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October 2008, after 81 patients had enrolled. With the amend- ment ... clonic seizures that did not result in drop attacks were counted as nondrop seizures.
Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome

Y.T. Ng, MD, FRACP J.A. Conry, MD R. Drummond, PhD J. Stolle M.A. Weinberg, MD, MBA On behalf of the OV-1012 Study Investigators

ABSTRACT

Objective: To evaluate efficacy and safety of clobazam, a 1,5-benzodiazepine, as adjunctive therapy for Lennox-Gastaut syndrome (LGS).

Methods: Patients aged 2–60 years were randomized to placebo or clobazam 0.25, 0.5, or 1.0 mg/kg/day. Study consisted of 4-week baseline, 3-week titration, and 12-week maintenance phases, followed by a 2- or 3-week taper or continuation in an open-label extension. Primary endpoint was percentage decrease in mean weekly drop seizure rates during maintenance vs baseline phases for modified intention-to-treat (mITT) population. Secondary outcomes included other seizure types, responder rates, and physicians’ and caregivers’ global assessments.

Results: A total of 305 patients were screened, 238 were randomized, and 217 composed the Address correspondence and reprint requests to Dr. Yu-tze Ng, Department of Neurology, University of Oklahoma Health Sciences Center, 711 Stanton L Young Boulevard #215, Oklahoma City, OK 73104 [email protected]

mITT population. Of patients enrolled after a protocol amendment, 125/157 (79.6%) completed. Average weekly drop seizure rates decreased 12.1% for placebo vs 41.2% (p ⫽ 0.0120), 49.4% (p ⫽ 0.0015), and 68.3% (p ⬍ 0.0001) for the clobazam 0.25-, 0.5-, and 1.0-mg/kg/day groups. Responder rates (ⱖ50%) were 31.6% (placebo) vs 43.4% (p ⫽ 0.3383), 58.6% (p ⫽ 0.0159), and 77.6% (p ⬍ 0.0001) for clobazam 0.25-, 0.5-, and 1.0-mg/kg/day groups. Physicians’ and caregivers’ assessments indicated clobazam significantly improved symptoms. Somnolence, pyrexia, upper respiratory infections, and lethargy were the most frequent adverse events reported for clobazam.

Conclusions: Clobazam significantly decreased weekly drop seizure rates in LGS. No new safety signals were identified. Classification of evidence: This study provides Class II evidence that clobazam as adjunctive therapy is efficacious, in a dosage-dependent manner, in reducing mean weekly drop seizure rates of patients with LGS over 12 weeks. Neurology® 2011;77:1473–1481 GLOSSARY AE ⫽ adverse event; CI ⫽ confidence interval; GERD ⫽ gastroesophageal reflux disease; LGS ⫽ Lennox-Gastaut syndrome; mITT ⫽ modified intention-to-treat; OLE ⫽ open-label extension; OR ⫽ odds ratio; SAE ⫽ serious adverse event.

Lennox-Gastaut syndrome (LGS) is a severe childhood epileptic encephalopathy characterized by a classic triad of 1) frequently generalized, slow spike-and-wave EEG, 2) several seizure types, and 3) developmental delay and behavioral disturbances.1 Onset generally occurs before 8 years of age, with peak occurrence between 3 and 5 years. LGS seizures are predominantly tonic, atonic, and atypical absence, and patients are often refractory to antiepileptic drugs.2 Clobazam, a 1,5-benzodiazepine, is available as adjunctive therapy for epilepsy and anxiety disorders in ⬎100 countries.3 It has been in US clinical development for LGS since 2005.3 In a phase II study, clobazam was well-tolerated and decreased weekly rates of drop and nondrop seizures for patients with LGS.4 Clobazam 1.0 mg/kg/day was more efficacious than clobazam Supplemental data at www.neurology.org

Supplemental Data

From the St. Joseph’s Hospital Medical Center and Barrow Neurological Institute (Y.T.N.), Phoenix, AZ; Children’s National Medical Center (J.A.C.), Washington, DC; and Lundbeck Inc. (R.D., J.S., M.A.W.), Deerfield, IL. Study funding: This study was funded by Lundbeck Inc. (Deerfield, IL). Manuscript preparation, including editing and formatting the manuscript, incorporating author comments, preparing tables and figures, and coordinating submission requirements, was provided by Robin L. Stromberg, PhD, of JK Associates, Inc. (Conshohocken, PA), and Michael A. Nissen, ELS, of Lundbeck Inc. This support was funded by Lundbeck. Disclosure: Author disclosures are provided at the end of the article. Presented at the American Epilepsy Society 64th annual meeting, December 3–7, 2010, San Antonio, Texas (poster 1.283); and the American Academy of Neurology 63rd annual meeting, April 9 –16, 2011, Honolulu, Hawaii (oral presentation S55.005). Copyright © 2011 by AAN Enterprises, Inc.

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Figure 1

Study design

Low-dosage clobazam ⫽ target of 0.25 mg/kg/day (maximum, 10 mg/day); medium-dosage clobazam ⫽ target of 0.5 mg/ kg/day (maximum, 20 mg/day); high-dosage clobazam ⫽ target of 1.0 mg/kg/day (maximum, 40 mg/day). *Patients not directly continuing in the open-label extension study tapered off study drug in a 2- or 3-week taper period, depending on weight, with the final visit 1 week after the last dose.

0.25 mg/kg/day. In the high-dosage group, mean (median) decrease in weekly drop seizure rate was 85% (93%), and 83% of those patients had ⱖ50% decreases in weekly rates of drop seizures. Clobazam’s efficacy as adjunctive LGS therapy has been notable.5–9 Similarly, a ⱖ50% responder rate of 56.3% was obtained in a pooled analysis of 80 patients with LGS from 8 open-label studies.3 This Phase III, Double-Blind, PlaceboControlled, Efficacy and Safety Study of ClObazam in PatieNTs with LennoxGAstaut SyNdrome (CONTAIN) further assessed the efficacy and safety of clobazam as adjunctive therapy. The primary objectives were to determine 1) efficacy of 3 dosages in decreasing weekly frequencies of drop and total seizures during a 12-week maintenance phase vs baseline and 2) safety of clobazam when administered ⱕ18 weeks at 3 dosages. METHODS Patients. Patients aged 2– 60 years weighing ⱖ12.5 kg were eligible to participate in the CONTAIN trial if they had onset of LGS before 11 years of age. A clinical diagnosis of LGS was evidenced by ⱖ1 type of generalized seizure (including drop seizures) for ⱖ6 months and a previous EEG report documenting generalized, slow spike-and-wave (⬍2.5 Hz) patterns.1 Study inclusion and exclusion criteria are provided in appendix e-1 on the Neurology威 Web site at www.neurology.org.

Standard protocol approvals, registrations, and patient consents. The study (ClinicalTrials.gov identifier: NCT00518713) was approved by an independent ethics com1474

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mittee or institutional review board at each study site. Written, informed consent was obtained from each patient or the patient’s parent/caregiver.

Study design. This phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial was conducted at 51 sites in the United States, India, Europe, and Australia between August 2007 and December 2009. The study included 4-week baseline, 3-week titration, and 12-week maintenance periods, followed by either continuation in an open-label study or a 2- or 3-week taper period, depending on weight, with a follow-up visit 1 week after last dose (figure 1). On day ⫺1, patients were stratified by weight (12.5 kg to ⱕ30 kg, ⬎30 kg) and randomly assigned (through central randomization via interactive voice response system) to one of 4 groups: 1) placebo; 2) low-dosage clobazam: target of 0.25 mg/ kg/day (maximum, 10 mg/day); 3) medium-dosage clobazam: target of 0.5 mg/kg/day (maximum, 20 mg/day); or 4) highdosage clobazam: target of 1.0 mg/kg/day (maximum, 40 mg/ day). Clobazam 5-mg tablets and matching placebo tablets were supplied. During titration, clobazam 5 mg/day or 10 mg/day or placebo (in divided doses) was initiated, and dosage was increased per schedule every 7 days until the assigned target dosage was attained. At any time beginning with week 1 during titration, investigators could decrease daily dosages by a single tablet (placebo or clobazam 5 mg/day) if patients developed any signs or symptoms representing difficulty tolerating study drug. Protocol amendment. At study inception, the protocol permitted patients to easily discontinue from OV-1012 (CONTAIN) and enter an open-label extension (OLE). This led to many premature discontinuations within 4 weeks of starting therapy. To address this issue, the study protocol was revised in October 2008, after 81 patients had enrolled. With the amendment, patients whose seizures worsened were required to have completed week 9 of the study (i.e., after an adequate trial of study drug) before discontinuing and entering the OLE.

Figure 2

Patient disposition

AE ⫽ adverse event. *Patient’s primary reason for discontinuation was “other.” AE was recorded as a secondary reason for discontinuation; this patient was included in the safety analysis of patients who discontinued because of AEs.

Efficacy assessments. The primary efficacy endpoint was percentage decrease in the average weekly rate of drop seizures from the 4-week baseline period to the 12-week maintenance period. Drop seizures were recorded by patients’ parents/caregivers in daily seizure diaries.4 Drop seizure was defined as a drop attack or spell involving the entire body, trunk, or head that led to a fall, injury, slumping in a chair, or the patient’s head hitting a surface or that could have led to a fall or injury, depending on the patient’s position at the time of the attack or spell. Drop seizures were recorded as a single seizure (occurring ⱖ15 minutes before and after the next seizure) or cluster of seizures (ⱖ2 drop seizures with ⬍5 minutes between any 2 consecutive seizures). For clusters, an exact number of drop seizures or a seizure range (10 –20 drop seizures or ⬎20 drop seizures) could have been recorded. Secondary efficacy assessments included percentage decreases in average weekly rate of nondrop seizures (classified according to International League Against Epilepsy guidelines10) and total (drop and nondrop) seizures; responder rates (percentages with ⱖ25%, ⱖ50%, ⱖ75%, and 100% decreases in drop seizures from baseline to maintenance period); and physicians’ and caregivers’ global evaluations of the patients’ overall changes in symptoms over time (using a 7-point Likert scale, with 1 ⫽ very

much improved and 7 ⫽ very much worse). Of note, tonicclonic seizures that did not result in drop attacks were counted as nondrop seizures.

Safety assessments. Safety assessments included laboratory assessments (chemistry, hematology, and urinalysis), physical and neurologic examinations, vital sign monitoring, EKG monitoring, and adverse event (AE) assessment.

Statistical analyses. For information on statistical analyses, see appendix e-2.

A total of 238 patients were randomized, including 165 patients at 33 sites in the United States, 55 patients at 13 sites in India, and 18 patients at 5 sites in Europe and Australia; 177 patients (74.4%) completed the study (figure 2). At the time of the amendment, 81 patients had enrolled. Of these, 29 (36%) discontinued, 26 before the amendment went into effect and 3 after. Twenty-three of those 29 entered the OLE. Following the amendment, 157 patients enRESULTS Patient disposition and baseline results.

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Table 1

Demographics and baseline characteristics (safety population) Clobazam dosage

Variable

Placebo (n ⴝ 59)

Low 0.25 mg/kg/day (n ⴝ 58)

Medium 0.5 mg/kg/day (n ⴝ 62)

High 1.0 mg/kg/day (n ⴝ 59)

Overall (n ⴝ 238)

Age, y, mean (SD)

13.0 (9.2)

10.9 (7.2)

14.1 (10.4)

11.7 (8.5)

12.4 (9.0)

3–54

2–34

3–49

2–39

2–54

2–11

36 (61.0)

39 (67.2)

33 (53.2)

38 (64.4)

146 (61.3)

12–16

10 (16.9)

9 (15.5)

11 (17.7)

10 (16.9)

40 (16.8)

>16

13 (22.0)

10 (17.2)

18 (29.0)

11 (18.6)

52 (21.9)

38 (64.4)

36 (62.1)

36 (58.1)

34 (57.6)

144 (60.5)

White

42 (71.2)

33 (56.9)

35 (56.5)

37 (62.7)

147 (61.8)

Asian

13 (22.0)

16 (27.6)

16 (25.8)

16 (27.1)

61 (25.6)

Black

3 (5.1)

8 (13.8)

9 (14.5)

5 (8.5)

25 (10.5)

Other

1 (1.7)

1 (1.7)

2 (3.2)

1 (1.7)

5 (2.1)

Mean (SD)

36.5 (22.2)

33.6 (22.6)

35.1 (20.3)

34.7 (22.1)

35.0 (21.7)

Range

13–107

13–133

11–118

12–93

11–133

Mean (SD)

95.6 (168.2)

98.3 (198.5)

58.8 (119.6)

94.9 (152.2)

86.6 (161.5)

Median

35.5

28.9

23.5

40.9

29.5

Range

2–920

2–1,077

2–798

2–856

2–1,077

Range Age category, y, n (%)

Male, n (%) Race, n (%)

Weight, kg

Baseline average weekly drop seizure ratea

a

Excludes one patient in the medium-dosage group with no single drop seizure data.

rolled, of which 32 (20%) discontinued. Further, 9 of these 32 entered the OLE. The most common reasons for discontinuing the study were lack of efficacy for placebo-treated patients and AEs for clobazam-treated patients. All 238 randomized patients were included in the safety population. The mITT population excluded 21 patients who did not have ⱖ1 daily seizure measurement during the maintenance period. Thus, efficacy analyses included 217 patients (57 for placebo and 53, 58, and 49 for the low-, medium-, and high-dosage clobazam groups). Demographics and baseline characteristics were comparable between groups (table 1) and were similar between the safety and mITT populations. Mean age was 12.4 years (range, 2–54 years), and the majority (60.5%) were male. Approximately 50% of all patients were receiving concomitant valproic acid, valproate semisodium, or valproate sodium. Primary efficacy. The mean percentage decrease in

average weekly rate of drop seizures from baseline to maintenance period was 12.1% for placebo vs 41.2% ( p ⫽ 0.0120), 49.4% ( p ⫽ 0.0015), and 68.3% ( p ⬍ 0.0001) for the clobazam 0.25-, 0.5-, and 1.01476

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mg/kg/day groups (figure 3A). Mean differences from the placebo group increased with increasing clobazam dosage (mean differences of 29.1%, 37.3%, and 56.1% for the low-, medium-, and highdosage groups). There was a linear trend ( p ⬍ 0.0001) of increasing efficacy with increasing dosage. Secondary efficacy. Percentage decreases in weekly rates of total and nondrop seizures. The mean percentage decrease in average weekly rate of total (drop and nondrop) seizures was 9.3% for placebo vs 34.8% ( p ⫽ 0.0414), 45.3% ( p ⫽ 0.0044), and 65.3% ( p ⬍ 0.0001) for the clobazam 0.25-, 0.5-, and 1.0mg/kg/day groups (figure 3B). Average weekly rates of nondrop seizures increased 76.3% for placebo, 53.3% for the low-dosage clobazam group, and 3.3% for the medium-dosage clobazam group; and decreased 40.0% for the highdosage clobazam group (differences not significant by analysis of covariance model). Mean differences in seizure reductions for the placebo group increased with increasing dosage of clobazam (absolute mean differences of 23.0%, 73.0%, and 116.3% for the low-, medium-, and high-dosage groups). The ranktransformed percentage decrease in weekly rates of

Figure 3

Mean percentage decreases (95% CI ⴝ confidence intervals) in weekly rate of seizures from the baseline to maintenance period

(A) Drop seizures. (B) Total (drop and nondrop) seizures. The p values were calculated from 2-sided, pairwise comparison of each clobazam dosage with placebo (analysis of covariance) with treatment, pooled center, and baseline seizure rate as model effects.

nondrop seizures was greater for the high-dosage group vs placebo ( p ⫽ 0.0070). Responder rates. Responder rates increased with increasing clobazam dosages (figure 4). The percentage of patients with ⱖ50% decreases from baseline to maintenance period in average weekly rate of drop seizures was 31.6% (18 of 57 patients) for placebo vs 43.4% (23 of 53 patients), 58.6% (34 of 58 patients), and 77.6% (38 of 49 patients) for the low-, medium-, and high-dosage clobazam groups, respectively. The likelihood of achieving ⱖ50% response was greater for the medium-dosage (odds ratio [OR] 2.8; 95% confidence interval [CI] 1.2– 6.5; p ⫽ 0.0159) and high-dosage (OR 7.5; 95% CI 3.0 – 18.5; p ⬍ 0.0001) clobazam groups compared with the placebo group. Two patients (3.5%) in the placebo group were seizure-free (100% decrease from baseline in drop seizure rates), compared with 4 (7.5%), 7 (12.1%), and 12 (24.5%) patients for the low-, medium-, and high-dosage clobazam groups. Because of the relatively small numbers of patients in these groups, logistic regression models were unable to provide valid statistical comparisons for the 100% response threshold. Physicians’ and caregivers’ global evaluations. All 3 clobazam dosages led to improvements in physicians’ and caregivers’ global evaluations of patients’ overall changes

in symptoms from baseline to week 15/end of treatment (figure e-1). The percentages of patients who were at least minimally improved ranged from 71.2% to 80.7% (physicians’ assessments) and 79.2% to 81.6% (caregivers’ assessments) for clobazam vs 47.3% (physicians’ assessments) and 45.5% (caregivers’ assessments) for placebo. Similarly, percentages of patients who were much improved or very much improved ranged from 46.2% to 64.9% (physicians’ assessments) and 41.5% to 59.2% (caregivers’ assessments) for clobazam vs 23.6% (physicians’ assessments) and 25.5% (caregivers’ assessments) for placebo. Safety. The percentages of patients with ⱖ1 AE were 67.8% for placebo, 72.4% for the low-dosage group, 88.7% for the medium-dosage group, and 76.3% for the high-dosage group. AEs experienced by ⱖ5% of patients in any treatment group are provided in table e-1. AEs with ⱖ10% difference between placebo and any clobazam group were somnolence, pyrexia, lethargy, drooling, and constipation. Sedation was reported for 8 (4.5%) clobazam-treated patients (1 in the lowdosage group, 2 in the medium-dosage group, and 5 in the high-dosage group). Of these AEs, somnolence and drooling increased in frequency with increasing clobazam dosage. A dosage-related trend was observed for the overall incidence of AEs leading to discontinuation. Neurology 77

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Figure 4

Responder rates

Percentages of patients with ⱖ25%, ⱖ50%, ⱖ75%, and 100% decreases from baseline to maintenance period in average weekly rate of drop seizures increased with increasing clobazam dosage. The logistic regression model was unable to provide valid estimates of statistical significance for the 100% response threshold. *p ⬍ 0.01 vs placebo. **p ⬍ 0.05 vs placebo.

Twenty-seven patients (2 in the placebo group, 4 in the low-dosage group, 8 in the medium-dosage group, and 13 in the high-dosage group) discontinued because of AEs. Treatment-emergent AEs that led to premature discontinuation for ⱖ2 patients were lethargy, somnolence, aggression, ataxia, insomnia, and fatigue. Few patients reported new seizure types (2 in the placebo group, 1 in the low-dosage group, 2 in the medium-dosage group, and 3 in the high-dosage group). There were 2 serious AEs (SAEs) related to seizures (myoclonic epilepsy for 1 patient in the medium-dosage group and grand mal convulsion for 1 patient in the high-dosage group). Sixteen patients experienced SAEs (2 in the placebo group and 3, 6, and 5 in the low-, medium-, and high-dosage groups, respectively) (table e-2). SAEs for ⱖ2 patients were lobar pneumonia (1 in the placebo group and 2 in the high-dosage group) and pneumonia (2 in the low-dosage group, 2 in the medium-dosage group, and 1 in the high-dosage group). No deaths were reported. Few treatment-emergent AEs associated with abnormal clinical laboratory results considered to be at least possibly related to study drug (thrombocytopenia and increased eosinophil count) were reported. No clinically meaningful trends were observed for clinical laboratory assessments, vital signs, EKG or EEG results, or in physical and neurologic examinations. 1478

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Twenty-nine patients had their dosages decreased at some point during the study because of an AE. Of these 29, 1 patient was in the placebo group, and 4, 9, and 15 patients were in the low-, medium-, and high-dosage groups, respectively. Ten of 29 discontinued because of an AE (1, 4, and 5 patients in the low-, medium-, and high-dosages groups.) In the CONTAIN trial, the largest study conducted in LGS, clobazam was efficacious as adjunctive therapy for drop seizures associated with LGS in patients aged 2 to 54 years. Safety was as anticipated, based on previous clinical studies of clobazam. Decreases in mean (median) weekly rates of drop seizures from 4-week baseline to the 12-week maintenance phase with clobazam were substantial and significant. There was a linear trend of increasing efficacy with increasing dosage. In contrast with previous studies that compared placebo with a titrated dosage of active drug,5–9 this phase III study was a true dosage-ranging study, enabling evaluation of benefit/risk ratios of lower and higher dosages of clobazam. All 3 clobazam dosages decreased weekly rates of total (drop and nondrop) seizures. Decreases were driven mainly by drop seizures. Of patients in the high-dosage group, approximately 3 of 4 had at least a 50% decrease and approximately 1 of 4 had a 100% decrease. Moreover, decreases in seizure frequency with clobazam were accompanied by significant improvements in LGS DISCUSSION

symptoms, as assessed by global evaluations by physicians and parents/caregivers. Currently, 5 AEDs (clonazepam, felbamate, lamotrigine, topiramate, rufinamide) have demonstrated clinical efficacy and are approved by the FDA for LGS.5–9,11–17 No new safety issues were identified. AEs were as expected, given what is known about clobazam from extensive previous clinical development efforts.4,18 –23 It has been suggested there are different incidences and severities of sedation between clobazam and other benzodiazepines.23–26 While some have hypothesized this observation is a result of differential binding of receptors,27,28 the clinical validity of these hypotheses could not be tested in this study, given that comparator data were not generated. Patients were tapered off clobazam by decreasing total daily dosages up to 20 mg/day on a weekly basis. During this tapering, withdrawal symptoms were not observed. In addition, there was no evidence of status epilepticus or severe seizure exacerbation. In clinical practice, physicians may choose to taper patients at the same rate or more slowly than the 2- to 3-week period employed in this study. Pneumonia was the only SAE occurring for more than a single patient during the study. Nine patients had pneumonia (any type) reported as an SAE. For 4 of these 9 patients, 3 had a history of gastroesophageal reflux disease (GERD), 2 had a history of G-tube placements, and 2 had a history of drooling (patients may have had more than one event). These findings should be interpreted with caution, but suggest there may be an association between presence of GERD, G-tubes, and drooling and occurrence of pneumonias in patients with LGS. The present 15-week study is insufficient for evaluating clobazam as long-term adjunctive therapy for LGS. An OLE is underway to assess the long-term effects of clobazam in patients with LGS. All patients from CONTAIN who entered the OLE received clobazam 0.5 mg/kg (maximum of 40 mg/day) for 2 days. Then the dosage could be adjusted to a maximum of 2.0 mg/kg/day (maximum of 80 mg/day). A total of 267 patients enrolled in the OLE: 61 of 68 patients from the phase II study4 and 206 of 238 patients from the present phase III study. As of July 1, 2010, 213 (79.8%) remained in the study and were receiving clobazam. Of these, 189 (89%) had received clobazam for ⱖ1 year, and 44 of 61 patients from phase II remained in the study approximately 4 years after entry.29 In addition, a retrospective study of 50 treatment responders (patients with intractable epilepsy who experienced ⱖ75% decreases in seizure frequency after the addition of clobazam to their current AED regimens) found that 43 (86%) remained

on clobazam therapy after 1 year, and 39 (78%) remained on clobazam therapy after 5 years.30 This retention of patients on clobazam therapy indicates that patients may continue to have a favorable benefit/risk profile with long-term treatment. The effect of clobazam on nondrop seizures was not significant as assessed in the prespecified analysis. This study was not designed nor powered to evaluate the effect of clobazam on nondrop seizures. Although most patients had a history of nondrop seizures, patients were not required to have had a minimum number of nondrop seizures during the baseline period to be randomized. As a result, the sample size for nondrop seizure analysis was smaller than for drop seizure analysis. Several confounding elements make interpretation of these results difficult. Nondrop seizure counts were highly variable by patient and by time point (because of the small sample size) during the course of the study, as evidenced by the finding that patients who received adjunctive placebo (and their stable dosages of AEDs) experienced a substantial worsening (i.e., 76.3% increase) in their nondrop seizure rate. This may be a result of variations in the natural course of LGS. Clobazam 0.25 mg/kg/day, 0.5 mg/kg/day, and 1.0 mg/kg/day for up to 12 weeks of maintenance therapy was efficacious for patients with LGS aged 2 to 54 years. Its safety profile was similar to what has been observed in clinical studies of clobazam for other epilepsy diseases. Lundbeck Inc. submitted a New Drug Application to the FDA for clobazam in the treatment of LGS in December 2010. With the lack of highly efficacious treatment options for medical management of LGS, clobazam, a 1,5-benzodiazepine, will be clinically helpful as adjunctive therapy for patients with this debilitating disease. AUTHOR CONTRIBUTIONS All authors contributed to the conduct of the research, data analysis/ interpretation, and development and revision of the manuscript. Drs. Ng and Conry were study investigators and co-chairs of the study’s executive study management committee, which was responsible for providing advice on scientific and medical matters to Lundbeck Inc., as well as the principal investigators. Dr. Drummond, Principal Biostatistician, Lundbeck Inc., managed the biostatistical analyses, which were conducted by biostatisticians at Quintiles Transnational Corp. (Morrisville, NC).

COINVESTIGATORS OV-1012 Study Investigators (by country): Australia—Roy Beran, MD (Strategic Health Evaluators, Chatswood, New South Wales, Site Investigator), Terence O’Brien, MD (Royal Melbourne Hospital, Parkville, Victoria, Site Investigator), Ingrid Scheffer, MD (The Austin and Repatriation Hospital, West Heidelberg, Victoria, Site Investigator). Belarus—Halina Navumava, MD (Vitebsk Regional Diagnostic Center, Vitebsk, Site Investigator). India—Arijit Chattopadhyay, MD (Apollo Gleneagles Hospitals Limited, Kolkata, Site Investigator), Anand Prakash Dubey, MD (Maulana Azad Medical College and Associated Lok Nayak Hospital, New Delhi, Site Investigator), Anaita Hegde, MD (Jaslok Hospital and Research Centre, Mumbai, Maharashtra, Site Investigator), Neurology 77

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Suman Kushwaha, MD (Institute of Human Behaviour and Allied Sciences, Delhi, Site Investigator), Lekha Pandit, MD (Justice K.S. Hegde Charitable Hospital, Mangalore, Karnataka, Site Investigator), Surekha Rajadhyaksha, MD (Deenanath Mangeshkar Hospital and Research Centre, Pune, Maharashtra, Site Investigator), Ajit Kumar Roy, MD (St. Johns Medical College Hospital, Bangalore, Site Investigator), Shalin D. Shah, MD (Neurology Center, Ahmedabad, Gujarat, Site Investigator), Nellikunja Shankar, MD (Mallikatta Neuro Center, Mangalore, Karnataka, Site Investigator), Maneesh Kumar Singh, MD (Chhatrapati Shahuji Maharaj Medical University, Uttar Pradesh, Site Investigator), Vrajesh Udani, MD (P.D. Hinduja Hospital and Medical Research Center, Mumbai, Maharashtra, Site Investigator), Devananthan Vasudevan, MD (Dr. Kamakshi Memorial Hospital, Pallikaranai, Chennai, Site Investigator), Nandan Yardi, MD (KEM Hospital, Pune, Mahara, Site Investigator). Lithuania—Nerija Vaiciene, MD (Kaunas University of Medicine Hospital, Kaunas, Site Investigator). United States—Susan T. Arnold, MD (University of Texas SW Medical Center, Dallas, TX, Site Investigator), Martina Bebin, MD (University of Alabama at Birmingham, Birmingham, AL, Site Investigator), Selim Benbadis, MD, MPA (University of South Florida, Tampa, FL, Site Investigator), Meriem BensalemOwen, MD (University of Kentucky Medical Center, Lexington, KY, Site Investigator), Jeffrey Buchhalter, MD, PhD (Phoenix Children’s Hospital, Phoenix, AZ, Site Investigator), Joan A. Conry, MD (Children’s National Medical Center, Washington, DC, Site Investigator, Author), Jose Ferreira, MD (Pediatric Epilepsy & Neurology Specialists, Tampa, FL, Site Investigator), David Ficker, MD (University Neurology, Inc., Cincinnati, OH, Site Investigator), Angel Hernandez, MD (Cook Children’s Health Care System, Fort Worth, TX, Site Investigator), Gregory L. Holmes, MD (Dartmouth-Hitchcock Medical Center, Lebanon, NH, Site Investigator), Andres M. Kanner, MD (Rush University Medical Center, Chicago, IL, Site Investigator), Lydia Kernitsky, MD (Virginia Commonwealth University, Richmond, VA, Site Investigator), Pavel Klein, MD (Mid-Atlantic Epilepsy and Sleep Center, Bethesda, MD, Site Investigator), Sookyong Koh, MD, PhD (Children’s Memorial Hospital, Chicago, IL, Site Investigator), Michael H. Kohrman, MD (University of Chicago Medical Center, Chicago, IL, Site Investigator), Paul Levisohn, MD (The Children’s Hospital, Aurora, CO, Site Investigator), Edwin Liu, MD (Pediatric Neurology and Epilepsy Center, Loxahatchee, FL, Site Investigator), Eric Marsh, MD, PhD (Children’s Hospital of Philadelphia, Philadelphia, PA, Site Investigator), Mark Mintz, MD (Clinical Research Center of New Jersey, Voorhees, NJ, Site Investigator), Wendy Mitchell, MD (Children’s Hospital Los Angeles, Los Angeles, CA, Site Investigator), Yu-tze Ng, MD (formerly St. Joseph’s Hospital and Medical Center, Phoenix, AZ, Principal Investigator, Author), Dipakumar Pandya, MD (St. Joseph’s Regional Medical Center, Paterson, NJ, Site Investigator), Yong D. Park, MD (Medical College of Georgia Neurology, Augusta, GA, Site Investigator), J. Ben Renfroe, MD (Children’s Neurology Center of NW FL, Gulf Breeze, FL, Site Investigator), Rosario Maria Riel-Romero, MD (Louisiana State University, Shreveport, LA, Site Investigator), Frank J. Ritter, MD (Minnesota Epilepsy Group, P.A., St. Paul, MN, Site Investigator), William Rosenfeld, MD (The Comprehensive Epilepsy Care Center for Children and Adults, Chesterfield, MO, Site Investigator), Michael R. Sperling, MD (Thomas Jefferson University, Philadelphia, PA, Site Investigator), Elizabeth A. Thiele, MD, PhD (Massachusetts General Hospital, Boston, MA, Site Investigator), David Wang, MD (University of Rochester Medical Center, Rochester, NY, Site Investigator), Robert Wechsler, MD, PhD (Consultants in Epilepsy & Neurology, Boise, ID, Site Investigator), James W. Wheless, MD (University of Tennessee Medical Group, Memphis, TN, Site Investigator), Angus Wilfong, MD (Texas Children’s Hospital, Houston, TX, Site Investigator), Brenda Y. Wu, MD (University of Medicine and Dentistry of NJ Robert Wood Johnson Medical School, New Brunswick, NJ, Site Investigator).

ACKNOWLEDGMENT Biostatistical analyses were conducted by biostatisticians at Quintiles Transnational Corp. and managed by Rebecca Drummond, PhD, Principal Biostatistician, Lundbeck Inc. 1480

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DISCLOSURE Dr. Ng has served as an investigator for Eisai Inc., Lundbeck Inc., and UCB; has received consulting and speaker honoraria from UCB and Lundbeck Inc.; and serves on the editorial boards of Journal of Child Neurology, Pediatric Neurology, and Journal of Paediatrics and Child Health. Dr. Conry has served on scientific advisory boards for Supernus Pharmaceuticals, Inc. and Lundbeck Inc.; has received funding for travel and speaker honoraria from Lundbeck Inc.; serves as a consultant for Lundbeck Inc.; and receives research support from Lundbeck Inc., Eisai Inc., Abbott, King Pharmaceuticals, Marinus Pharmaceuticals, Inc., Pfizer Inc., and UCB. Dr. Drummond is a full-time employee of Lundbeck Inc. J. Stolle is a full-time employee of Lundbeck Inc. Dr. Weinberg was an employee of Lundbeck Inc. at the time the analyses were conducted and is currently an employee of Astellas Pharma Global Development Inc.

Received February 18, 2011. Accepted in final form July 6, 2011. REFERENCES 1. Niedermeyer E. The Lennox-Gastaut Syndrome and its frontiers. Clin Electroencephalogr 1986;17:117–126. 2. Michoulas A, Farrell K. Medical management of LennoxGastaut syndrome. CNS Drugs 2010;24:363–374. 3. Ng YT, Collins SD. Clobazam. Neurotherapeutics 2007; 4:138 –144. 4. Conry JA, Ng YT, Paolicchi JM, et al. Clobazam in the treatment of Lennox-Gastaut syndrome. Epilepsia 2009; 50:1158 –1166. 5. Vassella F, Pavlincova E, Schneider HJ, Rudin HJ, Karbowski K. Treatment of infantile spasms and LennoxGastaut syndrome with clonazepam (Rivotril). Epilepsia 1973;14:165–175. 6. Sachdeo RC, Glauser TA, Ritter F, Reife R, Lim P, Pledger G. A double-blind, randomized trial of topiramate in Lennox-Gastaut syndrome: Topiramate YL Study Group. Neurology 1999;52:1882–1887. 7. Felbamate Study Group in Lennox-Gastaut Syndrome. Efficacy of felbamate in childhood epileptic encephalopathy (Lennox-Gastaut syndrome). N Engl J Med 1993;328: 29 –33. 8. Motte J, Trevathan E, Arvidsson JF, Barrera MN, Mullens EL, Manasco P. Lamotrigine for generalized seizures associated with the Lennox-Gastaut syndrome: Lamictal Lennox-Gastaut Study Group. N Engl J Med 1997;337: 1807–1812. 9. Glauser T, Kluger G, Sachdeo R, Krauss G, Perdomo C, Arroyo S. Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome. Neurology 2008;70: 1950 –1958. 10. Dreifuss FE, Bancaud J, Henriksen O. Proposal for revised clinical and electroencephalographic classification of epileptic seizures: from the Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1981;22:489 –501. 11. Riss J, Cloyd J, Gates J, Collins S. Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand 2008;118:69 – 86. 12. Hancock EC, Cross HH. Treatment of Lennox-Gastaut syndrome. Cochrane Database Syst Rev 2009;3: CD003277. 13. Felbatol威 [package insert]. Somerset, NJ: MEDA Pharmaceuticals, Inc.; 2009. 14. Topamax威 [package insert]. Titusville, NJ: OrthoMcNeil-Janssen Pharmaceuticals, Inc.; 2009. 15. Banzel威 [package insert]. Woodcliff Lake, NJ: Eisai Inc.; 2010.

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Call for Nominations: Editor-in-Chief, Continuum: Lifelong Learning in Neurology The Editorial Search Committee for Continuum: Lifelong Learning in Neurology威 is requesting that AAN members submit the names of eligible candidates for Editor-in-Chief of the Academy’s premier self-study continuing medical education program. Self-nominations or nominations of other AAN members are encouraged. A position description, including requirements, is available at www.aan.com/view/continuumeditor. The Editor-in-Chief is responsible for publishing six issues of Continuum威 a year. The appointment is six years beginning January 1, 2013, with a six-month transition with the current editor beginning July 2012. The Editorial Search Committee members are Robert C. Griggs, MD, FAAN, chair; Terrence L. Cascino, MD, FAAN; Bruce Sigsbee, MD, FAAN; Cynthia L. Comella, MD, FAAN; Robert A. Gross, MD, PhD, FAAN; and Steven P. Ringel, MD, FAAN. Please submit current curriculum vitae with a letter outlining scientific editing experience, a vision for Continuum’s role within the AAN, and an editorial vision for Continuum by November 30, 2011. All candidates will also be required to complete an AAN conflicts of interest disclosure. For more information, contact Andrea Weiss at [email protected] or (651) 695-2742. Submit nominations to:

Missy Render Administrator AAN Enterprises, Inc. 1080 Montreal Avenue St. Paul, MN, 55116 [email protected]

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