ORIGINAL CONTRIBUTION
A Phase 3, Multicenter, Open-Label, 12-Month Extension Safety and Tolerability Trial of Lisdexamfetamine Dimesylate in Adults With Binge Eating Disorder Maria Gasior, MD, PhD,* James Hudson, MD, ScD,† Javier Quintero, MD,‡ M. Celeste Ferreira-Cornwell, PhD,* Jana Radewonuk, MSc,* and Susan L. McElroy, MD§||
Abstract: Background: A 12-month, open-label extension study assessed the long-term safety and tolerability of lisdexamfetamine dimesylate (LDX) in adults with binge eating disorder (BED). Methods: Adults (aged 18–55 y) with BED who completed 1 of 3 antecedent studies were enrolled in a 52-week, open-label extension study (dose optimization, 4 weeks [initial titration dose, 30-mg LDX; target doses, 50- or 70-mg LDX]; dose maintenance, 48 weeks). Safety evaluations included the occurrence of treatment-emergent adverse events (TEAEs), vital sign and weight assessments, and Columbia-Suicide Severity Rating Scale responses. Results: Of the 604 enrolled participants, 599 (521 women and 78 men) comprised the safety analysis set, and 369 completed the study. Mean (SD) LDX exposure was 284.3 (118.84) days; cumulative LDX exposure duration was 12 months or longer in 344 participants (57.4%). A total of 506 participants (84.5%) reported TEAEs (TEAEs leading to treatment discontinuation, 54 [9.0%]; severe TEAEs, 42 [7.0%]; serious TEAEs, 17 [2.8%]). Treatment-emergent adverse events reported in greater than or equal to 10% of participants were dry mouth (27.2%), headache (13.2%), insomnia (12.4%), and upper respiratory tract infection (11.4%). Mean (SD) changes from antecedent study baseline in systolic and diastolic blood pressure, pulse, and weight at week 52/early termination (n = 597) were 2.19 (11.043) and 1.77 (7.848) mm Hg, 6.58 (10.572) beats per minute, and −7.04 (7.534) kg, respectively. On the Columbia-Suicide Severity Rating Scale, there were 2 positive responses for any active suicidal ideations; there were no positive responses for suicidal behavior or completed suicides. Conclusions: In this 12-month, open-label, extension study, the long-term safety and tolerability of LDX in adults with BED were generally consistent with its established profile for attention-deficit/hyperactivity disorder. Key Words: binge eating disorder, extension, lisdexamfetamine dimesylate, safety and tolerability (J Clin Psychopharmacol 2017;37: 315–322)
*Formerly of Shire, Lexington, MA; †McLean Hospital/Harvard Medical School, Belmont, MA; ‡Hospital Universitario Infanta Leonor, Madrid, Spain; §Lindner Center of HOPE, Mason; and ||University of Cincinnati College of Medicine, Cincinnati, OH. Received August 12, 2016; accepted after revision February 15, 2017. Reprints: Susan L. McElroy, MD, Lindner Center of HOPE, 4075 Old Western Row Rd, Mason, OH 45040 (e‐mail:
[email protected]). This study was funded by the study sponsor, Shire Development LLC (Lexington, MA). Supplemental digital contents are available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.psychopharmacology.com). Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. ISSN: 0271-0749 DOI: 10.1097/JCP.0000000000000702
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isdexamfetamine dimesylate (LDX) is approved by the US Food and Drug Administration (FDA) for treating adults with moderate to severe binge eating disorder (BED).1 Lisdexamfetamine dimesylate is absorbed by the gastrointestinal tract and subsequently metabolized to its active form, d-amphetamine, primarily by red blood cells after oral administration.2 The pharmacokinetics of LDX has been described in detail in a recent review.3 In brief, oral administration of LDX (30–70 mg) to adults is associated with rapid increases in plasma amphetamine levels (maximum concentrations, 32.2–88.9 ng/mL; time to maximum concentration, 3.5–5.5 hours), with the reported elimination half-life of amphetamine ranging from 9.69 to 15 hours.3 Approval of LDX was based on the results of a single phase 2 study and 2 phase 3, placebo-controlled, double-blind studies.1,4 In the phase 2 study, 50- and 70-mg LDX (but not 30-mg LDX) demonstrated efficacy versus placebo in decreasing binge eating days per week (primary efficacy end point) in adults with BED.4 In the 2 phase 3 pivotal trials,1 dose-optimized LDX (50 or 70 mg) produced statistically significant and clinically meaningful reductions compared with placebo in binge eating days per week (primary efficacy end point) in adults with BED. Furthermore, LDX demonstrated statistically greater improvement than placebo on key secondary efficacy end points in these studies, with the changes on the Clinical Global Impression-Improvement (CGI-I) scale, 4-week cessation of binge eating at end point, BEDrelated obsessive and compulsive psychopathology on the Yale-Brown Obsessive Compulsive Scale modified for Binge Eating, and percentage of body weight change also being considered clinically meaningful.1 In these short-term studies,1,4 the safety and tolerability profile of LDX was generally similar to its established safety profile in attention-deficit/hyperactivity disorder (ADHD).5–7 Treatmentemergent adverse events (TEAEs) reported by greater than or equal to 10% of participants with BED treated with LDX in any study were dry mouth, decreased appetite, insomnia, and headache.1,4 Across studies,1,4 increases (mean [SD]) from baseline in systolic blood pressure (SBP) and pulse at final visit/early termination (ET) with LDX ranged from 0.1 (9.85) to 1.45 (10.818) mm Hg for SBP and from 3.8 (11.57) to 6.31 (9.505) beats per minute for pulse; mean (SD) diastolic blood pressure (DBP) increases from baseline at the final visit/ET were 1.06 (7.905) and 1.83 (7.956) mm Hg in the 2 phase 3 studies.1 To understand the long-term safety and tolerability of LDX in adults with BED, a 12-month, open-label extension study was conducted. The primary objective of the study was to evaluate the long-term safety and tolerability of LDX in adults with BED as measured by the occurrence of TEAEs, responses on the Columbia-Suicide Severity Rating Scale (C-SSRS), and evaluation of vital signs, weight, and electrocardiogram (ECG). Secondary objectives included the evaluation of LDX effects on clinical outcome measures using the CGI-I and the Eating Disorder Examination Questionnaire (EDE-Q).
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MATERIALS AND METHODS Study Design and Treatment This 52-week, open-label extension study (ClinicalTrials. gov, NCT01657019) was conducted at 86 sites in the United States, Germany, and Spain and enrolled adults with BED who completed 1 of the 3 antecedent studies (NCT01291173, NCT01718483, and NCT01718509) described previously.1,4 The study consisted of a 2-week screening phase (only for those participants with an enrollment gap that was 30 or more days from antecedent study completion), a 52-week open-label phase (4 weeks of LDX dose optimization followed by 48 weeks of LDX dose maintenance), and a 1-week follow-up period. Postbaseline on-treatment study visits were conducted during each week of the dose optimization phase (weeks 1–4) and at 4-week intervals during the dose maintenance phase (weeks 8–52). In the open-label, dose optimization phase, participants were titrated to 50- or 70-mg LDX regardless of their antecedent study treatment. During week 1, all participants received 30-mg LDX (for initial titration only). During week 2, all participants received 50-mg LDX. Participants were titrated to 70-mg LDX based on safety, tolerability, and clinical response based on participants' daily self-reported binge eating diaries (as assessed and confirmed by experienced and trained clinicians) during weeks 3 and 4; the overall assessment of safety and tolerability was the key factor when deciding whether a dose increase was justified. Investigators were to evaluate each participant's overall clinical condition (safety, tolerability, and clinical response) at each visit and had the option to downtitrate to 50-mg LDX if 70-mg LDX was not tolerated. During the dose maintenance phase, a single adjustment between 70- and 50-mg LDX was allowed based on investigator assessment of tolerability and clinical response. When a dose titration was required, assessments of vital signs, adverse events (AEs), the 12-lead ECG, and the C-SSRS were to be performed. Participants not tolerating 50-mg LDX were discontinued. The study protocol, informed consent document, and relevant supporting information were approved by ethics committees and regulatory agencies before study initiation. The study was conducted in accordance with the International Conference on Harmonization Good Clinical Practice, the principles of the Declaration of Helsinki, and all applicable local ethical and legal requirements. All participants provided written informed consent before performance of any study procedures.
Participants Inclusion and Exclusion Criteria Study eligibility was based on the final treatment visit or the follow-up visit of the antecedent study if the enrollment gap was less than 30 days from antecedent study completion or on the extension study screening visit to reestablish baseline if the enrollment gap was 30 or more days from antecedent study completion. Eligible adults (aged 18–55 y at antecedent study consent) had completed 1 of 3 antecedent studies,1,4 with no clinically significant AEs during the antecedent study or clinically significant or relevant abnormalities that precluded LDX exposure. Key exclusion criteria included having a history of symptomatic cardiovascular disease or serious cardiac problems; having moderate to severe hypertension; having resting sitting SBP of greater than 139 mm Hg or DBP of greater than 89 mm Hg; having a lifetime history of psychosis, mania, hypomania, dementia, or ADHD; being considered a suicide risk, previously attempting suicide, or currently having active suicidal ideation; having a lifetime stimulant abuse or dependence history or an abuse or
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dependence history on substances other than stimulants within the past 6 months; having known or suspected intolerance or hypersensitivity to LDX or related compounds; having a history of significant neurological or cerebrovascular disease; having used an investigational product in an observational clinical study within 30 days of screening; or having participated in a previous clinical LDX trial other than the specified antecedent studies. Female participants of childbearing potential were required to screen negative on blood and urine pregnancy tests and be willing to use acceptable contraceptive methods. When the enrollment gap was 30 or more days from antecedent study completion, additional eligibility criteria included having a body mass index of 18 to 45 kg/m2 and having a confirmed diagnosis of BED from the antecedent study based on the eating disorder module of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (DSM), Fourth Edition, Text Revision and the EDE-Q. Additional exclusion criteria included having current anorexia nervosa or bulimia nervosa, receiving psychotherapy or weight loss support for BED (
