OPEN Neuropsychopharmacology (2016) 41, 1251–1260

Official journal of the American College of Neuropsychopharmacology. 0893-133X/16

www.neuropsychopharmacology.org

Lisdexamfetamine Dimesylate for Adults with Moderate to

Severe Binge Eating Disorder: Results of Two Pivotal Phase 3
Randomized Controlled Trials

Susan L McElroy*,1,2, James Hudson3,4, M Celeste Ferreira-Cornwell5, Jana Radewonuk6, Timothy Whitaker5
and Maria Gasior5
1
Lindner Center of HOPE, Mason, OH, USA; 2Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine,
Cincinnati, OH, USA; 3Biological Psychiatry Laboratory, McLean Hospital, Belmont, MA, USA; 4Department of Psychiatry, Harvard Medical School,
Belmont, MA, USA; 5Global Clinical Development, Shire, Wayne, PA, USA; 6Clinical Development Operations & Biometrics, Shire, Wayne, PA, USA

The efficacy and safety of lisdexamfetamine dimesylate (LDX) vs placebo in binge eating disorder (BED) was evaluated in two multicenter,
double-blind, placebo-controlled trials. Adults (study 1, n = 383; study 2, n = 390) meeting DSM-IV-TR BED criteria were randomized (1:1)
to placebo or LDX (50 or 70 mg/day) dose titration; optimized doses were maintained to the end of double-blind treatment (week 12/
early termination). Change from baseline in binge eating days/week at weeks 11−12 (primary efficacy endpoint) was assessed with mixed-
effects models for repeated measures. Secondary endpoints related to binge eating and medical parameters, safety, and treatment
compliance were also assessed. Least squares mean (95% CI) treatment differences for change from baseline binge eating days/week at
weeks 11–12 significantly favored LDX (study 1: –1.35 [–1.70, –1.01]; study 2: –1.66 [–2.04, –1.28]; both Po0.001). In both studies,
treatment-emergent adverse events (TEAEs) reported by ⩾ 10% of LDX participants were dry mouth, insomnia, and headache. Serious
TEAEs occurred in two (1.1%) placebo participants in each study and in three (1.6%) and one (0.6%) LDX participants in study 1 and study
2, respectively. Across studies, mean increases from baseline at week 12/early termination with LDX for pulse and systolic and diastolic
blood pressure ranged from 4.41–6.31 b.p.m. and 0.2–1.45 and 1.06–1.83 mm Hg, respectively. LDX (50 and 70 mg/day) was superior to
placebo in decreasing binge eating days/week from baseline and improving binge eating–related key secondary endpoints. Safety results
appear consistent with the known safety profile of LDX.
Neuropsychopharmacology (2016) 41, 1251–1260; doi:10.1038/npp.2015.275; published online 28 October 2015

INTRODUCTION and psychiatric comorbidities (Hudson et al, 2007; Kessler

et al, 2013); to be at increased risk for developing
The Diagnostic and Statistical Manual of Mental Disorders,
components of metabolic syndrome, including dyslipidemia
Fifth Edition (DSM-5) recognizes binge eating disorder and type 2 diabetes, even after controlling for body mass
(BED) as a distinct disorder (American Psychiatric index (BMI) (Hudson et al, 2010); to have reduced health-
Association, 2013). In BED, binge eating episodes occur related quality of life (Masheb and Grilo, 2004); and to have
⩾ 1 time per week for ⩾ 3 months; in the DSM-IV-TR increased healthcare utilization (Striegel-Moore et al, 2004).
provisional BED criteria, binge eating occurs on average Evidence suggests that binge eating pathology in BED may
⩾ 2 days per week for ⩾ 6 months (American Psychiatric respond to psychotherapy and pharmacotherapy (Reas and
Association, 2000). During these episodes, larger than usual Grilo, 2014; Vocks et al, 2010 ). Given the prevalence and
amounts of food are consumed during a discreet time period consequences of BED, more treatment options are needed.
and there is subjective lack of control and marked distress Lisdexamfetamine dimesylate (LDX), a d-amphetamine
over eating. Unlike in bulimia nervosa and anorexia nervosa, prodrug (Pennick, 2010) indicated for the treatment of
there are no recurrent and inappropriate compensatory attention-deficit/hyperactivity disorder, is also now approved
behaviors in BED, such as excessive exercise or purging. in the United States for the treatment of adults with
The estimated lifetime prevalence of BED is ~ 2−3% moderate to severe BED (Vyvanse [lisdexamfetamine
(Hudson et al, 2007; Kessler et al, 2013). Individuals with dimesylate], 2015). In a phase 2, fixed-dose, randomized,
BED have been reported to be at increased risk for obesity multicenter, double-blind, parallel-group, placebo-con-
trolled, dose-finding study, LDX (50 and 70 mg/day but not
*Correspondence: Dr SL McElroy, Lindner Center of HOPE, 4075 Old 30 mg/day) demonstrated efficacy vs placebo in decreasing
Western Row Rd, Mason, OH 45040, USA, Tel: +1 513 536-0700, Fax: binge eating days in individuals with BED (McElroy et al,
+1 513 536-0709, E-mail: [email protected] 2015). Here, the efficacy, safety, and tolerability findings
Received 1 April 2015; revised 2 July 2015; accepted 7 July 2015; of two phase 3, randomized, multicenter, double-blind,
accepted article preview online 9 September 2015 parallel-group, placebo-controlled trials in adults with
 Lisdexamfetamine for binge eating disorder
SL McElroy et al
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protocol-defined BED of at least moderate severity are These dual criteria designated moderate to severe BED as the
reported. presence of a binge eating frequency of ⩾ 3 binge eating
days/week for 2 consecutive weeks before baseline and a
Clinical Global Impressions-Severity score (Guy, 1976) at
MATERIALS AND METHODS screening and baseline of ⩾ 4. These criteria were considered
Trial Design clinically relevant because, in addition to accounting for
binge eating frequency, they incorporate a global assessment
Two randomized (1:1), placebo-controlled, parallel-group, of binge-related symptoms, distress, and impairment. BED
multicenter studies (Study 343, NCT01718483 [referred to as diagnosis was confirmed by the eating disorders module of
study 1 hereafter]; Study 344, NCT01718509 [referred to as the Structured Clinical Interview for the DSM-IV-TR Axis I
study 2 hereafter]) were conducted using the same design Disorders (SCID-I) (First et al, 2007) and the Eating
and methods. Study 1 included 50 unique sites Disorder Examination Questionnaire (Fairburn and Beglin,
(United States, n = 44; Sweden, n = 3; Spain, n = 1; Germany, 1994). At screening and baseline, eligible participants had
n = 2) between 26 November 2012 and 25 September 2013. BMI ⩾ 18 and ⩽ 45.
Study 2 included 43 unique sites (United States, n = 41; Key exclusion criteria included: current anorexia nervosa
Germany, n = 2) between 26 November 2012 and 20 (AN) or bulimia nervosa (BN), as defined by the SCID-I
September 2013. In studies 1 and 2, the mean number of eating disorders module; comorbid current psychiatric
randomized participants per site was 7.7 (median, 7; range, disorders either controlled with prohibited medications or
1–24) and 9.1 (median, 8; range, 1–25), respectively. For each uncontrolled and associated with significant symptoms or
site, there was only one principal investigator but multiple any condition/symptom that may confound clinical assess-
clinicians may have been involved at any individual site. ment; psychotherapy or weight loss support (including peer
Qualified clinicians were trained and approved to ensure support) for BED ⩽ 3 months before screening (psychother-
rigor, validity, and standardization. Standardized training apy for conditions other than BED was not recorded); use of
was provided by an expert in BED and included training on psychostimulants for fasting or dieting for BED ⩽ 6 months
the DSM-IV-TR criteria for BED, the core symptoms before screening; Montgomery–Åsberg Depression Rating
of BED, the definition of a binge eating episode, and on Scale total score ⩾ 18 at screening; being considered a suicide
the completion, content, and interpretation of the daily risk by the investigator, having previously made a suicide
binge diary. attempt, or currently demonstrating active suicidal ideation;
Subsequent to study completion and before unblinding, lifetime histories of psychosis, mania, hypomania, dementia,
two sites were excluded from study 2. One site was excluded or attention-deficit/hyperactivity disorder; histories of symp-
for Good Clinical Practice non-compliance; efficacy data tomatic cardiovascular disease, structural cardiac or heart
were excluded and safety data were included in primary rhythm abnormalities, cardiomyopathy, or coronary artery
analyses. One additional site was excluded due to an initiated disease; moderate or severe hypertension, resting average
external investigation for reasons unrelated to the respective sitting systolic blood pressure 4139 mm Hg, or average
study; safety and efficacy data from this site were excluded diastolic blood pressure 489 mm Hg at screening or baseline
from primary analyses. (mild, controlled hypertension was not exclusionary);
Each study included 2- to 4-week screening, 12-week a clinically significant electrocardiogram (ECG) at screening
double-blind treatment (dose optimization, 4 weeks; dose or baseline; lifetime amphetamine or stimulant
maintenance, 8 weeks), and 1-week follow-up phases abuse/dependence histories; recent history of substance
(Figure 1a). Dose-optimization designs, with target doses abuse/dependence (except nicotine); and having known/
established in the phase 2 study (50 and 70 mg LDX) suspected intolerance or hypersensitivity to LDX or related
(McElroy et al, 2015), were used. Study protocols were compounds.
approved by ethics committees; both studies were conducted
in accordance with International Conference on Harmonisa-
tion Good Clinical Practice and the principles of the Intervention
Declaration of Helsinki. Participants were required to After a 2- to 4-week screening period, eligible participants
provide written, informed consent before entering the were randomized 1:1 to 12 weeks of dose-optimized
studies. LDX or matching placebo (Figure 1a). The randomization
schedule was assigned by an interactive web response
Participants system. For blinding, both treatments were identical in
appearance; the blind was not to be broken during
Participants were recruited from investigators’ databases and the study.
via local/central advertisement. Eligible participants were During week 1, LDX was given at a daily dosage of 30 mg
men or nonpregnant women (18–55 years). These studies for initial titration only. During week 2, the daily LDX
were conducted before the release of the DSM-5, which states dosage was titrated to 50 mg. During weeks 3–4, increases to
that the minimum level of BED severity should be based on 70 mg LDX were made based on tolerability and clinical
the frequency of episodes of binge eating and that the need. A single downward titration to 50 mg was allowed
severity level may be increased to reflect other symptoms and at week 3 if the 70-mg dose was not tolerated. During
the degree of functional disability (American Psychiatric weeks 4–12, the optimized LDX dosage (50 or 70 mg) was
Association, 2013). These studies implemented dual criteria maintained. If a dose reduction occurred during optimiza-
for protocol-defined moderate to severe BED that were based tion phase, no further changes were allowed during
on DSM-IV-TR criteria and agreed upon by the authors. maintenance; participants requiring such a reduction were

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Figure 1 Study timeline and titration schedule (a) and participant disposition (b).

discontinued from the study. Throughout the study, Prespecified key secondary endpoints assessed global BED
participants were instructed to consume one capsule daily improvement (CGI–Improvement; CGI-I) at week 12/ET,
at ~ 0700 hours (±2 h). A follow-up visit occurred 1 week proportion of participants with 4-week binge eating cessation
after week 12/early termination (ET). at week 12/ET (no binge eating episodes for 28 consecutive
days before the last visit), Yale-Brown Obsessive Compulsive
Efficacy Assessments Scale Modified for Binge Eating (Y-BOCS-BE) total score
changes from baseline at week 12), and medical aspects
The primary efficacy endpoint was change from baseline in (percentage weight change from baseline at week 12 and
binge eating days/week at weeks 11–12 (visit 8) based on fasting triglyceride changes from baseline to week 12/ET) of
participants’ daily binge eating diaries, as reviewed and BED. CGI-I scores were assessed at weeks 1–4, 6, 8, 10, and
confirmed by investigators, as previously reported in a phase 12/ET. Body weight was assessed on a calibrated scale
2 study (McElroy et al, 2015). To allow for visit windows of (without shoes) at all study visits. The Y-BOCS-BE, a
± 2 days and for missing diary days, binge eating days/week modified version of Y-BOCS (Goodman et al, 1989) that has
was the number of confirmed binge eating days between previously been used in BED pharmacotherapy studies
visits multiplied by 7 and divided by the number of (McElroy et al, 2003, 2007a, b), was assessed at baseline
nonmissing diary days during the period. Binge eating days and weeks 4, 8, and 12/ET. The Y-BOCS-BE assesses
were recorded in daily participants’ diaries and assessed by obsessiveness of binge eating thoughts and compulsiveness
clinicians at all study visits except screening. of binge eating behaviors using a 10-item clinician-rated

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scale (0 [no symptoms] to 4 [extreme symptoms]); total that missingness was related to the data observed (Little et al,
scores range from 0–40. Fasting triglycerides were assessed at 2012). The first preplanned sensitivity analysis model used
screening and week 12/ET. multiple imputations based on the distribution of placebo
responses over time; the second model used multiple
Safety and Tolerability Assessments imputations with penalties applied to participants who
discontinued.
Safety and tolerability assessments included adverse events Dichotomized CGI-I scores of improved (very much
(AEs), vital signs, weight, ECGs, clinical laboratories, and improved or much improved) vs not improved (minimally
scores on the Columbia-Suicide Severity Rating Scale improved to very much worse) and the proportion of
(C-SSRS) and Amphetamine Cessation Symptom Assess- participants attaining 4-week binge eating cessation at week
ment (ACSA). The C-SSRS is a clinician-administered 12/ET were assessed with χ2 tests and CIs for binomial
prospective assessment of suicidal ideation and behavior proportions. Y-BOCS-BE total score changes and percentage
(Posner et al, 2011). The ACSA, a self-completed weight changes from baseline to week 12 were assessed using
questionnaire, contains 16 items rated on 5-point scales MMRM, as described above. Change from baseline to week
(0 [not at all] to 4 [extremely]); total score ranges from 0–64 12/ET in triglycerides was assessed using analysis of
(McGregor et al, 2008). Adverse events, vital signs, weight, covariance, with treatment as a factor and baseline as a
and C-SSRS scores were assessed at all study visits. Scores on covariate. Safety and tolerability assessments were conducted
the ACSA were assessed at baseline, week 12/ET, and daily in the safety analysis set (all randomized participants taking
through the follow-up period. Clinical laboratory evaluations ⩾ 1 study drug dose and having ⩾ 1 postbaseline safety
were assessed at screening and week 12/ET; ECGs were assessment) and are presented descriptively.
assessed at screening, baseline, week 4, and week 12/ET. Post hoc sensitivity analyses were also conducted that
Clinical adherence (participants taking 80–100% of study included data from the two aforementioned excluded sites
medication) was determined by the investigator at every visit using the same statistical methods described above.
for study management purposes; calculated adherence
(participants taking 80 − 120% of study medication: total
capsules taken × 100/total days of dosing) was determined as RESULTS
a statistical compliance assessment. Disposition and Demographics
Most participants from each treatment group completed
Statistical Analysis each study (Figure 1b). Demographic and clinical
Statistical assessments of the primary and key secondary characteristics are summarized in Table 1. In both studies,
efficacy endpoints were conducted in the full analysis set most participants were white, female, and obese
(all randomized participants taking ⩾ 1 study drug dose and (BMI ⩾ 30.0 kg/m2). The baseline mean ± SD number of
having ⩾ 1 postbaseline primary efficacy assessment); binge eating days/week was 4.69 ± 1.237 in study 1 and
statistical significance was set at a 2-sided Po0.05. 4.75 ± 1.359 in study 2.
Hierarchical testing procedures were used, with statistical The overall proportion of individuals with comorbid
assessments made in the following order based on clinical psychiatric disorders was low, with the most common
importance and likelihood of effect based on phase 2 results: psychiatric disorder in each study being past major
changes in binge eating days/week, CGI-I, 4-week binge depressive disorder (Supplementary Table 1). Few partici-
eating cessation, percentage body weight changes, Y-BOCS- pants had received psychotherapy for BED in the past (study
BE total score changes, and triglyceride changes. A later test 1: placebo, 2.1% [4/187]; LDX, 1.6% [3/192]; study 2:
was only significant if all earlier tests were significant. placebo, 1.1% [2/185]; LDX, 0%) or were currently receiving
Sample size was estimated for the primary efficacy psychotherapy for BED (study 1: placebo, 0.5% [1/187]; LDX,
endpoint using nQuery 6.0 (Statistical Solutions; Boston, 0%; study 2: placebo, 0.5% [1/185]; LDX, 0.6% [1/181]).
MA). Assuming an effect size of 0.4 (LDX vs placebo), it was No participant in either study met criteria for a
estimated that 133 participants completing each treatment current diagnosis of BN or AN or for diagnoses of BN or
would provide 90% power. AN within the last month. In study 1, two participants
Change in binge eating days/week was assessed using a reported lifetime histories of AN (at least 58 months had
mixed-effects model for repeated measures (MMRM), with elapsed since the last symptoms) and six participants
treatment, visit, and the treatment × visit interaction as reported lifetime histories of BN (at least 18 months
factors and baseline binge eating days/week as a covariate; had elapsed since the last symptoms). In study 2, one
the baseline binge eating days/week × visit interaction was participant reported a lifetime history of AN (at least
also included in the model. MMRM accounts for the 72 months had elapsed since the last symptoms) and two
repeated measures structure of the data by factoring in participants reported lifetime histories of BN (at least
correlations within each participant across multiple visits 36 months had elapsed since the last symptoms).
(Siddiqui, 2011) and is an analytic method that is widely
accepted for continuous endpoints in clinical trials. The
Drug Exposure and Adherence
primary efficacy analysis was based on the assumption of a
missing-at-random mechanism, namely, missingness was The mean ± SD daily LDX dosage during the entire double-
not related to the data not observed (Little et al, 2012). Two blind treatment phase was 56.9 ± 9.72 mg (study 1) and
preplanned sensitivity analyses were conducted using a 57.6 ± 9.24 mg (study 2). Most LDX participants received
different missing-not-at-random mechanism, which assumes 70 mg as the optimized dosage (study 1, 117/192 [60.9%];

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Table 1 Demographics and Baseline Clinical Characteristics, Safety Analysis Set
Study 1 Study 2

Placebo (n = 187) LDX (n = 192) Placebo (n = 185) LDX (n = 181)

Mean ± SD age, y 37.6 10.21 38.5 10.40 38.7 10.01 37.1 10.00

Sex, n (%)
Female 163 (87.2) 165 (85.9) 153 (82.7) 159 (87.8)

Race, n (%)
White 144 (77.0) 150 (78.1) 137 (74.1) 130 (71.8)
Black/African American 29 (15.5) 33 (17.2) 32 (17.3) 43 (23.8)
Native Hawaiian/Pacific Islander 1 (0.5) 2 (1.0) 0 2 (1.1)
Asian 5 (2.7) 3 (1.6) 4 (2.2) 3 (1.7)
American Indian/Alaska Native 2 (1.1) 2 (1.0) 4 (2.2) 0
Multiple 6 (3.2) 1 (0.5) 8 (4.3) 3 (1.7)
Mean ± SD weight, kg 92.70 19.331 94.30 19.732 93.05 20.330 94.75 21.745
Mean ± SD BMI, kg/m2 33.21 6.234 33.68 6.292 33.20 6.341 33.85 6.202

BMI category, n (%)

Underweight/Normal (o25.0 kg/m2)a 22 (11.8) 14 (7.3) 21 (11.4) 13 (7.2)
Overweight (⩾25.0–o30.0 kg/m2) 39 (20.9) 49 (25.5) 36 (19.5) 43 (23.8)
Obesity Class I (⩾30.0–o35.0 kg/m2) 49 (26.2) 48 (25.0) 54 (29.2) 48 (26.5)
Obesity Class II (⩾35.0–o40.0 kg/m2) 47 (25.1) 43 (22.4) 39 (21.1) 41 (22.7)
Obesity Class III (⩾40.0 kg/m2) 30 (16.0) 38 (19.8) 35 (18.9) 36 (19.9)
Any obesity Class (⩾30.0 kg/m2) 126 (67.4) 129 (67.2) 128 (69.2) 125 (69.1)
Mean ± SD triglycerides, mmol/l 1.266 0.6787 1.340 0.7322 1.273 0.6108 1.280 0.7500
Mean ± SD binge days/week 4.59 1.201 4.78 1.266 4.85 1.433 4.66 1.279
Mean ± SD binge episodes/week 5.96 2.535 6.41 2.957 6.65 3.787 6.39 3.439
Mean ± SD CGI-S 4.6 0.67 4.6 0.63 4.6 0.72 4.5 0.71

CGI-S,b n (%)
Moderately ill 88 (47.1) 99 (51.6) 100 (54.1) 105 (58.0)
Markedly ill 83 (44.4) 79 (41.1) 61 (33.0) 63 (34.8)
Severely ill 14 (7.5) 14 (7.3) 23 (12.4) 8 (4.4)
Among the most extremely ill 2 (1.1) 0 1 (0.5) 5 (2.8)
Mean ± SD Y-BOCS-BE total score 21.58 4.777 21.83 4.897 21.61 4.815 21.15 4.399
Mean ± SD MADRS 4.2 3.77 3.9 3.82 3.8 3.85 3.1 3.17

Abbreviations: BMI, body mass index; CGI-S, Clinical Global Impressions-Severity; LDX, lisdexamfetamine dimesylate; MADRS, Montgomery-Åsberg Depression Rating
Scale; Y-BOCS-BE, Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating.
a
Participants with BMI o18 kg/m2 were not enrolled.
b
Based on inclusion criteria, a CGI-S score ⩾ 4 (at least moderately ill) was required for study eligibility.

study 2, 113/181 [62.4%]); 50 mg was the optimized dosage Efficacy

in 29.7% (57/192) and 28.7% (52/181) of LDX participants
in study 1 and study 2, respectively. Mean (SD) days of Primary endpoint. The least squares mean (SEM)
exposure (placebo vs LDX) were 76.6 ± 20.72 and changes from baseline in binge eating days/week at weeks
75.7 ± 20.81 in study 1 and 73.1 ± 22.99 and 75.8 ± 20.14 in 11 − 12 were –2.51 (0.125) with placebo and –3.87
study 2. (0.124) with LDX in study 1 and –2.26 (0.137) with placebo
Most participants were regarded as clinically adherent; and –3.92 (0.135) with LDX in study 2 (Figure 2a and b; see
calculated adherence was high (study 1: placebo = 187/187 Table 1 for baseline values); least squares mean (95% CI)
[100%], LDX = 188/192 [97.9%]; study 2: placebo = 183/185 treatment differences for change from baseline at
[98.9%], LDX = 180/181 [99.4%]). No participant in either weeks 11 − 12 favored LDX for both studies (study 1: –1.35
study took 4120% of the medication. [–1.70, –1.01], Po0.001; effect size [95% CI], 0.83 [0.60,

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Differences in the reduction in triglyceride levels for LDX vs
placebo were also statistically significant in both studies
(Table 2), with mean values being within the normal range at
baseline and week 12/ET.

Safety and Tolerability

In each study, 450% of the participants in each treatment
group reported TEAEs (Table 3); more TEAEs were related
to study drug with LDX than with placebo. Most TEAEs in
each study were mild or moderate in severity. In each study,
TEAEs reported by 410% of LDX-treated participants were
dry mouth, headache, and insomnia; no TEAE was reported
in 410% of placebo-treated participants (Table 3).
Serious TEAEs were infrequent and reported in equal
proportions with LDX and placebo in each study (Table 3)
and generally reflected intercurrent illness and accidental or
potential BED-associated comorbidities. LDX-associated
SAEs were considered unrelated to treatment by investiga-
tors, except for two syncope cases which resulted in
participant discontinuation. One case did not require
medical intervention; the other was confounded by multiple
concomitant medications and a medical history of
narcolepsy and hypertension. A single instance of syncope
as a treatment-emergent SAE also occurred with placebo and
resulted in participant discontinuation. TEAEs leading to
discontinuation occurred infrequently in both groups in both
Figure 2 Change from baseline in binge eating days per week in Study 1 studies (Table 3); there were no deaths during either study.
(a) and Study 2 (b), full analysis set. LDX, lisdexamfetamine dimesylate. Across studies, mean increases from baseline at week
12/ET with LDX ranged from 4.41–6.31 b.p.m. for pulse rate,
0.2–1.45 mm Hg for systolic blood pressure, and
1.06–1.83 mm Hg for diastolic blood pressure (Table 3). All
baseline ECG measures were similar between treatments in
1.05]; study 2: –1.66 [–2.04, –1.28], Po0.001; effect size [95%
each study, with ECG-assessed heart rate changes being
CI], 0.97 [0.72, 1.21]).
similar to pulse rate changes (Table 3).
The pattern of missing values and the results of the
Mean ± SD ACSA total aggregate scores were low at
preplanned sensitivity analyses based on missing-not-at-
baseline in both groups (study 1: placebo = 9.6 ± 8.63,
random assumptions for the change from baseline in the
LDX = 10.3 ± 10.28; study 2: placebo = 7.6 ± 8.87, LDX = 7.3
number of binge days per week are summarized in
± 8.46); scores were below baseline scores during the
Supplementary Tables 2 and 3, respectively. The results of
post-cessation period (day of last dose: placebo = 7.3 ± 7.74
the preplanned sensitivity analysis were consistent with the
and LDX = 5.7 ± 7.37 in study 1 and placebo = 7.0 ± 7.69,
primary analysis results, indicating the data are robust to
LDX = 4.6 ± 5.83 in study 2); 7 days post treatment:
underlying missingness assumptions.
placebo = 5.5 ± 7.41 and LDX = 5.7 ± 7.42 in study 1 and
Subgroup analyses of the primary efficacy endpoint
placebo = 4.1 ± 6.02 and LDX = 5.1 ± 7.32 in study 2), with
by age (o40 vs ⩾ 40 years), sex, and race (white vs non-
no indication of withdrawal symptoms as measured
white) are depicted in Supplementary Figure 1. In all
by ACSA.
subgroups, least squares mean decreases from baseline in
On the C-SSRS, there were no positive affirmations
the number of binge eating days/week were noted for
including preparatory acts, actual, interrupted, or aborted
both treatment groups and were numerically greater for
suicide attempts with either treatment during either study.
LDX vs placebo. For the majority of subgroups, the 95% CIs
There were positive affirmations of active suicidal ideation in
(except for the male and non-white subgroups in study 1)
study 1 only with placebo (“any active suicidal ideation”:
fell to the left of zero, indicating greater mean improve-
n = 1 each at weeks 1 and 12). There were no positive
ment for LDX relative to placebo. However, because
affirmations of active suicidal ideation with either treatment
randomization was not stratified based on these subgroups,
in study 2.
the number of participants within each subgroup was
not consistently balanced and definitive conclusions cannot
be drawn.
Post Hoc Sensitivity Analyses
The overall efficacy, safety, and tolerability findings
Key secondary endpoints. Statistically significant treatment of study 2 did not change based on the inclusion of data
effects favoring LDX were seen for CGI-I, 4-week cessation, from the 2 aforementioned excluded study sites (data not
body weight, and Y-BOCS-BE in both studies (Table 2). shown).

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Table 2 Summary of Key Secondary Endpoints, Full Analysis Set
Study 1 Study 2

Placebo (n = 184) LDX (n = 190) Placebo (n = 176) LDX (n = 174)

a
CGI-I at week 12/ET, n (%)
Improved 87 (47.3) 156 (82.1) 75 (42.9) 150 (86.2)
95% CI for % improved (40.1, 54.5) (76.7, 87.6) (35.5, 50.2) (81.1, 91.3)
Not improved 97 (52.7) 34 (17.9) 100 (57.1) 24 (13.8)
Po0.001 Po0.001
Risk difference (95% CI) for improvedb 34.8 (25.8, 43.9) 43.3 (34.4, 52.3)
Odds ratio (95% CI)c 5.1 (3.2, 8.2) 8.3 (4.9, 14.1)

4-week binge cessation at week 12/ET,a n (%)

Cessation 26 (14.1) 76 (40.0) 23 (13.1) 63 (36.2)
95% CI for % cessation (9.1, 19.2) (33.0, 47.0) (8.1, 18.0) (29.1, 43.3)
No cessation 158 (85.9) 114 (60.0) 153 (86.9) 111 (63.8)
Po0.001 Po0.001
Risk difference (95% CI) for cessationb 25.9 (17.3, 34.5) 23.1 (14.4, 31.8)
Odds ratio (95% CI)c 4.1 (2.4, 6.7) 3.8 (2.2, 6.5)

Body weight percentage change from baseline at week 12d

LS mean (SEM) 0.11 (0.295) –6.25 (0.292) –0.15 (0.353) –5.57 (0.350)
LS mean (95% CI) treatment difference –6.35 (–7.17, –5.54) Po0.001 –5.41 (–6.39, –4.44) Po0.001
Effect size (95% CI) 1.64 (1.39, 1.90) 1.22 (0.97, 1.48)

Y-BOCS-BE total score change from baseline at week 12d

LS mean (SEM) –8.28 (0.550) –15.68 (0.546) –7.42 (0.571) –15.36 (0.563)
LS mean (95% CI) treatment difference –7.40 (–8.93, –5.88) Po0.001 –7.94 (–9.51, –6.36) Po0.001
Effect size (95% CI) 1.03 (0.80, 1.27) 1.11 (0.87, 1.36)

Triglycerides change from baseline at week 12/ET,e mmol/l

LS mean (SEM) 0.122 (0.0405) –0.077 (0.0393) 0.062 (0.0453) –0.133 (0.0449)
LS mean (95% CI) treatment difference –0.199 (–0.310, –0.088) Po0.001 –0.196 (–0.321, –0.070) P = 0.002
Effect size (95% CI) 0.38 (0.17, 0.59) 0.35 (0.12, 0.57)

Abbreviations: CGI-I, Clinical Global Impressions–Improvement; ET, early termination; LDX, lisdexamfetamine dimesylate; LS, least squares; Y-BOCS-BE, Yale-Brown
Obsessive Compulsive Scale Modified for Binge Eating.
a
P-values based on w2 tests; 95% CIs based on binomial proportions.
b
Difference calculated as LDX–placebo.
c
Ratio calculated as LDX/placebo.
d
P-values based on mixed-effects model for repeated measures, with treatment, visit, and the treatment × visit interaction as factors and baseline value as a covariate and
the interaction of baseline × visit included in the model; effect size based on the estimated SD from the unstructured covariance matrix.
e
P-values based on analysis of covariance, with treatment as a factor and baseline value as a covariate; effect size based on the estimated SD from the root mean
square error.

DISCUSSION In addition, the percent weight reduction from baseline

with LDX was statistically significantly greater than with
LDX produced statistically significant and clinically mean-
ingful reductions in binge eating days/week (primary efficacy placebo. Reductions from baseline in fasting triglycerides
endpoint) relative to placebo in adults with moderate to were statistically greater with LDX compared with placebo,
severe BED. This same effect was observed in both of the two but the clinical significance of these changes is unclear
identically designed studies. These results are consistent because mean baseline and week12/ET values were in the
with previous findings from a phase 2 trial of LDX for the normal range.
treatment of BED, in which 50 and 70 mg LDX (but not Although LDX is currently the only medication approved
30 mg) produced significantly greater decreases in binge for the treatment of adults with mild to moderate BED
eating days/week than placebo (McElroy et al, 2015). by the US Food and Drug Administration (Vyvanse
In the current studies, LDX was also associated with [lisdexamfetamine dimesylate], 2015), several other types of
statistically significant and clinically meaningful greater medications have been investigated for the treatment of BED.
response on outcomes of global improvement in BED Placebo-controlled studies of antidepressants have usually,
pathology, 4-week cessation of binge eating at endpoint, but not always, found a statistically significant reduction in
and BED-related obsessive and compulsive psychopathology. the frequency of binge eating and related measures of

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Table 3 TEAEs and Vital Sign Changes From Baseline at Week 12/ET, Safety Analysis Set
Study 1 Study 2

Placebo (n = 187) LDX (n = 192) Placebo (n = 185) LDX (n = 181)

Any TEAE, n (%) 110 (58.8) 158 (82.3) Any TEAE, n (%) 94 (50.8) 140 (77.3)
Serious TEAEsa 2 (1.1) 3 (1.6) Serious TEAEsa 2 (1.1) 1 (0.6)
TEAEs related to study drug 71 (38.0) 134 (69.8) TEAEs related to study drug 56 (30.3) 119 (65.7)
Severe TEAEs 6 (3.2) 17 (8.9) Severe TEAEs 6 (3.2) 7 (3.9)
TEAEs leading to discontinuationb 5 (2.7) 12 (6.3) TEAEs leading to discontinuationb 4 (2.2) 7 (3.9)

TEAEs in ⩾ 5% of participants in either treatment group, n (%) TEAEs in ⩾ 5% of participants in either treatment group, n (%)
Dry mouth 16 (8.6) 76 (39.6) Dry mouth 11 (5.9) 60 (33.1)
Insomnia 14 (7.5) 34 (17.7) Headache 16 (8.6) 32 (17.7)
Headache 17 (9.1) 26 (13.5) Insomnia 6 (3.2) 19 (10.5)
Decreased appetite 6 (3.2) 17 (8.9) Fatigue 9 (4.9) 17 (9.4)
Nausea 14 (7.5) 16 (8.3) Nausea 8 (4.3) 16 (8.8)
Irritability 13 (7.0) 16 (8.3) Diarrhea 3 (1.6) 11 (6.1)
Heart rate increased 5 (2.7) 14 (7.3) Decreased appetite 3 (1.6) 11 (6.1)
Anxiety 2 (1.1) 13 (6.8) Constipation 1 (0.5) 10 (5.5)
Feeling jittery 2 (1.1) 11 (5.7) Feeling jittery 0 10 (5.5)
Constipation 4 (2.1) 11 (5.7) Blood pressure increased 5 (2.7) 9 (5.0)
Hyperhidrosis 1 (0.5) 10 (5.2) Irritability 6 (3.2) 9 (5.0)
Upper respiratory tract infection 11 (5.9) 8 (4.2)
Fatigue 10 (5.3) 7 (3.6)

Vital signs, mean ± SD Vital signs, mean ± SD

SBP, mm Hg –3.18 8.544 0.20 10.216 SBP, mm Hg –1.87 8.947 1.45 10.818
DBP, mm Hg –1.67 6.976 1.06 7.905 DBP, mm Hg –1.17 7.376 1.83 7.956
Pulse rate, b.p.m. 1.62 8.983 6.31 9.505 Pulse rate, b.p.m. 1.95 8.725 4.41 11.370

ECG, mean ± SD ECG, mean ± SD

Heart rate, b.p.m. –1.38 9.149 3.57 10.939 Heart rate, b.p.m. (ECG) –0.15 8.424 3.57 10.916
Fridericia’s corrected QTc, ms –1.36 11.822 –1.60 13.883 Fridericia’s corrected QTc, ms 0.65 12.648 –1.22 13.204
Bazzett’s corrected QTc, ms –2.87 15.045 1.68 17.944 Bazzett’s corrected QTc, ms 0.53 15.251 2.21 17.243

Abbreviations: b.p.m., beats per minute; DBP, diastolic blood pressure; ECG, electrocardiogram; ET, early termination; LDX, lisdexamfetamine dimesylate; SBP, systolic
blood pressure; TEAE, treatment-emergent adverse event.
a
Study 1: anaphylactic reaction and conversion disorder (each 0.5%) with placebo, syncope (1.0%) and cholecystitis (0.5%) with LDX; study 2: fibula fracture, syncope,
agitation, and anxiety (each 0.5%) with placebo, lumbar vertebral fracture (0.6%) with LDX.
b
Study 1: chest discomfort, palpitations, conversion disorder, anaphylactic reaction, and venous insufficiency with placebo (each 0.5%), and syncope and irritability (each
1.0%) and feeling jittery, headache, tachycardia, cholecystitis, increased gamma-glutamyltransferase, fungal pneumonia, anxiety, and dyspnea (each 0.5%) with LDX; study
2: anxiety, fibula fracture, blood pressure increase, and bradycardia (each 0.5%) with placebo and initial insomnia, insomnia, optic atrophy, upper abdominal pain, lumbar
vertebral fracture, increased heart rate, and rash (each 0.6%) with LDX.

pathology compared with placebo, but only modest effects the sample sizes are small (Reas and Grilo, 2014). Statistically
on weight (Reas and Grilo, 2014). Placebo-controlled studies significant findings in favor of efficacy over placebo have
of topiramate (Claudino et al, 2007; McElroy et al, 2003, been reported in a limited number of studies (Corwin et al,
2007b) and sibutramine (Appolinario et al, 2003; Wilfley 2012; McElroy et al, 2006, 2007a; Pataky et al, 2013).
et al, 2008) have yielded significant effects on frequency of The safety and tolerability profile of LDX observed
binge eating, other BED-related psychopathology, and regarding overall TEAEs, TEAEs leading to discontinuation,
weight. However, sibutramine is no longer marketed and vital signs, and ECGs were consistent with published reports
the use of topiramate has been limited due to side effects, in adults with BED (McElroy et al, 2015) or attention-deficit/
mainly cognitive impairment (Arif et al, 2009). The results of hyperactivity disorder (Adler et al, 2008; Wigal et al, 2010).
several small randomized, controlled trials of orlistat in BED Headache, insomnia, and dry mouth were the most
have been mixed (Golay et al, 2005; Grilo et al, 2005; Grilo frequently reported TEAEs with LDX in each study.
and White, 2013). Clinical trials to assess other agents for Discontinuations due to TEAEs with LDX in these studies
BED have been conducted, but there has only been at most a (6.3% and 3.9%) are comparable to a published phase 2
single placebo-controlled trial for any given medication and study of LDX in BED (McElroy et al, 2015), to other clinical

Neuropsychopharmacology
 Lisdexamfetamine for binge eating disorder
SL McElroy et al
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studies of LDX for which LDX is indicated (Adler et al, 2008; writing and editing this manuscript. Although the sponsor
Wigal et al, 2010), and to other BED pharmacotherapy trials was involved in the design, collection, management, analysis,
with other agents (Claudino et al, 2007; McElroy et al, 2003, interpretation, and fact checking of the data, the decision to
2007a, b). submit it for publication in Neuropsychopharmacology was
These findings should be considered in light of potential made by the authors.
limitations. Study participants were mainly women,
white, overweight or obese, and did not have any current
psychiatric comorbidities. As a result, caution is needed ACKNOWLEDGMENTS
when generalizing to a more heterogeneous population. In Under the direction of the authors, Stefan Kolata, PhD, and
addition, the short-term nature of the studies precludes Craig Slawecki, PhD, employees of Complete Healthcare
extrapolations to the long-term efficacy, tolerability, and Communications, LLC (CHC), provided writing and for-
safety of LDX in individuals with BED. Also, comparisons of matting assistance for this manuscript. Editorial assistance in
the efficacy of LDX in participants receiving vs not receiving the form of proofreading, copyediting, and fact checking was
psychotherapy for BED were not conducted because the also provided by CHC.
number of participants receiving psychotherapy for BED in
the past or currently was small in both studies.
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