroups: age, race, gender, Baseline FEV1 and Investigative center (pooled)

No


mITT

Log-rank test. The survival curves will be estimated using Kaplan-Meier estimates.

No

No

No


mITT

Each visit- Mixed model repeated measures (MMRM) including treatment, stratification factor (prior ICS/LABA combination therapy dose), and pooled investigative center, visit and treatment-by-visit interaction as fixed effects and baseline as a covariate. Week 12 (LOCF)- ANCOVA model including factors for baseline, treatment, stratification factor (prior ICS/LABA combination therapy dose), and pooled investigative center.

No

No

No

Primary Endpoint Occurrence of an exacerbation of asthma during the treatment period

Secondary Endpoints


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Analysis

Supportive

Subgroup

Other


mITT


No

No

No


mITT


No

No

No

SNOT-22 score change from baseline at Week 12

mITT

ANCOVA model with factors for baseline, treatment, stratification factor (prior ICS/LABA combination therapy dose) and pooled investigative center

No

No

No


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Analysis

Supportive

Subgroup

Other


mITT


No

No

No

Change from baseline at Week 12 and change from baseline at each visit in number of inhalations/day of albuterol/levalbuterol for symptom relief

mITT


No

No

No


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SAFETY ANALYSES: Analysis

Supportive

Subgroup

Other

Endpoint

Population

Primary Analysis

Analysis*

Analysis*

Analyses*

Adverse Events

Safety

Follow safety guidelines; Descriptive

No

No

No

Lab/vital signs/ECGs

Safety

Follow safety guidelines; PCSA analysis; Descriptive

No

No

No


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Appendix B


Spirometry

Equipment The same spirometer and standard spirometric techniques including calibration will be used to perform pulmonary function tests at all visits. Spirometry will meet the specifications and performance criteria recommended in the ATS/ERS Task Force: Standardization of Lung Function Testing will be used (1) Preparing the patient Spirometry, an effort-dependent test, requires careful instruction and cooperation of the patient. It is important to ensure a good seal around the mouthpiece, and ensure that the patient’s posture is correct. Explain that maximum inspiration, followed by maximum forced expiration until no more can be exhaled (or for at least 6 seconds if possible) is required. Expiration must be rapid and complete. Maximum effort must be maintained during expiration. The results of spirometry should meet the following criteria for number of trials, acceptability, and reproducibility. The acceptability criteria should be applied before reproducibility is checked. Number of trials For screening spirometry and for pre-dose measurements at Visits 2 through 14, a minimum of 3 acceptable forced vital capacity (FVC) maneuvers should be performed. If a patient is unable to perform a single acceptable maneuver after 8 attempts, testing may be discontinued. However, after additional instruction and demonstration, more maneuvers may be performed depending on the patient's clinical condition and tolerance. Acceptability An acceptable maneuver has the following characteristics: •


•


•


•



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Reproducibility The 2 largest FVC values from 3 acceptable maneuvers should not vary by more than 0.150 L, Recording of Data The highest FEV1 resulting from any of the acceptable curves are recorded. Post-Bronchodilator Spirometry Perform spirometry approximately 20-30 minutes after giving 200 µg or 400 µg of albuterol/levalbuterol via a standard unit dose of albuterol/levalbuterol nebulization to achieve 12% and 200ml reversibility. Each nebulizer treatment will require a set-up consisting of a compressor and single patient use attachment system including a nebulizing cup for medication, a mouthpiece and connecting tube. Apply the same performance and measurement criteria described above for post-bronchodilator spirometry. Predicted Normal NHANES predicted normal values will be used to determine FEV1 (L) predicted normal values in adolescents and adults (2)


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Appendix C



Please answer Questions 1-5. Circle the number of the response that best describes how you have been during the past week. 1. On average, during the past week, how often were you woken by your asthma during the night? 0 Never 1 Hardly ever 2 A few times 3 Several times 4 Many times 5 A great many times 6 Unable to sleep because of asthma 2. On average, during the past week, how bad were your asthma symptoms when you woke up in the morning? 0 No symptoms 1 Very mild symptoms 2 Mild symptoms 3 Moderate symptoms 4 Quite severe symptoms 5 Severe symptoms 6 Very severe symptoms 3. In general, during the past week, how limited were you in your activities because of your asthma? 0 Not limited at all 1 Very slightly limited 2 Slightly limited 3 Moderately limited 4 Very limited 5 Extremely limited 6 Totally limited 4. In general, during the past week, how much shortness of breath did you experience because of your asthma? 0 None 1 A very little Property of the sanofi-aventis group - strictly confidential



2 A little 3 A moderate amount 4 Quite a lot 5 A great deal 6 A very great deal 5. In general, during the past week, how much of the time did you wheeze? 0 Not at all 1 Hardly any of the time 2 A little of the time 3 A moderate amount of the time 4 A lot of the time 5 Most of the time 6 All the time



Appendix D



Below you will find a list of symptoms and social/emotional consequences of your nasal rhinosinusitis. We would like to know more about these problems and would appreciate your answering the following question to the best of your ability. There are no right or wrong answers, and only you can provide us with this information. Please rate your problems, as they have been over the past two weeks. Thank you for your participation. Do not hesitate to ask for assistance if necessary. 1: Considering how severe the problem is when you experience it and how frequently it happens, please rate each item below on how ‘bad’ it is by circling the number that corresponds with how you feel using this scale Î

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12 13. 14. 15. 16. 17. 18. 19. 10. 21. 22.

Need to blow nose Nasal blockage Sneezing Runny nose Cough Post nasal discharge Thick nasal discharge Ear fullness Dizziness Ear pain Facial pain/pressure Decreased sense of smell/taste Difficulty falling asleep Waking up at night Lack of a good night’s sleep Waking up tired Fatigue Reduced productivity Reduced concentration Frustrated/restless/ irritable Sad Embarrassed

No Very problem mild problem

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

Mild or slight problem

Moderate problem

Severe problem

Problem as bad as it can be

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4

5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5

Most 5 important items

2. Please mark the most important items affecting your health (maximum of 5 items) ___________________________________



Appendix E



















Appendix F Potentially clinically significant abnormalities (PCSA) criteria CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES for phase 2/3 studies (oncology excepted) (From QSD-002295 – Version 3.0 –14-SEP-2009 based on content from PCSA List issued on 27-JAN-2009)

Parameter

PCSA

Comments

ALT

By distribution analysis : >3 ULN >5 ULN >10 ULN >20 ULN

Enzymes activities must be expressed in ULN, not in IU/L. Concept paper on DILI – FDA draft Guidance Oct 2007. Internal DILI WG Oct 2008. Categories are cumulative. First row is mandatory. Rows following one mentioning zero can be deleted.

AST

By distribution analysis : >3 ULN >5 ULN >10 ULN >20 ULN

Enzymes activities must be expressed in ULN, not in IU/L. Concept paper on DILI – FDA draft Guidance Oct 2007. Internal DILI WG Oct 2008. Categories are cumulative. First row is mandatory. Rows following one mentioning zero can be deleted.

Alkaline Phosphatase

>1.5 ULN

Enzymes activities must be expressed in ULN, not in IU/L. Concept paper on DILI – FDA draft Guidance Oct 2007. Internal DILI WG Oct 2008.

Total Bilirubin

>1.5 ULN >2 ULN

Must be expressed in ULN, not in µmol/L or mg/L. Categories are cumulative. Concept paper on DILI – FDA draft Guidance Oct 2007. Internal DILI WG Oct 2008.

Clinical Chemistry

Conjugated Bilirubin >35% Total Bilirubin and TBILI>1.5 ULN

Conjugated bilirubin dosed on a case-by-case basis.

ALT and Total Bilirubin

Concept paper on DILI – FDA draft Guidance Oct 2007. Internal DILI WG Oct 2008. To be counted within a same treatment phase, whatever the interval between measurement.

ALT>3 ULN and TBILI>2 ULN




CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES for phase 2/3 studies (oncology excepted) (From QSD-002295 – Version 3.0 –14-SEP-2009 based on content from PCSA List issued on 27-JAN-2009)

Parameter

PCSA

Comments

CPK

>3 ULN >10 ULN

FDA Feb 2005. Am J Cardiol April 2006. Categories are cumulative. First row is mandatory. Rows following one mentioning zero can be deleted.

Creatinine

≥150 µmol/L (Adults) ≥30% change from baseline ≥100% change from baseline

Benichou C., 1994.

ULN (if ULN≥0.5 Giga/L)

Harrison- Principles of internal Medicine 17th Ed., 2008.

Hemoglobin

≤115 g/L (Male); ≤95 g/L (Female) ≥185 g/L (Male); ≥165 g/L (Female)

Criteria based upon decrease from baseline are more relevant than based on absolute value. Other categories for decrease from baseline can be used (≥30 g/L, ≥40 g/L, ≥50 g/L).

Hematology

Decrease from Baseline ≥20 g/L

International Consensus meeting on drug-induced blood cytopenias, 1991. FDA criteria.

Hematocrit

≤0.37 v/v (Male) ; ≤0.32 v/v (Female) ≥0.55 v/v (Male) ; ≥0.5 v/v (Female)

RBC

≥6 Tera/L

Unless specifically required for particular drug development, the analysis is redundant with that of Hb. Otherwise, consider FDA criteria.

Platelets

450 ms (Male); >470 ms (Female) ≥500 ms Increase from baseline Borderline: Increase from baseline 30-60 ms Prolonged: Increase from baseline >60 ms


*QTc prolonged and ∆QTc>60 ms are the PCSA to be identified in individual subjects/patients listings.

1.1.1.1 Changes occurring between the statistical analysis plan and database lock

A few modifications were made from the SAP to database lock. The changes are summarized below. Table - Statistical analysis plan statistical changes SAP Version No.

Approved Date

1

13 January 2012

Rationale

Description of statistical changes

Avoid non-converge for statistical model

Pooled center was removed from the covariate list for all the statistical models and no subgroup analysis was performed by centers due to small number of exacerbation events in the treatment group.

Adjust baseline for by-visit analysis

A baseline by visit interaction term was included as covariate for all the MMRM models

Small number of patients had significant liver function test elevation

The pre-specified additional DILI analyses were not performed due to small number of patients had PCSA values for the liver function test (1 placebo patient for ALT elevation and 2 placebo patients for AST elevation)