Clinical trial NCT03107026
Conditions: Binge Eating Disorder
Keywords: Binge eating Disorder dasotraline
Sponsor: Sumitomo Pharma America, Inc.
Start date: 2017-03-31; Completion date: 2018-05-16
Enrollment: 491 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A study to evaluate a drug (dasotraline) on the safety, effectiveness and how well the body tolerates it, in adults with moderate to severe binge eating disorder

Detailed description:
This is a randomized, double-blind, parallel-group, multicenter, outpatient study evaluating the efficacy and safety of 2 doses of dasotraline (4 and 6 mg/day) versus placebo over a 12-week treatment period in adults with BED. This study is projected to randomize approximately 480 subjects to 3 treatment groups in a 1:1:1 ratio (4 mg/day dasotraline, 6 mg/day dasotraline, and placebo).

Subjects randomized to placebo will receive placebo for the duration of the treatment period.

Subjects randomized to 4 mg/day dasotraline will receive 4 mg/day for the duration of the treatment period.

Subjects randomized to 6 mg/day dasotraline will be dosed with 4 mg/day dasotraline for the first 2 weeks of the treatment period and will be increased to 6 mg/day at Week 2.

If, in the judgment of the Investigator, the subject does not tolerate the assigned dose, he or she will be discontinued from the study.

The study will consist of 3 periods: Screening (up to 3 weeks), 12-weeks of treatment, and a 3-week study drug withdrawal period. Subjects who complete the 12-week double-blind treatment period in this study may be eligible to enroll and continue treatment for an additional 12 months in an open-label extension study (Study SEP360-322). Subjects who do not enter the extension study will complete the study drug withdrawal period in this study.

Arms: arm 1: dasotraline 4mg once daily arm 2: dasotraline 6mg once daily arm 3: Placebo, once daily
Interventions: intervention 1: dasotraline 4mg intervention 2: dasotraline 6mg intervention 3: Placebo
Intervention descriptions: intervention 1: dasotraline 4mg tablet once daily intervention 2: dasotraline 6mg tablet once daily intervention 3: Placebo tablet once daily

Protocol documents:
Prot_000.pdf: 
 
 
 
Titlpage
 
 
 
SEP-225289 
Dasotraline 
Clinical Study Protocol SEP360-321 
 
A 12-week, Randomized, Double-blind, Parallel-group, 
Placebo-controlled, Fixed-dosed, Multicenter Study to Evaluate the 
Efficacy, Safety, and Tolerability of Dasotraline in Adults with 
Moderate to Severe Binge Eating Disorder 
 
IND No. 125,078 
 
 
Version 3.00 
17 Nov 2017 
 
 
 
SUNOVION PHARMACEUTICALS INC. 
84 Waterford Drive 
Marlborough, MA 01752, USA 
(508) 481-6700 
 


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RESTRICTED DISTRIBUTION OF PROTOCOLS 
This document contains information confidential and/or of proprietary interest to Sumitomo 
Dainippon Pharma Co. Ltd. and/or Sunovion Pharmaceuticals Inc. (including their 
The information cannot be disclosed to any third party or 
predecessors, subsidiaries or affiliates). 
used for any purpose other than the purpose for which it is being submitted without the prior 
written consent of the appropriate Sumitomo Dainippon Pharma company. 
This information is being provided to you for the purpose of conducting a clinical study for 
Sunovion Pharmaceuticals Inc. You may disclose the contents of this protocol to the study 
personnel under your supervision and to your Institutional Review Board or Independent Ethics 
Committee for the above purpose. You may not disclose the contents of this protocol to any 
other parties, unless such disclosure is required by government regulations or laws, without the 
prior written permission of Sunovion Pharmaceuticals Inc. 
Any data gathered during the conduct of this protocol and supplemental information (eg, a 
 
protocol amendment) that may be added to this document is also proprietary to Sunovion 
Pharmaceuticals Inc., and should be handled consistently with that stated above. 


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EMERGENCY CONTACTS 
Table 1: Emergency Contact Information 
Role in Study 
Name 
Contact Information 
Responsible Physician 
 
Medical Monitor 
 
SAE/Pregnancy Reporting 


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1.
SYNOPSIS
Name of Sponsor: Sunovion Pharmaceuticals Inc. 
Name of Investigational Product: Dasotraline 
Title of Study: A 12-week, Randomized, Double-blind, Parallel-group, Placebo-controlled, 
Fixed-dosed, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of Dasotraline in 
Adults with Moderate to Severe Binge Eating Disorder 
Proposed Indication: Binge Eating Disorder (BED) 
Study Centers: approximately 50 clinical sites in the United States 
Planned Study Period: approximately 15 months from first subject screened to last subject last visit 
Study Objective: 
Primary: Evaluate the efficacy of 2 doses of dasotraline (4 and 6 mg/day) compared with placebo in 
adults with moderate to severe BED as measured by the number of binge days per week 
Key Secondary: Evaluate the efficacy of 2 doses of dasotraline (4 and 6 mg/day) compared with 
placebo in adults with moderate to severe BED as measured by: 
•
Binge-eating Clinical Global Impression-Severity (BE-CGI-S)
•
4-Week cessation from binge eating defined as a 100% reduction for at least 28 consecutive
days in the number of binge eating episodes
•
Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating (Y-BOCS-BE)
Other Secondary: 
•
Evaluate the efficacy of 2 doses of dasotraline (4 and 6 mg/day) compared with placebo in
adults with moderate to severe BED as measured by:
o
Number of binge episodes per week
o
Proportion of binge eating responders at Week 12 who show > 75% reduction in the
number of binge eating episodes
o
Sheehan Disability Scale (SDS)
o
Montgomery-Asberg Depression Rating Scale (MADRS)
o
Hamilton Anxiety Rating Scale (HAM-A)
o
Eating Disorder Examination Questionnaire (EDE-Q) modified
•
Evaluate the safety and tolerability of 2 doses of dasotraline (4 and 6 mg/day) using physical
examinations, 12-lead electrocardiograms (ECG), vital signs, adverse event (AE) reports,
clinical laboratory results, body weight, body mass index (BMI), and Columbia – Suicide
Severity Rating Scale (C-SSRS)
•
Assess potential withdrawal effects upon abrupt discontinuation of dasotraline after 12 weeks
of continuous daily treatment using the following assessments (administered during the
withdrawal period):


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o
Cocaine Selective Severity Assessment (CSSA)
o
Discontinuation-Emergent Signs and Symptoms (DESS) Scale
o
Symptoms of anxiety utilizing the HAM-A
o
Symptoms of depression utilizing the MADRS
•
Assess the abuse potential of dasotraline utilizing a comprehensive abuse potential monitoring
plan (APMP)
•
Assess the relationship between dasotraline plasma concentration and the primary efficacy and
selected secondary efficacy and safety endpoints
Study Design: This is a randomized, double-blind, parallel-group, multicenter, outpatient study 
evaluating the efficacy and safety of 2 doses of dasotraline (4 and 6 mg/day) versus placebo over a 
12-week treatment period in adults with BED. Subjects will be randomized to 3 treatment groups in a 
1:1:1 ratio (4 mg/day dasotraline, 6 mg/day dasotraline, and placebo). 
Subjects randomized to placebo will receive placebo for the duration of the treatment period. 
Subjects randomized to 4 mg/day dasotraline will receive 4 mg/day for the duration of the treatment 
period. 
Subjects randomized to 6 mg/day dasotraline will be dosed with 4 mg/day dasotraline for the first 
2 weeks of the treatment period and will be increased to 6 mg/day at Week 2. 
If, in the judgment of the Investigator, the subject does not tolerate the assigned dose, he or she will be 
discontinued from the study. 
The study will consist of 3 periods: Screening (up to 3 weeks), 12-weeks of treatment, and a 3-week 
study drug withdrawal period. Subjects who complete the 12-week double-blind treatment period in 
this study may be eligible to enroll and continue treatment for an additional 12 months in an open-label 
extension study (Study SEP360-322; see Figure 1). Subjects who do not enter the extension study will 
complete the study drug withdrawal period in this study. 
Efficacy will be evaluated at each visit using the subject binge eating diary and a clinician interview to 
assess the frequency of binge episodes and the number of binge days, defined as days with at least one 
binge episode. Additional assessments will include BE-CGI-S, Y-BOCS-BE, MADRS, HAM-A, SDS, 
and EDE-Q modified. Safety and tolerability will be monitored throughout the study by collection of 
physical examination results, ECGs, vital signs, AEs, clinical laboratory parameters, C-SSRS, body 
weight, and BMI will be calculated. Subjects who have significant findings for suicidal ideation upon 
completion of the C-SSRS at any time during the study must be referred to the Investigator for follow-
up evaluation. Assessment of potential withdrawal effects will be conducted via administration of the 
CSSA, DESS, HAM-A, and MADRS at the end of treatment and during the 3-week study medication 
withdrawal period. 
Blood samples for pharmacokinetics (PK) and biomarkers associated with eating disorders (to be 
determined) will be collected. Blood samples collected for PK assessment will be analyzed for plasma 
concentrations of dasotraline. The relationship between dasotraline plasma concentration and the 
primary and selected secondary clinical outcome measures will be evaluated. The relationship between 
biomarkers associated with eating disorders in relationship to the severity of BED and response to 
dasotraline will be evaluated at a later date in the development program. Plasma samples collected for 
PK and biomarker concentration analysis may also be used for the additional characterization of and/or 
bioanalytical method development for dasotraline. 
A blood sample will be collected from subjects who provide separate informed consent for 
pharmacogenomics (PGx) analysis for potential evaluation of associations between genetic 
polymorphisms such as, but not limited to Taq1DRD2, OPRM1, and DRD4-7R, and the severity of 


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BED, the clinical response to dasotraline, in addition to the safety, efficacy, and PK profiles of 
dasotraline to be conducted at a later date in the development program. Separate consent is required for 
collection of this specific blood sample and will be obtained at Screening for subjects who agree to 
provide this sample (note: this separate consent is not required for participation in the study, it is 
required only for subjects who will provide this sample). 
A comprehensive Abuse Potential Monitoring Plan (APMP) for dasotraline designed to detect potential 
abuse of the compound and to more closely monitor AEs consistent with the known pharmacology for 
dasotraline will be implemented. 
An independent Data and Safety Monitoring Board (DSMB) will review safety data at regular 
intervals. 
Screening Period (Days -22 to -2): Informed consent will be obtained from each subject before any 
study procedures are performed for this study. Study eligibility criteria will be assessed during this 
period, and subjects will be required to have discontinued from any protocol prohibited medications 
within 3 months of screening. The subject’s eligibility assessment will be reviewed by the contract 
research organization’s (CRO) oversight quality team along with the sponsor based on protocol 
specified inclusion and exclusion criteria. The sponsor will participate in the eligibility review process 
with the CRO to ascertain the subject’s eligibility and will be copied on all communications between 
the CRO and the site. In the event the CRO/sponsor and site do not agree on a subject’s eligibility then 
the subject will not be enrolled. Subjects may be rescreened once for out of range clinical laboratory 
results including urine drug screen (UDS) or ECG results following authorization of the medical 
monitor. During the screening visit, subjects will be trained to complete the daily binge eating diary 
and then complete the diary at home for at least 14 consecutive days immediately prior to the Baseline 
visit and starting no sooner than the day after the screening visit. 
Baseline Visit (Day -1): Subjects who meet eligibility criteria at Screening will return to the study site 
on Day -1 for confirmation of screening evaluations as well as completion of predose assessments and 
procedures including clinician review of the daily binge eating diary. Any lapse in diary completion 
during the 14 day period (eg, 1 or more days are skipped) will be discussed with the subject. If 1 or 
2 days per week are incomplete or missing, the subject may complete the diary with the clinician. 
However, if the subject cannot recall enough information to complete the diary in full after clinician 
review, the subject will be ineligible. Subjects will also be ineligible for randomization if there are 
more than 2 missed diary days in 1 week. Eligible subjects (based on confirmation of study entry 
criteria) will be randomized and dispensed study drug at Day -1. 
Treatment Period (Day 1 [Week 0] through Day 84 [Week 12]): Subjects will self-administer the 
study drug on an outpatient basis once a day with or without food beginning on Day 1, the day after the 
Baseline visit, and continue for 12 weeks. Subjects will be instructed to administer study drug at 
approximately the same time each morning including on days when clinic visits occur. During the 
treatment period subjects will continue to complete a daily binge eating diary, which will be reviewed 
at each visit. During the treatment period, subjects will have one clinic visit every week for the first 
month, then one clinic visit every 2 weeks thereafter. In order to facilitate scheduling of clinic visits, a 
window of ± 2 days will be allowed for each weekly clinic visit and a window of ± 3 days will be 
allowed for each biweekly clinic visit. 
Subjects who complete the 12-week Treatment Period may be eligible for participation in the open 
label extension study (SEP360-322). For subjects enrolling in the open label extension study, Week 12 
will be the last visit for this study. 
Study Medication Withdrawal Period (Day 85 through Day 105 [Week 15]): Subjects who do not 
enroll in the extension study for whatever reason, eg, less than 12 weeks treatment in this study, lack of 
interest in the extension study, or failure to meet all eligibility criteria for the extension study will 
return to the clinic at Weeks 13, 14, and 15, to assess safety and potential study medication withdrawal 
effects during the study medication withdrawal period. Subjects who discontinue from study drug 


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before completion of the 12-week treatment period will be asked to return to the clinic and complete 
the End of Treatment (EOT) visit as soon as possible following discontinuation of study drug and 
complete the 3 week withdrawal period. In addition, subjects will continue to complete the binge eating 
diary during this period. 
Assessment of potential withdrawal effects will be conducted via administration of the CSSA, DESS, 
HAM-A, and MADRS at Week 12 (End of Treatment), then again at Weeks 13, 14, and 15 during the 
3-week study medication withdrawal period. 
The CSSA and DESS will also be completed during the 3-week study medication withdrawal period on 
non-clinic visit days. Clinical site staff will call the subject every other day during the study medication 
withdrawal period, beginning the second day after the last dose of study drug, unless a clinic visit is 
scheduled for that day (up to 3 times per day if the clinical site staff are unable to contact the subject on 
the first 2 attempts). Clinical site staff will record the responses in the subject’s source information and 
in the case report form (CRF) with the contact date and time. 
A window of ± 1 day will be allowed for each weekly clinic visit and telephone call. If the subject 
cannot be contacted on a given day, during the next contact the study site staff will retrospectively 
collect the missed CSSA and DESS, in addition to the current day’s CSSA and DESS. 
Number of Subjects (planned): approximately 480 subjects (160 per treatment group) 
Diagnosis and Main Criteria for Subject Inclusion: Male or female subjects between 18-55 years of 
age, inclusive, who meet the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
(DSM-5) criteria for a diagnosis of BED confirmed based on the eating-disorders module of the 
Structured Clinical Interview for DSM-IV Axis I Disorders, Module H (SCID-I Module H), 
clinician review of subject diaries, and the Eating Disorder Examination Questionnaire (EDE-Q) are 
eligible for this study. Subjects must have a BED diagnosis or be diagnosed at screening, have a history 
of at least 2 binge eating days a week for at least 6 months prior to screening, have BED of at least 
moderate severity with reports of at least 3 binge eating days for each of the 2 weeks prior to baseline 
as documented in the subject's binge diary, and have a BE-CGI-S score ≥ 4 at screening and baseline. 
Subjects with any of the following are not eligible for the study: BMI of 18 kg/m2or less, or greater 
than 45 kg/m2; lifetime history or current symptoms consistent with bulimia nervosa or anorexia 
nervosa; started psychotherapy (eg, supportive psychotherapy, cognitive behavior therapy, 
interpersonal therapy) within 3 months prior to screening; participating in a formal weight loss program 
(eg, Weight Watchers®) within 3 months prior to screening; used a psychostimulant or mood stabilizer 
within the 3 months prior to screening, or used any medications for the treatment of binge eating, other 
eating disorders, obesity, or weight gain or any other medication that could result in weight gain or 
weight loss including over-the-counter and herbal products within the 3 months prior to screening; 
started a new physical training/exercise program for the purpose of managing his or her weight or 
binge eating within 3 months prior to screening; a lifetime history of psychotic disorder, bipolar 
disorder, hypomania, dementia, or attention deficit hyperactivity disorder (ADHD) as defined by the 
DSM-5 criteria; a history of moderate to severe depression based on Investigator’s judgment within the 
6 months prior to screening or is currently taking or has taken any medication for depression during the 
3 months prior to screening or has a MADRS score ≥ 18; a history of substance use disorder including 
alcohol use disorder (excluding nicotine and caffeine) within the 12 months prior to screening, as 
defined by the DSM-5 criteria. 
See Section 8 of the full protocol for complete eligibility information. 
Investigational Product, Dosage and Mode of Administration: Dasotraline 4 mg and 6 mg capsules 
for once a day oral administration will be supplied.  
Subjects randomized to 4 mg/day dasotraline will receive 4 mg/day for the duration of the treatment 
period. 


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Subjects randomized to 6 mg/day dasotraline will be dosed with 4 mg/day dasotraline for the first 
2 weeks of the treatment period and will be increased to 6 mg/day at Week 2. 
Duration of Treatment: 12 weeks 
Reference Therapy, Dosage and Mode of Administration: Matching placebo capsules for once a 
day oral administration will be supplied. 
Selected Concomitant Medications: Use of certain medications, including but not limited to the 
following, is prohibited throughout the study from screening through the last in-clinic visit: 
• 
psychostimulants 
• 
any medications for the treatment of binge eating or other eating disorders, obesity, or weight 
gain  
• 
antidepressant medications (eg, bupropion, selective serotonin reuptake inhibitor (SSRI)/ 
serotonin norepinephrine reuptake inhibitor (SNRI), monoamine oxidase (MAO) inhibitors, 
tricyclics) and St. John’s Wort 
• 
medications that are CYP2B6 substrates or inhibitors or inducers of CYP2B6, eg, bupropion, 
cyclophosphamide, carbamazepine, etc.  
• 
medications for the treatment of ADHD such as but not limited to lisdexamfetamine, 
methylphenidate, atomoxetine, clonidine, guanfacine, modafinil, and armodafinil  
• 
corticosteroids and anabolic steroids (Note: Topical, intra-nasal, and inhaled corticosteroids are 
permitted. Other formulations of corticosteroids may be permitted following consultation with 
the Medical Monitor.) 
• 
antiepileptic medications 
• 
benzodiazepines except for sleep (see Section 10.3.3) 
• 
mood stabilizers (eg, lithium, anticonvulsants) 
• 
antipsychotic medications 
• 
suvorexant 
• 
any medication that can result in either weight gain or weight loss (eg, insulin, liraglutide, 
metformin, diphenhydramine except topical formulations, etc.) including over-the-counter and 
herbal products 
Initiation of psychotherapy (eg, supportive psychotherapy, cognitive behavior therapy, interpersonal 
therapy) is prohibited within 3 months prior to screening and throughout the study. 
Any participation in a formal weight loss program such as Weight Watchers® is prohibited within 
3 months of screening and throughout the study. 
See Section 10.3 of the full protocol for further information. 


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Study Endpoints:  
Primary Efficacy Endpoint:  
Change from baseline in number of binge days (defined as days during which at least 1 binge episode 
occurs) per week at Week 12. 
Key Secondary Efficacy Endpoints: 
• 
Change from baseline in BE-CGI-S score at Week 12 
• 
Percent of subjects with a 4-week cessation from binge eating (defined as a 100% 
reduction for at least 28 consecutive days in the number of binge eating episodes prior to 
Week 12/EOT) 
• 
Change from baseline in Y-BOCS-BE total score at Week 12 
Other Secondary Efficacy Endpoints: 
• 
Change from baseline in number of binge days per week at Weeks 1, 2, 3, 4, 6, 8, and 10  
• 
Change from baseline in number of binge episodes per week at Weeks 1, 2, 3, 4, 6, 8, 10, 
and 12 
• 
Change from baseline in BE-CGI-S score at Weeks 2, 4, 6, 8, and 10 
• 
Change from baseline in Y-BOCS-BE total score at Weeks 2, 4, 6, 8, and 10 and subscale 
scores (obsessions and compulsions) at Weeks 2, 4, 6, 8, 10, and 12 
• 
Change from baseline in SDS total score and subscale scores (school/work disability, 
social life disability, and family life disability) at Weeks 6 and 12 
• 
Change from baseline in MADRS total score at Week 12 
• 
Change from baseline in HAM-A total score at Week 12 
• 
Proportion of binge eating responders who have ≥ 75% reduction in the number of binge 
eating episodes from Baseline at Week 12 
• 
Change from baseline in EDE-Q modified including EDE-Q7 global score and 3 subscale 
scores (dietary restraint, shape/weight overvaluation, and body dissatisfaction) at Week 12 
Safety Endpoints: 
• 
The incidence of overall AEs, serious AEs (SAEs), and AEs (or SAEs) leading to 
discontinuations 
• 
Clinical laboratory evaluations (serum chemistry, hematology, and urinalysis) 
• 
Clinical evaluations (vital signs including orthostatic effects, and 12-lead ECGs) 
• 
Frequency and severity of suicidal ideation and suicidal behavior as assessed by the 
C-SSRS 
• 
Change and percent change from baseline in body weight at Weeks 1, 2, 3, 4, 6, 8, 10, 
and 12 


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• 
Change and percent change from baseline in BMI at Weeks 1, 2, 3, 4, 6, 8, 10, and 12 
• 
Change from baseline in a fasting lipid panel (triglycerides, total cholesterol, high-density 
lipoprotein [HDL] cholesterol, and low-density lipoprotein [LDL] cholesterol) at Weeks 6 
and 12 
• 
Change from baseline in hemoglobin A1c level at Weeks 6 and 12 
• 
Change from baseline in fasting glucose level at Weeks 6 and 12 
• 
Change from baseline in insulin and high-sensitivity C-reactive protein (hs-CRP) 
• 
Occurrence of symptoms of withdrawal from dasotraline measured by change from 
Week 12/EOT in:  
− 
CSSA total score at Weeks 13, 14, and 15 
− 
DESS total score at Weeks 13, 14, and 15 
− 
HAM-A total score at Weeks 13, 14, and 15 
− 
MADRS total score at Weeks 13, 14, and 15 
Pharmacokinetic Endpoint:  
Relationship between dasotraline plasma concentration and the primary endpoint in addition to selected 
secondary efficacy and safety endpoints 
Statistical Methods:  
Primary Efficacy Endpoint Analyses 
The primary efficacy analyses of the primary efficacy endpoint (the change from baseline in the 
number of binge days per week at Week 12) will be performed using a likelihood-based mixed model 
for repeated measures (MMRM) model on the Intent-to-Treat (ITT) population. The response 
(dependent) variable is the change from baseline in the number of binge days per week assessed at 
Weeks 1, 2, 3, 4, 6, 8, 10, and 12. Specifically, the MMRM model includes fixed effects terms for 
treatment, visit (as a categorical variable), pooled center, baseline binge days category (stratification 
factor; refer to Section 7.2.1 for categories), the number of binge days per week at baseline, and 
treatment-by-visit interaction. Restricted maximum likelihood estimation method will be applied using 
an unstructured covariance model. The Kenward Roger approximation will be used to estimate 
denominator degrees of freedom. In case of a failure of convergence with the unstructured covariance, 
the following structures will be assessed in a sequential order: heterogeneous Toeplitz, Toeplitz, spatial 
exponential covariance pattern model. Of the above 3 covariance structures, the first covariance 
structure yielding convergence in the MMRM model will be used for the MMRM analysis. The spatial 
exponential model is selected for the analysis of data with unequally spaced time points. The least 
squares (LS) mean treatment differences (each dasotraline group minus placebo) of change from 
baseline at Week 12, their 2-sided 95% confidence intervals (CIs), and the associated p-values will be 
calculated based on this model. The model assumptions underlying the primary analysis will be 
assessed. 
The primary efficacy analysis will be repeated for the Per Protocol (PP) population to examine the 
impact of premature dropouts and/or protocol deviations. 
The primary efficacy endpoint also will be analyzed using an analysis of covariance (ANCOVA) 
model and the last observation carried forward (LOCF) approach, as a supportive analysis. The model 
will include terms for treatment, pooled center, baseline binge days category (stratification factor), and 


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the number of binge days per week at baseline as covariates. 
To address early dropouts under the assumption of missing not at random (MNAR), a pattern-mixture 
model using a placebo-based multiple imputation method and a pattern mixture model using multiple 
imputations with penalties (ie, deflating the individually estimated treatment effect size by known 
factors) will be performed as sensitivity analyses to explore the robustness of the MMRM results for 
the primary analysis. In case of a deviation from the assumptions required for the primary analysis, to 
confirm the robustness of the primary analysis result, 2 additional sensitivity analyses will be 
performed: (1) permutation test: fit a large number of datasets based on a same MMRM for the primary 
analysis with randomly assigning pseudo-treatment group designations; (2) generalized linear mixed 
model (GLMM) analysis: fit count data over time (ie, number of binge days among number of assessed 
days at each period) based on a binomial distribution. 
Key Secondary Efficacy Endpoint Analyses 
Continuous key secondary variables (ie, change in BE-CGI-S score and Y-BOCS-BE total score) will 
be analyzed with an MMRM model similar to the primary efficacy analysis (adjusted with the 
corresponding baseline). The LS mean treatment differences (each dasotraline group minus placebo) of 
change from baseline at Week 12, their 2-sided 95% CIs, and the associated p-values will be calculated 
based on the model. Categorical key secondary efficacy endpoints (ie, percent of subjects with a 
4-week cessation from binge eating) will be analyzed using a logistic regression model with treatment, 
baseline binge days category (stratification factor), and baseline number of binge days per week as 
covariates using a LOCF approach based on the ITT population. The odds ratios, their 2-sided 
95% CIs, and the associated p-values for each dasotraline group over the placebo group will be derived 
from the model. Additional supportive and sensitivity analyses may be conducted as needed for the key 
secondary endpoints to address early dropouts or potential deviations from the model assumption(s). 
Multiplicity Adjustment 
To control the overall type I error rate strongly at 5% for the primary and key secondary endpoints, for 
the hypotheses to be tested (see Section 15.2), a sequential testing strategy will be used. Following the 
fixed sequence closed testing procedure provided in Figure 2, testing will only proceed conditional on 
the statistical significance of the test(s) of prior level(s) at a 2-sided 5% significance level. 
Safety Analyses: 
Safety data will be analyzed by treatment group based on the Double-blind (DB) Safety population (for 
data up to the end of treatment period) and Withdrawal safety population (for data collected during the 
withdrawal period), separately, as appropriate. 
Overall AEs (or SAEs) and AEs (or SAEs) leading to discontinuation will be summarized by system 
organ class, preferred term, and treatment group by presenting the number and percentage of subjects 
with each AE. 
Descriptive statistics will be provided by visit and treatment group for observed values or changes from 
baseline of the safety variables. The change from baseline value at endpoint for selected laboratory 
parameters (eg, hemoglobin A1c, fasting glucose, fasting total cholesterol, fasting triglycerides, fasting 
HDL cholesterol, and fasting LDL cholesterol) will be evaluated using an ANCOVA model with terms 
for treatment and baseline binge days group, and corresponding baseline as covariate or nonparametric 
rank ANCOVA, as appropriate. A similar MMRM model as for the primary efficacy variable (with the 
corresponding baseline) will be applied to compare dasotraline with placebo for the following safety 
variables: change and percent change from baseline in body weight (kg); and change and percent 
change from baseline in BMI. Frequency and severity of suicidality using the C-SSRS will be 
summarized by treatment for the post-baseline treatment period and for the withdrawal period, 
separately. 
CSSA total score, DESS total score, MADRS total score, and HAM-A total score will be summarized 
by presenting descriptive statistics of actual values and change from Week 12/EOT by treatment and 


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visit for the withdrawal period. 
All PK data will be summarized descriptively by visit and treatment group. 
Sample Size: The sample size for this study was estimated based on 2 hypotheses associated with the 
primary efficacy endpoint (change from baseline in number of binge days per week at Week 12). A 
fixed sequence closed testing procedure was used to adjust for 2 comparisons of dasotraline doses vs 
placebo (ie, with dasotraline 6 mg vs placebo tested first and dasotraline 4 mg vs placebo tested after if 
the previous one is significant at the 0.05 level ) for the sample size justification. Based on the Study 
SEP360-221 results, assuming a common standard deviation (SD) of 1.75 and a mean improvement of 
0.9 (effect size 0.517) and 0.8 (effect size 0.457) over placebo for change from baseline in number of 
binge days per week at Week 12 for dasotraline 6 mg/day and 4 mg/day doses respectively, a sample 
size of 96 subjects per treatment group will provide at least 85% conjunctive power to reject both null 
hypotheses. An upward adjustment of approximately 40% is assumed to compensate for subjects who 
are randomized but discontinue from the study, thus, a total sample of 480 subjects (160 subjects per 
group) will be randomized with a ratio of 1:1:1 for placebo, and dasotraline 4 mg/day and 6 mg/day. 
The sample size calculation was based on Monte Carlo simulation from EAST 6.4. 
 


Protocol SEP360-321, Version 3.00 
 
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Confidential and Proprietary 
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Table 2: Schedule of Assessments 
Procedures 
Screening 
Baseline 
Treatment Period 
Withdrawal Perioda,b 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10c 
V11 
V12 
V13 
 
 
 
Week 
1 
Week 
2 
 
Week 
3 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12/EOTa 
Week 
13 
Week 
14 
Week 
15 
Day 
-22 to -2 
 
Day -1 
Day 
7 
(± 2) 
Day 
14 
(± 2) 
Day 
21 
(± 2) 
Day 
28 
(± 2) 
Day 
42 
(± 3) 
Day 
56 
(± 3) 
Day 
70 
(± 3) 
Day 
84 (± 1) 
Day 
91 
(± 1) 
Day 
98 
(± 1) 
Day 
105 
(± 1) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent for 
PGx (optional) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Duplicate Enrollment 
Check 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CST Reviewe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Dispense Study Drugf 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Study Drug 
Accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Psychiatric Historyd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
 
 
 
 
 
X 
 
 
X 
Neurological 
Examination 
X 
X 
 
 
 
 
 
 
 
X 
 
 
X 
Prior and/or 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Protocol SEP360-321, Version 3.00 
 
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Confidential and Proprietary 
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17 Nov 2017 
Table 2: 
Schedule of Assessments (Continued) 
Procedures 
Screening 
Baseline 
Treatment Period 
Withdrawal Perioda,b 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10c 
V11 
V12 
V13 
 
 
 
Week 
1 
Week 
2 
 
Week 
3 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12/EOTa 
Week 
13 
Week 
14 
Week 
15 
Day 
-22 to -2 
 
Day -1 
Day 
7 
(± 2) 
Day 
14 
(± 2) 
Day 
21 
(± 2) 
Day 
28 
(± 2) 
Day 
42 
(± 3) 
Day 
56 
(± 3) 
Day 
70 
(± 3) 
Day 
84 (± 1) 
Day 
91 
(± 1) 
Day 
98 
(± 1) 
Day 
105 
(± 1) 
Mini International 
Neuropsychiatric 
Interview (MINI) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Structured Clinical 
Interview for DSM-
IV Axis I 
Disorders, 
Module H (SCID-I 
Module H) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eating Disorder 
Examination 
Questionnaire 
(EDE-Q) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eating Disorder 
Examination 
Questionnaire 
(EDE-Q) modified 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Binge eating diary 
trainingg 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
 
Binge eating diaryh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Binge-eating 
Clinical Global 
Impression-
Severity 
(BE-CGI-S) 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 


Protocol SEP360-321, Version 3.00 
 
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17 Nov 2017 
Table 2: 
Schedule of Assessments (Continued) 
Procedures 
Screening 
Baseline 
Treatment Period 
Withdrawal Perioda,b 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10c 
V11 
V12 
V13 
 
 
 
Week 
1 
Week 
2 
 
Week 
3 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12/EOTa 
Week 
13 
Week 
14 
Week 
15 
Day 
-22 to -2 
 
Day -1 
Day 
7 
(± 2) 
Day 
14 
(± 2) 
Day 
21 
(± 2) 
Day 
28 
(± 2) 
Day 
42 
(± 3) 
Day 
56 
(± 3) 
Day 
70 
(± 3) 
Day 
84 (± 1) 
Day 
91 
(± 1) 
Day 
98 
(± 1) 
Day 
105 
(± 1) 
Yale-Brown 
Obsessive 
Compulsive Scale 
Modified for Binge 
Eating 
(Y-BOCS-BE) 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
Montgomery-
Asberg Depression 
Rating Scale 
(MADRS)i 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
Sheehan Disability 
Scale (SDS) 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
Hamilton Anxiety 
Rating Scale 
(HAM-A)j 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
Cocaine Selective 
Severity 
Assessment 
(CSSA) 
 
 
 
 
 
 
 
 
 
Xk 
X 
X 
X 
Cocaine Selective 
Severity 
Assessment 
(CSSA) – 
Telephone contact 
 
 
 
 
 
 
 
 
 
In order to collect this assessment, 
clinical site staff will call the subject 
every other day (± 1 day) during the 
study medication withdrawal period, 
beginning the second day after the last 
dose of study drug, unless a clinic visit is 
scheduled for that day.l 


Protocol SEP360-321, Version 3.00 
 
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17 Nov 2017 
Table 2: 
Schedule of Assessments (Continued) 
Procedures 
Screening 
Baseline 
Treatment Period 
Withdrawal Perioda,b 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10c 
V11 
V12 
V13 
 
 
 
Week 
1 
Week 
2 
 
Week 
3 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12/EOTa 
Week 
13 
Week 
14 
Week 
15 
Day 
-22 to -2 
 
Day -1 
Day 
7 
(± 2) 
Day 
14 
(± 2) 
Day 
21 
(± 2) 
Day 
28 
(± 2) 
Day 
42 
(± 3) 
Day 
56 
(± 3) 
Day 
70 
(± 3) 
Day 
84 (± 1) 
Day 
91 
(± 1) 
Day 
98 
(± 1) 
Day 
105 
(± 1) 
Discontinuation-
Emergent Signs 
and Symptoms 
(DESS) Scale 
 
 
 
 
 
 
 
 
 
Xk 
X 
X 
X 
Discontinuation-
Emergent Signs 
and Symptoms 
(DESS) Scale – 
Telephone contact 
 
 
 
 
 
 
 
 
 
In order to collect this assessment, 
clinical site staff will call the subject 
every other day (± 1 day) during the 
study medication withdrawal period, 
beginning the second day after the last 
dose of study drug, unless a clinic visit is 
scheduled for that day.l 
Vital Sign 
Measurements 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight and body 
mass index (BMI)m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead 
electrocardiogram 
(ECG) 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
Columbia – Suicide 
Severity Rating 
Scale (C-SSRS)n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Eventso 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
Lipid panelp 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 


Protocol SEP360-321, Version 3.00 
 
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Confidential and Proprietary 
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17 Nov 2017 
Table 2: 
Schedule of Assessments (Continued) 
Procedures 
Screening 
Baseline 
Treatment Period 
Withdrawal Perioda,b 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10c 
V11 
V12 
V13 
 
 
 
Week 
1 
Week 
2 
 
Week 
3 
Week 
4 
Week 
6 
Week 
8 
Week 
10 
Week 
12/EOTa 
Week 
13 
Week 
14 
Week 
15 
Day 
-22 to -2 
 
Day -1 
Day 
7 
(± 2) 
Day 
14 
(± 2) 
Day 
21 
(± 2) 
Day 
28 
(± 2) 
Day 
42 
(± 3) 
Day 
56 
(± 3) 
Day 
70 
(± 3) 
Day 
84 (± 1) 
Day 
91 
(± 1) 
Day 
98 
(± 1) 
Day 
105 
(± 1) 
Hemoglobin A1c  
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
Insulinp 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
hs-CRP 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Hematology 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
Urinalysis 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
Serum Pregnancy 
Test (in females of 
child-bearing 
potential) 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine Pregnancy 
Test (in females of 
child-bearing 
potential) 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Urine Drug Screen 
X 
X 
 
 
 
 
X 
 
 
X 
X 
X 
X 
Breath alcohol test 
X 
X 
 
 
 
 
X 
 
 
X 
X 
X 
X 
Blood sampling for 
plasma PK levelsq 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Blood sampling for 
potential 
biomarkers  
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Blood sampling 
genotyping 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Footnotes are on the next page. 


Protocol SEP360-321, Version 3.00 
 
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17 Nov 2017 
Abbreviations: CST = Clinical Surveillance Team; EOT = End of Treatment; hs-CRP = high-sensitivity C-reactive protein; PK = pharmacokinetic; V = visit 
a Subjects who discontinue from study drug before completion of the 12-week treatment period will be asked to return to the clinic and complete the End of Treatment visit as 
soon as possible following discontinuation of study drug and complete the 3-week withdrawal period. 
b Subjects who complete the 12-week treatment period and do not enter the extension study (Study SEP360-322) will complete the 3-week withdrawal period. 
c For subjects who complete the 12-week double-blind treatment period and enter the extension study (Study SEP360-322), Visit 10 will be the last visit in this study. 
d  Includes family history of psychiatric disorders. 
e For the prebaseline review, sites will be required to submit specific screening information for clinician and sponsor review, prior to proceeding to baseline. Details are provided 
in the Clinical Surveillance Team (CST) site manual. 
f All study drug will be administered by the subject, beginning on Day 1, the day after the Baseline visit, once a day at approximately the same time each morning including on the 
days when clinic visits occur. 
g Missing data, if any, will be reviewed by the clinical site staff with the subject and additional training on diary completion will be provided at other visits as needed. 
h Subjects complete a daily binge eating diary to record the date, duration (total hours of binging), type of binge episode (meal or non-meal), amount and type of food, and number 
of binges beginning 14 days prior to the Baseline visit and continue through the final clinic visit. At each in-clinic visit, the Investigator will review the diary with the subject. In 
addition, diaries will be sent to Bracket for central review. 
i The Structured Interview Guide for the MADRS (SIGMA) will be used for the administration of the MADRS. 
j The Structured Interview Guide for the HAM-A (SIGH-A) will be used for the administration of the HAM-A. 
k Only for subjects not entering the extension study. 
l Clinical site staff will call the subject every other day (± 1 day) during the study medication withdrawal period, beginning the second day after the last dose of study drug, unless 
a clinic visit is scheduled for that day, in order to collect the Cocaine Selective Severity Assessment (CSSA) and Discontinuation-Emergent Signs and Symptoms (DESS). 
Clinical site staff may call up to 3 times per day if the clinical site staff are unable to contact the subject on the first 2 attempts. If the subject cannot be contacted on a given day, 
during the next contact the study site staff will retrospectively collect the CSSA and DESS from the missed day(s) and the current day. 
m Body mass index (BMI) at screening will be calculated by the clinical site using BMI table or the BMI formula provided (Section 27, Appendix VIII). BMI on all other visits 
will be derived within the Electronic Data Capture (EDC) system. 
n Subjects who answer “yes” to “suicidal ideation” item 4 (active suicidal ideation with some intent to act, without specific plan) or item 5 (active suicidal ideation with specific 
plan and intent) on the C-SSRS assessment at Screening (in the past month) must be referred to the Investigator for follow up evaluation. 
o Untoward medical occurrences that occur prior to the first dose of study drug will be collected as pre-treatment events. 
p Subjects must be fasting for at least 8 hours (may have water and study drug) prior to the indicated laboratory tests. Visits should be scheduled in the morning. 
q The date and time of the last 3 doses of study drug prior to PK blood sample collection are to be recorded in the source documents and the CRF. 
 


Protocol SEP360-321, Version 3.00 
 
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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
RESTRICTED DISTRIBUTION OF PROTOCOLS ......................................................................2 
EMERGENCY CONTACTS...........................................................................................................3 
1. 
SYNOPSIS ...................................................................................................................4 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............19 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................26 
4. 
INTRODUCTION ......................................................................................................31 
4.1. 
Background .................................................................................................................31 
4.1.1. 
Neurobiology of Binge Eating Disorder .....................................................................32 
4.1.2. 
Pharmacological Management of Binge Eating Disorder ..........................................33 
4.2. 
Study Conduct Rationale ............................................................................................33 
4.3. 
Risk-Benefit Assessment ............................................................................................34 
4.4. 
Hypotheses ..................................................................................................................35 
4.4.1. 
Primary Hypotheses ....................................................................................................35 
4.4.2. 
Secondary Hypotheses ................................................................................................35 
5. 
STUDY OBJECTIVES ..............................................................................................36 
5.1. 
Primary Objective .......................................................................................................36 
5.2. 
Key Secondary Objectives ..........................................................................................36 
5.3. 
Other Secondary Objectives .......................................................................................36 
6. 
STUDY ENDPOINTS ................................................................................................38 
6.1. 
Primary Efficacy Endpoint .........................................................................................38 
6.2. 
Key Secondary Efficacy Endpoints ............................................................................38 
6.3. 
Other Secondary Efficacy Endpoints ..........................................................................38 
6.4. 
Safety Endpoints .........................................................................................................38 
6.5. 
Pharmacokinetic Endpoint ..........................................................................................39 
7. 
INVESTIGATIONAL PLAN .....................................................................................40 
7.1. 
Overall Study Design ..................................................................................................40 
7.2. 
Treatment Assignment and Blinding ..........................................................................43 
7.2.1. 
Treatment Assignment ................................................................................................43 
7.2.2. 
Blinding ......................................................................................................................43 


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7.2.3. 
Emergency Unblinding Procedures ............................................................................44 
7.3. 
Rationale .....................................................................................................................44 
7.3.1. 
Rationale for the Study Design ...................................................................................44 
7.3.2. 
Rationale for the Dosages ...........................................................................................44 
7.3.3. 
Rationale for the Study Population .............................................................................45 
7.3.4. 
Rationale for the Endpoints ........................................................................................45 
7.4. 
Prevention of Missing Data ........................................................................................45 
8. 
SELECTION OF SUBJECTS ....................................................................................46 
8.1. 
Subject Inclusion Criteria ...........................................................................................46 
8.2. 
Subject Exclusion Criteria ..........................................................................................47 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................51 
9.1. 
Description of Study Drug ..........................................................................................51 
9.2. 
Study Drug Packaging and Labeling ..........................................................................51 
9.2.1. 
Package Description ...................................................................................................51 
9.2.2. 
Labeling Description ..................................................................................................51 
9.3. 
Study Drug Storage .....................................................................................................52 
9.4. 
Dispensing of Study Drug ..........................................................................................52 
9.5. 
Study Drug Accountability .........................................................................................52 
9.6. 
Study Drug Handling and Disposal ............................................................................52 
10. 
TREATMENT OF SUBJECTS ..................................................................................53 
10.1. 
Study Medication ........................................................................................................53 
10.1.1. 
Dose or Dosage for Study Drug..................................................................................53 
10.2. 
Treatment Compliance ................................................................................................53 
10.3. 
Concomitant Medications and Therapies ...................................................................54 
10.3.1. 
Prohibited Medications ...............................................................................................54 
10.3.2. 
Prohibited Therapies ...................................................................................................55 
10.3.3. 
Permitted Medications ................................................................................................55 
10.3.4. 
Permitted Therapies ....................................................................................................55 
10.4. 
Contraception Requirements ......................................................................................55 
10.5. 
Guidance for Overdose ...............................................................................................56 
10.6. 
Cautions ......................................................................................................................56 
11. 
STUDY ASSESSMENTS ..........................................................................................57 
11.1. 
Demographics and Baseline Characteristics ...............................................................57 


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11.2. 
Diagnostic Scales to Determine Study Eligibility ......................................................58 
11.2.1. 
Structured Clinical Interview for DSM-IV Axis I Disorders, Module H 
(SCID-I Module H) .....................................................................................................58 
11.2.2. 
Eating Disorder Examination Questionnaire (EDE-Q) ..............................................58 
11.2.3. 
Mini International Neuropsychiatric Interview (MINI) .............................................58 
11.3. 
Efficacy Assessments and Scales ...............................................................................58 
11.3.1. 
Binge Eating Diary .....................................................................................................58 
11.3.2. 
Sheehan Disability Scale (SDS) .................................................................................59 
11.3.3. 
Montgomery-Asberg Depression Rating Scale (MADRS) ........................................59 
11.3.4. 
Hamilton Anxiety Rating Scale (HAM-A) .................................................................59 
11.3.5. 
Binge-eating Clinical Global Impressions–Severity of Illness (BE-CGI-S) ..............59 
11.3.6. 
Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating 
(Y-BOCS-BE) .............................................................................................................59 
11.3.7. 
Eating Disorder Examination Questionnaire (EDE-Q) Modified ..............................60 
11.4. 
Safety Assessments and Scales ...................................................................................60 
11.4.1. 
Safety Assessments .....................................................................................................60 
11.4.1.1. 
Adverse Events ...........................................................................................................60 
11.4.1.2. 
Clinical Laboratory Tests ...........................................................................................60 
11.4.1.3. 
Physical and Neurological Examinations ...................................................................61 
11.4.1.4. 
Vital Signs ..................................................................................................................61 
11.4.1.5. 
Electrocardiograms .....................................................................................................61 
11.4.2. 
Safety Scales ...............................................................................................................61 
11.4.2.1. 
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................................61 
11.4.2.2. 
Cocaine Selective Severity Assessment (CSSA) ........................................................62 
11.4.2.3. 
Discontinuation-Emergent Signs and Symptoms (DESS) Scale ................................62 
11.4.2.4. 
Hamilton Anxiety Rating Scale (HAM-A) .................................................................62 
11.4.2.5. 
Montgomery-Asberg Depression Rating Scale (MADRS) ........................................62 
11.5. 
Pharmacokinetic Assessments ....................................................................................63 
11.6. 
Collection of Blood Samples for Biomarker Analysis ...............................................63 
11.7. 
Collection of Specimens for Genetic Analysis ...........................................................63 
11.8. 
Study Visits and Assessments ....................................................................................64 
11.8.1. 
Screening: Visit 1 (Day -22 to -2) ..............................................................................64 
11.8.1.1. 
Baseline: Visit 2 (Day -1) ...........................................................................................65 


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11.8.2. 
Week 1 (Day 7 [± 2 days]): Visit 3 .............................................................................66 
11.8.3. 
Week 2 (Day 14 [± 2 days]): Visit 4 ...........................................................................66 
11.8.4. 
Week 3 (Day 21 [± 2 days]): Visit 5 ...........................................................................67 
11.8.5. 
Week 4 (Day 28 [± 2 days]): Visit 6 ...........................................................................67 
11.8.6. 
Week 6 (Day 42 [± 3 days]): Visit 7 ...........................................................................67 
11.8.7. 
Week 8 (Day 56 [± 3 days]): Visit 8 ...........................................................................68 
11.8.8. 
Week 10 (Day 70 [± 3 days]): Visit 9 .........................................................................69 
11.8.9. 
Week 12 (Day 84 [± 1 day]) End of Treatment (EOT): Visit 10 ...............................69 
11.8.10. 
Three-week Study Medication Withdrawal Period ....................................................70 
11.8.10.1. Week 13 (Day 91 [± 1 day]): Visit 11 ........................................................................70 
11.8.10.2. Week 14 (Day 98 [± 1 day]): Visit 12 ........................................................................71 
11.8.10.3. Week 15 (Day 105 [± 1 day]) Visit 13 .......................................................................72 
12. 
SAFETY REPORTING ..............................................................................................73 
12.1. 
Definitions ..................................................................................................................73 
12.1.1. 
Adverse Events ...........................................................................................................73 
12.1.2. 
Serious Adverse Events ..............................................................................................73 
12.2. 
Objective Findings ......................................................................................................74 
12.3. 
Collection and Recording of Adverse Events .............................................................75 
12.4. 
Immediately Reportable Events ..................................................................................76 
12.4.1. 
Serious Adverse Event ................................................................................................76 
12.4.2. 
Pregnancy ...................................................................................................................77 
12.5. 
Data Monitoring Committee/Data and Safety Monitoring Board ..............................77 
13. 
TERMINATION OF SUBJECT FROM STUDY/DISCONTINUATION OF 
STUDY DRUG ...........................................................................................................78 
13.1. 
Criteria for Study Drug Discontinuation ....................................................................78 
13.2. 
Criteria for Subject Termination from the Withdrawal Period ...................................78 
13.3. 
Clinical Assessments After Study Drug Discontinuation ...........................................79 
14. 
STUDY TERMINATION ..........................................................................................80 
15. 
STATISTICS ..............................................................................................................81 
15.1. 
Sample Size ................................................................................................................81 
15.2. 
Statistical Hypotheses .................................................................................................81 
15.3. 
Analysis Populations ..................................................................................................82 
15.4. 
Data Analysis ..............................................................................................................82 


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15.4.1. 
Efficacy Analyses .......................................................................................................82 
15.4.1.1. 
Assessments from Binge Eating Diary .......................................................................82 
15.4.1.2. 
Primary Efficacy Endpoint Analyses ..........................................................................83 
15.4.1.3. 
Key Secondary Efficacy Endpoints Analyses ............................................................84 
15.4.1.4. 
Multiplicity Adjustment..............................................................................................85 
15.4.1.5. 
Other Secondary Efficacy Endpoints Analyses ..........................................................86 
15.4.1.6. 
Subgroup Analyses .....................................................................................................87 
15.4.2. 
Safety Analyses ..........................................................................................................87 
15.4.2.1. 
Adverse Events ...........................................................................................................88 
15.4.2.2. 
Clinical Laboratory Assessments ...............................................................................88 
15.4.2.3. 
Centrally-read ECG ....................................................................................................89 
15.4.2.4. 
Vital Signs, Weight, and BMI ....................................................................................89 
15.4.2.5. 
Neurological Examination ..........................................................................................90 
15.4.2.6. 
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................................90 
15.4.2.7. 
Endpoints to Assess Physical Dependence and Withdrawal Symptoms 
during Withdrawal Period ...........................................................................................90 
15.4.2.8. 
Prior and Concomitant Medications ...........................................................................90 
15.4.3. 
Interim Analysis ..........................................................................................................90 
16. 
PROCEDURE FOR CLINICAL STUDY QUALITY CONTROL/DATA 
COLLECTION, MANAGEMENT, AND QUALITY ASSURANCE ......................91 
16.1. 
Data Collection/Electronic Data Capture (EDC) ........................................................91 
16.2. 
Computerized Systems Used for Source Data ............................................................91 
16.3. 
Study Monitoring ........................................................................................................93 
16.4. 
Audits ..........................................................................................................................93 
16.5. 
Study Documentation .................................................................................................93 
16.6. 
Clinical Laboratory Certification and Normal Values ................................................94 
17. 
ETHICAL AND REGULATORY OBLIGATIONS..................................................95 
17.1. 
Study Conduct ............................................................................................................95 
17.2. 
Institutional Review Board/Independent Ethics Committee ......................................95 
17.3. 
Informed Consent .......................................................................................................96 
17.4. 
Subject Privacy ...........................................................................................................96 
17.5. 
Protocol Amendments and Emergency Deviations ....................................................97 
17.6. 
Records Retention .......................................................................................................97 


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17.7. 
Inspection of Records .................................................................................................97 
17.8. 
Financial Disclosure ...................................................................................................97 
17.9. 
Publication Policy .......................................................................................................97 
18. 
REFERENCES ...........................................................................................................99 
19. 
INVESTIGATOR APPROVAL ...............................................................................103 
20. 
APPENDIX I. CARDIAC SAFETY MONITORING (ECG) ..................................104 
21. 
APPENDIX II. CLINICAL LABORATORY TESTS .............................................105 
22. 
APPENDIX III. PHARMACOKINETIC SAMPLING AND SAMPLE 
HANDLING GUIDELINE .......................................................................................106 
23. 
APPENDIX IV. SAMPLING FOR POTENTIAL BIOMARKER 
ANALYSIS AND SAMPLE HANDLING GUIDELINES .....................................107 
24. 
APPENDIX V. PHARMACOGENETIC SAMPLING AND SAMPLE 
HANDLING GUIDELINES ....................................................................................109 
25. 
APPENDIX VI. CLINICALLY RELEVANT CYP2B6 SUBSTRATES OR 
INDUCERS OR INHIBITORS (GENERIC NAMES) ............................................110 
26. 
APPENDIX VII. ABUSE POTENTIAL MONITORING PLAN ............................111 
27. 
APPENDIX VIII. BODY MASS INDEX DETERMINATION ..............................119 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Schedule of Assessments ............................................................................................13 
Table 3: 
List of Abbreviations ..................................................................................................26 
Table 4: 
Definition of Key Study Terms ..................................................................................30 
Table 5: 
Investigational Product ...............................................................................................51 
Table 6: 
Recommended Schedule for Clinical Assessments ....................................................57 
Table 7: 
Computerized Systems Used for Source Data ............................................................91 
Table 8: 
Schedule for Blood (for Plasma) for PK Analysis....................................................106 
Table 9: 
Schedule for Blood (Plasma and Serum) for Biomarker Analysis ...........................107 
Table 10: Sample List of Events Subject to Additional Monitoring ........................................113 
Table 11: Body Mass Index (BMI) in kg/m2 According to Height and Weight .......................120 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................40 
Figure 2: 
Fixed Sequence of Hypothesis Testing for Primary and Key Secondary 
Efficacy Endpoints ......................................................................................................85 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The abbreviations and the definition of key study terms used in the clinical study protocol are 
shown in Table 3 and Table 4. 
Table 3: List of Abbreviations 
Abbreviation 
Full Form 
ADHD 
Attention deficit hyperactivity disorder 
ADHD-RS-IV 
ADHD Rating Scale Version IV with adult prompts 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
APMP 
Abuse Potential Monitoring Plan 
AST 
Aspartate aminotransferase 
BE-CGI-S 
Binge-eating Clinical Global Impression-Severity 
BED 
Binge eating disorder 
BMI 
Body mass index  
BN 
Bulimia nervosa 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CR 
Controlled release 
CRF 
Case report form 
CRO 
Clinical research organization 
C-SSRS 
Columbia-suicide severity rating scale 
CSSA 
Cocaine Selective Severity Assessment 
CST 
Clinical Surveillance Team 
CTM 
Clinical trial material 
DA 
Dopamine 
DAT 
Dopamine transporter 
DB 
Double blind 
DBL 
Database lock 
DEAE 
Discontinuation-emergent adverse event 
DESS 
Discontinuation-Emergent Signs and Symptoms 


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Table 3: 
List of Abbreviations (Continued) 
Abbreviation 
Full Form 
DHPG 
3,4-dihydroxyphenylglycol 
DMP 
Data Management Plan 
DNA 
Deoxyribonucleic acid 
DNRI 
Dopamine and norepinephrine reuptake inhibitor 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
DSM-IV-TR 
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition 
Text Revised 
DSMB 
Data and Safety Monitoring 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EDE-Q 
Eating Disorder Examination Questionnaire 
EOT 
End of treatment 
ESAM 
Event subject to additional monitoring 
FDA 
U.S. Food and Drug Administration 
GCP 
Good Clinical Practice 
GEE 
Generalized Estimating Equations 
GLMM 
Generalized linear mixed model 
5-HT 
5-hydroxytryptamine (serotonin) 
HAM-A 
Hamilton Anxiety Rating Scale 
HDL 
High-density lipoprotein (cholesterol) 
HIV 
Human immunodeficiency virus  
HR 
Heart rate  
hs-CRP 
High-sensitivity C-reactive protein 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee  
IND 
Investigational New Drug 
IPW 
Inverse probability weighting 
IRB 
Institutional Review Board 
ITT 
Intention-to-Treat 
IUD 
Intrauterine device 
IXRS 
Interactive Response System 


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Table 3: 
List of Abbreviations (Continued) 
Abbreviation 
Full Form 
LDL 
Low-density lipoprotein (cholesterol) 
LOCF 
Last Observation Carried Forward 
LS  
Least squares 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MAO 
Monoamine oxidase 
MDD 
Major Depressive Disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHI 
Medication Handling Irregularity 
MINI 
Mini International Neuropsychiatric Interview  
MMRM 
Mixed-effects Models Repeated Measures 
MNAR 
Missing not at random 
MRI 
Magnetic resonance imaging 
NE 
Norepinephrine 
NET 
Norepinephrine transporter 
OTC 
Over-the-counter (medications) 
PCOS 
Polycystic ovarian syndrome  
PET 
Positron emission tomography 
PGx 
Pharmacogenomics 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PP 
Per-Protocol 
PR 
Time between P wave and QRS in electrocardiography 
PT 
Preferred term 
QRS 
Electrocardiographic wave (complex or interval) 
QT 
Electrocardiographic interval from the beginning of the QRS 
complex to the end of the T wave 
QTc 
QT interval corrected for heart rate  
QTcB 
corrected QT interval using Bazett’s formula 
QTcF 
corrected QT interval using Fridericia’s formula 
RR 
RR interval 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 


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Table 3: 
List of Abbreviations (Continued) 
Abbreviation 
Full Form 
SCID-I Module H Structured Clinical Interview for DSM-IV Axis I Disorders, 
Module H 
SD 
Standard deviation 
SDS 
Sheehan Disability Scale 
SERT 
Serotonin transporter 
SIGH-A 
Structured Interview Guide for the HAM-A 
SIGMA 
Structured Interview Guide for the MADRS 
SNRI 
Serotonin norepinephrine reuptake inhibitor 
SSRI 
Selective serotonin reuptake inhibitor 
SOC 
System organ class 
SOP 
Standard operating procedure  
tmax 
Time to maximum concentration 
UDS 
Urine drug screen 
ULN 
Upper limit of normal 
USP 
United States Pharmacopeia 
VAS 
Visual analog scale 
WBC 
White blood cells 
WHO-DD 
World Health Organization drug dictionary 
Y-BOCS-BE 
Yale-Brown Obsessive Compulsive Scale Modified for Binge 
Eating 


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Table 4: Definition of Key Study Terms 
Terms 
Definition of terms 
CRF 
A printed, optical, or electronic document designed to record all 
of the protocol required information to report to the Sponsor for 
each study subject. 
Study Drug (or 
Study medication) 
Term to cover investigational drug, placebo, and/or active 
control. 
Treatment Period 
The period of the study in which the study drug is administered. 
Randomized Subject 
Any subject who was randomized into the treatment period of the 
study and is assigned a randomization number. 
End of Treatment 
The day that the subject receives protocol-defined last dose of the 
study drug.  
 


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4. 
INTRODUCTION 
4.1. 
Background 
Binge eating disorder (BED) is a neuropsychiatric disorder characterized by recurrent episodes 
(on average at least once per week for 3 months) of excessive food consumption during a limited 
time period, accompanied by feelings of loss of control and distress in the absence of regular 
compensatory behaviors characteristic of bulimia nervosa (BN) (Diagnostic and Statistical 
Manual of Mental Disorders, 5th Edition [DSM-5]). BED is the most common eating disorder in 
the United States and Western Europe, with an estimated lifetime prevalence of 2.5% in adults 
(~3.5% in adult women, 2.0% in adult men, and 1.6% in adolescents) and a mean age of onset of 
25.4 ± 1.2 years (McElroy-2012, Kessler-2013, Hudson-2007). Binge eating disorder is defined 
in DSM-5 as: 
• Recurrent episodes of binge eating characterized by both: 
− Eating an amount of food larger than what most people would eat, in a discrete 
period of time (eg, 2 hours) 
− Sense of lack of control over eating episode 
• Binge eating episode associated with ≥ 3: 
− Eating much more rapidly than normal 
− Eating until uncomfortably full 
− Eating large amounts when not feeling hungry 
− Eating alone because of embarrassment 
− Feeling disgusted with oneself, guilty afterward 
• Marked distress regarding binge eating is present 
• Binge eating occurs, on average, at least once a week for 3 months 
• Not associated with recurrent use of compensatory behavior (eg, bulimia nervosa). 
Patients with BED show significantly higher prevalence or risk for a range of comorbid 
psychiatric and medical disorders when compared to healthy individuals. The majority of 
patients fulfill Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) 
criteria for one or more psychiatric disorders, including depression, anxiety, and phobias. BED 
patients also have a 2-3 fold greater risk for physical ailments, including obesity, hypertension, 
diabetes mellitus, and chronic pain. Taken together, these findings signify that BED presents a 
major public health problem with significant social and economic consequences (Kessler-2013). 
Considering the severity of clinical symptomology, the negative impact on quality of life and 
physical measures of health, there is a significant need for safe and efficacious treatments for 
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4.1.1. 
Neurobiology of Binge Eating Disorder 
Non-clinical and clinical studies have implicated dopamine, opioid, and norepinephrine systems 
within the brain reward circuit in the pathogenesis of eating and addictive disorders, including 
binge eating disorder (Murray-2014, Gold-2013, Smith-2013, Hoebel-1989). In particular, 
disturbances in dopamine and the dopamine D2/3 receptor play a key role in binge eating, 
suggesting that drugs targeting disturbances in dopaminergic transmission may be effective in 
treating the disorder. 
Non-clinical studies show that rats continue to self-administer substances that act like dopamine, 
or stimulate dopamine release, in response to a dysregulated reward circuit (Murray-2014, 
Ikemoto-1997, Carlezon-1995). Rats continuously fed a cafeteria diet or a high-fat, high sugar 
meal show reduced levels of dopamine and dopamine D2/3 receptors in the dorsal striatum and 
nucleus that form part of the reward circuit (van de Giessen-2012, van de Giessen-2013). 
Knockout of striatal dopamine D2 receptors induces compulsive-type behavior in response to 
highly palatable food (Johnson-2010). High-fat diets are associated with reduced dopamine 
transporter (DAT) expression and dopamine efflux (Speed-2011). In non-clinical studies of drug 
abuse, reduced availability of dopamine D2 receptors in the striatum lead to increased and 
habitual drug intake, further supporting the importance of this transmitter system in addictive 
behaviors, and suggesting that BED and other impulse control disorders, such as substance 
abuse, share overlapping neural mechanisms (Trifilieff-2014, Smith-2013). 
Clinical, genetic, and neuroimaging studies of eating behaviors in humans have shown parallel 
disturbances in the brain reward circuit and dopamine transmission in patients with BED, 
including reduced availability of dopamine D2 receptors in the striatum (Murray-2014, 
Smith-2013). Down regulation of dopamine D2 receptors in response to overeating leads to a 
hyper-responsive reward system that is sensitized to food, perpetuating patterns of recurrent food 
craving and overconsumption that result in BED in susceptible individuals. Further evidence for 
a hyper-responsive reward circuit in BED patients comes from neuroimaging studies using 
positron emission tomography (PET). Administration of methylphenidate, an inhibitor of the 
dopamine reuptake transporter, results in greater increases in dopamine levels in the caudate 
nucleus in response to food in BED patients when compared to individuals without BED. These 
increases are significantly correlated with binge eating scores (Wang-2011). Further in vivo 
support for the role of the dopaminergic system in regulating reward behaviors has come from 
PET studies in methamphetamine addicted individuals and healthy volunteers, which have 
shown negative correlations between impulsivity, a core personality trait in BED patients, and 
availability of dopamine D2/3 receptors in the striatum and midbrain (Lee-2009, 
Buckholtz-2010). 
Similar to findings from the PET studies, functional magnetic resonance imaging (MRI) studies 
show a dysregulated and hyper-responsive reward circuit in response to food in BED patients. 
Exposure to high-calorie or highly palatable food stimuli elicits greater activation in reward 
areas, such as the nucleus accumbens and orbital frontal cortex in BED patients compared to 
controls, which directly correlates with the severity of binge eating symptoms (Schienle-2009, 
Filbey-2012). Together results from these studies show that dysregulation of the dopaminergic 
driven reward circuit is associated with BED and suggest that therapies targeting this system may 
offer effective interventions for the disorder. 


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4.1.2. 
Pharmacological Management of Binge Eating Disorder 
Although cognitive, behavioral and interpersonal psychotherapies improve binge eating 
symptoms, many patients do not respond (McElroy-2012). Recent studies suggest that 
pharmacotherapies that target one or more of the neurotransmitter systems implicated in BED 
may play a critical role in its management (McElroy-2012). 
Several classes of pharmacological agents have been evaluated for the treatment of BED in 
randomized, double-blind, placebo-controlled or open-label studies, including selective serotonin 
reuptake inhibitors (SSRIs), antiobesity agents, anticonvulsants, and stimulants (Hudson-1998, 
McElroy-2000, Arnold-2002, McElroy-2003A, Stunkard-1996, Appolinario-2003, Grilo-2005, 
McElroy-2003B, McElroy-2006, McElroy-2007, Leombruni-2006, NCT01718483, 
NCT01718509). 
Lisdexamfetamine dimesylate is a central nervous stimulant indicated for the treatment of attention 
deficit hyperactivity disorder (ADHD). In two 12–week, randomized, placebo-controlled 
registration studies, lisdexamfetamine dimesylate showed significant reductions in binge eating 
frequency (NCT01718483, NCT01718509) and these results supported FDA approval of 
Vyvanse® as a treatment for adults with BED (Shire-2015). 
4.2. 
Study Conduct Rationale 
Dasotraline (also known as SEP-225289), a new chemical entity currently in clinical trials for 
BED and ADHD, blocks the pre-synaptic dopamine transporter (DAT) and the norepinephrine 
transporter (NET). Unlike psychostimulants such as amphetamine, which facilitate the direct 
release of dopamine and norepinephrine (Hutson-2014, Minzenberg-2012), dasotraline is a dual 
reuptake inhibitor (dopamine/norepinephrine reuptake inhibitor; DNRI). Dasotraline has a long 
time to maximum concentration (tmax; approximately 10 to 12 hours after dosing) and mean 
apparent half-life (47.1 to 77.0 hours). 
A non-clinical study was conducted to compare the acute effects of dasotraline in a rat model of 
BED with lisdexamfetamine dimesylate, and its pharmacologically active metabolite, 
d-amphetamine. Rats that were allowed irregular and limited access to chocolate developed 
robust and intermittent hyperphagia that mirrored BED without any associated obesity. Binge 
eating of chocolate was markedly reduced by a single oral dose of dasotraline. The reduction in 
chocolate consumption was dose dependent and comparable to the effects observed with both 
lisdexamfetamine dimesylate and d-amphetamine in this rat BED model. 
Previous clinical studies support dasotraline as a potentially safe and efficacious treatment option 
for adults with ADHD. In one study, adults taking dasotraline 8 mg/day experienced a significant 
improvement in ADHD symptoms compared to placebo, as measured by the Attention Deficit 
Hyperactivity Disorder Rating Scale Version IV (ADHD-RS-IV) with adult prompts total score 
(P = .010, effect size 0.41). A trend was seen for efficacy of the dasotraline 4 mg/day dose 
compared to placebo on the ADHD-RS-IV at Week 4 study endpoint (P = .076). Statistically 
significant improvement compared to placebo was observed in Clinical Global Impression-
Severity scale (CGI-S) scores at Week 4 for both the 4 and 8 mg/day doses. In a second study, 
the dasotraline 6 mg/day group showed numerically greater improvement relative to placebo in 
ADHD symptoms at Week 8 study endpoint, as measured by the ADHD-RS-IV with adult 
prompts, that was not statistically significant after adjustment for multiple comparisons (least 


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squares [LS] mean change from baseline: -16.51 vs -13.9; P = .074). Notably, the dasotraline 
6 mg/day group was statistically superior to placebo on the ADHD-RS-IV at the Week 4 
(P =.027), Week 6 (P =.019), and Week 8 (P = .037) timepoints (non-adjusted p-values). 
Statistically significant improvement on the CGI-S was also observed for the 6 mg/day group at 
Weeks 4 and 6, as well as at the Week 8 study endpoint (P = .011). The dasotraline 4 mg/day 
group did not show improvement relative to placebo on the ADHD-RS-IV and CGI-S 
assessments at the Week 8 study endpoint. 
Consistent with DNRI pharmacology, the most frequent adverse events (AEs) reported in these 
ADHD studies were insomnia, decreased appetite, and dry mouth. In addition, significant dose 
dependent decreases were observed in appetite and weight. Increases in mean supine and 
standing heart rate (HR) observed during treatment and follow-up were generally dose 
dependent. 
A recently completed 12-week, randomized, double-blind, placebo-controlled, flexibly-dosed, 
study (SEP360-221) of dasotraline (4, 6, or 8 mg/day) in adults with BED showed significant 
reduction in the number of binge eating days/week compared to placebo at Week 12 (P < .0001) 
with an effect size of 0.74. Significant separation from placebo was observed at all weeks 
starting at Week 1 (P < .0001). In addition, dasotraline achieved significant results compared to 
placebo in the key secondary endpoints including improvement in the BE-CGI-S (P < .0001, 
effect size = 0.95); reduction in the Yale-Brown Obsessive Compulsive Scale Modified for 
Binge Eating (YBOCS-BE) score (P < .0001, effect size = 0.96); and a greater number of 
subjects achieving 4-week cessation from binge eating (P < .0001; effect size = 0.66). The 
highest incidence of AEs for subjects receiving dasotraline (≥ 5%) in descending order were 
insomnia, dry mouth, decreased appetite, anxiety, nausea, decreased weight, headache, dizziness, 
irritability, dyspepsia, constipation, thirst, and diarrhoea. There were no deaths in this study and 
1 serious adverse event (SAE) was reported (suicidal ideation). There were no clinically 
important changes in vital signs or electrocardiograms (ECG) observed except for a mild 
increase in pulse rate and orthostatic pulse rate, consistent with the known pharmacology of 
dasotraline. 
The current study is being conducted to replicate the efficacy results from Study SEP360-221, to 
explore the dose response, and to further assess the safety and tolerability of dasotraline in the 
treatment of BED. 
4.3. 
Risk-Benefit Assessment 
Overall, in previous clinical studies dasotraline was generally safe and well tolerated. An 
overview of safety results from the recently completed study in adult subjects with BED is 
presented in Section 4.2. To date, over 2700 subjects have received one or more doses of 
dasotraline during the clinical development programs in ADHD, BED, and major depressive 
disorder (MDD) in the range of 0.5 to 32 mg/day. A total of > 400 subjects have been exposed to 
dasotraline for a minimum of 6 months. 
Risks associated with dasotraline treatment have been well characterized and are as expected 
given the DAT/NET pharmacology. The most common AEs in the BED study were similar to 
findings in studies of adult subjects with ADHD. 


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In an effort to maximize tolerability, an initial dose of 4 mg/day for 2 weeks will be used for the 
dasotraline 6 mg/day treatment arm in this study. 
Dasotraline was evaluated in a dedicated human abuse liability study and compared with 
methylphenidate and placebo. Unlike methylphenidate, dasotraline did not differentiate from 
placebo on the primary end-point of Drug Liking and was disliked at the highest dose studied 
(36 mg). Standardized queries, as well as a comprehensive Abuse Potential Monitoring Plan 
(APMP), have not detected signals of drug abuse, dependence or withdrawal across clinical 
studies with dasotraline. 
The current study will be conducted in accordance with relevant regulatory guidance and law 
with regards to handling, distribution, storage, dispensation, accountability, and destruction of 
study drug. In addition the APMP will be implemented for this study (Section 26, 
Appendix VII). Additionally, a Data and Safety Monitoring Board (DSMB) will be established 
for this study to review safety data at regular intervals. 
An overview of efficacy results from the recently completed study in adult subjects with BED is 
presented in Section 4.2. Dasotraline was statistically superior to placebo in change from 
baseline in the number of binge eating days/week at Week 12 with highly statistically significant 
separation from placebo observed at each week starting at Week 1. The study also met all 3 key 
secondary endpoints. 
The current study is designed to optimize the balance of efficacy and tolerability of dasotraline in 
the treatment of adult subjects with BED. 
4.4. 
Hypotheses 
4.4.1. 
Primary Hypotheses 
In adults with moderate to severe BED, after 12 weeks of treatment, 
• Dasotraline 6 mg/day reduces change from baseline in the number of binge days per 
week relative to placebo 
• Dasotraline 4 mg/day reduces change from baseline in the number of binge days per 
week relative to placebo 
4.4.2. 
Secondary Hypotheses 
In adults with moderate to severe BED, after 12 weeks of treatment, 6 mg/day dasotraline or both 
doses of dasotraline: 
• Reduce change from baseline in BE-CGI-S score relative to placebo 
• Provide a greater proportion of subjects with a 4-week cessation from binge eating at 
Week 12 relative to placebo 
• Reduce change from baseline in Y-BOCS-BE total score relative to placebo 
 


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5. 
STUDY OBJECTIVES 
5.1. 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of 2 doses of dasotraline 
(4 and 6 mg/day) compared with placebo in adults with moderate to severe BED as measured by 
the number of binge days per week. 
5.2. 
Key Secondary Objectives 
To evaluate the efficacy of 2 doses of dasotraline (4 and 6 mg/day) compared with placebo in 
adults with moderate to severe BED as measured by: 
• Binge-eating Clinical Global Impression-Severity (BE-CGI-S) 
• 4-Week cessation from binge eating defined as a 100% reduction for at least 
28 consecutive days in the number of binge eating episodes 
• Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating (Y-BOCS-BE) 
5.3. 
Other Secondary Objectives 
The other secondary objectives of the study are: 
• To evaluate the efficacy of 2 doses of dasotraline (4 and 6 mg/day) compared with 
placebo in adults with moderate to severe BED as measured by: 
− Number of binge episodes per week 
− Proportion of binge eating responders at Week 12 who show > 75% reduction in 
the number of binge eating episodes 
− Sheehan Disability Scale (SDS) 
− Montgomery-Asberg Depression Rating Scale (MADRS) 
− Hamilton Anxiety Rating Scale (HAM-A) 
− Eating Disorder Examination Questionnaire (EDE-Q) modified 
• To evaluate the safety and tolerability of 2 doses of dasotraline (4 and 6 mg/day) using 
physical examinations, 12-lead electrocardiograms (ECG), vital signs, AE reports, 
clinical laboratory results, body weight, body mass index (BMI), and Columbia – 
Suicide Severity Rating Scale (C-SSRS) 


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• To assess potential withdrawal effects upon abrupt discontinuation of dasotraline after 
12 weeks of continuous daily treatment using the following assessments (administered 
during the withdrawal period):  
− Cocaine Selective Severity Assessment (CSSA) 
− Discontinuation-Emergent Signs and Symptoms (DESS) Scale 
− Symptoms of anxiety utilizing the HAM-A 
− Symptoms of depression utilizing the MADRS 
• To assess the abuse potential of dasotraline utilizing a comprehensive abuse potential 
monitoring plan (APMP) 
• To assess the relationship between dasotraline plasma concentration and the primary 
efficacy and selected secondary efficacy and safety endpoints 
 


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6. 
STUDY ENDPOINTS 
6.1. 
Primary Efficacy Endpoint 
Change from baseline in number of binge days (defined as days during which at least 1 binge 
episode occurs) per week at Week 12. 
6.2. 
Key Secondary Efficacy Endpoints 
The key secondary efficacy endpoints are: 
• Change from baseline in BE-CGI-S score at Week 12 
• Percent of subjects with a 4-week cessation from binge eating (defined as a 100% 
reduction for at least 28 consecutive days in the number of binge eating episodes prior 
to Week 12/end of treatment [EOT]) 
• Change from baseline in Y-BOCS-BE total score at Week 12 
6.3. 
Other Secondary Efficacy Endpoints 
The other secondary efficacy endpoints are: 
• Change from baseline in number of binge days per week at Weeks 1, 2, 3, 4, 6, 8, 
and 10 
• Change from baseline in number of binge episodes per week at Weeks 1, 2, 3, 4, 6, 8, 
10, and 12 
• Change from baseline in BE-CGI-S score at Weeks 2, 4, 6, 8, and 10 
• Change from baseline in Y-BOCS-BE total score at Weeks 2, 4, 6, 8, and 10 and 
subscale scores (obsessions and compulsions) at Weeks 2, 4, 6, 8, 10, and 12 
• Change from baseline in SDS total score and subscale scores (school/work disability, 
social life disability, and family life disability) at Weeks 6 and 12 
• Change from baseline in MADRS total score at Week 12 
• Change from baseline in HAM-A total score at Week 12 
• Proportion of binge eating responders who have ≥ 75% reduction in the number of 
binge eating episodes from Baseline at Week 12 
• Change from baseline in EDE-Q modified including EDE-Q7 global score and 
3 subscale scores (dietary restraint, shape/weight overvaluation, and body 
dissatisfaction) at Week 12 
6.4. 
Safety Endpoints 
The safety endpoints are: 
• The incidence of overall AEs, serious AEs (SAEs), and AEs (or SAEs) leading to 
discontinuations 


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• Clinical laboratory evaluations (serum chemistry, hematology, and urinalysis) 
• Clinical evaluations (vital signs including orthostatic effects, and 12-lead ECGs) 
• Frequency and severity of suicidal ideation and suicidal behavior as assessed by the 
C-SSRS 
• Change and percent change from baseline in body weight at Weeks 1, 2, 3, 4, 6, 8, 10, 
and 12 
• Change and percent change from baseline in BMI at Weeks 1, 2, 3, 4, 6, 8, 10, and 12 
• Change from baseline in a fasting lipid panel (triglycerides, total cholesterol, 
high-density lipoprotein [HDL] cholesterol, and low-density lipoprotein [LDL] 
cholesterol) at Weeks 6 and 12 
• Change from baseline in hemoglobin A1c level at Weeks 6 and 12 
• Change from baseline in fasting glucose level at Weeks 6 and 12  
• Change from baseline in insulin and high-sensitivity C-reactive protein (hs-CRP) 
• Occurrence of symptoms of withdrawal from dasotraline measured by change from 
Week 12/EOT in:  
− CSSA total score at Weeks 13, 14, and 15 
− DESS total score at Weeks 13, 14, and 15 
− HAM-A total score at Weeks 13, 14, and 15 
− MADRS total score at Weeks 13, 14, and 15 
6.5. 
Pharmacokinetic Endpoint 
Relationship between dasotraline plasma concentration and the primary endpoint in addition to 
selected secondary efficacy and safety endpoints 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a randomized, double-blind, parallel-group, multicenter, outpatient study evaluating the 
efficacy and safety of 2 doses of dasotraline (4 and 6 mg/day) versus placebo over a 12-week 
treatment period in adults with BED. This study is projected to randomize approximately 
480 subjects to 3 treatment groups in a 1:1:1 ratio (4 mg/day dasotraline, 6 mg/day dasotraline, 
and placebo). 
Subjects randomized to placebo will receive placebo for the duration of the treatment period. 
Subjects randomized to 4 mg/day dasotraline will receive 4 mg/day for the duration of the 
treatment period.  
Subjects randomized to 6 mg/day dasotraline will be dosed with 4 mg/day dasotraline for the 
first 2 weeks of the treatment period and will be increased to 6 mg/day at Week 2. 
If, in the judgment of the Investigator, the subject does not tolerate the assigned dose, he or she 
will be discontinued from the study. 
The study will consist of 3 periods: Screening (up to 3 weeks), 12-weeks of treatment, and a 
3-week study drug withdrawal period. Subjects who complete the 12-week double-blind 
treatment period in this study may be eligible to enroll and continue treatment for an additional 
12 months in an open-label extension study (Study SEP360-322). Subjects who do not enter the 
extension study will complete the study drug withdrawal period in this study. A study schematic 
is presented in Figure 1. 
 
Figure 1: 
Study Schematic 
 
 


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Note: Subjects randomized to placebo will receive placebo for the duration of the treatment period. Subjects randomized to 
4 mg/day dasotraline will receive 4 mg/day for the duration of the treatment period. Subjects randomized to 6 mg/day 
dasotraline will be dosed with 4 mg/day dasotraline for the first 2 weeks of the treatment period and will be increased to 
6 mg/day at Week 2. 
a Subjects who do not enter the extension study will return to the clinic for withdrawal (Cocaine Selective Severity Assessment 
[CSSA], Discontinuation-Emergent Signs and Symptoms [DESS], Hamilton Anxiety Rating Scale [HAM-A], and 
Montgomery-Asberg Depression Rating Scale [MADRS]) and safety assessments at Weeks 13, 14, and 15 during the study 
medication withdrawal period. 
Efficacy will be evaluated at each visit using the subject binge eating diary and a clinician 
interview to assess the frequency of binge episodes and the number of binge days, defined as 
days with at least one binge episode. Additional assessments will include BE-CGI-S, 
Y-BOCS-BE, MADRS, HAM-A, SDS, and EDE-Q modified. Safety and tolerability will be 
monitored throughout the study by collection of physical examination results, ECGs, vital signs, 
AEs, clinical laboratory parameters, C-SSRS, body weight, and BMI will be calculated. Subjects 
who have significant findings for suicidal ideation upon completion of the C-SSRS at any time 
during the study must be referred to the Investigator for follow-up evaluation. Assessment of 
potential withdrawal effects will be conducted via administration of the CSSA, DESS, HAM-A, 
and MADRS at the end of treatment and during the 3-week study medication withdrawal period. 
Blood samples for pharmacokinetics (PK) and biomarkers associated with eating disorders (to be 
determined) will be collected. Blood samples collected for PK assessment will be analyzed for 
plasma concentrations of dasotraline. The relationship between dasotraline plasma concentration 
and the primary and selected secondary clinical outcome measures will be evaluated. The 
relationship between biomarkers associated with eating disorders in relationship to the severity 
of BED and response to dasotraline will be evaluated at a later date in the development program. 
Plasma samples collected for PK and biomarker concentration analysis may also be used for the 
additional characterization of and/or bioanalytical method development for dasotraline. 
A blood sample will be collected from subjects who provide separate informed consent for 
pharmacogenomics (PGx) analysis for potential evaluation of associations between genetic 
polymorphisms such as, but not limited to Taq1DRD2, OPRM1, and DRD4-7R, and the severity 
of BED, the clinical response to dasotraline, in addition to the safety, efficacy, and PK profiles of 
dasotraline to be conducted at a later date in the development program. Separate consent is 
required for collection of this specific blood sample and will be obtained at Screening for 
subjects who agree to provide this sample (note: this separate consent is not required for 
participation in the study, it is required only for subjects who will provide this sample). 
A comprehensive APMP for dasotraline designed to detect potential abuse of the compound and 
to more closely monitor AEs consistent with the known pharmacology for dasotraline will be 
implemented (see Section 26, Appendix VII for details). 
An independent Data and Safety Monitoring Board (DSMB) will review safety data at regular 
intervals. 
Screening Period (Days -22 to -2): Informed consent will be obtained from each subject before 
any study procedures are performed for this study. Study eligibility criteria will be assessed 
during this period, and subjects will be required to have discontinued from any protocol 
prohibited medications within 3 months of screening. The subject’s eligibility assessment will be 
reviewed by the contract research organization’s (CRO) oversight quality team along with the 
sponsor based on protocol specified inclusion and exclusion criteria. The sponsor will participate 


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in the eligibility review process with the CRO to ascertain the subject’s eligibility and will be 
copied on all communications between the CRO and the site. In the event the CRO/sponsor and 
site do not agree on a subject’s eligibility then the subject will not be enrolled. Subjects may be 
rescreened once for out of range clinical laboratory results including urine drug screen (UDS) or 
ECG results following authorization of the medical monitor. During the screening visit, subjects 
will be trained to complete the daily binge eating diary and then complete the diary at home for 
at least 14 consecutive days immediately prior to the Baseline visit and starting no sooner than 
the day after the screening visit. 
Baseline Visit (Day -1): Subjects who meet eligibility criteria at Screening will return to the 
study site on Day -1 for confirmation of screening evaluations as well as completion of predose 
assessments and procedures including clinician review of the daily binge eating diary. Any lapse 
in diary completion during the 14 day period (eg, 1 or more days are skipped) will be discussed 
with the subject. If 1 or 2 days per week are incomplete or missing, the subject may complete the 
diary with the clinician. However, if the subject cannot recall enough information to complete 
the diary in full after clinician review, the subject will be ineligible. Subjects will also be 
ineligible for randomization if there are more than 2 missed diary days in 1 week. Eligible 
subjects (based on confirmation of study entry criteria) will be randomized and dispensed study 
drug at Day -1. 
Treatment Period (Day 1 [Week 0] through Day 84 [Week 12]): Subjects will self-administer 
the study drug on an outpatient basis once a day with or without food beginning on Day 1, the 
day after the Baseline visit, and continue for 12 weeks. Subjects will be instructed to administer 
study drug at approximately the same time each morning including on days when clinic visits 
occur. During the treatment period subjects will continue to complete a daily binge eating diary, 
which will be reviewed at each visit. During the treatment period, subjects will have one clinic 
visit every week for the first month, then one clinic visit every 2 weeks thereafter. In order to 
facilitate scheduling of clinic visits, a window of ± 2 days will be allowed for each weekly clinic 
visit and a window of ± 3 days will be allowed for each biweekly clinic visit, and a window of 
± 1 day for the end of treatment (EOT) visit and each clinic visit of the withdrawal period. 
Subjects who complete the 12-week Treatment Period may be eligible for participation in the 
open label extension study (SEP360-322). For subjects enrolling in the open label extension 
study, Week 12 will be the last visit for this study. 
Study Medication Withdrawal Period (Day 85 through Day 105 [Week 15]): Subjects who 
do not enroll in the extension study for whatever reason, eg, less than 12 weeks treatment in this 
study, lack of interest in the extension study, or failure to meet all eligibility criteria for the 
extension study will return to the clinic at Weeks 13, 14, and 15, to assess safety and potential 
study medication withdrawal effects during the study medication withdrawal period. Subjects 
who discontinue from study drug before completion of the 12-week treatment period will be 
asked to return to the clinic and complete the End of Treatment visit as soon as possible 
following discontinuation of study drug and complete the 3 week withdrawal period. In addition, 
subjects will continue to complete the binge eating diary during this period. 
Assessment of potential withdrawal effects will be conducted via administration of the CSSA, 
DESS, HAM-A, and MADRS at Week 12 (End of Treatment), then again at Weeks 13, 14, 
and 15 during the 3-week study medication withdrawal period. 


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The CSSA and DESS will also be completed during the 3-week study medication withdrawal 
period on non-clinic visit days. Clinical site staff will call the subject every other day during the 
study medication withdrawal period, beginning the second day after the last dose of study drug, 
unless a clinic visit is scheduled for that day (up to 3 times per day if the clinical site staff are 
unable to contact the subject on the first 2 attempts). Clinical site staff will record the responses 
in the subject’s source information and in the CRF with the contact date and time. 
A window of ± 1 day will be allowed for each weekly clinic visit and telephone call. If the 
subject cannot be contacted on a given day, during the next contact the study site staff will 
retrospectively collect the missed CSSA and DESS, in addition to the current day’s CSSA and 
DESS. 
7.2. 
Treatment Assignment and Blinding 
7.2.1. 
Treatment Assignment 
After successfully meeting study entry criteria, subjects will be randomly assigned in a 
1:1:1 ratio to 1 of 3 treatment arms: 
• Dasotraline 4 mg/day 
• Dasotraline 6 mg/day 
• Placebo 
To avoid potential imbalanced treatment allocation among subjects with different baseline levels 
of BED, the randomization will be balanced using permuted blocks with baseline number of 
binge eating days per week, which is defined as number of binge days/week determined from the 
2 weeks before the Baseline visit (3 – 4 binge eating days per week, > 4 binge eating days per 
week). The stratification process will be handled by an IXRS, an integrated web-based subject 
and drug-management system. 
An IXRS will be used to manage randomization at Day -1 and, if necessary, for emergency 
unblinding (see Section 7.2.3) of treatment assignment during the study. 
Study medication will be assigned by an IXRS at Day -1 based on the randomization schedule. 
The IXRS will generate instructions on which medication number to assign to a subject. Each 
randomized subject will be dispensed one 10-day blister pack per scheduled visit up to and 
including Visit 5 and two 10-day blister packs per scheduled visit thereafter through Visit 9. 
7.2.2. 
Blinding 
This is a double-blind study. 
Subjects, Investigator staff, persons performing the assessments, clinical operations personnel, 
data analysts, and personnel at central laboratories will remain blind to the identity of the 
treatment from the time of randomization until database lock (DBL) and unblinding, using the 
following methods: (1) randomization data are kept strictly confidential until the time of 
unblinding, and will not be accessible by anyone else involved in the study with the following 
exceptions: external bioanalytical personnel involved in the analysis of PK samples, DSMB 
members involved in regular review of safety data, external statistician and programmer who 
prepare materials for DSMB review, and Clinical Trial Materials Management personnel and 


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(2) the identity of the treatments will be concealed by the use of study medication that are all 
identical in packaging, labeling, schedule of administration, and appearance. 
During the study and prior to database lock, the treatment assignments for all subjects will be 
provided to the Bioanalytical Contract Research Organization (CRO) to facilitate plasma PK 
sample handling and analysis. No PK samples will be analyzed for placebo subjects. 
7.2.3. 
Emergency Unblinding Procedures 
The IXRS will be used, if necessary, for emergency unblinding of treatment assignment during 
the study. The blinded dose information is to be broken only in an emergency when knowledge 
of such treatment may have an impact on further treatment decisions or aid in the emergency 
treatment of the subject. Every effort must be made to contact the CRO Medical Monitor 
(Table 1) before any unblinding of the study drug. The circumstances that lead to unblinding are 
to be promptly communicated via telephone and in writing to the CRO Medical Monitor. Any 
subject for whom the blind is broken is to be discontinued from receiving any additional study 
medication and should undergo final evaluation procedures, in accordance with the EOT Visit as 
described in Section 11.8.9. 
7.3. 
Rationale 
7.3.1. 
Rationale for the Study Design 
This study is being conducted in order to replicate the efficacy results from SEP360-221 and to 
evaluate dose response to dasotraline in adult subjects with BED. 
Similar to Study SEP360-221, the current study is a randomized, double-blind, parallel-group, 
placebo-controlled study designed to evaluate the efficacy and safety of dasotraline over a 
12-week outpatient treatment period. 
In order to evaluate dose response to dasotraline, this study is a fixed-dose design of 2 doses of 
dasotraline compared with placebo. 
7.3.2. 
Rationale for the Dosages 
The dasotraline doses to be utilized in this study (4 mg/day and 6 mg/day) were selected based 
on the effects of dasotraline in the initial BED study in adults, Study SEP360-221. 
In the current study, dasotraline will be administered once daily based on its pharmacokinetic 
profile. One dasotraline treatment arm will receive 4 mg/day for the duration of the treatment 
period, and the other arm randomized to 6 mg/day will receive 4 mg/day for the first 2 weeks of 
treatment.  
The 4 mg/day dose was chosen because efficacy analyses in Study SEP360-221 at Week 2, 
where all dasotraline treated subjects were on 4 mg/day, showed a significant change from 
baseline in the number of binge days per week with an effect size 0.5. The 6 mg/day dasotraline 
dose was chosen because the results in Study SEP360-221 showed its use resulted in an 
acceptable balance of safety and efficacy, further evidenced by the fact that it was the modal 
dose in that study, whereas subjects on 8 mg/day were those who failed to respond to the lower 
doses. One-half of these subjects, however, did not respond to 8 mg/day. Together these results 


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suggest that 6 mg/day is the optimal dose with regards to benefit and risk and 4 mg/day is the 
minimum effective dose in the treatment of BED. SEP360-321 will test these 2 hypotheses. 
7.3.3. 
Rationale for the Study Population 
The patient population for this study will range from 18 to 55 years of age, inclusive, and have 
symptoms consistent with a diagnosis of moderate to severe BED. Subjects must meet the 
DSM-5 criteria for a diagnosis of BED established using the eating-disorders module of the 
Structured Clinical Interview for DSM-IV Axis I Disorders, Module H (SCID-I Module H), 
clinician review of subject diaries, and the EDE-Q. These instruments have been extensively 
used in previous trials and show excellent reliability (McElroy-2007, Hudson-1998, Grilo-2005). 
To optimize signal detection for the primary endpoint, enrolled subjects must have moderate to 
severe BED, as demonstrated by at least 3 binge eating days for each of the 2 weeks prior to the 
Baseline visit, and have a diagnosis of BED or is diagnosed at screening and has had a history of 
at least 2 binge eating days a week for at least 6 months prior to screening. 
Treatment effects observed in the proposed population will be generalizable to BED patients 
diagnosed based on DSM-5 criteria as studies have shown that patients with mild BED are 
behaviorally comparable to those who binge more frequently (Wilson-2009). To reduce the 
potential confounding effects of comorbid disorders and certain concomitant medications on the 
efficacy and safety measures, subjects will be excluded who have significant or unstable 
comorbid medical disorders (eg, cardiovascular disease, diabetes mellitus); psychiatric disorders 
(eg, psychosis, bipolar disorder); and/or are taking medications used for the treatment of BED 
(eg, lisdexamfetamine dimesylate, topiramate, SSRIs); or medications associated with weight 
gain or weight loss (eg, insulin, liraglutide, metformin, stimulants). 
7.3.4. 
Rationale for the Endpoints 
The efficacy assessments and their timing are considered appropriate to assess the efficacy of 
dasotraline in adults with BED and are consistent with those used in previous trials 
(McElroy-2007, NCT01718483, and NCT01718509). The symptom and functional assessments 
were selected to address the potential effectiveness of dasotraline on these parameters. The 
standard safety assessments and their timing are appropriate to assess the safety of dasotraline in 
adults with BED. 
7.4. 
Prevention of Missing Data 
In an effort to minimize the number of subjects who are terminated from the study before study 
completion, the following study design and conduct elements are implemented: (i) clinic visits 
every week for the first month, every 2 weeks for the remainder of double-blind treatment, and 
every week during the study drug withdrawal period, (ii) during the treatment period a window 
of ± 2 days for each weekly clinic visit, a window of ± 3 days for each biweekly clinic visit, and 
a window of ± 1 day for the EOT visit (iii) training the sites on the importance of continued 
follow-up and on the informed consent process, ensuring subjects understand the commitment 
they are making, including the intent to complete the trial, (iv) the clinical sites will train subjects 
on appropriate binge eating diary completion at Visits 1, 2, 3, and 5 and retraining will be 
provided throughout the study as needed, and (v) monitoring of data collection for adherence 
during the study. 


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8. 
SELECTION OF SUBJECTS 
Approximately 480 total subjects will be randomized (160 subjects per treatment group) at 
approximately 50 clinical sites in the United States. 
The subject’s eligibility assessment will be reviewed by the CRO’s Clinical Surveillance Team 
(CST) along with the sponsor based on protocol specified inclusion and exclusion criteria to 
promote appropriate subject enrollment and data quality. For the prebaseline review, sites will be 
required to submit specific screening information for clinician and sponsor review, prior to 
proceeding to baseline. The sponsor will participate in the eligibility review process with the 
CRO to ascertain the subject’s eligibility and will be copied on all communications between the 
CRO and the site. In the event the CRO/sponsor and site do not agree on a subject’s eligibility, 
then the subject will not be enrolled. Decisions regarding inclusion of subjects and assessment of 
subject safety throughout the trial primarily remain at the discretion of the Investigator; however, 
the Medical Monitor or Sponsor may request exclusion or discontinuation of a subject based on 
entry criteria or subject safety. 
Subjects must meet all inclusion criteria and no exclusion criteria at both the Screening and 
Baseline visits unless otherwise noted under the Inclusion or Exclusion Criteria. Eligibility 
criteria involving clinical laboratory values will be based on results from samples obtained at 
Screening. 
Subjects may be rescreened once for out of range clinical laboratory results including UDS or 
ECG results following authorization of the medical monitor. Each time a subject is rescreened a 
new subject number will be assigned. Screening numbers cannot be reassigned to another 
subject. 
Subjects whose study participation is prematurely terminated will not be replaced. 
8.1. 
Subject Inclusion Criteria 
Subjects must meet all of the inclusion criteria in order to be eligible for the study. 
1. Male or female subject between 18-55 years of age, inclusive, at time of informed 
consent. 
2. Subject meets the following DSM-5 criteria for a diagnosis of BED. An episode of binge 
eating is characterized by both: 
• Eating an amount of food larger than what most people would eat, in a 
discrete period of time (eg, 2 hours) 
• Sense of lack of control over eating episode 
Binge eating episodes are associated with ≥ 3 of the following: 
• Eating much more rapidly than normal 
• Eating until uncomfortably full 
• Eating large amounts when not feeling hungry 
• Eating alone because of embarrassment 


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• Feeling disgusted with oneself, guilty afterward 
Binge eating episodes are also associated with marked distress regarding the 
episode and not associated with recurrent use of compensatory behavior 
(eg, bulimia nervosa). Note: A subject using compensatory behavior less than 
1 time every 2 weeks over the 3 months prior to screening may be permitted to 
enroll in the study. 
3. Diagnosis is confirmed based on the Structured Clinical Interview for DSM-IV Axis I 
Disorders, Module H (SCID-I Module H), clinician review of subject diaries, and the 
EDE-Q. 
4. Subject has a BED diagnosis or is diagnosed at screening and has a history of at least 
2 binge eating days a week for at least 6 months prior to screening. 
5. Subject’s BED is of at least moderate severity with subject reporting at least 3 binge 
eating days for each of the 2 weeks prior to baseline as documented in the subject’s binge 
diary. A binge eating day is defined as having at least one binge eating episode. 
6. Subject has a BE-CGI-S score ≥ 4 at screening and baseline. 
7. Subject has a negative breath alcohol test and a negative UDS for any illicit drug. 
8. Female subject must have a negative serum pregnancy test at screening; females who are 
post-menopausal (defined as at least 12 months of spontaneous amenorrhea) and those 
who have undergone hysterectomy or bilateral oophorectomy will be exempted from the 
pregnancy test. 
9. Female subject of childbearing potential and male subject with female partner of 
childbearing potential must agree to use an effective and medically acceptable form of 
birth control (see Section 10.4 throughout the study period. Note: Continued use of an 
effective and medically acceptable form of birth control is recommended for 30 days 
after study completion. 
10. Subject must be able to comply with study drug administration and adhere to protocol 
requirements including all study assessments. 
11. Subject can read well enough to understand the informed consent form and other subject 
materials. 
8.2. 
Subject Exclusion Criteria 
Subjects meeting any of the exclusion criteria are not eligible for the study: 
1. Subject has BMI of 18 kg/m2or less, or greater than 45 kg/m2 (see Section 27, 
Appendix VIII). 
2. Subject has a lifetime history or current symptoms consistent with bulimia nervosa or 
anorexia nervosa. 
3. Subject has started psychotherapy (eg, supportive psychotherapy, cognitive behavior 
therapy, interpersonal therapy) within 3 months prior to screening. Note: Subjects 
receiving stable ongoing psychotherapy for longer than 3 months are permitted to enroll. 


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4. Subject has participated in a formal weight loss program (eg, Weight Watchers®) within 
3 months prior to screening. 
5. Subject has used a psychostimulant or mood stabilizer within the 3 months prior to 
screening. 
6. Subject has used any medications for the treatment of binge eating, other eating 
disorders, obesity, or weight gain or any other medication that could result in weight gain 
or weight loss including over-the-counter and herbal products within the 3 months prior 
to screening. 
7. Subject has received lisdexamfetamine dimesylate (Vyvanse®) for any reason, including 
but not limited to participation in any Phase 2 or 3 trial. 
8. Subject has a lifetime history of psychotic disorder, bipolar disorder, hypomania, 
dementia, or ADHD as defined by the DSM-5 criteria. 
9. Subject has a history of moderate to severe depression based on Investigator’s judgment 
within the 6 months prior to screening or is currently taking or has taken any medication 
for depression during the 3 months prior to screening. 
10. Subject has MADRS score ≥ 18 at screening and Baseline visit. 
11. Subject has a history of substance use disorder including alcohol use disorder (excluding 
nicotine and caffeine) within the 12 months prior to screening, as defined by the DSM-5 
criteria. 
12. Subject is considered a suicide risk in the investigator’s opinion or has any previous 
history of suicide attempt within the past 12 months. 
13. Subject answers “yes” to “suicidal ideation” item 4 (active suicidal ideation with some 
intent to act, without specific plan) or item 5 (active suicidal ideation with specific plan 
and intent) on the C-SSRS assessment at screening (in the past month). Subjects who 
answer “yes” to this question must be referred to the Investigator for follow-up 
evaluation. 
14. Subject has type I diabetes mellitus or insulin-dependent diabetes mellitus. 
15. Subject with type II diabetes mellitus, has hemoglobin A1c ≥ 6.5% at screening, or has 
initiated treatment with or changed the dose of a glucose-lowering agent within 3 months 
prior to screening. 
16. Subject has known history of symptomatic cardiovascular disease, advanced 
arteriosclerosis, structural cardiac abnormality, cardiomyopathy, documented heart 
rhythm abnormalities, coronary artery disease, or other serious cardiac problems. 
17. Subject has initiated treatment with or changed the dose of a lipid-lowering medication 
within the 3 months prior to screening. 
18. Subject has a history of moderate or severe hypertension that in the Investigator’s opinion 
has not been medically stable or has required a change in dosage and/or medication 
during the 3 months prior to screening. 


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19. Subject has a history of focal or diffuse brain disorder including but not limited to 
epilepsy, seizures (except childhood febrile seizures), stroke, benign or malignant tumors, 
or head trauma with loss of consciousness lasting more than 5 minutes; unexplained 
syncope or other unexplained blackouts (except single incident); or a history of clinically 
significant repeated head-traumas without loss of consciousness. 
20. Subject has had polycystic ovarian syndrome (PCOS) in the previous 12 months, even if 
no treatment was provided. 
21. Subject is female and pregnant or nursing. 
22. Subject has had major bariatric surgery, eg, gastric jejunal bypass, Roux-en-Y gastric 
bypass, sleeve gastrectomy, duodenal switch with biliopancreatic diversion for weight 
loss at any time. 
23. Minor bariatric surgery (eg, lap bands) within 3 years of screening. Note: Surgeries for 
cosmetic reasons are not exclusionary but should be discussed with the medical monitor. 
24. Subject has a history of positive test for either Hepatitis B surface antigen or Hepatitis C 
antibody, and has liver function test results at screening above the upper limit of normal 
(ULN) for the reference laboratory. 
25. Subject without a history of positive test for Hepatitis B surface antigen or Hepatitis C 
antibody has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value 
≥ 2 times the ULN at screening. 
26. Subject has a blood urea nitrogen (BUN) value ≥ 1.5 times the ULN for the reference 
range, serum creatinine  > 1.5 times the ULN for the reference range, fasting blood 
glucose ≥ 126 mg/dL (7.0 mmol/L), or hemoglobin A1c ≥ 6.5% at screening. 
27. Subject is known to have tested positive for human immunodeficiency virus (HIV). 
28. Subject has a clinically significant abnormality on screening evaluation including 
physical examination, vital signs, ECG, or laboratory tests that the Investigator considers 
to be inappropriate to allow participation in the study. 
29. The subject’s screening ECG shows a corrected QT interval using Fridericia’s formula 
(QTcF) of ≥ 450 msec for male subjects or ≥ 470 msec for female subjects. Eligibility 
will be based on the core laboratory ECG interpretation report. 
30. Subject has any life-time history of abuse or diversion of stimulants. 
31. Subject has a history of allergic reaction or has a known or suspected sensitivity to any 
substance that is contained in the study drug formulation. 
32. Subject who in the opinion of the Sponsor and Investigator has any other psychiatric or 
medical condition or disorder or any other psychosocial or work-related issue not 
previously listed that could interfere with the diagnosis of BED at screening or 
subsequent evaluations during the course of the study. 
33. Subject who may experience or who is currently experiencing significant psychosocial or 
environmental stressors (eg, loss of employment, loss of housing, financial hardship, 
divorce) that could impede their ability to adhere to protocol requirements, as judged by 
the Investigator. 


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34. Subject is currently participating in or has participated in any clinical trial within the last 
90 days or has participated in more than 2 clinical trials within the past year. This 
includes studies using marketed compounds or devices. 
35. Subject has previously been enrolled in a clinical trial of dasotraline (SEP-225289). 
36. Subject is an investigational site staff member or the relative of an investigational site 
staff member. 
37. Subject has started a new physical training/exercise program for the purpose of managing 
his or her weight or binge eating within 3 months prior to screening. Note. Subjects 
participating in a stable physical training/exercise program for longer than 3 months are 
permitted to enroll. 
38. Subject has a history of malignancy within 5 years prior to the Screening visit, except for 
adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer. 
History of a pituitary tumor, whether benign or malignant, is exclusionary. 


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9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
9.1. 
Description of Study Drug 
The study medication is described in Table 5. 
Table 5: 
Investigational Product 
Attribute 
Study Medication 
Product name 
Dasotraline 
4.0 mg 
Dasotraline 
6.0 mg 
Matching 
Placebo 
Dosage form 
capsules 
capsules 
capsules 
Unit dose 
capsule 
capsule 
capsule 
Route of administration 
oral 
oral 
oral 
Physical description 
Swedish orange, 
size #4 
Swedish orange, 
size #4 
Swedish orange, 
size #4 
In addition to dasotraline, the active ingredient, each capsule contains: mannitol, sodium starch 
glycolate, talc, and magnesium stearate. 
Matching placebo capsules contain all ingredients except active dasotraline. 
9.2. 
Study Drug Packaging and Labeling 
9.2.1. 
Package Description 
Study drug will be provided in 1-week blister cards containing 10 capsules of dasotraline 4 mg or 
6 mg capsules or placebo capsules (7 days + 3 extra days). 
9.2.2. 
Labeling Description  
All packaging for the study medications will be labeled with: 
• Protocol number 
• Sponsor’s name and address 
• Content (eg number of tablets) 
• Investigational New Drug statement 
• Instructions for use and storage 
• Blank space for subject identifiers 
• Batch number 
• Blank space to record visit number identifier 
• Unique medication number 


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9.3. 
Study Drug Storage 
All study medication should be stored at United States Pharmacopeia (USP) Controlled Room 
Temperature: 20°C to 25°C (68°F - 77°F); excursions are permitted to 15°C to 30°C 
(59°F - 86°F) but must still be reported to CRO (please see Clinical Trial Material Manual for 
instructions). The subject will be instructed to store the study medication at room temperature. 
9.4. 
Dispensing of Study Drug 
An IXRS will be used to manage subject screening and enrollment. The IXRS is an integrated 
web-based subject and drug management system. 
Study drug blister cards will be assigned by the IXRS based on the treatment schedule and dose 
adjustment criteria. The IXRS will generate instructions with regard to which medication number 
to assign to a subject. Each subject will be dispensed one or two 10-day blister cards per 
scheduled visit depending on the timing of the next scheduled visit (see Section 7.2.1). 
Subjects will self-administer the study drug on an outpatient basis. Subjects will take one capsule 
of study drug per day at approximately the same time each morning including on the days when 
clinic visits occur. 
9.5. 
Study Drug Accountability 
The Investigator or designee is responsible for storing the drug in a secure location and for 
maintaining adequate records of drug disposition that include the dates, quantity, and use by 
subjects. If the study is stopped for any reason or completed, all unused supplies of drug will be 
returned to the Sponsor, unless other instructions are provided in writing by Sponsor/ CRO. 
Upon receipt of clinical trial material (CTM), the Investigator or designee will inventory the 
supplies and verify receipt of supplies. The site will send an Acknowledgement of Receipt to 
Sunovion Pharmaceuticals, or designee, confirming date of receipt, inventory, and condition of 
CTM received. 
The Investigator on an ongoing basis must maintain a drug inventory record of supplied, 
received, dispensed, and returned study medication for use as the primary source for study drug 
accountability. 
9.6. 
Study Drug Handling and Disposal 
On an ongoing basis, the Investigator or designee must maintain a study medication inventory 
record of supplied, received, dispensed, and returned medication.  
The study medication will not be dispensed to any person who is not a study subject under this 
protocol. 
The Investigator or designee is required to return all used and unused study medication to the 
Sponsor or designee as instructed. The Investigator or designee is required to maintain copies of 
medication shipping receipts, study medication accountability records, and records of return of 
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10. 
TREATMENT OF SUBJECTS 
10.1. 
Study Medication  
Dasotraline 4 mg and 6 mg capsules and placebo capsules for oral administration will be 
supplied for the study as described in Section 9. 
Subjects will self-administer the study drug on an outpatient basis once a day beginning on 
Day 1, the day after the Baseline visit, and continue for 12 weeks. Subjects will be instructed to 
administer study drug at approximately the same time each morning including on days when 
clinic visits occur. If an individual subject requires a change to time of dosing (eg, evening shift 
worker), this must be approved by the Medical Monitor, and the subject should take the study 
drug at the same time of day throughout the study. All doses of study drug will consist of 
1 capsule taken orally. 
Subjects may take study medication with or without food. 
Study medication capsules should not be opened or tampered with in any way; the active 
ingredient is an ocular irritant. 
10.1.1. 
Dose or Dosage for Study Drug 
Subjects randomized to placebo will receive placebo for the duration of the treatment period. 
Subjects randomized to 4 mg/day dasotraline will receive 4 mg/day for the duration of the 
treatment period.  
Subjects randomized to 6 mg/day dasotraline will be dosed with 4 mg/day dasotraline for the 
first 2 weeks of the treatment period and will be increased to 6 mg/day at Week 2. 
No other changes in dose are allowed during the study. Subjects who cannot tolerate the assigned 
dose at any time in the study will be discontinued. 
10.2. 
Treatment Compliance 
Compliance with study medication will be monitored closely and determined at each visit during 
treatment. Subjects will be instructed to bring all unused study medication with them to each 
visit. Compliance will be assessed by counting capsules and dividing the actual number of doses 
taken (per capsule count) by the number of doses the subject should have taken within a visit 
period and multiplying by 100. Subjects who miss more than 25% of scheduled doses or take 
more than 125% of the scheduled doses will be considered noncompliant. Evidence of 
noncompliance must be immediately reported to the Medical Monitor. Potential noncompliance 
will be discussed with subjects, and at the Investigator’s discretion may result in termination of 
the subject from the study. All subjects will be reminded of the importance of strict compliance 
with taking study medication for the accurate evaluation of the safety, tolerability, and 
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10.3. 
Concomitant Medications and Therapies 
The following information on all medication administered between Screening and Week 15 
(Day 105) or at study discontinuation will be recorded on the CRF: Medication name, dose, 
frequency, route, start date, stop date, and indication. 
Information on the format and version of the coding dictionary is provided in the Data 
Management Plan (DMP). All medications will be coded using World Health Organization drug 
dictionary (WHO-DD). 
Directions regarding prior medications are provided in Section 11.1. 
10.3.1. 
Prohibited Medications 
Any discontinuation of medications at any time prior to study participation is at the discretion of 
the potential subject in conjunction with the prescribing physician. 
Use of certain medications, including but not limited to the following, is prohibited throughout 
the study from screening through the last in-clinic visit: 
• psychostimulants 
• any medications for the treatment of binge eating or other eating disorders, obesity, or 
weight gain 
• antidepressant medications (eg, bupropion, SSRI/ serotonin norepinephrine reuptake 
inhibitor (SNRI), monoamine oxidase (MAO) inhibitors, tricyclics) and St. John’s 
Wort 
• medications that are CYP2B6 substrates or inhibitors or inducers of CYP2B6, eg, 
bupropion, cyclophosphamide, carbamazepine, etc. (see Section 25, Appendix VI) 
• medications for the treatment of ADHD such as but not limited to lisdexamfetamine, 
methylphenidate, atomoxetine, clonidine, guanfacine, modafinil, and armodafinil 
• corticosteroids and anabolic steroids (Note: Topical, intra-nasal, and inhaled 
corticosteroids are permitted. Other formulations of corticosteroids may be permitted 
following consultation with the Medical Monitor.) 
• antiepileptic medications 
• benzodiazepines except for sleep (see Section 10.3.3) 
• mood stabilizers (eg, lithium, anticonvulsants) 
• antipsychotic medications 
• suvorexant 
• any medication that can result in either weight gain or weight loss (eg, insulin, 
liraglutide, metformin, diphenhydramine except topical formulations, etc.) including 
over-the-counter and herbal products. Periodic use of diphenhydramine or 
diphenhydramine containing products for sleep or allergies is permitted with 
authorization from the Medical Monitor. 


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10.3.2. 
Prohibited Therapies 
Initiation of psychotherapy (eg, supportive psychotherapy, cognitive behavior therapy, 
interpersonal therapy) is prohibited within 3 months prior to screening and throughout the study. 
Any participation in a formal weight loss program such as Weight Watchers® is prohibited 
within 3 months of screening and throughout the study. 
For permitted therapies, see Section 10.3.4. 
10.3.3. 
Permitted Medications 
The following medications are permitted during the study, with the restrictions noted: 
• Sleep aids should be administered no more than once nightly and should not be used 
in combination. Concomitant use of lorazepam, temazepam, eszopiclone, zaleplon, 
zolpidem, zolpidem controlled release (CR), and melatonin is permitted at the 
discretion of the Investigator with the following restrictions: 
− Lorazepam (or equivalent benzodiazepine) is a permitted hypnotic up to a 
maximum daily dose of 2 mg/day 
− Temazepam (≤ 30 mg/day), eszopiclone (≤ 3 mg/day), zaleplon (≤ 20 mg/day), 
zolpidem (≤ 10 mg/day for males; ≤ 5 mg/day for females), zolpidem CR 
(≤ 12.5 mg/day for males; ≤ 6.25 mg/day for females), and melatonin 
(≤ 5 mg/day) may be administered at bedtime for insomnia, as needed 
− Use of any other sleep aids should be approved by the Medical Monitor 
• Opiates may be allowed in rare cases for a limited period of time with prior 
authorization from the Medical Monitor 
• Contraceptives 
The date and time of the last dose taken prior to scheduled efficacy assessments of any sleep aid 
listed above must be recorded at each visit. 
10.3.4. 
Permitted Therapies 
Subjects receiving a stable course of psychotherapy (eg, supportive psychotherapy, cognitive 
behavior therapy, interpersonal therapy) ongoing for more than 3 months prior to screening are 
eligible to enroll in the study and to continue that therapy during the study. 
New programs of psychotherapy are not permitted to be started during the study from screening 
through the last clinic visit. 
10.4. 
Contraception Requirements 
Female subjects of childbearing potential and male subjects with female partners of childbearing 
potential must agree to use an effective and medically acceptable form of birth control 
throughout the study period. Medically acceptable and effective contraceptives for females 
include one or more of the following: abstinence, prescription hormonal contraceptives (oral, 
patch, vaginal ring, implant, or injection), diaphragm with spermicide, intrauterine device (IUD), 
condom with spermicide, surgical sterilization, or vasectomy of male partner. For male subjects 


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adequate contraception is defined as abstinence or continuous use of 2 barrier methods of 
contraception (eg, male condom in addition to a diaphragm or a contraceptive sponge). 
It is recommended that female subjects of childbearing potential and male subjects with female 
partners of childbearing potential continue to use an effective and medically acceptable form of 
birth control for 30 days after study completion. 
10.5. 
Guidance for Overdose 
There is no overdose experience with dasotraline in humans. Signs and symptoms of overdose in 
non-clinical studies were consistent with exaggerated pharmacology and included hyperactivity, 
stereotypy, aggressiveness, and reduced food intake and body weight loss. 
Activated charcoal may be of value if administered very soon after a dasotraline overdose 
(ie, during the absorption process). 
10.6. 
Cautions 
Dasotraline is an ocular irritant. Therefore appropriate precautions should be taken to avoid 
ocular exposure to the contents of the dasotraline capsules. 


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11. 
STUDY ASSESSMENTS 
A study schematic is presented in Figure 1. A summary of assessments to be conducted at each 
visit is presented in Table 2. 
Training, as appropriate, will be provided for study site staff administering each of the 
effectiveness and safety assessments. In an effort to improve the consistency of subject 
assessment across sites, an independent rater qualification service will provide training on the 
Mini International Neuropsychiatric Interview (MINI), SCID-I Module H, EDE-Q, EDE-Q 
modified, Y-BOCS-BE, BE-CGI-S, MADRS, SDS, HAM-A, CSSA, and DESS rating scales. In 
an effort to improve rater consistency and precision, an independent rater qualification service, in 
collaboration with the sponsor, will develop a credential and experience survey to identify raters 
with appropriate experience. The sponsor has final discretion regarding allowing raters to 
participate in the study. 
Table 6 outlines the clinical assessments that will be conducted by site raters or self-report by 
subject. It is recommended that the assessments are conducted in the sequence noted in Table 6. 
Table 6: 
Recommended Schedule for Clinical Assessments 
Screening Visit 
(Visit 1) 
Baseline Visit (Visit 2) 
Visits 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 
and 13 (as applicable, see Table 2, 
schedule of assessments above and 
Section 11.8 
SCID-I Module H 
Review binge diary 
Review binge diary 
MINI 
Y-BOCS-BE 
Y-BOCS-BE 
EDE-Q (by subject) 
EDE-Q modified (by subject) 
EDE-Q modified (by subject) 
MADRS 
SDS (by subject) 
SDS (by subject) 
C-SSRS 
MADRS  
MADRS  
BE-CGI-S 
C-SSRS 
C-SSRS 
Binge-diary training 
BE-CGI-S 
BE-CGI-S 
 
HAM-A 
HAM-A 
 
 
CSSA 
 
 
DESS 
 
11.1. 
Demographics and Baseline Characteristics 
Subject self-report will be acceptable for listing all prior and concomitant medication use, 
demographics, medical history, psychiatric history including family history of psychiatric 
disorders, and evaluation for inclusion/exclusion except where specific protocol procedures are 
mandated to ensure appropriate enrollment (eg, certain baseline laboratory values). All 
medications taken within the 90 days before screening will be recorded as prior medications; 
data collected will be the same as for concomitant medications (see Section 10.3). 


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Demographics collected at screening will include sex, race, ethnicity, date of birth, weight, and 
height. BMI will be calculated from weight and height. 
For medical history, only relevant/significant medical history and recurrence of any condition 
will be collected. 
At screening, subjects will be checked for multiple study enrollments by clinical site staff using 
an available registry(s) of subjects participating in clinical trials. Clinical site staff will be 
provided training 
11.2. 
Diagnostic Scales to Determine Study Eligibility 
11.2.1. 
Structured Clinical Interview for DSM-IV Axis I Disorders, Module H (SCID-I 
Module H) 
The Structured Clinical Interview for DSM-IV Axis I Disorders, Module H (SCID-I Module H) 
is a primary diagnostic measure developed to establish the presence of binge eating disorder in 
adults. The SCID is often used to characterize a study population in terms of current and past 
psychiatric diagnoses (Spitzer-1992, First-2007). 
11.2.2. 
Eating Disorder Examination Questionnaire (EDE-Q)  
The Eating Disorder Examination Questionnaire (EDE-Q) is a self-report version of the eating 
disorder examination (EDE) (Fairburn-1994). Like the EDE, the EDE-Q measures 
eating-disorder psychopathology in the past 28 days, and over longer intervals for diagnostic 
items. The EDE-Q yields scores on the same subscales (dietary restraint, eating concern, weight 
concern, and shape concern), global score, and binge eating frequency variables as the EDE 
interview. Research with clinical samples of patients with BED has reported acceptable 
agreement between the EDE-Q and EDE interview (Grilo-2001A; Grilo-2001B). 
11.2.3. 
Mini International Neuropsychiatric Interview (MINI) 
The MINI is a short structured diagnostic interview, developed for Diagnostic and Statistical 
Manual of Mental Disorders, 4th Edition Text Revised (DSM-IV-TR) and DSM-5 psychiatric 
disorders (Sheehan-1989). With an administration time of approximately 15 minutes, it was 
designed to meet the need for a short but accurate structured psychiatric interview for multicenter 
clinical trials and epidemiology. The MINI 7 will be used for this study. 
11.3. 
Efficacy Assessments and Scales 
11.3.1. 
Binge Eating Diary 
All binge episodes will be captured daily by the subject in a binge eating diary using paper 
format provided by the CRO to record the date, duration (total hours of binging), type of binge 
episode (meal or non-meal), amount and type of food, and number of binges. At each visit, the 
Investigator will review the completed diary with the subject and assess the number of binges for 
each day. The Investigator assessment of number of binges for each day will be recorded in the 
diary and recorded in the CRF. Missing data, if any, will be reviewed by the clinical site staff 
with the subject and additional training on diary completion will be provided as needed. 


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11.3.2. 
Sheehan Disability Scale (SDS) 
The SDS was developed to assess functional impairment in 3 domains: work/school, social, and 
family life. The subject rates the extent to which work/school, social life, and home life have 
been impaired by his/her symptoms on an 11-point visual analog scale. The 3 items can be 
summed into a single global measure of impairment that ranges from 0 (unimpaired) to 
30 (highly impaired). This anchored visual analog scale uses spatiovisual, numeric, and verbal 
descriptive anchors simultaneously to assess disability across 3 domains: work; social life, and 
family life. There are verbal descriptors for the points on the scale as well as numerical scores 
that provide more precise levels of the verbal descriptors. The SDS takes approximately 
10 minutes to complete. 
11.3.3. 
Montgomery-Asberg Depression Rating Scale (MADRS) 
The Montgomery-Asberg Depression Rating Scale (MADRS) is a widely used clinician-rated 
assessment of the subject’s level of depression. The measure contains 10 items that measure 
apparent and reported sadness, inner tension, reduced sleep and appetite, difficulty concentrating, 
lassitude, inability to feel, and pessimistic and suicidal thoughts. Each item is scored in a range 
of 0 to 6 points, with higher scores indicating increased depressive symptoms. 
The Structured Interview Guide for the MADRS (SIGMA) will be used for the administration of 
the MADRS. 
11.3.4. 
Hamilton Anxiety Rating Scale (HAM-A) 
The HAM-A is a widely used and well-validated tool for measuring the severity of a patient’s 
anxiety. It should be administered by an experienced clinician. The HAM-A consists of 14 items, 
each defined by a series of symptoms, and measures both psychic anxiety (mental agitation and 
psychological distress) and somatic anxiety (physical complaints related to anxiety). Each item is 
scored on a 5-point scale, ranging from 0 = not present to 4 = severe. 
The Structured Interview Guide for the HAM-A (SIGH-A) will be used for the administration of 
the HAM-A. 
11.3.5. 
Binge-eating Clinical Global Impressions–Severity of Illness (BE-CGI-S) 
The BE-CGI-S (based on Guy-1976) asks the clinician one question: “Considering your total 
clinical experience with this population, how mentally ill is the subject at this time?” The 
clinician’s answer is rated on the following 7-point scale: 1 = normal, not at all ill; 2 = borderline 
mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the 
most extremely ill subjects. 
This rating is based upon observed and reported BED symptoms, behavior, and function in the 
past 7 days. Clearly, symptoms and behavior can fluctuate over a week; the score should reflect 
the average severity level across the 7 days. 
11.3.6. 
Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating 
(Y-BOCS-BE) 
The Yale Brown Obsessive Compulsive Scale Modified for Binge Eating (Y-BOCS-BE) is a 
clinician-rated scale that measures the obsession of binge eating, thoughts and compulsiveness of 


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binge eating behaviors. The 10-item scale, is rated from 0 (no symptoms) to 4 (extreme 
symptoms). Total scores range from 0 to 40. A score of 0-7 is sub-clinical; 8-15 is mild; 16-23 is 
moderate; 24-31 is severe; and 32-40 is extreme (Goodman-1989). The Y-BOCS-BE can be 
divided into 2 subscales: obsessions and compulsions. 
11.3.7. 
Eating Disorder Examination Questionnaire (EDE-Q) Modified 
Convergent findings from confirmatory factor analyses of item data from the EDE-Q obtained 
from patients with BED (Grilo-2010) and patients with overweight/obesity (Grilo-2012; 
Grilo-2013; Hrabosky-2008) as well as non-clinical groups (Grilo-2015) support an alternative, 
brief version of the EDE-Q and EDE comprising 7 items to generate a global score and 
3 subscales (dietary restraint, shape/weight overvaluation, and body dissatisfaction) referred to as 
the EDE-Q7 (Grilo-2015). In the present study, the EDE-Q7 along with 3 items to assess binge 
eating, including the number of binge eating days will be used and referred to as the EDE-Q 
modified. 
11.4. 
Safety Assessments and Scales 
11.4.1. 
Safety Assessments 
The Investigator or appropriate designee will review results of safety assessments on a regular 
basis and the Sponsor must be kept fully informed of any clinically significant findings either at 
Screening or subsequently during study conduct. 
11.4.1.1. Adverse Events 
Adverse events will be collected for each subject. Subjects should be queried in a non-leading 
manner, without specific prompting (eg, “Has there been any change in your health status since 
your last visit?”). See Section 12 , Safety Reporting. 
AEs and SAEs will be monitored throughout the study at all visits following the first dose of 
study drug. 
Untoward medical occurrences that occur prior to the first dose of study drug will be collected as 
pre-treatment events. 
11.4.1.2. Clinical Laboratory Tests 
Clinical laboratory tests will include routine serum chemistry, hematology, urinalysis, lipid 
panel, hemoglobin A1c, insulin, and hs-CRP. The specific clinical laboratory tests required by 
protocol are listed in Section 21, Appendix II. 
Blood and urine samples will be collected for clinical laboratory tests. All clinical laboratory 
tests will be performed centrally to ensure consistency. For detailed instructions regarding 
clinical laboratory procedures, sampling, and shipping guidelines refer to the Central Laboratory 
Instructions Manual. All clinical laboratories will be College of American Pathologists (CAP) 
and Clinical Laboratory Improvement Amendments (CLIA) (or equivalent) certified. 
If a subject has an unscheduled visit, clinical laboratory tests may be repeated (as necessary). 
Blood samples for clinical laboratory tests should be collected after scheduled 12-lead ECG and 
vital signs assessments. 


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11.4.1.3. Physical and Neurological Examinations 
Clinically significant physical and neurological examination findings, as judged by the 
Investigator, at screening will be recorded as medical history and after screening will be recorded 
as AEs. 
The physical examination will consist of an assessment of body systems including but not 
limited to head, ears, eyes, nose and throat (HEENT), cardiovascular (heart and vascular system), 
respiratory (lungs and chest), gastrointestinal (abdomen), and skin. 
Neurological examinations will include a brief assessment of mental status, cranial nerves, motor 
strength and coordination, sensory function in addition to deep tendon reflexes. 
11.4.1.4. Vital Signs 
Following 5 minutes of rest, respiration rate, oral temperature, and supine systolic and diastolic 
blood pressures and pulse rate will be measured. Systolic and diastolic blood pressures and pulse 
rate will be taken again with the subject standing after the subject has been standing for 2 to 
4 minutes. The same arm should be used during each assessment of blood pressure and pulse rate 
throughout the study. If a subject develops symptoms consistent with orthostatic hypotension 
(light-headedness, dizziness, or changes in sensorium upon standing) at any point, his or her 
supine and standing blood pressure and pulse rate should be collected at that time in the manner 
described above. Vital signs will be obtained prior to clinical laboratory collection and 
performance of an ECG, whenever possible. 
11.4.1.5. Electrocardiograms 
All ECGs will be obtained in the supine position, after the subject has been resting supine for at 
least 10 minutes. ECGs will be 12-lead with a 10-second rhythm strip. ECGs should be obtained 
before drawing blood samples. All attempts should be made to use the same ECG recorder for all 
visits within individual subjects. ECGs will be centrally read at a core laboratory according to 
established quality additional information assurance procedures for inter/intra reader variability. 
Refer to Section 20, Appendix I for additional information. 
Standard 12-lead ECG will record heart rate (HR), PR interval, RR interval, QT interval, QTc 
intervals (QTcB and QTcF), and QRS duration. 
11.4.2. 
Safety Scales 
11.4.2.1. Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS (Posner-2007) is a tool designed to systematically assess and track suicidal AEs 
(suicidal behavior and suicidal ideation) throughout the study. The strength of this suicide 
classification system is in its ability to comprehensively identify suicidal events while limiting 
the over-identification of suicidal behavior. The scale takes approximately 5 minutes to 
administer. The C-SSRS will be administered by a trained rater at the site. 
This study will utilize 2 versions of the C-SSRS. At the screening visit, the “Baseline/Screening” 
version will be completed; for all subsequent visits, the “Since Last Visit” version of the C-SSRS 
will be administered. 


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Subjects who answer “yes” to “suicidal ideation” item 4 (active suicidal ideation with some 
intent to act, without specific plan) or item 5 (active suicidal ideation with specific plan and 
intent) on the C-SSRS assessment at Screening (in the past month) must be referred to the 
Investigator for follow-up evaluation. 
11.4.2.2. Cocaine Selective Severity Assessment (CSSA) 
The CSSA (Kampman-1998) is a clinician-administered scale designed to evaluate withdrawal 
signs and symptoms related to stimulants over the past 24 hours. It takes approximately 
10 minutes to administer the 18-item scale. 
Included in the CSSA are those symptoms most often associated with early cocaine abstinence, 
including change in appetite, depression, fatigue, anhedonia, anxiety, irritability, sleep 
disturbance, and inability to concentrate, paranoia, carbohydrate craving, bradycardia, and 
suicidality. The CSSA is scored as follows: cocaine craving scores are obtained by having 
subjects record the highest intensity and frequency of cocaine craving experienced during the 
preceding 24 hours using visual analog scales. All items except item 14, are scored 0 to 7 
according to instructions on the CSSA generally with 0 = no symptoms and 7 = maximum score 
on any individual item. Item 14 is scored 0 to 8 with 0 = no symptoms and 8 = maximum score. 
Heart rate is determined by radial pulse measurement. 
On non-clinic days, the CSSA will be completed by site staff during a call to the subject. 
In order to complete the visual analog scale (VAS) portion of the CSSA on days when there are 
no scheduled clinic visits, subjects will be provided with copies of the VAS in advance, and will 
record their response at the time of scale administration. 
In order to complete the radial pulse portion of the CSSA on days when there are no scheduled 
clinic visits, subjects will measure their own radial pulse and provide the measurement to the site 
staff over the phone. 
For consistency of radial pulse measurements, subjects also will take their own radial pulse for 
the CSSA completed during in-clinic visits. 
11.4.2.3. Discontinuation-Emergent Signs and Symptoms (DESS) Scale 
The DESS Scale (Rosenbaum-1998) is a clinician-rated instrument of 43 items used to evaluate 
signs and symptoms associated with discontinuation or interruption of monoamine reuptake 
inhibitor treatment. 
On non-clinic days, the DESS Scale will be completed by site staff during a call to the subject. 
11.4.2.4. Hamilton Anxiety Rating Scale (HAM-A) 
The HAM-A will be use to evaluate changes in severity of anxiety during the study medication 
withdrawal period. See Section 11.3.4. 
11.4.2.5. Montgomery-Asberg Depression Rating Scale (MADRS) 
The MADRS will be use to evaluate changes in severity of anxiety during the study medication 
withdrawal period. See Section 11.3.3. 


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11.5. 
Pharmacokinetic Assessments 
The plasma concentrations for dasotraline will be determined using a validated bioanalytical 
method. PK samples collected from placebo subjects will not be analyzed. The relationship 
between dasotraline plasma concentration and the primary and selected secondary efficacy and 
safety endpoints will be evaluated. 
Plasma samples collected from the study could be utilized for relevant exploratory research work 
such as further method development and metabolic profiling and identification. 
Blood samples for PK assessments should be collected at the same time as other blood samples, 
whenever possible. 
The dates and times of the previous 3 doses of study drug prior to PK blood sample collection 
are to be recorded in the CRF. 
11.6. 
Collection of Blood Samples for Biomarker Analysis 
A blood sample will be collected to evaluate biomarkers associated with eating disorders to be 
determined in relationship to the severity of BED and response to dasotraline at a later date in the 
development program. 
Plasma/serum samples collected for biomarker concentration analysis may also be used for the 
additional characterization of and/or bioanalytical method development for dasotraline. 
11.7. 
Collection of Specimens for Genetic Analysis 
A blood sample will be collected from subjects who provide a separate informed consent for 
pharmacogenomics (PGx) analysis for potential evaluation of associations between genetic 
polymorphisms such as, but not limited to Taq1DRD2, OPRM1, and DRD4-7R, and the severity 
of BED, the clinical response to dasotraline, in addition to the safety, efficacy, and PK profiles of 
dasotraline to be conducted at a later date in the development program. 
Pharmacogenetic sampling and sample handling guidelines are provided in Section 24, 
Appendix V. Pharmacogenetic blood samples will be shipped in anonymized fashion to a 
qualified central laboratory for processing. Processing will include extraction of 
deoxyribonucleic acid (DNA) genetic material. The DNA material will be stored for no more 
than 15 years, unless a written request for destruction of the sample is provided by a subject to 
the site at which the subject participated in the Sunovion-sponsored dasotraline clinical trial. 
Subjects must provide a written request requesting destruction of their genetic sample to the 
study site at which they participated in a Sunovion-sponsored clinical trial. The request will be 
sent to the Sponsor for processing using the study subject number identifier. The Sponsor will 
identify the sample using the study subject number and instruct the central laboratory to destroy 
the stored anonymized sample corresponding to the study subject number. Upon destruction of 
the sample, the Sponsor will provide written documentation to the site that the sample has been 
destroyed. Genetic information obtained from individual subjects (including genotype 
information) will be stored in anonymized fashion in the Sponsor’s pharmacogenetic database. 
When reported, the data will not include any subject-level identifying information and will 
reflect anonymized information regarding subject characteristics. 


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The DNA samples collected in this study will be maintained exclusively by Sunovion or 
designee. Processing, analysis, or storage of these samples by third parties will be conducted 
only by qualified third parties. The scope of genetic analysis performed by third parties using 
DNA extracted from samples provided by subjects in a Sunovion-sponsored trial will be 
determined by the Sponsor. 
The timing of the analysis will be following completion of this study and as such may be 
reported separately. 
11.8. 
Study Visits and Assessments 
11.8.1. 
Screening: Visit 1 (Day -22 to -2) 
Subjects will be evaluated at the Screening Visit to determine their eligibility to enroll in the 
study. The screening visit should be scheduled in the morning. Subjects must be fasting for at 
least 8 hours (may have water only) prior to the indicated laboratory tests. 
The following study related procedures will be performed at Screening: 
• Obtain informed consent and optional informed consent for PGx 
• Review inclusion/exclusion criteria 
• Collect demographics 
• Collect medical history, and psychiatric history including family history of 
psychiatric disorders 
• Record prior and concomitant medications 
• Perform physical and neurological examinations 
• Measure height and weight, calculate BMI 
• Collect vital signs 
• Perform ECG 
• Administer scales: 
− SCID-I Module H 
− MINI 
− EDE-Q 
− MADRS (with SIGMA) 
− C-SSRS 
− BE-CGI-S 
• Collect samples for hematology, serum chemistry, fasting lipid panel, 
hemoglobin A1c level, urinalysis, UDS, serum pregnancy test for females of 
child-bearing potential 
• Perform breath alcohol test 


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• Binge eating diary training  
• Remind subject to fast for at least 8 hours (may have water only) prior to the Baseline 
visit (Day -1) 
Subjects will be checked for multiple study enrollments by site staff. 
Subjects will complete the daily binge eating diary each day for 14 consecutive days 
immediately prior to the Baseline visit and starting no sooner than the day after the screening 
visit. 
Subjects may be rescreened once for out of range clinical laboratory results including UDS or 
ECG results following authorization of the medial monitor. If the retest for out of range 
laboratory or ECG results can be conducted within the allotted screening period then a complete 
rescreen is not required. 
For the prebaseline review, sites will be required to submit specific screening information for 
clinician and sponsor review, prior to proceeding to baseline. Details are provided in the Clinical 
Surveillance Team (CST) site manual. 
11.8.1.1. Baseline: Visit 2 (Day -1) 
The Baseline visit should be scheduled in the morning. Subjects must be fasting for at least 
8 hours (may have water only) prior to the indicated laboratory tests. The following study related 
procedures will be performed: 
• Review inclusion/exclusion criteria 
• Record concomitant medications 
• Perform physical and neurological examinations 
• Collect vital signs and weight 
• Perform ECG 
• Clinician review of binge eating diary 
• Administer scales: 
− Y-BOCS-BE 
− EDE-Q modified 
− SDS 
− MADRS (with SIGMA) 
− C-SSRS 
− BE-CGI-S 
− HAM-A (with SIGH-A) 
• Collect samples for hematology, serum chemistry, fasting lipid panel, 
hemoglobin A1c level, insulin, hs-CRP, urinalysis, UDS, urine pregnancy test for 
females of child-bearing potential 


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• Collect blood samples for biomarkers and genotyping 
• Perform breath alcohol test 
• Randomization 
• Dispense study medication 
• Binge eating diary training 
Subjects will complete the daily binge eating diary each day until the next clinic visit. 
11.8.2. 
Week 1 (Day 7 [± 2 days]): Visit 3 
The following study related procedures will be performed: 
• Record concomitant medications 
• Collect vital signs and weight 
• Record AEs 
• Clinician review of binge eating diary and retraining 
• Administer scales: 
− C-SSRS 
• Perform study medication accountability 
• Dispense study medication 
Subjects will complete the daily binge eating diary each day until the next clinic visit. 
11.8.3. 
Week 2 (Day 14 [± 2 days]): Visit 4 
The following study related procedures will be performed: 
• Record concomitant medications 
• Collect vital signs and weight 
• Record AEs 
• Clinician review of binge eating diary 
• Administer scales: 
− Y-BOCS-BE 
− C-SSRS 
− BE-CGI-S 
• Collect blood sample for plasma PK levels 
• Perform study medication accountability 
• Dispense study medication 
Subjects will complete the daily binge eating diary each day until the next clinic visit. 


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11.8.4. 
Week 3 (Day 21 [± 2 days]): Visit 5 
The following study related procedures will be performed: 
• Record concomitant medications 
• Collect vital signs and weight 
• Record AEs 
• Clinician review of binge eating diary and retraining 
• Administer scales: 
− C-SSRS 
• Perform study medication accountability 
• Dispense study medication 
Subjects will complete the daily binge eating diary each day until the next clinic visit. 
11.8.5. 
Week 4 (Day 28 [± 2 days]): Visit 6 
The following study related procedures will be performed: 
• Record concomitant medications 
• Collect vital signs and weight 
• Perform ECG 
• Record AEs 
• Clinician review of binge eating diary and retraining, as necessary 
• Administer scales: 
− Y-BOCS-BE 
− C-SSRS 
− BE-CGI-S 
• Collect sample for urine pregnancy test for females of child-bearing potential 
• Perform study medication accountability 
• Dispense study medication 
• Remind subject to fast for at least 8 hours (water and study drug only) prior to the 
Visit 7 Week 6 (Day 42) visit. 
Subjects will complete the daily binge eating diary each day until the next clinic visit. 
11.8.6. 
Week 6 (Day 42 [± 3 days]): Visit 7 
The Week 6 visit should be scheduled in the morning. Subjects must be fasting for at least 
8 hours (may have water and study drug only) prior to the indicated laboratory tests. The 
following study related procedures will be performed: 


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• Record concomitant medications 
• Collect vital signs and weight 
• Record AEs 
• Clinician review of binge eating diary and retraining, as necessary 
• Administer scales: 
− SDS 
− Y-BOCS-BE 
− C-SSRS 
− BE-CGI-S 
• Collect sample for UDS 
• Perform breath alcohol test 
• Collect samples for hematology, serum chemistry, fasting lipid panel, hemoglobin 
A1c level, urinalysis 
• Collect blood sample for plasma PK levels 
• Perform study medication accountability 
• Dispense study medication 
Subjects will complete the daily binge eating diary each day until the next clinic visit. 
11.8.7. 
Week 8 (Day 56 [± 3 days]): Visit 8  
The following study related procedures will be performed: 
• Record concomitant medications 
• Collect vital signs and weight 
• Perform ECG 
• Record AEs 
• Clinician review of binge eating diary and retraining, as necessary 
• Administer scales: 
− Y-BOCS-BE 
− C-SSRS 
− BE-CGI-S 
• Collect samples for urine pregnancy test for females of child-bearing potential 
• Perform study medication accountability 
• Dispense study medication 


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Subjects will complete the daily binge eating diary each day until the next clinic visit. 
11.8.8. 
Week 10 (Day 70 [± 3 days]): Visit 9 
The following study related procedures will be performed: 
• Record concomitant medications 
• Collect vital signs and weight 
• Record AEs 
• Clinician review of binge eating diary and retraining, as necessary 
• Administer scales: 
− Y-BOCS-BE 
− C-SSRS 
− BE-CGI-S 
• Perform study medication accountability 
• Dispense study medication 
Remind subject to fast for at least 8 hours (water and study drug only) prior to the Visit 10 
Week 12 (Day 84) visit. 
Subjects will complete the daily binge eating diary each day until the next clinic visit. 
11.8.9. 
Week 12 (Day 84 [± 1 day]) End of Treatment (EOT): Visit 10 
The EOT should be scheduled in the morning. Subjects must be fasting for at least 8 hours (may 
have water and study drug only) prior to the indicated laboratory tests. The following study 
related procedures will be performed: 
• Record concomitant medications 
• Perform physical and neurological examinations 
• Collect vital signs and weight 
• Perform ECG 
• Record AEs 
• Clinician review of binge eating diary and retraining, as necessary 
• Administer scales: 
− Y-BOCS-BE 
− MADRS (with SIGMA) 
− EDE-Q modified 
− SDS 
− C-SSRS 


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− BE-CGI-S 
− HAM-A (with SIGH-A) 
− CSSA (only for subjects not entering the extension study) 
− DESS (only for subjects not entering the extension study) 
• Collect samples for hematology, serum chemistry, fasting lipid panel, 
hemoglobin A1c level, insulin, hs-CRP, urinalysis, UDS, urine pregnancy test 
for females of child-bearing potential 
• Collect blood samples for plasma PK levels and biomarkers 
• Perform breath alcohol test 
• Perform study medication accountability 
Subjects will complete the daily binge eating diary each day until the next clinic visit. 
At this visit, subjects who have completed treatment will have the option to enroll and continue 
treatment for an additional 12 months in an extension study, Study SEP360-322. For subjects 
entering the extension study, Week 12 in this study will be baseline for the extension study and 
subjects will not need to return for further visits for this study. 
Subjects who do not enter the extension study, for any reason, will complete the study 
medication withdrawal period assessments and visits. 
11.8.10. 
Three-week Study Medication Withdrawal Period 
In addition to during in-clinic visits, the CSSA and DESS will be completed during the 3-week 
study medication withdrawal period on non-clinic visit days. Clinical site staff will call the 
subject every other day during the study medication withdrawal period, beginning the second day 
after the last dose of study drug, unless a clinic visit is scheduled for that day (up to 3 times per 
day if the clinical site staff are unable to contact the subject on the first 2 attempts). Clinical site 
staff will record the responses to the CSSA and DESS in the subject’s source information and in 
the CRF with the contact date and time. During these calls, clinical site staff will also assess and 
record AE(s) and concomitant medications. 
A window of ± 1 day will be allowed for each weekly clinic visit and telephone call. If the 
subject cannot be contacted on a given day, during the next contact the study site staff will 
retrospectively collect the missed CSSA and DESS, in addition to the current day’s CSSA and 
DESS. 
11.8.10.1. Week 13 (Day 91 [± 1 day]1): Visit 11 
The following study related procedures will be performed: 
                                                     
 
 
1 For early terminating subjects 7 days post last dose ± 1 day 


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• Record concomitant medications 
• Collect vital signs and weight 
• Perform ECG 
• Record AEs 
• Clinician review of binge eating diary and retraining, as necessary 
• Administer scales: 
− MADRS (with SIGMA) 
− C-SSRS 
− HAM-A (with SIGH-A) 
− CSSA 
− DESS 
• Collect sample for UDS 
• Perform breath alcohol test 
Subjects will complete the daily binge eating diary each day until the next clinic visit. 
11.8.10.2. Week 14 (Day 98 [± 1 day]2): Visit 12 
The following study related procedures will be performed: 
• Record concomitant medications 
• Collect vital signs and weight 
• Perform ECG 
• Record AEs 
• Clinician review of binge eating diary and retraining, as necessary 
• Administer scales: 
− MADRS (with SIGMA) 
− C-SSRS 
− HAM-A (with SIGH-A) 
− CSSA 
− DESS 
                                                     
 
 
2 For early terminating subjects 14 days post last dose ± 1 day 


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• Collect sample for UDS 
• Perform breath alcohol test 
• Remind subject to fast for at least 8 hours (water only) prior to Visit 13. 
Subjects will complete the daily binge eating diary each day until the next clinic visit. 
11.8.10.3. Week 15 (Day 105 [± 1 day]3) Visit 13 
The Week 15 visit should be scheduled in the morning. Subjects must be fasting for at least 
8 hours (may have water) prior to the indicated laboratory tests. The following study related 
procedures will be performed: 
• Record concomitant medications 
• Perform physical and neurological examinations 
• Collect vital signs and weight 
• Perform ECG 
• Record AEs 
• Clinician review of binge eating diary 
• Administer scales: 
− Y-BOCS-BE 
− MADRS (with SIGMA) 
− C-SSRS 
− SDS  
− BE-CGI-S 
− HAM-A (with SIGH-A) 
− CSSA 
− DESS 
• Collect sample for UDS 
• Perform breath alcohol test 
• Collect samples for hematology, serum chemistry, fasting lipid panel, 
hemoglobin A1c level, urinalysis, serum pregnancy test for females of child-bearing 
potential 
                                                     
 
 
3 For early terminating subjects 21 days post last dose ± 1 day 


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12. 
SAFETY REPORTING 
12.1. 
Definitions 
12.1.1. 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
Untoward medical occurrences that occur between the time of signing the informed consent form 
(ICF) and first drug administration are pre-treatment events. Those that occur after first 
administration of study drug are considered AEs. 
An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease occurring after the administration of a medicinal (investigational) 
product, whether or not considered related to the medicinal (investigational) product. AEs may 
include the onset of new illness and the exacerbation of pre-existing conditions. AEs will be 
collected from after first administration of study drug to the last study visit. 
Lack of efficacy may be an expected potential outcome and should not be reported as an AE 
unless the event is unusual in some way. 
New signs and symptoms of underlying disease, or signs and symptoms of emerging disease 
must be recorded as AEs. 
The Investigator should attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis should be documented as the AE 
and not the individual signs/symptoms. 
12.1.2. 
Serious Adverse Events 
A serious adverse event (SAE) is an AE that meets one or more of the following criteria: 
• Results in death. 
• Is life-threatening. 
• Requires hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly or birth defect. 
• Is an important medical event that may jeopardize the subject or may require a 
medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization. 
The term “severe” is often used to describe the severity of a specific event (as in mild, moderate, 
or severe myocardial infarction) (see Section 12.3); the event itself, however, may be of 
relatively minor medical significance (such as severe headache). This is not the same as 


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“serious,” which is based on subject/event outcome or action criteria usually associated with 
events that pose a threat to a subject's life or functioning as defined by the criteria above. 
During the study, if a subject has a hospitalization or procedure (eg, elective surgery) that was 
scheduled before the study entry, ie, before informed consent for an event/condition that 
occurred before the study, the hospitalization is considered a therapeutic intervention and not the 
result of a SAE. However, if the event/condition worsens during the study, it should be reported 
as an AE (or SAE, if the event/condition results in a serious outcome such as prolongation of 
hospitalization). 
Life-threatening means that the subject was, in the view of the Investigator, at immediate risk of 
death from the event as it occurred. This definition does not include an event that had it occurred 
in a more severe form might have caused death. 
SAE criteria information will be captured on the case report form (CRF). 
12.2. 
Objective Findings 
Clinically significant abnormal objective findings (eg, clinical laboratory value, ECG value, and 
physical examination observation) will also be recorded as AEs. 
When a clear diagnosis is available that explains the objective findings, this diagnosis will be 
recorded as the AE, and not the abnormal objective finding (eg, viral hepatitis will be recorded as 
the AE, not transaminase elevation). If a definite diagnosis is not available, then record the sign 
(eg, clinically significant elevation of transaminase levels) or symptom (eg, abdominal pain) as 
the AE. 
Clinical laboratory test results will be reviewed by the Investigator. The Investigator must 
determine the clinical significance of all out of range values. Clinical laboratory test with 
possibly drug-related or clinically relevant abnormal values of uncertain causality may be 
repeated. Any abnormal values that persist should be followed at the discretion of the 
Investigator. Laboratory reports will be initialed and dated on all pages by the Investigator. 
• Clinical Laboratory Tests Outside the Normal Range: Any value outside the normal 
range will be flagged for the attention of the Investigator or appropriate designee at 
the study center. The Investigator or appropriate designee will indicate whether or not 
the value is of clinical significance. If the result of any test (or repeat test, if done) 
from the samples taken during Screening is indicated as clinically significant and is 
not covered by the inclusion or exclusion criteria in Section 8, the subject will not be 
allowed into the study. Additional testing during the study may be done if medically 
indicated. If a clinically significant abnormality is found in the samples taken after 
dosing, during the study, and/or during the withdrawal period this should be recorded 
as an AE and the subject will be followed until the test(s) has (have) normalised or 
stabilised. 
All on-site ECG tracings and ECG over-read reports will be reviewed by the Investigator. The 
Investigator must determine the clinical significance of all abnormal ECGs. ECG with possibly 
drug-related or clinically relevant abnormal findings of uncertain causality may be repeated. Any 
abnormal ECGs that persist should be followed at the discretion of the Investigator. ECG 
tracings will be initialed and dated on all pages by the Investigator. 


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12.3. 
Collection and Recording of Adverse Events 
All pre-treatment events and AEs must be recorded in the subject’s study records/source 
documents in accordance with the Investigator’s normal clinical practice. All pre-treatment 
events and AEs/all AEs must be recorded on the CRF. 
All AEs will be followed until resolution, stabilization of the condition, the event is otherwise 
explained, or the subject is lost to follow-up. 
Each AE is to be evaluated for duration, severity, frequency, seriousness, action taken with the 
study treatment, outcome, and causal relationship to the study treatment. Definitions for severity, 
frequency, action taken with the study treatment, outcome, and causal relationship to the study 
treatment are presented below. 
The severity of AE: 
• Mild – Ordinarily transient symptoms that do not influence performance of subject’s 
daily activities. Other treatment is not ordinarily indicated. 
• Moderate – Marked symptoms sufficient to make the subject uncomfortable. 
Moderate influence on performance of subject’s daily activities. Other treatment may 
be necessary. 
• Severe – Symptoms cause considerable discomfort. Substantial influence on subject’s 
daily activities. May be unable to continue the study, and other treatment may be 
necessary. 
The frequency of AE: 
• Once – an isolated episode. 
• Intermittent – occurs on two or more separate occasions. 
• Continuous – does not abate from date of onset to date of resolution. 
The action taken with the study treatment: 
• Drug Interrupted – Study drug stopped temporarily. 
• Drug Withdrawn – Study drug stopped permanently. 
• Dose Not Changed 
• Not Applicable 
The outcome of the AE: 
• Recovered/Resolved 
• Recovering/Resolving 
• Not Recovered/Not Resolved 
• Recovered/Resolved with Sequelae 
• Fatal 
• Unknown 


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The causal relationship of the AE to the study treatment:  
• Not related 
o Not related – Improbable temporal relationship and is plausibly related to 
other drugs or underlying disease. 
o Unlikely – occurred within a reasonable time frame after 
administration/discontinuation of the study medication, but there is a likely 
association of an intercurrent/underlying medical condition or other drugs. 
• Related 
o Possible – occurred in a reasonable time after study drug administration, but 
could be related to concurrent drugs or underlying disease. 
o Probable – occurred in a reasonable time after study drug administration, is 
unlikely to be attributable to concurrent drugs or underlying disease, and there 
is a plausible mechanism to implicate the study drug. 
o Definite – occurred in a reasonable time after study drug administration and 
cannot be explained by concurrent drugs or underlying disease. The adverse 
event should respond to dechallenge/rechallenge, however, this is not 
mandatory before assigning a definite causality. 
The Medical Monitor is the initial contact person for protocol related questions or discussion of 
AEs. The contact information for the Medical Monitor as well as other emergency contact 
information can be found in Table 1 of this protocol. 
12.4. 
Immediately Reportable Events 
The following medical events must be immediately reported to the Sponsor: 
• SAE 
• Pregnancy 
Emergency contact information can be found in Table 1. 
12.4.1. 
Serious Adverse Event 
If the Investigator or study center staff becomes aware of a SAE that occurs in a study subject 
after first administration of study drug through 30 days following the last dose of the study 
medication, this must be reported within 24 hours to PPD-PVG, the medical monitor, and 
Sunovion responsible physician whether considered related or unrelated to the study drug. SAEs 
must be recorded on the CRF and the data recorded should agree with that on the SAE form. 
Following the end of subject participation in the study, the Investigator or an authorized delegate 
should report SAEs “spontaneously” to the PPD-PVG if considered at least possibly related to 
the study drug. 
SAEs will be followed until resolution, loss to follow-up, stabilization of condition, or the event 
is otherwise explained. 


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In addition to the initial telephone notification, an initial SAE form as applicable must be 
completed and signed and sent via fax or email (see Table 1) to PPD-PVG within 1 business day 
of the Investigator or study center staff becoming aware of the event. The SAE form must be 
signed by the Investigator or appropriate designee. The Sponsor provides the SAE form used to 
report SAEs. 
The Sponsor or designee will promptly notify all study centers and Investigators of a SAE that is 
determined to be expedited to the Regulatory Authorities in accordance with applicable law(s) 
and regulation(s). These SAEs must be promptly reported to the Institutional Review Board 
(IRB) by the Investigator or the appropriate person at the study center if required per IRB 
guidelines. 
12.4.2. 
Pregnancy 
Pregnancies that occur from the time that informed consent is signed through 30 days following 
the last dose of the study medication will be collected and reported on the Pregnancy Event Form. 
If a subject becomes pregnant during the course of the study, she will be instructed to 
immediately stop taking the study medication. Further, the subject will be instructed to return 
promptly/within 48 hours of the first notification of pregnancy to the research site and undergo a 
serum pregnancy test, as confirmation of pregnancy. If positive, the subject will no longer 
receive any additional study medication. All pregnancies, whether or not the subject received any 
additional study medication, will be followed until resolution (ie, termination [voluntary or 
spontaneous] or birth). 
If a pregnancy is reported for the study subject’s partner, the study subject must agree to 
complete abstinence for the duration of the study or until resolution of the pregnancy, whichever 
comes first, or discontinue study drug and withdraw from the study. If the subject chooses to 
withdraw from the study, continued abstinence is recommended for 30 days after the last dose of 
study medication. 
To report a pregnancy, the Pregnancy Event Form must be completed and sent via fax to 
PPD-PVG within 1 business day of the Investigator or study center staff becoming aware of the 
pregnancy. The Sponsor provides the Pregnancy Event Form. 
If the subject received blinded study medication, unblinding of the study medication will be 
offered to the subject when knowledge of such treatment may have an impact on further 
treatment decisions. Otherwise, information regarding to what treatment the subject was assigned 
may be provided when the study has ended. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study drug may have 
interfered with the effectiveness of a contraceptive medication or other AEs were detected. 
12.5. 
Data Monitoring Committee/Data and Safety Monitoring Board 
The Data and Safety Monitoring Board (DSMB) will monitor safety throughout the study (and 
may review blinded, partially blinded, or unblinded data). The DSMB will be independent of the 
Sponsor, CRO, and the Investigators and will be empowered to recommend stopping the study 
due to safety concerns but not for efficacy or futility. The membership of the DSMB and its 
mandate will be described in a separate DSMB charter. 


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13. 
TERMINATION OF SUBJECT FROM 
STUDY/DISCONTINUATION OF STUDY DRUG 
13.1. 
Criteria for Study Drug Discontinuation 
Subjects may be discontinued from the study drug at any time during the treatment period. The 
possible reasons for discontinuation of study drug are as follows: 
• Adverse event 
• Lack of efficacy (specify) 
• Lost to follow-up (specify) 
• Non-compliance with study drug (specify) 
• Protocol violation (specify) 
• Pregnancy 
• Withdrawal by subject (specify) 
• Other (specify) 
If, at any time during the course of the treatment period, in the opinion of the Investigator, the 
subject may no longer safely participate due to a change in medical status (eg, experiences an 
AE, becomes pregnant), the subject must be discontinued from the study drug. 
The primary reason and information for study drug discontinuation will be recorded on the 
appropriate CRF. In case of death, the date of death should be captured on the CRF. 
13.2. 
Criteria for Subject Termination from the Withdrawal Period 
Subjects may terminate during the withdrawal period for any reason. 
The possible reasons for termination during the withdrawal period are as follows: 
• Adverse event 
• Lost to follow-up (specify) 
• Pregnancy 
• Withdrawal by subject (specify) 
• Protocol deviation (specify) 
• Other (specify) 
The reason for termination during the withdrawal period will be recorded on the appropriate 
CRF. 
Subjects who prematurely terminate study participation will not be replaced. 


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13.3. 
Clinical Assessments After Study Drug Discontinuation 
Subjects who discontinue study medication before completion will be asked to return to the site 
and complete the EOT visit assessments (Section 11.8.9), as soon as possible following 
discontinuation of study drug, and complete the study medication withdrawal assessments and 
visits (Section 11.8.10). 


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14. 
STUDY TERMINATION 
The Sponsor reserves the right to discontinue the study at this study center or at multiple centers 
for safety or administrative reasons at any time while safeguarding that early termination does 
not compromise subjects’ safety or well-being. In particular, a study center that does not recruit 
at an acceptable rate may be closed. Should the study be terminated and/or the study center 
closed for whatever reason, all documentation and study medications pertaining to the study 
must be returned to the Sponsor or its representative. 
If, in the opinion of the Investigator, clinical observations suggest it may be unsafe to continue, 
the Investigator may terminate part or the entire study at his or her site after consultation with the 
Sponsor. 
In the event of study or site termination, subjects will be asked to return to the site and complete 
the EOT visit assessments (Section 11.8.9) as soon as possible after discontinuation of study 
drug. 


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15. 
STATISTICS 
The Statistical Analysis Plan (SAP) will provide details on the statistical methods planned for 
this study and will be finalized before data base lock. 
15.1. 
Sample Size  
The sample size for this study was estimated based on 2 hypotheses associated with the primary 
efficacy endpoint (change from baseline in number of binge days per week at Week 12). A fixed 
sequence closed testing procedure was used to adjust for 2 comparisons of dasotraline doses vs 
placebo (ie, with dasotraline 6 mg vs placebo tested first and dasotraline 4 mg vs placebo tested 
after if the previous one is significant at the 0.05 level ) for the sample size justification. Based 
on the Study SEP360-221 results, assuming a common standard deviation (SD) of 1.75 and a 
mean improvement of 0.9 (effect size 0.517) and 0.8 (effect size 0.457) over placebo for change 
from baseline in number of binge days per week at Week 12 for dasotraline 6 mg/day and 
4 mg/day doses, respectively, a sample size of 96 subjects per treatment group will provide at 
least 85% conjunctive power to reject both null hypotheses. An upward adjustment of 
approximately 40% is assumed to compensate for subjects who are randomized but discontinue 
from the study, thus, a total sample of 480 subjects (160 subjects per group) will be randomized 
with a ratio of 1:1:1 for placebo, and dasotraline 4 mg/day and 6 mg/day, respectively. The 
sample size calculation was based on Monte Carlo simulation from EAST 6.4. 
15.2. 
Statistical Hypotheses 
The hypotheses associated with the primary endpoint and key secondary endpoints will be tested 
using a testing procedure in Section 15.4.1.4. 
Primary Hypotheses 
In adults with moderate to severe BED, after 12 weeks of treatment,  
• Dasotraline 6 mg/day reduces change from baseline in the number of binge days per 
week relative to placebo 
• Dasotraline 4 mg/day reduces change from baseline in the number of binge days per 
week relative to placebo  
Key Secondary Hypotheses 
In adults with moderate to severe BED, after 12 weeks of treatment, 6 mg/day dasotraline or both 
doses of dasotraline: 
• Reduce change from baseline in BE-CGI-S score relative to placebo 
• Provide a greater proportion of subjects with a 4-week cessation from binge eating at 
Week 12 relative to placebo 
• Reduce change from baseline in Y-BOCS-BE total score relative to placebo 


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15.3. 
Analysis Populations 
Intent-to-Treat (ITT) Population: All randomized subjects who receive at least one dose of study 
medication and have at least 1 post-baseline result in any efficacy evaluation. The ITT 
population is the primary population for efficacy analyses, ie, unless otherwise specified, all 
efficacy analyses will be based on ITT population. 
Per-Protocol (PP) Population: All ITT subjects who have no major protocol violations that may 
affect the interpretation of the primary efficacy endpoint. 
The PP population will be used to assess robustness of the primary efficacy analysis. Major 
protocol violations and the PP population will be determined through a blinded data review 
meeting and identified prior to the database lock. 
Subjects in the ITT and PP populations will be analyzed based on the treatment to which they are 
randomized. 
Double-blind (DB) Safety Population: All randomized subjects who receive at least one dose of 
study medication. 
The DB Safety population mainly will be used for the data analyses of the safety data collected 
through Week 12 or during the treatment period. Subjects will be analyzed based on the 
predominant treatment received, in the event that a subject receives a treatment other than the 
one to which he or she is randomized. The predominant treatment is defined as the treatment (ie, 
placebo, dasotraline 4 mg/day, or dasotraline 6 mg/day) to which the subject is exposed for the 
greatest duration during the treatment period. The predominant treatment will generally be the 
same as the randomized treatment group, unless the subject takes incorrect study medication 
during the entire study. 
Withdrawal Safety Population: The Withdrawal safety population includes all randomized 
subjects who receive at least one dose of study medication, and either discontinue the study drug 
during the treatment period before the Week 12 visit or complete the 12-week treatment period 
but do not enter the extension study (Study SEP360-322), and have at least one assessment after 
the last dose of study medication for any safety or efficacy evaluation. The Withdrawal safety 
population mainly will be used to summarize the assessments collected in the withdrawal period. 
15.4. 
Data Analysis 
All statistical inference analyses will be performed with 2-sided tests at a significance level of 
0.05, and 2-sided 95% confidence intervals (CI) will be calculated whenever appropriate. All 
data will be summarized by treatment group and visit as appropriate. All subject data will be 
presented in data listings by subject. 
15.4.1. 
Efficacy Analyses 
15.4.1.1. Assessments from Binge Eating Diary 
The number of binge days per week at each assessment timepoint will be derived based on 
clinician review of the binge eating diary collected in the time intervals as follows: 
• Baseline: binge eating diary completed for 14 consecutive days immediately prior to 
the Baseline visit and starting no sooner than the day after the screening visit; 


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• Weeks 1, 2, 3, and 4 (ie, Visits 3, 4, 5, and 6): binge eating diary collected at each 
visit, which will span from the previous visit to the current visit and therefore cover 
Weeks 1, 2, 3, and 4, respectively; 
• Weeks 6, 8, 10 and 12 (ie, Visits 7, 8, 9, and 10): binge eating diary collected at each 
visit, which will span from the previous visit to the current visit and therefore cover 
Weeks 5/6, 7/8, 9/10, and 11/12, respectively. 
Specifically, the number of binge eating days per week at baseline is calculated as the number of 
binge eating days in the 14 days immediately prior to the Baseline visit multiplied by 7 and 
divided by the number of days in the Baseline period (ie, 14 days); the number of binge days per 
week in a visit that spans between 2 scheduled visits is calculated as (total number of binge 
days) x 7 / (total number of assessed days in the visit span). If missing diary entries exist during 
an assessed period for a subject, the available non-missing diaries from the subject will be used 
to derive the number of binge days per week adjusted by the number of non-missing diary days 
accordingly. 
15.4.1.2. Primary Efficacy Endpoint Analyses 
The primary efficacy endpoint is the change from baseline in the number of binge days per week 
at Week 12. 
15.4.1.2.1. Primary Efficacy Analyses 
The primary efficacy analyses of the primary efficacy endpoint (the change from baseline in the 
number of binge days per week at Week 12) will be performed using a likelihood-based mixed 
model for repeated measures (MMRM). The response (dependent) variable is the change from 
baseline in the number of binge days per week assessed at Weeks 1, 2, 3, 4, 6, 8, 10, and 12. 
Specifically, the MMRM model includes fixed effects terms for treatment, visit (as a categorical 
variable), pooled center, baseline binge days category (stratification factor; refer to Section 7.2.1 
for categories), the number of binge days per week at baseline, and treatment-by-visit interaction. 
Restricted maximum likelihood estimation method will be applied using an unstructured 
covariance model. The Kenward Roger approximation will be used to estimate denominator 
degrees of freedom. In case of a failure of convergence with the unstructured covariance, the 
following structures may be assessed in a sequential order: heterogeneous Toeplitz, Toeplitz, and 
spatial exponential covariance pattern model. Of the above 3 covariance structures, the first 
covariance structure yielding convergence in the MMRM model will be used for the MMRM 
analysis. The spatial exponential model is selected for the analysis of data with unequally spaced 
time points. The LS mean treatment differences (each dasotraline group minus placebo group) of 
change from baseline at Week 12, their 2-sided 95% CIs, and the associated p-values will be 
calculated based on this model. 
The normality assumption underlying the primary MMRM model will be assessed graphically. 
Conditional studentized and scaled residuals will be plotted against the predicted values, 
respectively, and Q-Q (quantile-quantile) plots of these residuals versus the expected quantiles of 
the standard normal distribution will be presented to provide a graphical view of similarity and 
difference in the two distributions. Cumulative distribution function (CDF) of the primary 
endpoint will be also provided by treatment group. 


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The primary efficacy analysis will be repeated for the PP population to examine the impact of 
premature dropouts and/or protocol deviations. 
15.4.1.2.2. Supportive Analyses  
The primary efficacy endpoint also will be analyzed using an analysis of covariance (ANCOVA) 
model and the last observation carried forward (LOCF) approach, as a supportive analysis. The 
model will include terms for treatment, pooled center, baseline binge days category (stratification 
factor), and the number of binge days per week at baseline as covariates. 
15.4.1.2.3. Sensitivity Analyses  
To address early dropouts under the assumption of missing not at random (MNAR), a pattern-
mixture model using a placebo-based multiple imputation method and a pattern mixture model 
using multiple imputations with penalties (ie, deflating the individually estimated treatment 
effect size by known factors) will be performed as sensitivity analyses to explore the robustness 
of the MMRM results for the primary analysis. In case of a deviation from the assumptions 
required for the primary analysis, to confirm the robustness of the primary analysis result, 
2 additional sensitivity analyses will be performed: (1) permutation test: fit a large number of 
datasets based on a same MMRM for the primary analysis with randomly assigning pseudo-
treatment group designations; (2) generalized linear mixed model (GLMM) analysis: fit count 
data over time (ie, number of binge days among number of assessed days at each period) based 
on a binomial distribution. The details of these sensitivity analyses will be outlined in the SAP. 
15.4.1.3. Key Secondary Efficacy Endpoints Analyses 
The key secondary efficacy endpoints involved in the hypothesis testing of each dasotraline dose 
(4 mg/day and 6 mg/day) versus placebo include change from baseline at Week 12 in BE-CGI-S 
score and Y-BOCS-BE total score, and percent of subjects with a 4-week cessation from binge 
eating. If a subject is early terminated in the double-blind treatment period prior to collection of 
28 days of diary data or the subject has missing diary data in the last 28 days prior to 
Week 12/EOT the subject will be counted as having no cessation. 
Continuous key secondary variables (ie, change in BE-CGI-S score and Y-BOCS-BE total score) 
will be analyzed with an MMRM model similar to the primary efficacy analysis 
(Section 15.4.1.2.1) adjusted with the corresponding baseline. The LS mean treatment 
differences (each dasotraline group minus placebo) of change from baseline at Week 12, their 
2-sided 95% CIs, and the associated p-values will be calculated based on the model. 
Categorical secondary efficacy endpoints (ie, percent of subjects with a 4-week cessation from 
binge eating) will be analyzed using a logistic regression model with treatment, baseline binge 
days category (stratification factor; refer to Section 7.2.1 for categories), and baseline number of 
binge days per week as covariate using a LOCF approach based on the ITT population. The odds 
ratios, their 2-sided 95% CIs, and the associated p-values for each dasotraline group over the 
placebo group will be derived from the model. 
Additional supportive and sensitivity analyses may be conducted as needed for the key 
secondary endpoints to address early dropouts or potential deviation from the model 
assumption(s).To address early dropouts or potential deviation from the model assumption(s), 
supportive and sensitivity analyses similar to those described in Section 15.4.1.2.3 may be 


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conducted as needed for the continuous key secondary endpoints. For the categorical key 
secondary endpoint, supportive and sensitivity analyses, such as a GLMM analysis with random 
effect(s) and a pattern-mixture model using placebo-based multiple imputations, may be 
conducted as appropriate. The details will be provided in the SAP. 
15.4.1.4. Multiplicity Adjustment 
To control the overall type I error rate strongly at 5% for the primary and key secondary 
endpoints, for the hypotheses to be tested (see Section 15.2), a sequential testing strategy will be 
used. Following the fixed sequence closed testing procedure in Figure 2, testing will only 
proceed conditional on the statistical significance of the test(s) of prior level(s) at a 2-sided 5% 
significance level. See Section 15.2 for details about the definition of statistical hypotheses. 
Figure 2: 
Fixed Sequence of Hypothesis Testing for Primary and Key Secondary 
Efficacy Endpoints 
 
Number of binge days per week, 
Dasotraline 6 mg vs placebo 
α = 0.050 
 
↓ 
 
 
Number of binge days per week, 
dasotraline 4 mg vs placebo 
 
 
↓ 
 
 
BE-CGI-S score, 
dasotraline 6 mg vs placebo 
 
 
↓ 
 
 
Subjects with a 4-week cessation, 
dasotraline 6 mg vs placebo 
 
 


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Figure 2: 
Fixed Sequence of Hypothesis Testing for Primary and Key Secondary 
Efficacy Endpoints (Continued) 
 
Y-BOCS-BE total score, 
dasotraline 6 mg vs placebo 
↓ 
BE-CGI-S score, 
dasotraline 4 mg vs placebo 
↓ 
subjects with a 4-week cessation, 
dasotraline 4 mg vs placebo 
↓ 
Y-BOCS-BE total score 
dasotraline 4 mg vs placebo 
 
15.4.1.5. Other Secondary Efficacy Endpoints Analyses 
The other secondary endpoints are:  
• Change from baseline in number of binge days per week at Weeks 1, 2, 3, 4, 6, 8, 
and 10 
• Change from baseline in number of binge episodes per week at Weeks 1, 2, 3, 4, 6, 8, 
10, and 12 
• Change from baseline in BE-CGI-S score at Weeks 2, 4, 6, 8, and 10 
• Change from baseline in Y-BOCS-BE total score at Weeks 2, 4, 6, 8, and 10 and 
subscale scores (obsessions and compulsions) at Weeks 2, 4, 6, 8, 10, and 12 
• Change from baseline in MADRS total score at Week 12 
• Change from baseline in HAM-A total score at Week 12 
• Change from baseline in SDS total score and subscale scores (school/work disability, 
social life disability, and family life disability) at Weeks 6 and 12 
• Proportion of binge eating responders (ie, ≥ 75% reduction in the number of binge 
eating episodes) at Week 12 
• Change from baseline in EDE-Q modified including EDE-Q7 global score and 
3 subscale scores (dietary restraint, shape/weight overvaluation, and body 
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Continuous variables (ie, change in number of binge days per week, number of binge episodes 
per week, BE-CGI-S, Y-BOCS-BE total score, and SDS total score and subscale scores) will be 
analyzed using an MMRM model similar to the primary efficacy analysis (Section 15.4.1.2.1) 
adjusting for the corresponding baseline. Other continuous variables (eg, change in EDE-Q7 
global score and subscale scores) will be analyzed using an ANCOVA model similar to the 
supportive analysis for the primary efficacy endpoint (Section 15.4.1.2.2), adjusting for the 
corresponding baseline as a covariate. 
The proportion of binge eating responders at Week 12 will be analyzed using a logistic 
regression model and LOCF approach with factors of treatment, pooled center, baseline binge 
days category (stratification factor), and baseline number of binge episodes per week as 
covariate. For subjects who are discontinued, binge eating responders at Week 12 LOCF is 
defined per the last post-baseline time period during the treatment period that binge diary is 
assessed. To ensure that the logistic regression model is feasible, pooled center may be removed 
from the analysis model if some pooled center has no responder either because of a small number 
of subjects in the pooled center or subjects experiencing little change. As a supportive analysis, 
the proportion of binge eating responders over time will be analyzed by an inverse probability 
weighting (IPW) Generalized Estimating Equations (GEE) model. The details will be provided 
in the SAP. 
In addition, the number and percentage of subjects in the following categories for reduction in 
the number of binge eating episodes from baseline will be summarized over time by treatment: 
• cessation (defined as 100% reduction) 
• 99% to 75% reduction 
• 74% to 50% reduction 
• other 
15.4.1.6. Subgroup Analyses 
The primary efficacy variable (the change from baseline in the number of binge days per week at 
Week 12) and a key secondary variable (ie, change from baseline in BE-CGI-S at Week 12) will 
be examined to explore the consistency of the treatment effect across certain subgroups at 
Week 12. Subgroups, including but not limited to gender, race and age group, will be detailed in 
the SAP. For each subgroup, subgroup analysis will be conducted based on a similar MMRM 
model to the corresponding primary efficacy analysis with 3 additional terms: subgroup, 
treatment-by-subgroup interaction, and 3-way interaction of treatment*subgroup*visit. Summary 
statistics with 95% CIs will be provided by treatment group within each subgroup, as well. 
15.4.2. 
Safety Analyses 
Safety data including AEs, laboratory values, ECG, vital signs, weight, C-SSRS, and other 
assessments will be analyzed by treatment group based on the DB Safety population (for data up 
to the end of treatment period) and Withdrawal safety population (for data collected during the 
withdrawal period), separately, as appropriate. 


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The data (including CSSA, DESS, MADRS, and HAM-A), which are used to assess physical 
dependence and withdrawal symptoms, will be analyzed by treatment for data collected in the 
withdrawal period based on the Withdrawal safety population. 
Unless otherwise specified, for continuous data collected in the withdrawal period, the actual 
value and change from Week 12/EOT (last value during the treatment period) will be 
summarized by treatment and visit. 
15.4.2.1. Adverse Events 
All AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
version 18.0 or higher. 
The terms used in the CRFs by Investigators to identify adverse events. 
An adverse event (AE) is defined as having a start date on or after the date of first dose through 
7 days after study drug discontinuation (14 days for serious adverse events and deaths) for 
subjects who complete or discontinue this study but do not enter into the extension study), or 
through the last study day of the double-blind treatment period for subjects continuing into the 
extension study. 
A discontinuation-emergent adverse event (DEAE) is defined as an AE with a start date after the 
date of last dose of study drug through the last study visit in the withdrawal period for subjects 
who either complete the 12-week treatment period but do not enter into the extension study, or 
for subjects who are terminated early in the treatment period. 
The summary of overall AEs (and SAEs) will be limited to AEs and DEAEs. 
The overall incidence (ie, number and percent of subjects with one or more AE in each category) 
of AEs, serious AEs, deaths, AEs leading to discontinuation, study drug-related AEs, serious 
study drug-related AEs, study drug-related AEs leading to discontinuation, and serious AEs 
leading to discontinuation, serious study drug-related AEs, will be summarized by treatment 
group. 
The AEs also will be summarized by system organ class (SOC) and preferred term (PT) by 
presenting the number and percentage of subjects with each AE category. The incidence of AEs 
(by PT, grouped by SOC, and presented by treatment group) also will be summarized by 
severity, by the relationship to study medication, by the action taken regarding the study 
medication, as well as by the outcome. 
The overall incidence of DEAEs and serious DEAEs will be summarized by treatment group. 
The DEAEs also will be summarized by SOC and PT by presenting the number and percentage 
of subjects with each AE category. 
The incidence of AEs of special interest, including but not limited to neuropsychiatric-related 
and cardiovascular-related AEs, will be summarized by treatment group. 
15.4.2.2. Clinical Laboratory Assessments 
Treatment Period 
Laboratory data will be summarized by presenting descriptive statistics of actual values and 
changes from baseline and shift tables. The number and percentage of subjects with markedly 


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abnormal post-baseline values for selected parameters will be presented. Individual subject 
listings of laboratory data also will be provided. 
The change from baseline value at endpoint for selected laboratory parameters (eg, 
hemoglobin A1c, fasting glucose, fasting total cholesterol, fasting triglycerides, fasting HDL 
cholesterol, fasting LDL cholesterol, fasting insulin, and hs-CRP) will be evaluated using an 
ANCOVA model with terms for treatment and baseline binge days group, and corresponding 
baseline as covariate or nonparametric rank ANCOVA, when appropriate. 
Withdrawal Period 
Laboratory data will be summarized by presenting descriptive statistics of actual values, change 
from baseline, and changes from Week 12/EOT by treatment. 
15.4.2.3. Centrally-read ECG 
Treatment Period 
Standard 12-lead ECG parameters HR, PR interval, RR interval, QT interval, Bazett’s corrected 
QT (QTcB) and Fridericia’s corrected QT (QTcF) intervals, and QRS duration will be assessed. 
Results of each ECG parameter and their changes from baseline will be summarized by visit 
using descriptive statistics. 
The number and percentage of subjects with markedly abnormal post-baseline ECG results will 
be summarized for the overall treatment period. 
Withdrawal Period 
Results for each ECG parameter, changes from baseline, and changes from Week 12/EOT will 
be summarized by treatment and visit using descriptive statistics. 
15.4.2.4. Vital Signs, Weight, and BMI 
Treatment Period 
Vital signs parameters will be summarized by presenting descriptive statistics of actual values 
and change from baseline values. The number and percentage of subjects with markedly 
abnormal post-baseline values for selected parameters will be presented. 
Descriptive statistics of actual value, and change and percent change from baseline value will be 
presented by treatment and study visit for weight and BMI. A similar MMRM model as for the 
primary efficacy variable (with the corresponding baseline) will be applied to compare 
dasotraline with placebo for the following safety variables: 
• Change and percent change from baseline in body weight (kg) at Weeks 1, 2, 3, 4, 6, 
8, 10, and 12. 
• Change and percent change from baseline in BMI at Weeks 1, 2, 3, 4, 6, 8, 10, and 12. 
Withdrawal Period 
Vital signs parameters, weight, and BMI will be summarized by presenting descriptive statistics 
of actual values, change from baseline values, and change from Week 12/EOT by treatment and 
visit. 


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15.4.2.5. Neurological Examination  
The number and percentage of neurological abnormalities will be summarized by visit and 
treatment. Shift from baseline to endpoint in neurological examinations will be presented by 
treatment. 
15.4.2.6. Columbia Suicide Severity Rating Scale (C-SSRS) 
The number and percentage of subjects with suicidal ideation, suicidal behavior, emergence or 
worsening of suicidal ideation or suicidal behavior will be summarized by treatment for overall 
post-baseline treatment period and for the withdrawal period, separately. Shift from baseline to 
any post-baseline in the treatment period (worst case) in suicidal ideation score will be presented 
by treatment. 
15.4.2.7. Endpoints to Assess Physical Dependence and Withdrawal Symptoms during 
Withdrawal Period 
CSSA total score, DESS total score, MADRS total score, and HAM-A total score will be 
summarized by presenting descriptive statistics of actual values and change from Week 12/EOT 
by treatment and visit for the withdrawal period. 
15.4.2.8. Prior and Concomitant Medications 
All medications will be coded using the World Health Organization drug dictionary (WHO-DD). 
The prior medications will include medications taken before initiation and stopped prior to 
initiation of double-blind study medication. The concomitant medications will include 
medications taken after initiation of double-blind study medication that were either started prior 
to or after initiation of double-blind study medication. 
The number and percentage of subjects taking prior and concomitant mediation will be 
summarized by anatomical therapeutic chemical (ATC) classification and preferred name by 
treatment group. 
15.4.3. 
Interim Analysis 
No interim analysis is planned for this study. 


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16. 
PROCEDURE FOR CLINICAL STUDY QUALITY 
CONTROL/DATA COLLECTION, MANAGEMENT, AND 
QUALITY ASSURANCE 
16.1. 
Data Collection/Electronic Data Capture (EDC) 
The results from Screening and data collected during the study (except clinical laboratory test 
results, electrocardiogram results, and IXRS data) will be recorded in the subject’s electronic 
CRF. The study sites will use an EDC system that is compliant with relevant FDA regulatory 
requirements per 21 CFR Part 11, Medidata Rave®. The binge eating diary, SDS, MINI, SCID-I 
Module H, C-SSRS, EDE-Q, EDE-Q modified, MADRS, Y-BOCS-BE, BE-CGI-S, HAM-A, 
CSSA, and DESS will be completed on paper forms and then entered into the EDC system. 
Password protected access to the EDC system will be via a secure website. Data queries and data 
corrections will be handled through the same system. All transactions within the EDC system are 
fully documented within an electronic audit trail. Each set of completed CRFs must be reviewed 
and electronically signed and dated by the Investigator. 
16.2. 
Computerized Systems Used for Source Data 
A list of the computerized systems that will be used to create, modify, maintain, archive, retrieve, 
or transmit source data are presented below, pursuant to the Guidance for Industry Computerized 
Systems Used in Clinical Investigations, May 2007. 
Table 7: 
Computerized Systems Used for Source Data 
Protocol Step  
Computerized System Type or 
Description 
Informed Consent 
A 
Informed Consent for PGx (optional) 
A 
Inclusion/Exclusion Criteria 
A 
Duplicate Enrollment Check 
NA 
CST Review 
NA 
Randomization 
A, D 
Dispense Study Drug 
A, D 
Study Drug Accountability 
A 
Demographics 
A 
Medical History 
A 
Psychiatric History 
A 
Physical Examination 
A 
Neurological Examination 
A 
Prior and/or Concomitant Medications 
A 
Mini International Neuropsychiatric Interview (MINI) 
A 


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Table 7: 
Computerized Systems Used for Source Data (Continued) 
Protocol Step  
Computerized System Type or 
Description 
Structured Clinical Interview for DSM-IV Axis I Disorders, Module H 
(SCID-I Module H) 
A 
Eating Disorder Examination Questionnaire (EDE-Q) 
A 
Eating Disorder Examination Questionnaire (EDE-Q) modified 
A 
Binge eating diary training 
NA 
Binge eating diary 
A 
Binge-eating Clinical Global Impression-Improvement (BE-CGI-S) 
A 
Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating 
(Y-BOCS-BE) 
A 
Montgomery-Asberg Depression Rating Scale (MADRS) 
A 
Sheehan Disability Scale (SDS) 
A 
Hamilton Anxiety Rating Scale (HAM-A) 
A 
Cocaine Selective Severity Assessment (CSSA) 
A 
Cocaine Selective Severity Assessment (CSSA) – Telephone contact 
A 
Discontinuation-Emergent Signs and Symptoms (DESS) 
A 
Discontinuation-Emergent Signs and Symptoms (DESS) – Telephone 
contact 
A 
Vital Sign Measurements 
A 
Height 
A 
Weight and body mass index (BMI) 
A 
12-lead electrocardiogram (ECG) 
C 
Columbia – Suicide Severity Rating Scale (C-SSRS) 
A 
Adverse Events 
A 
Serum chemistry 
B 
Lipid Panel 
B 
Hemoglobin A1c 
B 
Hematology 
B 
Urinalysis 
B 
Serum Pregnancy Test (in females of child-bearing potential) 
B 
Urine Pregnancy Test (in females of child-bearing potential) 
A 
Urine Drug Screen 
A 
Breath alcohol test 
A 
Blood sampling for plasma PK levels 
B 
Blood sampling for biomarkers  
B 


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Table 7: 
Computerized Systems Used for Source Data (Continued) 
Protocol Step  
Computerized System Type or 
Description 
Blood sampling genotyping 
B 
Statistical analysis 
SAS®, version 9.1.3 or higher 
A = EDC (Medidata Rave®); B = LIMS; C = Core Lab Over-read; D = IXRS. 
 Abbreviations: CST = Clinical Surveillance Team; EDC = electronic data capture; IXRS = interactive response 
system; LIMS = laboratory information management system; NA = not applicable. 
 
16.3. 
Study Monitoring 
This study will be monitored from initiation to completion by the Sponsor or its representative. 
Monitoring will include personal visits and telephone communication to assure that the 
investigation is conducted according to protocol and in order to comply with International 
Conference on Harmonization (ICH) Good Clinical Practice (GCP). On-site review of CRFs will 
include a review of forms for completeness and clarity, and consistency with source documents 
available for each subject. 
16.4. 
Audits 
The study may be subject to audit by the Sponsor/designee. If such an audit occurs, the 
Investigator must agree to allow access to required subject records. This is dependent on the 
subject granting consent by signing the ICF. By signing this protocol, the Investigator grants 
permission to personnel from the Sponsor or its representatives for on-site monitoring and 
auditing of all appropriate study documentation, as well as on-site review of the procedures 
employed in CRF generation, where clinically appropriate. 
In accordance with ICH GCP the Sponsor may select this study for audit. During the audit the 
Sponsor representative will carry out an inspection of center facilities (eg, pharmacy, drug 
storage areas, laboratory) and review study related records in order to evaluate the study 
compliance with the Sponsor/center standard operating procedures (SOPs), protocol, ICH GCP, 
and local regulations. The principal investigator (PI) or appropriate designee must also agree to 
inspection of all study documents by the regulatory authorities and the IRB. Should the PI or 
appropriate designee be notified of a regulatory inspection involving this study they should 
notify the Sponsor immediately. 
16.5. 
Study Documentation 
Study records are comprised of source documents, CRFs, and all other administrative 
documents, eg, IRB correspondence, clinical study materials and supplies shipment manifests, 
monitoring logs, Sponsor and CRO correspondence, etc. A study specific binder will be provided 
with instructions for the maintenance of study records. 
Source document is defined as any hand written or computer generated document that contains 
medical information or test results that have been collected for or are in support of the protocol 
specifications, eg, clinical laboratory reports, clinic notes, drug disbursement log, subject sign in 
sheets, subject completed questionnaires if applicable, telephone logs, ECGs, etc. All draft, 


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preliminary, and pre-final iterations of a final report are also considered to be source documents, 
eg, faxed laboratory reports and hard copy laboratory reports, faxed initial results and hard copy, 
final report. 
16.6. 
Clinical Laboratory Certification and Normal Values 
A central laboratory will be used for analysis for most of the clinical laboratory tests for this 
study. The central laboratory will provide the Investigator, Sponsor/CRO with laboratory 
certification(s), a dated copy of normal range values for the central clinical laboratory selected to 
analyze clinical specimens. If an exception is granted to use a local laboratory, the Investigator 
must supply the Sponsor/CRO with laboratory certification, lab director’s curricula vitae and a 
current, dated copy of normal range values. 


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17. 
ETHICAL AND REGULATORY OBLIGATIONS 
17.1. 
Study Conduct 
The Investigator agrees that the study will be conducted according to the protocol, ICH GCP, 
ICH guidelines, and the ethical principles that have their origin in the Declaration of Helsinki. 
The Investigator will conduct all aspects of the study in accordance with applicable local law(s) 
and regulation(s). 
The Investigator will assure proper implementation and conduct of the study including those 
study-related duties delegated to other appropriately qualified individuals. The Investigator will 
assure that study staff cooperate with monitoring and audits. 
The Investigator must sign and return to Sponsor/CRO the “Investigator Approval” page. 
The Investigator must provide a copy of current curriculum vitae (including a copy of a current 
medical license, current Drug Enforcement Agency [DEA] license, where applicable), and 
financial disclosure information. In countries where medical licensure is not issued, the 
following documentation is acceptable, as applicable: 
• Registration number/stamp with a registration number stated on curriculum vitae. 
• Appropriate diploma number stated on curriculum vitae. 
• Copy of the diploma. 
The Investigator must sign and return a completed Form FDA 1572 “Statement of Investigator” 
to Sponsor/CRO. 
17.2. 
Institutional Review Board/Independent Ethics Committee 
Documented approval for conducting the study from appropriate Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) will be obtained for all participating study centers 
prior to initiation of the study, according to ICH GCP, applicable local law(s) and regulation(s). 
When necessary, an extension, amendment or renewal of the IRB/IEC approval must be obtained 
and also forwarded to the Sponsor. The IRB/IEC must supply the Sponsor a list of the IRB/IEC 
membership, and a statement to confirm that the IRB/IEC is organized and operates according to 
ICH GCP, applicable law(s) and regulation(s). 
A copy of written IRB/IEC approval or favorable opinion of the protocol, informed consent form 
and subject recruitment material (if applicable) must be provided to Sponsor/CRO prior to start 
of the study. The approval or favorable opinion letter must be signed by the IRB/IEC chairman 
or designee identify the IRB/IEC name and address, identify the clinical protocol by title and/or 
protocol number, and include the date that approval or favorable opinion was granted. The letter 
must also contain a statement that the IRB/IEC complies with the requirements in 
21 CFR Part 56 for a study conducted under a US IND or ICH GCP, as applicable. 
The Investigator/CRO is responsible for obtaining from the IRB/IEC continued review of the 
clinical research or submitting periodic progress reports, in accordance with applicable 
regulations, at intervals not to exceed one year and (if applicable) as otherwise additionally 


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specified by the IRB/IEC. The Sponsor must be supplied with written documentation of 
continued review of the clinical research. 
The Investigator must promptly inform their IRB/IEC of all SAEs reported by subjects enrolled 
in the study or other safety information reported from Sponsor/CRO in accordance with 
applicable law(s) and regulation(s). 
17.3. 
Informed Consent 
The informed consent form will be approved by the Sponsor/CRO prior to submission to the 
IRB/IEC. The Sponsor/CRO may provide a template informed consent form to be qualified by 
each research facility to conform to local requirements. All informed consent forms must contain 
the minimum elements as mandated by ICH GCP, applicable local law(s) and regulations and 
will be subject to Sponsor/CRO approval as well as IRB/IEC approval. The Sponsor/CRO may 
submit informed consent forms to a central IRB/IEC for review and approval or favorable 
opinion contingent upon prior Investigator permission and review. 
Before recruitment and enrollment, each prospective subject will be given a full explanation of 
the study, allowed to read the approved informed consent form and be provided ample time and 
the opportunity to ask any questions that may arise. Once all questions have been answered and 
the Investigator is assured that the prospective subject understands the implications of 
participating in the study, the prospective subject will be asked to give consent to participate in 
the study by signing the informed consent form. As part of the consent process, each prospective 
subject must consent to direct access to his/her medical records for study-related monitoring, 
auditing, IRB/IEC review, and regulatory inspection. It should be clearly explained to each 
prospective subject that participation in each and every clinical visit and assessment is expected. 
The subject may be discontinued from study medication, but that does not necessarily negate the 
expectation that the subject will continue to participate in the study through the final 
visit/assessment. The Investigator will provide a copy of the signed informed consent form to 
each subject, and will record the date of the informed consent on the CRF. 
If an amendment to the protocol changes the subject participation schedule in scope or activity, 
or if important new information becomes available that may be relevant to the subject’s consent, 
the informed consent form must be revised, submitted to the IRB/IEC for review and approval or 
favorable opinion. The revised informed consent form must be used to obtain consent from a 
subject currently enrolled in the study if he or she is affected by the amendment. The revised 
informed consent form must be used to obtain consent from any new subjects who are enrolled 
into the study after the date of the approval or favorable opinion of the protocol amendment. 
17.4. 
Subject Privacy 
The Sponsor (or Sponsor representative) or any designees affirm uphold the subjects 
confidentiality. The subject will be identified by unique code only; full names will be masked 
prior to transmission to the Sponsor. The confidentiality of the subject’s personal data shall be 
protected in accordance with appropriate laws and regulations. 
If any cases are identified where the subject’s confidentiality has been breached, this must be 
rectified immediately. All subject identifiable information should be removed and the Sponsor 
notified. 


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17.5. 
Protocol Amendments and Emergency Deviations 
All revisions and/or amendments to this protocol must be approved in writing by the Sponsor 
and the appropriate IRB/IEC. The Investigator will not make any changes to the conduct of the 
study or the protocol without first obtaining written approval from the Sponsor and the IRB/IEC, 
except where necessary to eliminate an apparent immediate hazard to a study subject. 
Emergency deviations or modifications may be initiated without Sponsor or IRB/IEC approval or 
favorable opinion, only in cases where the deviation or modification is necessary to eliminate or 
avoid an immediate apparent hazard to subjects. Emergency deviations or modifications must be 
reported to the Sponsor/CRO and the IRB/IEC immediately/within 5 business days of the 
occurrence, or in accordance with applicable regulatory requirements. 
17.6. 
Records Retention 
The Investigator/the study center must arrange for retention of study records at the study center 
for at least 15 years from time of participation in the study or longer in accordance with 
applicable regulations and Sponsor SOPs. The Investigator/site should take measures to prevent 
accidental or premature destruction of these documents. Documents cannot be destroyed without 
written Sponsor authorization. The Sponsor will inform the Investigator/the study center when 
the destruction of documents is permitted. 
17.7. 
Inspection of Records 
In the event of an inspection, the Investigator agrees to allow representatives of the Sponsor and 
its representative and, the regulatory authorities’ access to all study records. The Investigator will 
promptly notify the Sponsor/CRO of all requests to inspect a Sunovion-sponsored study by 
government agencies and will promptly forward a copy of all such inspection reports. 
17.8. 
Financial Disclosure 
By signing this protocol, the Investigator agrees to provide to the Sponsor prior to start of study 
accurate financial information to allow the Sponsor to submit complete and accurate certification 
and disclosure statements as required by the US FDA regulations (21 CFR Part 54). The 
Investigator further agrees to provide this information on a Financial Disclosure/Certification 
Form that is provided by the Sponsor. The Investigator will update this information if there are 
any relevant changes during the conduct of the study and for one year after completion of the 
study. 
The Investigator also consents to the transmission of this information to the Sponsor for these 
purposes. This may involve the transmission of information to countries that do not have laws 
protecting personal data. 
17.9. 
Publication Policy 
Any formal presentation or publication of data collected as a direct or indirect result of the study 
will be considered a joint publication by the Investigators and the appropriate personnel of the 
Sponsor. For multicenter studies, it is mandatory that the first publication is based on all data 
obtained from all analyses as stipulated in the protocol. Investigators participating in multicenter 
studies must agree not to present data gathered individually or by a subgroup of centers before 


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the full, initial publication, unless this has been agreed to by all other Investigators and by the 
Sponsor. 


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18. 
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Hudson JI, Hiripi E, Pope HG, Kessler RC. The prevalence and correlates of eating disorders in 
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McElroy SL, Arnold LM, Shapira NA, Keck PE, Rosenthal NR, et al. Topiramate in the 
treatment of binge eating disorder associated with obesity: a randomized, placebo-controlled 
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McElroy SL, Kotwal R, Guerdjikova AI, Welge JA, Nelson EB, et al. Zonisamide in the 
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Suicide Assessment (C-CASA): classification of suicidal events in the FDA’s pediatric suicidal 
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Inhibitor Discontinuation Syndrome: A Randomized Clinical Trial. Biol Psychiatry. 1998;44: 
77-87. 
Schienle A, Schafer A, Hermann A, Vaitl D. Binge-eating disorder: reward sensitivity and brain 
activation to images of food. Biol Psychiat. 2009; 65: 654-61. 
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Mini-International Neuropsychiatric Interview (M.I.N.I): the development and validation of a 
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Speed N, Saunders C, Davis AR, Owens WA, Matthies HJG, et al. Impaired striatal Akt 
signaling disrupts dopamine homeostasis and increases feeding. PLoS ONE. 2011; 6(9): e25169.  
Spitzer RL, Williams JB, Gibbon M, First MB: The Structured Clinical Interview for DSM-III-R 
(SCID). I: History, rationale, and description. Arch Gen Psychiatry. 1992 Aug; 49(8): 624-9. 
Stunkard A, Berkowitz R, Tanrikut C, Reiss E, Young L. d-Fenfluramine treatment of binge 
eating disorder. Am J Psychiatr. 1996; 153: 1455-9. 
Trifilieff P, Martinez D. Imaging addiction: D2 receptors and dopamine signaling in the striatum 
as biomarkers for impulsivity. Neuropharmacology. 2014; 76: 498-509.  
Van de Giessen E, la Fleur SE, de Bruin K, van den Brink W, Booij J. Free-choice and no-choice 
high-fat diets affect striatal dopamine D2/3 receptor availability, caloric intake, and adiposity. 
Obesity. 2012; 20: 1737-40.  
Van de Giessen E, la Fleur SE, Eggels L, de Bruin K, van den Brink W, et al. High 
fat/carbohydrate ratio but not total energy intake induces lower striatal dopamine D2/3 receptor 
availability in diet-induced obesity. Int J Obesity. 2013; 37: 754-7.  
Vyvanse® (lisdexamfetamine dimesylate) Capsules (CII) Becomes First and Only Treatment 
Approved by the FDA for Adults with Moderate to Severe Binge Eating Disorder [press release]. 
Lexington, MA: Shire plc; January 30, 2015. 
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50130-vyvanse-b-e-d-in-adults-approval.pdf?la=en. Accessed 16 June 2014. 
Wang GJ, Geliebter A, Volkow ND, Telang FW, Logan J, et al. Enhanced striatal dopamine 
release during food stimulation in binge eating disorder. Obesity. 2011; 19: 1601-8.  
Wilson GT, Sysko R. Frequency of binge eating episodes in bulimia nervosa and binge eating 
disorder: diagnostic characteristics. Int J Eat Disord. 2009; 42(7). 


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19. 
INVESTIGATOR APPROVAL 
I have read the protocol, SEP360-321, Version 3.00, “A 12-week, Randomized, Double-blind, 
Parallel-group, Placebo-controlled, Fixed-dosed, Multicenter Study to Evaluate the Efficacy, 
Safety, and Tolerability of Dasotraline in Adults with Moderate to Severe Binge Eating 
Disorder,” and agree that it contains all necessary details for conducting the study and to conduct 
the study in strict accordance with the specifications outlined herein. 
I agree that no additional procedure(s) will be added during the conduct of the study except 
through protocol amendment by Sunovion Pharmaceuticals Inc. and after documentation of IRB 
approval. 
Investigator Signature: ____________________________________________________ 
Print Investigator Name: __________________________________________________ 
Date: ___________________________________________ 


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APPENDIX I. CARDIAC SAFETY MONITORING (ECG) 
1. Requirements for Testing 
ECG equipment and supplies will be provided by the ECG vendor and should be used for all 
in-clinic protocol ECG assessments. 
• All 12-lead ECGs will be recorded in the same manner. 
• The site personnel must be adequately trained in performing ECGs on the specific 
ECG equipment used in this protocol that is provided by the cardiac safety vendor. 
• To the extent possible, the same ECG machine and personnel should be used to 
acquire a subject’s ECGs throughout the period of their participation in the study. 
2. Subject Restrictions and Instructions 
• Prior to ECG acquisition, the subject will have rested for at least 10 minutes in the 
supine position and will remain so until the ECG is obtained. 
3. Reporting 
• It is the responsibility of the Investigator to perform a safety review of the ECG data 
for changes from previous assessments and/or emergent cardiac dysfunction, and to 
determine subject eligibility or continuance in the study. 
• ECGs will be reviewed, signed and dated by the Investigator listed on the Form 
FDA 1572 (MD or DO) after each ECG collection. The same Investigator should 
review all ECG reports for a given subject whenever possible. 
• For all ECGs, a report will be provided by the cardiac safety vendor to the site for 
review and signature. 
• The ECG tracing will be kept with subject’s source documentation. The original ECG 
and the cardiologist’s over-read will be retained at the site. 
4. Data Standardization 
ECG data will be transmitted to a centralized cardiac safety vendor and centrally over-read 
and interpreted using standardized procedures. 


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21. 
APPENDIX II. CLINICAL LABORATORY TESTS 
The following clinical laboratory tests are to be performed: 
Clinical Safety Panel 
HEMATOLOGY: (Differential reported as % and absolute value) 
Hemoglobin, Hematocrit, Platelet Count, red blood cell (RBC) Count, white blood cell 
(WBC) - Total Count, WBC Differential, (Basophils, Eosinophils, Lymphocytes, Monocytes, 
Neutrophils) 
BLOOD CHEMISTRIES: 
Alanine aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate aminotransferase 
(AST), Bicarbonate (HCO3), Bilirubin (Total, Direct, Indirect), Blood Urea Nitrogen (BUN), 
Calcium (Ca), Chloride (Cl), Creatinine, Glucose, Magnesium (Mg), Phosphorus (P), Potassium 
(K), Protein (Total), Sodium (Na), Uric Acid, Albumin 
URINALYSIS: 
Blood, Glucose, Ketones, Leukocyte esterase, Microscopic examination, Nitrites, pH, Protein 
URINE DRUG SCREENING: 
Amphetamines, Barbiturates, Benzodiazepines, Cannabinoids, Cocaine, Methamphetamines, 
Methadone, Methylenedioxymethamphetamine (MDMA), Phencyclidine (PCP), Opiates, 
Oxycodone, Tricyclic Antidepressants 
LIPID PANEL:  
Total Cholesterol, LDL-Cholesterol, HDL-Cholesterol, Triglycerides 
OTHER TESTS:  
Hemoglobin A1c, Insulin, hs-CRP, Breath Alcohol Test, Serum Pregnancy Test (β-hCG) (in 
female subjects of child-bearing potential only), Urine Pregnancy Test (in female subjects of 
child-bearing potential only). 
Laboratory reports will be initialed and dated on all pages by the Investigator listed on the Form 
FDA 1572 (MD or DO). Laboratory test results will be reviewed by the Investigator as they 
become available. The Investigator must determine the clinical significance of all out-of-range 
lab values (except drug screens). Possibly drug-related or clinically relevant abnormal values of 
uncertain causality must be repeated. Any abnormal values that persist should be followed at the 
discretion of the Investigator. 


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22. 
APPENDIX III. PHARMACOKINETIC SAMPLING AND 
SAMPLE HANDLING GUIDELINE 
 
Please refer to the Laboratory Investigator Manual for all collection and shipping instructions. 
All collection devices, labels, and requisitions will be provided by the central laboratory. 
PK Plasma Samples 
Collect the blood sample in a 4 mL Vacutainer® (or equivalent) tube for the preparation of 
plasma. The anticoagulant is lithium heparin for PK samples. Within 30 minutes of drawing 
blood, the blood sample will be centrifuged for 15 minutes at ca. × 2000 g to isolate plasma at 
ambient temperatures. Transfer 2 aliquots of plasma into 2 prelabeled polypropylene tubes 
(PK-Set 1 and PK-Set 2). Store samples at -20°C freezer before shipping to the central laboratory 
(within 15 min of plasma transfer). Samples may be placed on dry ice prior to shipping, if the 
site does not have a -20°C freezer. 
Blood (for PK plasma) samples will be collected from study subjects at the time points indicated 
in Table 8. Samples from subjects that receive placebo will not be analyzed. 
Table 8: 
Schedule for Blood (for Plasma) for PK Analysis 
Specimen 
Week (Day) 
Plasma (PK) 
(Anticoagulant: Lithium Heparin) 
Week 2 (Day 14 ±2) 
Week 6 (Day 42 ±3) 
Week 12 (Day 84 ±1) or End of Treatment 
 
Shipping: 
PK-Set 1 and PK-Set 2 plasma samples will be shipped in 2 separate shipments to the 
appropriate Central Laboratory. 
Refer to the LABORATORY Investigator Manual for additional collection instructions 
and detailed procedures. 


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APPENDIX IV. SAMPLING FOR POTENTIAL BIOMARKER 
ANALYSIS AND SAMPLE HANDLING GUIDELINES 
 
Please refer to the Laboratory Investigator Manual for all collection and shipping instructions. 
 
BLOOD SAMPLES FOR POTENTIAL BIOMARKER ANALYSES 
All collection devices, labels, and requisitions will be provided by the central laboratory.  
Plasma Samples 
Collect the blood sample in a 4-mL K2EDTA Vacutainer® (or equivalent) tube for the 
preparation of plasma. The anticoagulant is ethylene diamine tetraacetic acid (EDTA) for plasma 
samples. Within 5 minutes of drawing blood, the blood sample will be centrifuged for 
15 minutes at ca. 1,000 – 1,200 g to isolate plasma at refrigerated conditions (recommended if 
available).  
If the sample will not be centrifuged promptly, it must be kept on ice until it is centrifuged. 
Transfer 2 aliquots of plasma into 2 prelabeled cryovials (PD-Plasma Set 1 and PD-Plasma 
Set 2) immediately after centrifugation.  
Store samples at -70 C prior to shipping to the central laboratory (within 15 min of plasma 
transfer). If samples cannot be stored at -70°C, refer to the Laboratory Investigator Manual for 
appropriate storage and shipping instructions. 
Serum Samples 
Collect blood in a 4-mL serum separator tube and allow clotting for 30 to 60 minutes at room 
temperature before centrifugation. Within 1 hour of collection, centrifuge for 10 minutes at 
ca. 2,000 g. Transfer 2 aliquots of serum into 2 prelabeled cryovials (PD-Serum Set 1 and 
PD-Serum Set 2) immediately after centrifugation. 
 
Store samples at -70°C prior to shipping to the central laboratory (within 15 min of serum 
transfer). If samples cannot be stored at -70°C, refer to the Laboratory Investigator Manual for 
appropriate storage and shipping instructions. 
Blood (biomarker in plasma and serum) samples will be collected from study subjects at the time 
points indicated in Table 9. 
 
Table 9: 
Schedule for Blood (Plasma and Serum) for Biomarker Analysis 
Specimen 
Week (Day) 
Plasma (Anticoagulant: EDTA) 
Baseline visit (Day -1) 
Serum 
Week 12 (Day 84 ±1) or End of Treatment 


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Shipping: 
Shipment to the appropriate Central Laboratory of PD-Set 1 Plasma and Serum samples will be 
done separately from shipment of PD-Set 2 Plasma and Serum samples. 
Refer to the LABORATORY Investigator Manual for additional collection instructions 
and detailed procedures. 


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24. 
APPENDIX V. PHARMACOGENETIC SAMPLING AND 
SAMPLE HANDLING GUIDELINES 
 
Please refer to the Laboratory Investigator Manual for all collection and shipping instructions. 
 
BLOOD SAMPLES FOR PHARMACOGENETICS/PHARMACOGENOMICS 
• A blood sample (approximately 4 mL) will be collected from each subject using a 4 mL 
Vacutainer® (or equivalent) collection tube containing EDTA as an anticoagulant. 
• The tubes containing the blood sample will be labeled with a unique barcode (if 
possible), protocol number, subject number, and sample date of collection. 
• The blood samples will be kept on wet ice during transfer and labeling. 
• All blood samples will be stored in an upright position within 10 minutes of collection in 
a freezer set to maintain -70°C (± 10°C) until shipment to the appropriate laboratory. If 
samples cannot be stored at -70°C, refer to the Laboratory Investigator Manual for 
appropriate storage and shipping instructions. 
• Freeze samples for at least several hours before shipping to the appropriate laboratory. 
 


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25. 
APPENDIX VI. CLINICALLY RELEVANT CYP2B6 
SUBSTRATES OR INDUCERS OR INHIBITORS (GENERIC 
NAMES) 
The following drugs are prohibited during this study. 
Substrate 
Inhibitor 
Inducer 
artemisinin 
clopidogrel 
artemisinin 
bupropion 
thiotepa 
carbamazepine 
cyclophosphamide 
ticlopidine 
efavirenz 
efavirenz 
voriconazole 
nevirapine 
ifosphamide 
 
phenobarbital 
ketamine 
  
phenytoin 
meperidine 
  
rifampin 
methadone 
  
  
nevirapine 
  
  
propafol 
  
  
selegiline 
  
  
sorafenib 
  
  
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. 
Indiana University School of Medicine (2007). 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx. Accessed 4 March 2016. 
 


Protocol SEP360-321, Version 3.00 
 
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26. 
APPENDIX VII. ABUSE POTENTIAL MONITORING PLAN 
Overview of Abuse Potential Monitoring Plan 
Dasotraline is a new chemical entity being investigated for the treatment of Binge Eating 
Disorder (BED). Dasotraline is a diastereomer of the major metabolite of sertraline but is not a 
metabolite of sertraline, nor is it converted to the demethylated metabolite of sertraline in vivo. 
Dasotraline is a potent inhibitor of the reuptake of serotonin (5-HT), norepinephrine (NE), and 
dopamine (DA) via the respective transporters SERT, NET, and DAT, with preferential 
inhibition of the dopamine transporter (DAT) and norepinephrine transporter (NET) relative to 
the serotonin transporter (SERT) without significant off-target activities. Clinical studies 
demonstrated central SERT occupancies in healthy subjects well below those attained at DAT, in 
addition decreases in 3,4-dihydroxyphenylglycol (DHPG) were observed, indicating central NET 
inhibition. This pharmacological profile warrants the implementation of an Abuse Potential 
Monitoring Plan, which surpasses the clinical monitoring, and adverse event (AE) reporting 
historically implemented in development programs for SSRIs. 
The Abuse Potential Monitoring Plan (APMP) for dasotraline has been designed to detect 
potential abuse of the compound and to more closely monitor AEs consistent with the 
pharmacology. The plan will detect irregularities in the handling of dasotraline in clinical trials 
and identify the misuse of dasotraline or other psychoactive substances. Moreover, the APMP 
provides a process by which events subject to additional monitoring are identified, processed, 
and reviewed. Events subject to additional monitoring were identified based on the 
pharmacology of dasotraline, as well as adverse event profiles of compounds with similar 
mechanisms of action. 
Procedure for Managing Medication Irregularities 
Defining Threshold Criteria 
The purpose of this procedure is to capture information about all medication-handling 
irregularities that meet the predefined threshold criteria. All instances meeting the medication 
irregularity threshold criteria will require a clinical risk assessment by the Investigator with 
classification of the nature of the irregularity. The Investigator will be required to complete 
Attachment A, the Medication Handling Irregularity (MHI) form in these situations. 
For clinical trials utilizing dasotraline, we define the threshold criteria for medication 
irregularities as any one of the following: 
• 10% or more of dispensed drug is either used in excess of prescribed dose or is 
unaccounted for; and/or 
• Suspected abuse or diversion of dasotraline; and/or 
• Suspected abuse of any other substance including alcohol, illicit substances, and 
over-the-counter (OTC) medications or prescription drugs. 


Protocol SEP360-321, Version 3.00 
 
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Instances of Medication Irregularity 
For all instances where the predefined threshold criteria are met covering medication 
irregularities, the Investigator must complete the Medication Handling Irregularity (MHI) form 
(Attachment A) and fax to the contact provided within 3 business days of its occurrence or 
discovery every time a threshold medication handling irregularity occurs. The contact will fax 
the completed MHI form to Sunovion within 1 business day of receipt and determine whether 
further action is warranted (ie, discontinuation of subject due to noncompliance with study 
protocol, education of the subject, etc.). Attachment B displays the process flow for handling 
medication irregularities. Any instance of medication irregularity may further be classified as an 
event subject to additional monitoring (ESAM). 
The management of documented medication handling irregularities will be driven by the 
particular classification of the irregularity. As shown on Attachment A, items coded #1-3 
describe situations of accounting errors and/or noncompliance with study procedures without 
evidence of study medication misuse or abuse of other substances. In these instances (code #1-3 
on the MHI form), the Investigator will complete Attachment A and fax to the contact provided 
within 3 business days of knowledge of the irregularity. 
 
Suspected or Known Abuse or Diversion of Study Medication 
All cases of suspected or known abuse or diversion of study medication should be documented 
on the MHI form and coded #4. The Investigator will complete Attachment A and fax to the 
contact provided within 3 business days of knowledge of the irregularity. For all cases of 
medication irregularities coded as #4, the Investigator will attempt to obtain a urine drug screen 
from the subject, perform early termination procedures and discontinue the subject from the 
study. 
 
Suspected or Known Abuse of Alcohol or Other Substances 
The abuse of alcohol, illicit substances, OTC medication or prescription drugs while a subject is 
participating in a dasotraline clinical trial should be documented on the MHI form and coded #5. 
The Investigator will complete Attachment A and fax to the contact provided within 3 business 
days of knowledge of the irregularity. For all cases of medication irregularities coded as #5, the 
Investigator will attempt to obtain a urine drug screen from the subject, perform early 
termination procedures and discontinue the subject from the study. 
 
Event Subject to Additional Monitoring (ESAM) 
A key objective of the Abuse Potential Monitoring Plan is to monitor for instances of abuse or 
diversion of the study medication and other psychoactive substances. In addition to monitoring 
for irregularities in medication handling, AEs that may be suggestive of a developing abuse 
issue, will also receive special attention. The following adverse experiences or related signs and 
symptoms may be associated with increased risk to subjects and will require additional 
monitoring. This list is a guide as to the types of events that require additional medical 
surveillance; it is not comprehensive and other events may be identified that require similar 


Protocol SEP360-321, Version 3.00 
 
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medical surveillance. Subjects experiencing an event subject to additional monitoring may need 
to be discontinued from the study. 
 
Table 10: 
Sample List of Events Subject to Additional Monitoring 
Abuse and Dependence  
Perceptual Effects  
Drug dependence 
Abnormal dreams 
Drug abuse 
Disinhibition 
Dependence 
Disorientation 
Drug diversion 
Dissociation 
Intentional drug misuse 
Feeling abnormal 
Substance abuse 
Hallucination (including auditory, 
olfactory, visual, etc.) 
Mood Elevation Effects 
Hyperaesthesia 
Euphoric mood 
Hypoaesthesia 
Elevated mood 
Illusion 
Feeling drunk 
Inappropriate affect 
Sedative Effects 
Mood altered 
Apathy 
Paraesthesia 
Asthenia 
Paranoia 
Depressed level of consciousness 
Psychotic Disorder 
Fatigue 
Sensory disturbance 
Feeling of relaxation 
Thinking abnormal 
Hypokinesia 
Cognitive/Motor Impairment 
Indifference 
Ataxia 
Lethargy  
Amnesia 
Sedation 
Aphasia 
Sluggishness 
Balance disorder 
Somnolence 
Clumsiness 
Stimulant Effects 
Cognitive disorder 
Agitation 
Confusional state 
Aggression 
Coordination abnormal 
Anxiety 
Disturbance in attention 
Energy increased 
Gait disturbance 
Feeling jittery 
Fine Motor Delay 
Hypervigilance 
Memory impairment 
Insomnia 
Mental impairment 
Irritability 
 
Nervousness 
 
Psychomotor hyperactivity 
 
Restlessness 
 
 
 


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Preparation of a Narrative for an Event Subject to Additional Monitoring (ESAM) 
To ensure clarity and completeness of information, all Events Subject to Additional Monitoring 
will require the preparation of a narrative by the Investigator. This narrative will be reviewed by 
the medical monitor/sponsor/Investigator to determine if the subject should be discontinued from 
the study. A narrative summary template will be provided to the Investigators (Attachment C). 
Handling of the Event Subject to Additional Monitoring (ESAM) 
• Investigators will report all Events Subject to Additional Monitoring with narratives 
to the Medical Monitor within 24 hours (Attachment C) 
• The medical monitor will review all ESAM in real time and forward a copy of the 
report to the sponsors’ Medical Director within one business day 
 
Urine Drug Screens 
The protocol incorporates exclusion criteria targeting individuals with a history of substance use 
disorders (eg, alcohol abuse or dependence and illicit drug abuse or dependence). The protocol 
includes urine drug screens at screening and at various post-randomization visits as well as 
providing the Investigator with the discretion to obtain random urine drug screens. Investigators 
will be directed to obtain urine drug screens in instances where there is known or suspected 
abuse of study medication and/or other substances. 


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Protocol SEP360-321, Version 3.00 
 
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27. 
APPENDIX VIII. BODY MASS INDEX DETERMINATION 
Body mass index (BMI) will be calculated by measuring the subject’s height and weight (both 
determined without subject wearing shoes) and using these measurements (in centimeters and 
kilograms) in the following formulae. 
Formula:  
BMI = weight (kg) ÷ height (m) ÷ height (m) 
The entries in the following table list the BMI values for males and females of a given height and 
weight. Please note this table is not inclusive of all possible height and weight combinations. 


Protocol SEP360-321, Version 3.00 
 
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Table 11: 
Body Mass Index (BMI) in kg/m2 According to Height and Weight 
 
 

SAP_001.pdf: 
                                                                                                             
 
 
Statistical Analysis Plan 
 
A 12-week, Randomized, Double-blind, Parallel-group, 
Placebo-controlled, Fixed-dosed, Multicenter Study to Evaluate the 
Efficacy, Safety, and Tolerability of Dasotraline in Adults with 
Moderate to Severe Binge Eating Disorder 
 
 
DASOTRALINE (SEP-225289) 
Protocol SEP360-321 
 
Version Number: V 1.0  
Version Date: June 22, 2018 
 
Prepared by INC Research  
3201 Beechleaf Court 
Raleigh, NC 27604-1547 
 
Notice of Confidential and Proprietary Information: 
The information in this document contains trade secrets and commercial information that are privileged or confidential belonging 
to Sunovion Pharmaceuticals Inc. and may not be disclosed unless such disclosure is required by applicable law or regulations. In 
any event, persons to whom the information is disclosed must be informed that the information is privileged or confidential and 
may not be further disclosed by them. These restrictions on disclosure will apply equally to all future information supplied to you 
that is indicated as privileged or confidential. Acceptance of this document constitutes agreement by the recipient that no 
information contained herein will be published or disclosed without prior written authorization from an official of Sunovion 
Pharmaceuticals Inc.   


Statistical Analysis Plan                                                                                                      Sunovion Pharmaceuticals 
Inc.  
                                                                                                                                                                        SEP360-
321 
Version 1.0 
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Authorization Signature Page 
 
A 12-WEEK, RANDOMIZED, DOUBLE-BLIND, PARALLEL-GROUP, 
PLACEBO-CONTROLLED, FIXED-DOSED, MULTICENTER STUDY TO 
EVALUATE THE EFFICACY, SAFETY, AND TOLERABILITY OF DASOTRALINE 
IN ADULTS WITH MODERATE TO SEVERE BINGE EATING DISORDER 
  
Author: 
 
 
 
 
 
 
Name:   
 
Date 
Position:   Principal Biostatistician 
 
 
Company:  INC Research 
 
 
 
 
 
Approved by: 
 
 
 
 
 
_______________________________________________ 
Manager, Biostatistics,  
INC Research 
 
 
_________________ 
Date 
 
 
_______________________________________________ 
Sr. Director, Clinical Research,  
Sunovion Pharmaceuticals Inc. 
 
 
_________________ 
Date 
 
 
_______________________________________________ 
 Sr. Director, Biostatistics, 
Sunovion Pharmaceuticals Inc. 
 
 
_________________ 
Date 
 
 
_______________________________________________ 
Executive Director, Biostatistics, 
Sunovion Pharmaceuticals Inc. 
 
 
_________________ 
Date 
 


Statistical Analysis Plan                                                                                                      Sunovion Pharmaceuticals 
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Table of contents 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................8 
1. 
INTRODUCTION ......................................................................................................11 
2. 
STUDY OBJECTIVES ..............................................................................................12 
2.1. 
Primary Objective .......................................................................................................12 
2.2. 
Key Secondary Objective ...........................................................................................12 
2.3. 
Other Secondary Objective .........................................................................................12 
3. 
STUDY DESIGN .......................................................................................................14 
3.1. 
Determination of Sample Size ....................................................................................15 
3.2. 
Randomization, Stratification and Blinding ...............................................................15 
4. 
CHANGES IN PLANNED ANALYSES ...................................................................18 
5. 
EFFICACY AND SAFETY VARIABLES ................................................................19 
5.1. 
Efficacy Variables ......................................................................................................19 
5.1.1. 
Variables Derived Per Binge Eating Diary .................................................................19 
5.1.1.1. 
Number of Binge Days, Number of Binge Episodes, and Number of 
Assessed Days During a Visit Period .........................................................................20 
5.1.1.2. 
Number of Binge Days per Week and Number of Binge Episodes per Week 
for a Visit Period .........................................................................................................20 
5.1.1.3. 
Percent Reduction in the Number of Binge Eating Episodes from Baseline at 
Post-baseline Visits in DB Treatment Period .............................................................20 
5.1.1.4. 
4-Week Cessation .......................................................................................................21 
5.1.2. 
Binge-eating Clinical Global Impression-Severity (BE-CGI-S) ................................21 
5.1.3. 
Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating 
(Y-BOCS-BE) .............................................................................................................21 
5.1.4. 
Eating Disorder Examination Questionnaire (EDE-Q) and Eating Disorder 
Examination Questionnaire (EDE-Q) Modified .........................................................22 
5.1.5. 
Sheehan Disability Scale (SDS) .................................................................................25 
5.1.6. 
Montgomery-Asberg Depression Rating Scale (MADRS) ........................................26 
5.1.7. 
Hamilton Anxiety Rating Scale (HAM-A) .................................................................26 
5.2. 
Safety Assessment ......................................................................................................26 
5.2.1. 
Columbia – Suicide Severity Rating Scale (C-SSRS) ................................................27 
5.2.2. 
Withdrawal Assessment for Physical Dependence and Withdrawal 
Symptoms ...................................................................................................................28 


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5.2.2.1. 
Cocaine Selective Severity Assessment (CSSA) ........................................................28 
5.2.2.2. 
Discontinuation-Emergent Signs and Symptoms (DESS) Scale ................................29 
5.2.2.3. 
HAM-A .......................................................................................................................29 
5.2.2.4. 
MADRS ......................................................................................................................29 
5.3. 
Other Assessment .......................................................................................................29 
6. 
STATISTICAL METHODS .......................................................................................30 
6.1. 
General Analysis Definition .......................................................................................30 
6.1.1. 
Analysis Period and Study Day ..................................................................................30 
6.1.1.1. 
Double-Blind Treatment Period (On Treatment) .......................................................30 
6.1.1.2. 
Withdrawal Period (Off Treatment) ...........................................................................30 
6.1.1.3. 
Overall Study Period ...................................................................................................31 
6.1.2 
Baseline .......................................................................................................................31 
6.1.2.1 
DB Baseline for Assessment Based on Diary Data ....................................................32 
6.1.2.2 
DB Baseline for Other Data ........................................................................................32 
6.1.2.3 
Withdrawal Baseline for Assessment Based on Diary Data .......................................32 
6.1.2.4 
Withdrawal Baseline for Other Data ..........................................................................32 
6.1.3 
Endpoint ......................................................................................................................32 
6.1.3.1 
Week 12 Endpoint ......................................................................................................32 
6.1.3.2 
Withdrawal Endpoint ..................................................................................................32 
6.1.4 
Visit Windows ............................................................................................................32 
6.1.4.1 
Early Termination (ET) Visit in Double-Blind Treatment Period ..............................32 
6.1.4.2 
Visit Window for Visits in Withdrawal Period ..........................................................34 
6.1.5 
Protocol Amendment for Region Stratification ..........................................................35 
6.1.5.1 
Stratification Error of ‘Region’ ..................................................................................35 
6.1.5.2 
IXRS Update ...............................................................................................................36 
6.1.6 
Pooling Strategy for Analysis of Centers ...................................................................37 
6.1.7 
Definition of Planned Region Group and Actual Region Group (‘Modified’ 
Region Strata) .............................................................................................................37 
6.1.8 
Adjustments for Covariates ........................................................................................38 
6.1.9 
Analysis Populations ..................................................................................................39 
6.1.10 
Stratification Factor ‘Baseline Number of Binge Days’ vs. Baseline Number 
of Binge Days Group ..................................................................................................40 
6.1.11 
Handling of Dropouts or Missing Data ......................................................................40 


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6.1.11.1 
Missing Diary Entry ...................................................................................................40 
6.1.11.2 
Unknown or Unconfirmed Last Study Dose Date ......................................................40 
6.1.11.3 
Composite Score .........................................................................................................40 
6.1.11.4 
Incomplete/Missing Dates ..........................................................................................41 
6.1.11.4.1  Start/End Dates for Adverse Event .............................................................................41 
6.1.11.4.2  Start/End Dates for Prior/Concomitant Medication ...................................................41 
6.1.11.4.3  Psychotherapy Dates /Psychiatric History Dates ........................................................41 
6.1.11.4.4  Lab Data ......................................................................................................................41 
6.2. 
Methods of Analysis ...................................................................................................41 
6.2.1 
General Methodology .................................................................................................41 
6.2.2 
Statistical Hypotheses for Trial Objectives ................................................................42 
6.2.2.1 
Hypotheses for Primary Objective ..............................................................................42 
6.2.2.2 
Hypotheses for Key Secondary Objectives ................................................................42 
6.2.3 
Interim Analysis ..........................................................................................................42 
6.2.4 
Data Monitoring ..........................................................................................................42 
6.2.5 
Multiple Comparisons/Multiplicity ............................................................................42 
7. 
STATISTICAL ANALYSES .....................................................................................44 
7.1 
Subject Information ....................................................................................................44 
7.1.1 
Demographic and Baseline Characteristics ................................................................44 
7.1.2 
Psychiatric History ......................................................................................................45 
7.1.2.1 
Psychiatric Family History .........................................................................................46 
7.1.3 
Disposition Information ..............................................................................................46 
7.1.4 
Treatment Compliance ................................................................................................46 
7.1.5 
Extent of Exposure .....................................................................................................47 
7.1.6 
Protocol Deviations ....................................................................................................48 
7.1.7 
Study Medication and Prior and Concomitant Medications .......................................49 
7.1.7.1 
Prior and Concomitant Medications ...........................................................................49 
7.1.8 
Medical History ..........................................................................................................50 
7.1.9 
Psychotherapy .............................................................................................................50 
7.2 
Efficacy .......................................................................................................................50 
7.2.1 
Analysis Specifications ...............................................................................................50 
7.2.1.1 
Level of Significance ..................................................................................................50 


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7.2.2 
Presentation of Analysis Result from Statistical Model .............................................50 
7.2.3 
Primary Efficacy Endpoint .........................................................................................50 
7.2.3.1 
Definition ....................................................................................................................50 
7.2.3.2 
Analysis Methods .......................................................................................................51 
7.2.3.2.1 
Primary Efficacy Analysis ..........................................................................................51 
7.2.3.2.2 
Assessment of Model Assumptions in the Primary Efficacy Analysis ......................51 
7.2.3.2.3 
Supportive Analysis ....................................................................................................52 
7.2.3.2.4 
Sensitivity Analyses ....................................................................................................52 
7.2.3.2.5 
Exploratory Analyses Related to Planned Region and Actual Region Group ............53 
7.2.3.2.6 
Assessment of Dropout and Dropout Profiles ............................................................53 
7.2.3.2.7 
Missingness of Diary Entry ........................................................................................54 
7.2.4 
Key Secondary Endpoints Analyses ...........................................................................54 
7.2.4.1 
Definition ....................................................................................................................54 
7.2.4.2 
Analysis Methods .......................................................................................................55 
7.2.5 
Multiplicity Adjustment ..............................................................................................56 
7.2.6 
Other Secondary Endpoints Analyses ........................................................................56 
7.2.6.1 
Definition ....................................................................................................................56 
7.2.6.2 
Analysis Methods .......................................................................................................57 
7.2.7 
Subgroup Analysis ......................................................................................................58 
7.3 
Pharmacokinetics (PK) Analysis ................................................................................59 
7.4 
Safety ..........................................................................................................................59 
7.4.1 
Analysis Specifications ...............................................................................................59 
7.4.2 
Adverse Events ...........................................................................................................59 
7.4.3 
Laboratory Measurements ..........................................................................................62 
7.4.3.1 
Treatment Period ........................................................................................................62 
7.4.3.2 
Withdrawal Period ......................................................................................................64 
7.4.4 
ECG Evaluations ........................................................................................................65 
7.4.4.1 
Treatment Period ........................................................................................................65 
7.4.4.2 
Withdrawal Period ......................................................................................................66 
7.4.5 
Vital Signs, Weight, and BMI ....................................................................................66 
7.4.5.1 
Treatment Period ........................................................................................................66 
7.4.5.2 
Withdrawal Period ......................................................................................................68 


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7.4.6 
Assessments of Withdrawal Effects (CSSA, DESS, HAM-A, and MADRS) ...........68 
7.4.7 
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................................68 
7.4.7.1 
Treatment Period ........................................................................................................69 
7.4.7.2 
Withdrawal Period ......................................................................................................70 
7.4.8 
Other Safety Assessments ...........................................................................................70 
7.4.8.1 
Breath Alcohol Test ....................................................................................................70 
7.4.8.2 
Neurological Examination ..........................................................................................70 
7.4.8.3 
Abuse Potential Monitoring Plan (APMP) .................................................................71 
7.4.8.3.1 
Medication Handling Irregularities .............................................................................71 
7.4.8.3.2 
Events Subject to Additional Monitoring (ESAMs) ...................................................71 
  
 
 


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List of Abbreviations and Definition of Terms 
Abbreviation  
Full Form  
AE  
Adverse event  
ALT  
Alanine aminotransferase  
ANCOVA  
Analysis of covariance  
APMP  
Abuse Potential Monitoring Plan  
AST  
Aspartate aminotransferase  
BDRM 
Blind Data Review Meeting 
BE-CGI-S  
Binge-eating Clinical Global Impression-Severity  
BED  
Binge eating disorder  
BMI  
Body mass index  
BUN  
Blood urea nitrogen  
CFR  
Code of Federal Regulations  
CI  
Confidence interval  
CRF  
Case report form  
C-SSRS  
Columbia-suicide severity rating scale  
CSSA  
Cocaine Selective Severity Assessment  
CST  
Clinical Surveillance Team  
DAS  
Dasotraline  
DB 
Double-Blind 
DBL  
Database lock  
DEAE  
Discontinuation-emergent adverse event  
DESS  
Discontinuation-Emergent Signs and Symptoms  
DHPG  
3,4-dihydroxyphenylglycol  
DNA  
Deoxyribonucleic acid  
DSM-5  
Diagnostic and Statistical Manual of Mental Disorders, 
5th Edition  
DSMB  
Data and Safety Monitoring  
ECG  
Electrocardiogram  
EDC  
Electronic data capture  
EDE-Q  
Eating Disorder Examination Questionnaire  
EDE-Q7  
Eating Disorder Examination Questionnaire Brief Version  
EDE-QM 
Eating Disorder Examination Questionnaire Modified 
EOT  
End of treatment  
FDA  
U.S. Food and Drug Administration  
GEE  
Generalized Estimating Equations  
GLMM  
Generalized linear mixed model  


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Abbreviation  
Full Form  
HAM-A  
Hamilton Anxiety Rating Scale  
HDL  
High-density lipoprotein (cholesterol)  
HR  
Heart rate  
ICF  
Informed consent form  
IPW  
Inverse probability weighting  
IRT 
Interactive Response Technology 
ITT  
Intention-to-Treat  
IXRS 
Interactive Response System 
LDL  
Low-density lipoprotein (cholesterol)  
LOCF  
Last Observation Carried Forward  
MADRS  
Montgomery-Asberg Depression Rating Scale  
MCS 
Mental Component Summary 
MINI  
Mini International Neuropsychiatric Interview  
MMRM  
Mixed-effects Models Repeated Measures  
MNAR  
Missing not at random  
NE  
Norepinephrine  
NET  
Norepinephrine transporter  
NNT 
Number Needed to Treat 
PCS 
Physical Component Summary 
PGx  
Pharmacogenomics  
PK  
Pharmacokinetic(s)  
PMM  
Pattern mixture model  
PP  
Per-Protocol  
PR  
Time between P wave and QRS in electrocardiography  
PT  
Preferred term  
QRS  
Electrocardiographic wave (complex or interval)  
QT  
Electrocardiographic interval from the beginning of the 
QRS complex to the end of the T wave  
QTc  
QT interval corrected for heart rate  
QTcB  
corrected QT interval using Bazett’s formula  
QTcF  
corrected QT interval using Fridericia’s formula  
RR  
RR interval  
SAE  
Serious adverse event  
SAP  
Statistical analysis plan  
SCID  
Structured clinical interview for DSM disorder  
SD  
Standard deviation  
SDS  
Sheehan disability Scale  


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Abbreviation  
Full Form  
SI 
International System of Units 
SIGH-A  
Structured Interview Guide for the HAM-A  
SIGMA  
Structured Interview Guide for the MADRS  
SOC  
System organ class  
TEAE  
Treatment-emergent adverse event  
tmax  
Time to maximum concentration  
UDS  
Urine drug screen  
ULN  
Upper limit of normal  
URS 
User Requirements Specifications 
USP  
United States Pharmacopeia  
VAS  
Visual analog scale  
WBC  
White blood cells  
Y-BOSC-BE  
Yale-Brown Obsessive Compulsive Scale Modified for 
Binge Eating  
 


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1. 
Introduction 
This statistical analysis plan (SAP) contains the definitions of analysis populations, derived 
variables, and statistical methods for the analyses of efficacy and safety data from study 
Dasotraline SEP360-321. It outlines the analyses to be performed for data collected both through 
the Week 12 visit and through withdrawal period. It is developed based on the version of the 
study protocol Version 3.00 dated Nov 17, 2017. This SAP is developed and finalized prior to 
database lock for unblinding of the clinical database for study SEP360-321. 
 If additional analyses are required to supplement the planned analyses described in the SAP 
after the database lock, they may be performed and will be identified in Clinical Study Report 
(CSR).  
 


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2. 
Study Objectives 
2.1. 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of 2 doses of dasotraline (4 and 6 
mg/day) compared with placebo in adults with moderate to severe binge eating disorder (BED) 
as measured by the number of binge days per week. .  
2.2. 
Key Secondary Objective 
To evaluate the efficacy of 2 doses of dasotraline (4 and 6 mg/day) compared with placebo in 
adults with moderate to severe BED as measured by:  
• 
Binge-eating Clinical Global Impression-Severity (BE-CGI-S)  
• 
4-Week cessation from binge eating defined as a 100% reduction for at least 28 
consecutive days in the number of binge eating episodes  
• 
Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating (Y-BOCS-BE)  
2.3. 
Other Secondary Objective 
The other secondary objectives of the study are:  
• 
To evaluate the efficacy of 2 doses of dasotraline (4 and 6 mg/day) compared with 
placebo in adults with moderate to severe BED as measured by:  
− Number of binge episodes per week  
− Proportion of binge eating responders at Week 12 who show ≥ 75% reduction in 
the number of binge eating episodes  
− Eating Disorder Examination Questionnaire (EDE-Q) modified 
− Sheehan Disability Scale (SDS)  
− Montgomery-Asberg Depression Rating Scale (MADRS)  
− Hamilton Anxiety Rating Scale (HAM-A)  
• 
To evaluate the safety and tolerability of 2 doses of dasotraline (4 and 6 mg/day) using 
physical examinations, 12-lead electrocardiograms (ECG), vital signs, adverse event 
(AE) reports, clinical laboratory results, body weight, body mass index (BMI), and 
Columbia – Suicide Severity Rating Scale (C-SSRS)  
• 
To assess potential withdrawal effects upon abrupt discontinuation of dasotraline after 12 
weeks of continuous daily treatment using the following assessments (administered 
during the withdrawal period):  
− Cocaine Selective Severity Assessment (CSSA)  
− Discontinuation-Emergent Signs and Symptoms (DESS) Scale  
− Symptoms of anxiety utilizing the HAM-A  
− Symptoms of depression utilizing the MADRS  


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• 
To assess the abuse potential of dasotraline utilizing a comprehensive abuse potential 
monitoring plan (APMP)  
• 
To assess the relationship between dasotraline plasma concentration and the primary 
efficacy and selected secondary efficacy and safety endpoints  
 


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3. 
Study Design 
This is a randomized, double-blind, parallel-group, multicenter, outpatient study evaluating the 
efficacy and safety of 2 doses of dasotraline in adults with BED using dasotraline (4 and 6 
mg/day) versus placebo over a 12-week treatment period. This study is projected to randomize 
approximately 480 subjects to 3 treatment groups in a 1:1:1 ratio (4 mg/day dasotraline, 6 
mg/day dasotraline and placebo). Subjects randomized to placebo receive placebo for the 
duration of the treatment throughout the study. Subjects randomized to 4 mg/day dasotraline 
receive 4 mg/day for the duration of the treatment period. Subjects randomized to 6 mg/day 
dasotraline are dosed with 4 mg/day dasotraline for the first 2 weeks of the treatment period and 
are increased to 6 mg/day at Week 2. 
The study consists of 3 periods: Screening (up to 3 weeks), 12-weeks of treatment, and 3-week 
study drug withdrawal period. Subjects who complete the 12-week double-blind treatment period 
in this study may be eligible to enroll and continue treatment for an additional 12 months in an 
open-label extension study (Study SEP360-322). Subjects who do not enter the extension study 
complete the study drug withdrawal period in this study. See protocol Section 7.1 Figure 1 for 
study schematic. 
Efficacy is evaluated at each visit using the subject binge eating diary and a clinician interview to 
assess the frequency of binge episodes and the number of binge days defined as days with at 
least one binge episode. Additional assessments include BE-CGI-S, Y-BOCS-BE, MADRS, 
HAM-A, SDS and EDE-Q modified. Safety and tolerability are monitored throughout the study 
by collection of physical examination results, ECGs, vital signs, AEs, clinical laboratory 
parameters, C-SSRS, body weight, and BMI. Subjects who have significant findings for suicidal 
ideation upon completion of the C-SSRS at any time during the study must be referred to the 
investigator for follow-up evaluation. Assessment of potential withdrawal effects is conducted 
via administration of the CSSA, DESS, HAM-A, and MADRS at the end of treatment and during 
the 3-week study medication withdrawal period.  
Blood samples for pharmacokinetic (PK) and biomarkers associated with eating disorders to be 
determined are collected. Blood samples collected for PK assessment are analyzed for plasma 
concentrations of dasotraline. The relationship between dasotraline plasma concentration and the 
primary and selected secondary clinical outcome measures are evaluated. The relationship 
between biomarkers associated with eating disorders in relationship to the severity of BED and 
response to dasotraline will be explored at a later date in the development program. Plasma 
samples collected for PK and biomarker concentration analysis may also be used for the 
additional characterization of and/or bioanalytical method development for dasotraline.  
A blood sample is collected from subjects who provide separate informed consent for 
pharmacogenomics (PGx) analysis for potential evaluation of associations between genetic 
polymorphisms such as, but not limited to Taq1DRD2, OPRM1, and DRD4-7R, and the severity 


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of BED, the clinical response to dasotraline, in addition to the safety, efficacy, and PK profiles of 
dasotraline to be conducted at a later date in the development program. Separate consent is 
required for collection of this specific blood sample and is obtained at Screening for subjects 
who agree to provide this sample (note: this separate consent is not required for participation in 
the study, it is required only for subjects who provide this sample). 
A comprehensive Abuse Potential Monitoring Plan (APMP) for dasotraline designed to detect 
potential abuse of the compound and to more closely monitor AEs consistent with the known 
pharmacology for dasotraline is implemented. 
An independent Data and Safety Monitoring Board (DSMB) will review safety data at regular 
intervals. 
The schedule of assessments for this study is in Attachment 9.1; also see protocol Section 11.8 
for study visits and assessments detail.  
3.1. 
Determination of Sample Size 
The sample size for this study was estimated based on 2 hypotheses associated with the primary 
efficacy endpoint (change from baseline in number of binge days per week at Week 12). A fixed 
sequence closed testing procedure was used to adjust for 2 comparisons of dasotraline doses vs 
placebo (ie, with dasotraline 6 mg vs placebo tested first and dasotraline 4 mg vs placebo tested 
after if the previous one is significant at the 0.05 level ) for the sample size justification. Based 
on the Study SEP360-221 results, assuming a common standard deviation (SD) of 1.75 and a 
mean improvement of 0.9 (effect size 0.517) and 0.8 (effect size 0.457) over placebo for change 
from baseline in number of binge days per week at Week 12 for dasotraline 6 mg/day and 4 
mg/day doses respectively, a sample size of 96 subjects per treatment group will provide at least 
85% conjunctive power to reject both null hypotheses. An upward adjustment of approximately 
40% is assumed to compensate for subjects who are randomized but discontinue from the study, 
thus, a total sample of 480 subjects (160 subjects per group) will be randomized with a ratio of 
1:1:1 for placebo, and dasotraline 4 mg/day and 6 mg/day. The sample size calculation was 
based on Monte Carlo simulation from EAST 6.4. 
3.2. 
Randomization, Stratification and Blinding 
After successfully meeting study entry criteria, subjects are randomly assigned in a 1:1:1 ratio to 
1 of 3 treatment arms: 
• Dasotraline 4 mg/day 
• Dasotraline 6 mg/day 
• Placebo 
Study protocol V1.00 (dated Feb 23, 2017) and V2.00 (dated May 18, 2017) state that the 
randomization was to be balanced using permuted blocks with 2 stratification criteria: (1) 
baseline number of binge eating days per week, which is defined as number of binge days/week 


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determined from the 2 weeks before the Baseline visit (3 – 4 binge eating days per week, > 4 
binge eating days per week); and (2) regions in the United States, which are detailed in the User 
Requirements Specification (URS) (see Attachment 9.2.2).  
The stratification process is handled by an  Interactive Response Technology System (IRT), an 
integrated web-based subject and drug-management system. An IRT is used to manage 
randomization at Day -1 and, if necessary, for emergency unblinding of treatment assignment 
during the study. 
Study medication is assigned by an IRT at Day -1 based on the randomization schedule. The IRT 
generates instructions on which medication number to assign to a subject. Each randomized 
subject is dispensed one 10-day blister pack per scheduled visit up to and including Visit 5 and 
two 10-day blister packs per scheduled visit thereafter through Visit 9. 
This is a double-blind study. Subjects, Investigator staff, persons performing the assessments, 
clinical operations personnel, data analysts, and personnel at central laboratories remain blind to 
the identity of the treatment from the time of randomization until database lock (DBL) and 
unblinding, using the following methods: (1) randomization data are kept strictly confidential 
until the time of unblinding, and are not accessible by anyone else involved in the study with the 
following exceptions: external bioanalytical personnel involved in the analysis of PK samples, 
DSMB members involved in regular review of safety data, external statistician and programmer 
who prepare materials for DSMB review, and Clinical Trial Materials Management personnel 
and (2) the identity of the treatments are concealed by the use of study medication that are all 
identical in packaging, labeling, schedule of administration, and appearance. 
During the study and prior to database lock, the treatment assignments for all subjects are 
provided to the Bioanalytical Contract Research Organization (CRO) to facilitate plasma PK 
sample handling and analysis. No PK samples are analyzed for placebo subjects.   
Protocol and IRT Amendment for Stratification Factor of Region 
For this US study, there is no concern of ‘region’ difference for treatment effect. Sponsor’s 
initial intention of including stratification factor of region was to provide an optimization 
approach to ensure a balanced treatment assignment within each region. It should be noted that 
stratification by region was not implemented in study SEP360-221, which is also a US study 
with a similar study design.  
The study team noticed on July 20, 2017 that the stratification by region was not implemented as 
planned, ie, the initiated sites in IRT were linked to incorrect regions (See Section 6.1.5.1 for 
details). As of July 20, 2017, among 50 planned sites of this study, a total of 44 sites were 
screening subjects; and 137 subjects from 35 sites had already been randomized. Due to the 
‘random’ nature of the incorrect assignment of region according to the root cause of this incident, 
the study team decided to remove stratification criteria related to ‘region’ to minimize the impact 
of this mistake. Stratification criteria were amended in study protocol V3.00 and randomization 
is to be balanced using only permuted blocks with baseline number of binge eating days per 


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week (3 – 4 binge eating days per week, > 4 binge eating days per week). 


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4. 
Changes in Planned Analyses  
There is not any change made in this SAP from the analyses planned in the protocol. 
 


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5. 
Efficacy and Safety Variables  
Section 6.1.2 provides definitions of DB Baseline and Withdrawal Baseline. For the sake of 
simplicity, hereafter, Baseline and DB Baseline will be used in an interchangeable way.  
5.1. 
Efficacy Variables 
5.1.1. Variables Derived Per Binge Eating Diary  
All binge episodes will be captured daily by the subject in a binge eating diary using paper 
format to record the date, duration (total hours of binging), type of binge episode (meal or non-
meal), amount and type of food, and number of binges. The number of binge days per week and 
the number of binge episodes per week at each assessment timepoint will be derived based on 
clinician review of the binge eating diary collected in the time intervals as follow: 
 Baseline: binge eating diary completed for 14 consecutive days immediately prior to the 
Baseline visit; 
 Weeks 1, 2, 3, and 4 (ie, Visits 3, 4, 5, and 6): binge eating diary collected at each visit, 
which will span from the previous visit to the current visit and therefore cover Weeks 1, 
2, 3, and 4, respectively; Particularly, Week 1 visit period will span from Day 1 (ie, 1st 
dose day) to one day before Week 1 visit date (inclusive). 
 Weeks 6, 8, 10 and 12 (ie, Visits 7, 8, 9, and 10): binge eating diary collected at each 
visit, which will span from the previous visit to the current visit and therefore cover 
Weeks 5/6, 7/8, 9/10, and 11/12, respectively. 
 Withdrawal Weeks  1, 2, 3 (ie, Week 13, 14, and15): binge eating diary collected at each 
withdrawal visit, which will span from the previous visit to the current visit and therefore 
cover Visits 11, 12, and 13, respectively. 
Specifically, the diary information collected on the post-DB baseline visits will be counted into 
the corresponding week span; for an example, diary collected on Week 1 visit data will be 
counted into the diary data at Week 1; diary collected on Week 2 visit data will be counted into 
the diary data at Week 2; and so on. 
Diary records reviewed at early termination visit will be mapped into scheduled visit. Mapping 
rule of early terminated visit for binge eating diary based on study day is provided in Section 
6.1.4.1.  
For very rare situations, a subject might miss a scheduled visit and come back at the next 
scheduled visit. For such a case, diary records are expected to be collected continuously without 
interruption. The collected diary will be reviewed on the next scheduled visit.  During the 
double-blind treatment period, if a diary contains binge eating diary records for a missed visit, 
the diary records will be split into two parts by using the target day of the missed visit (see Table 
2 in study protocol) as a data cut:  part 1 starts from the previous scheduled visit date (inclusive) 


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to the target day of the missed visit (exclusive), and part 2 starts from the target day of the 
missed visit (inclusive) to the current visit (exclusive). Part 1 and Part 2 data will be used to 
derive binge diary related variables for previous scheduled visit and the missed visit, 
respectively. 
5.1.1.1. 
Number of Binge Days, Number of Binge Episodes, and Number of 
Assessed Days During a Visit Period  
Number of assessed days at baseline will be 14 days. The number of binge eating days per week 
at baseline is calculated as the number of binge eating days in the 14 days immediately prior to 
the Baseline visit multiplied by 7 and divided by the number of days in the Baseline period. No 
missing diary entry is expected. In case there is a missing diary, the non-missing diary days in 14 
days immediately before randomization will be used to derive these variables.  
For each post-baseline assessment visit defined in Section 5.1.1, 
 Number of assessed days within the visit period is defined as the difference in study 
day between the current visit and the previous visit (ie, study day of current visit – 
study day of previous visit). If missing diary entries exist during the assessed period 
for a subject, the number of assessed days will be derived based on the days with non-
missing diaries.  
 Number of binge days is counted as the binge days that occur between the previous 
visit date (inclusive) and a day before the current visit date (inclusive).  
 Number of binge episodes is counted in a similar way. If missing diary entries exist 
during the assessed period for a subject, number of binge days and number of binge 
episodes will be derived based on the days with non-missing diaries. 
5.1.1.2. 
Number of Binge Days per Week and Number of Binge Episodes per 
Week for a Visit Period 
Based on the number of binge days and number of assessed days (defined in Section 5.1.1.1) 
at each visit, the number of binge eating days per week is calculated as  
       (total number of binge days) x 7 / (total number of assessed days in the visit span); 
the number of binge eating episodes per week is calculated as 
       (total number of binge episodes) x 7 / (total number of assessed days in the visit span). 
5.1.1.3. 
Percent Reduction in the Number of Binge Eating Episodes from 
Baseline at Post-baseline Visits in DB Treatment Period 
Percent change in the number of binge eating episodes from baseline at a post-baseline visit is 
calculated as: 


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   (value at the post-baseline visit  – value at baseline) / value at baseline for number of binge 
eating episodes per week; 
Binary indicator for subjects who have ≥ 75% reduction in the number of binge-eating episodes 
from baseline will be derived for each post-baseline visit in DB treatment period, respectively.  
5.1.1.4. 
4-Week Cessation  
4-Week cessation from binge eating is defined as a 100% reduction for at least 28 consecutive 
days in the number of binge eating episodes at Week 12/EOT visit. If a subject is early 
terminated in the double-blind treatment period prior to collection of 28 days of diary data or the 
subject has missing diary data in the last 28 days prior to Week12/EOT, the subject will be 
counted as no cessation. See below for specific details about how to derive the variable:   
Count the number of days from the first study dose date to the Week 12/EOT visit date,   
 If a subject has less than 28 days, 4-week cessation flag will be set as ‘No’; 
 If a subject has ≥ 28 days, 
− If missing diary entries exist during the last 28 days or no missing diary exist in 
the last 28 days but reduction <100%, 4-week cessation flag will be set as ‘No’. 
− If no missing diary entries exist in the last 28 days and reduction =100%, 4-week 
cessation flag will be set as ‘Yes’. 
5.1.2. Binge-eating Clinical Global Impression-Severity (BE-CGI-S) 
The BE-CGI-S is a single value, clinician-rated assessment of illness severity, and 7-point scale 
with range from 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = 
moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill subjects. A 
higher score is associated with greater illness severity.  
BE-CGI-S score is collected at Baseline, Weeks 2, 4, 6, 8, 10, and 12/EOT for randomized 
subjects, and at Week 15 for subjects who enter into the withdrawal period. 
5.1.3. Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating 
(Y-BOCS-BE) 
Yale Brown Obsessive Compulsive Scale Modified for Binge Eating (Y-BOCS-BE) is a 
clinician-rated scale that measures the obsession of binge eating, thoughts and compulsiveness of 
binge eating behaviors. 10 questions are included in this assessment.  
1. Time occupied by obsessive thoughts to binge eat 
2. Interference due to thoughts to binge eat 
3. Distress associated with thoughts to binge eat 
4. Resistance of thoughts to binge eat 


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5. Degree of control over obsessive thoughts to binge eat 
6. Time spent on compulsive behaviors to binge eat 
7. Interference due to binge eating 
8. Distress associated with binge eating 
9. Resistance 
10. Degree of control over binge eating 
The 10-item scale, is rated from 0 (no symptoms) to 4 (extreme symptoms). Total scores range 
from 0 to 40. A score of 0-7 is sub-clinical; 8-15 is mild; 16-23 is moderate; 24-31 is severe; and 
32-40 is extreme. 
Y-BOCS-BE is divided into 2 subscales: obsessions and compulsions. The Y-BOCS-BE 
obsessions subscale is calculated as the sum of raw scores from obsessions questions (questions 
1 to 5); and the subscale score ranges from 0 to 20.The compulsions subscale is calculated as the 
sum of raw scores from compulsions questions (questions 6 to 10); and the subscale score ranges 
from 0 to 20. Higher values of Y-BOCS-BE score and subscale scores represent greater severity 
of illness. 
If there are any missing responses on the YBOCS-BE, the total score and corresponding subscale 
score are set as missing. Y-BOCS-BE score is collected at Baseline, Weeks 2, 4, 6, 8, 10, and 
12/EOT for randomized subjects, and at Week 15 for subjects who enter the withdrawal period.   
5.1.4. Eating Disorder Examination Questionnaire (EDE-Q) and Eating Disorder 
Examination Questionnaire (EDE-Q) Modified 
The Eating Disorder Examination Questionnaire (EDE-Q) is a self-report version of the eating 
disorder examination (EDE) (Fairburn-1994). Like the EDE, the EDE-Q measures eating-
disorder psychopathology in the past 28 days and over longer intervals for diagnostic items. 
EDE-Q generates two types of data. First, it provides frequency data (ie, numerical data) on key 
behavioral features of eating disorders in term of number of episodes of the behavior and in some 
instance number of days which behavior has occurred; Second, they provide ratings (ie, 
categorical data), 4 subscale scores, and a EDE-Q global score reflecting the severity of aspects 
of the psychopathology of eating disorders. The 4 subscale scores are Restraint, Eating Concern, 
Shape Concern, and Weight Concern.  Severity rating ranges 0- 6, where 0 represents absence of 
the feature and 6 represents an extreme degree. Frequency ratings range from 0 to 6 where 
0=’No days’ or absence of the feature, 6=’every day’. 
Both of the Eating Disorder Examination Questionnaire Brief Version (EDE-Q7) and EDE-Q 
modified (EDE-QM) are brief versions of the EDE-Q. EDE-Q7 was used in study SEP360-221 
while EDE-QM is used in this study (SEP360-321). 
EDE-Q7 comprises 7 items to generate a global score and 3 subscale scores (Restraint, Shape 
Concern, and Weight Concern). The EDE-Q7 along with 3 items (see below) to assess binge 
eating, including the number of binge eating days, is referred to as the EDE-Q modified. 


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 Item 4: Over the past 28 days, how many times have you eaten what other people would 
regard as an unusually large amount of food (given the circumstances)? 
 Item 5: On how many of these times did you have a sense of having lost control over 
your eating (at the time that you were eating)? 
 Item 6: Over the past 28 days, on how many DAYS have such episodes of overeating 
occurred (i.e., you have eaten an unusually large amount of food and have had a sense of 
loss of control at the time)? 
See Table 1 below for definition of rating data for EDE-Q, EDE-Q7, EDE-Q modified, and their 
relationship. Table 2 provides the definition of frequency data for EDE-Q, EDE-Q modified, and 
their mapping relationship. 
Table 1:  Rating Data of EDE-Q , EDE-Q7, and EDE-Q modified Items 
EDE-Q 
Modified Item 
EDE-Q7 Item 
EDE-Q Item 
Abbreviated Content 
Subscale 
1 
1 
1 
Restraint over eating  
Restraint 
 
 
 
 
2 
Avoidance of eating  
2 
2 
3 
Food avoidance  
3 
3 
4 
Dietary Rules  
 
 
5 
Empty stomach  
 
 
 
 
7 
Preoccupation with food, eating 
or calories  
Eating Concern 
 
 
9 
Fear of losing control over 
eating  
 
 
19 
Eating in secret  
 
 
21 
Social eating  
 
 
20 
Guilt about eating  
 
 
 
 
6 
Flat stomach  
Shape Concern 
 
 
8 
Preoccupation with shape or 
weight  
8 
5 
23 
Importance of shape  
 
 
10 
Fear of weight gain  
10 
7 
26 
Dissatisfaction with shape  
 
 
27 
Discomfort seeing body  
 
 
28 
Avoidance of exposure  
 
 
11 
Feelings of fatness 
 
 
7 
4 
22 
Importance of weight  
Weight Concern 
 
 
24 
Reaction to prescribed weighing  
 
 
8 
Preoccupation with shape or 
weight  
9 
6 
25 
Dissatisfaction with weight  
 
 
12 
Desire to lose weight  


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Reference: Fairburn C.G., 2014, EDE Edition 17.D, Cognitive Behavior Therapy and Eating Disorders[1] 
 


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Table 2:   Frequency Data of EDE-Q and EDE-Q modified Items 
EDE-Q 
Modified Item 
EDE-Q Item 
Abbreviated Content 
4 
13 
Times of unusually large amount of food  
5 
14 
Times of having lost control eating  
6 
15 
Days of overeating episodes 
 
16 
Times of having made of sick for controlling shape or weight 
 
17 
Times of having taken laxatives for controlling shape or weight  
 
18 
Times of having exercised  in a “driven” or “compulsive” for controlling 
shape or weight 
 
For EDE-Q, EDE-Q Modified, and EDE-Q7, the subscale scores are calculated as average of the 
corresponding individual scores. If any individual score of the subscale is missing, the 
corresponding subscale score will be set as missing and no imputation will be done. An EDE-Q 
global score is calculated as average of 4 EDE-Q subscale scores. An EDE-Q7 global score is 
calculated as average of 3 EDE-Q7 subscale scores, and an EDE-Q modified global score is 
calculated as average of 3 EDE-Q modified subscale scores.  The EDE-Q global score, EDE-Q 
modified global score, and EDE-Q7 global score will be missing if any of corresponding 
subscale score is missing. For EDE-Q, EDE-Q modified, and EDE-Q7, higher scores of the global 
score and subscale scores indicate greater levels of symptomatology. The global scores and 
subscale scores of EDE-Q modified and EDE-Q7 are equivalent. 
EDE-Q is collected only at screening visit. EDE-QM is collected at Baseline and Week 12/EOT. 
Both EDE-Q and EDE-QM are designed to collect the data in the past 28 days; for a subject who 
is early terminated from the treatment period, these questionnaires may not be appropriate since 
the subject may have much less days since last visit compared to the targeted 28 days. In order to 
collect more accurate information for early terminated subjects, a modified version of EDE-QM 
28 days version, named as EDE-QM 14-days look-up version, having a very similar rating scale 
as the regular EDE-QM, will be applied on early termination subjects who discontinue between 
12 and 24 days, inclusive, following the previous administration of the EDE-QM. For those who 
discontinue more than 24 days following the previous visit, the regular EDE-QM (28 day 
lookback version) is administered. Data collected by using EDE-QM 14-days look-up version 
and regular version (ie, 28 days look-up version) will be summarized together. 
5.1.5. Sheehan Disability Scale (SDS) 
The Sheehan Disability Scale (SDS) is to assess functional impairment in 3 domains: (1) 
work/school; (2) social life; and (3) home life. The subject rates the extent to which work/school, 
social life and home life have been impaired by his/her symptoms on a 10-point anchored visual 
analog scale (VAS). The subject’s responses for each domain are rated on the following scale: 0 
= not at all; 1-3 = mildly; 4-6 = moderately; 7-9 =markedly; 10 = extremely. The 3 items can be 
combined into a single global measure of impairment (SDS total score) that ranges from 0 
(unimpaired) to 30 (highly impaired). If any of the 3 SDS subscale scores is missing at a visit, 


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the SDS total score for that visit is also missing. A higher subscale score and total score are 
associated with greater illness severity. 
The SDS is collected at Baseline, Weeks 6, and 12/EOT for randomized subjects, and at Week 
15 for subjects who enter the withdrawal period. 
5.1.6. Montgomery-Asberg Depression Rating Scale (MADRS) 
The MADRS is a clinician-rated assessment of the subject’s level of depression. This scale 
contains 10 items that measure apparent and reported sadness, inner tension, reduced sleep and 
appetite, difficulty concentrating, lassitude, inability to feel, and pessimistic and suicidal 
thoughts. Each item is scored in a range of 0 to 6, with higher scores indicating increased 
depressive symptoms. The score for each question will be summed to compute a total score 
ranging from 0 to 60. If the response to any question is missing, the total score will be missing. 
The MADRS is collected at screening, Baseline and Week 12/EOT for randomized subjects, and 
at Weeks 13, 14 and 15 for subjects who enter the withdrawal period. 
5.1.7. Hamilton Anxiety Rating Scale (HAM-A) 
The HAM-A is a rating scale developed to quantify the severity of anxiety symptomatology.  It 
consists of 14 items, each defined by a series of symptoms.  The 14 items are: anxious mood, 
tension, fears, insomnia, intellectual, depressed mood, somatic (muscular), somatic (sensory), 
cardiovascular symptoms, respiratory symptoms, gastrointestinal symptoms, genitourinary 
symptoms, autonomic symptoms, and behavior at interview.  Each item is rated on a 5-point 
scale, ranging from 0 (not present) to 4 (severe/disabling).  The score for each question are 
summed to compute a total score ranging from 0 to 56. If the response to any question is missing, 
the total score is missing. A higher score is associated with a greater degree of anxiety.  A score 
of ≥ 14 has been suggested to indicate clinically significant anxiety.  
The HAM-A is collected at Baseline and Week 12/EOT for randomized subjects, and at Weeks 
13, 14 and 15 for subjects who enter  the withdrawal period. 
5.2. 
Safety Assessment 
The safety assessments/endpoints are 
 adverse event (AE) reports,  including the incidence of overall AEs, serious AEs (SAEs), 
and AEs (or SAEs) leading to discontinuations 
 Clinical laboratory evaluations (serum chemistry, hematology, and urinalysis) 
 Clinical evaluations (vital signs including orthostatic effects, and 12-lead ECGs)  
 weight and body mass index (BMI) 
 concomitant medication reports 
 physical examinations 
 Columbia – Suicide Severity Rating Scale (C-SSRS) 


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The following safety measurements will also be collected to assess the occurrence of symptoms 
of withdrawal from dasotraline:  
 Cocaine Selective Severity Assessment (CSSA) 
 Discontinuation-Emergent Signs and Symptoms (DESS) Scale 
 Symptoms of anxiety utilizing the HAM-A 
 Symptoms of depression utilizing the MADRS 
5.2.1. Columbia – Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is an instrument designed to systematically assess and track suicidal behavior and 
suicidal ideation for life time, one month prior to screening and throughout the trial. The strength 
of this suicide classification system is in its ability to comprehensively identify suicidal events 
while limiting the over-identification of suicidal behavior. The C-SSRS includes the following 
four sections: Suicidal Ideation, Ideation Intensity, Suicidal Behavior and Actual Suicide 
Attempts. The C-SSRS is administered by a trained rater at the site. 
Severity of suicidal ideation is rated on a 6-point scale from 0=’No ideation present’ to 
5=’Active ideation with plan and intent’. A score of 4 or 5 on this scale indicates serious suicidal 
ideation.  Subjects with Type 4 (active suicidal ideation with some intent to act, without specific 
plan) or Type 5 (active suicidal ideation with specific plan and intent) suicidal ideation during 
the study will be discontinued from the study and referred to a mental health professional. 
Suicidal ideation score is defined as the most severe suicidal ideation score (1-5 on the CSSRS) 
present at the assessment; assign a score of 0 if no ideation is present. The ideation intensity total 
score is calculated as summation of the five items from the Ideation Intensity scale: frequency, 
duration, controllability, deterrents, and reasons for ideation. If one or more of these 5 items are 
missing at a visit, no imputation will be made and the corresponding ideation intensity total score 
will be set as missing. Items corresponding to frequency and duration are each rated on a scale 
from 1 to 5 and items corresponding to controllability, deterrents, and reasons for ideation are 
each rated on a scale from 0 to 5. If the patient did not endorse any suicidal ideation, set the 
intensity rating to 0. Thus, the possible range for the intensity total score is 0 to 25.  
Suicidal behavior is collected as presence/absence of actual attempts, non-suicidal self-injurious 
behavior, interrupted attempts, aborted attempts, preparatory acts or behavior, and any suicidal 
behavior. In addition, the number of actual attempts, interrupted attempts, and aborted attempts is 
captured. Any attempt will be defined as suicidal behavior.  
The lethality associated with actual attempts is rated on a 6-point scale from 0=’No physical 
damage or very minor physical damage’ to 5=’Death’. Potential lethality of attempts is rated on a 
3-point scale from 0=’Behavior not likely to result in injury’ to 2=’Behavior likely to result in 
death despite available medical care’. 
The C-SSRS is collected at screening, Baseline, Weeks 1, 2, 3, 4, 6, 8, 10 and 12/EOT for 
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This study utilizes 2 versions of the C-SSRS. At the screening visit, the “Baseline/Screening” 
version will be completed. C-SSRS at ‘Baseline/Screening’ consists of two parts: part 1 – life 
time; part 2 – past 1 month. For all subsequent visits, the “Since Last Visit” version of the C-
SSRS is administered. 
5.2.2. Withdrawal Assessment for Physical Dependence and Withdrawal 
Symptoms 
Subjects who either are early terminated in treatment period or complete 12-week treatment 
period but not enter into extension study need to complete the study medication withdrawal 
period assessments and visits.  
Assessment of potential withdrawal effects will be conducted via administration of the CSSA, 
DESS, HAM-A, and MADRS at Week 12 (End of Treatment), then again at Weeks 13, 14, and 
15 during the 3-week study medication withdrawal period. The CSSA and DESS will also be 
completed during the 3-week study medication withdrawal period on non-clinic visit days. 
Clinical site staff will call the subject every other day during the study medication withdrawal 
period, beginning the second day after the last dose of study drug, unless a clinic visit is 
scheduled for that day. Clinical site staff will record the responses in the subject’s source 
information and in the CRF with the contact date and time. A window of ± 1 day is allowed for 
each weekly clinic visit and telephone call. If the subject cannot be contacted on a given day, 
during the next contact the study site staff will retrospectively collect the missed CSSA and 
DESS, in addition to the current day’s CSSA and DESS. 
5.2.2.1. 
Cocaine Selective Severity Assessment (CSSA) 
The CSSA is a clinician-administered scale designed to evaluate withdrawal signs and symptoms 
related to stimulants over the past 24 hours. Included in the CSSA are those symptoms most 
often associated with early cocaine abstinence, including change in appetite, depression, fatigue, 
anhedonia, anxiety, irritability, sleep disturbance, and inability to concentrate, paranoia, 
carbohydrate craving, bradycardia, and suicidality. The CSSA scale contains 18 items. All items 
except item 14, are scored 0 to 7 according to instructions generally with 0 = no symptoms and 7 
= maximum score on any individual item. Item 14 is scored 0 to 8 with 0 = no symptoms and 8 = 
maximum score. The score for each question will be summed to compute a total score ranging 
from 0 to 127 with higher score indicates severe withdrawal signs and symptoms. If the response 
to any question is missing, the total score will be missing. 
The CSSA is collected at clinic visits: Week 12/EOT, and Weeks 13, 14 and 15 for subjects who 
enter the withdrawal period, as well as at phone contacts during the withdrawal period, beginning 
the second day after the last dose of study drug. 


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5.2.2.2. 
Discontinuation-Emergent Signs and Symptoms (DESS) Scale 
The DESS Scale is a clinician-rated instrument of 43 items used to evaluate signs and symptoms 
associated with discontinuation or interruption of monoamine reuptake inhibitor treatment. Each 
of the 43 signs and symptoms is assessed and placed in one of the following categories: new 
symptom, old symptom but worse, old symptom but improved, old symptom but unchanged, and 
symptom not present. Each sign and symptom that is placed in the category new symptom or in 
the category old symptom but worse receives 1 point. All other categories receive 0 points. The 
total DESS score is the sum of the number of points, which corresponds to the number of 
symptoms rated as either a new symptom or as an old symptom but worse. The score ranges 
from 0 to 43, where higher scores indicate more discontinuation-emergent signs and symptoms.  
The DESS is collected at clinic visits: Week 12/EOT, and Weeks 13, 14 and 15 for subjects who 
enter the withdrawal period, as well as at phone contacts during the withdrawal period, beginning 
the second day after the last dose of study drug. 
5.2.2.3. 
HAM-A 
See Section 5.1.7 
5.2.2.4. 
MADRS  
See Section 5.1.6 
5.3. 
Other Assessment 
Pharmacokinetic (PK) endpoints include dasotraline plasma concentration which is collected at 
Weeks 2, 6 and 12/EOT and biomarkers concentration which is collected at Baseline and Week 
12/EOT visit.  
PK analysis will be based on the PK population. Subjects will be analyzed based on the last 
treatment prior to the collection of PK sample. See Section 6.1.7 for definition of PK population. 
The relationship between SEP-225289 plasma concentration and the primary and selected 
secondary clinical outcome measures of SEP-225289 using population PK methods will not be 
done by INC Research and the analysis is not included in the SAP. 
 


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6. 
Statistical Methods  
6.1. 
General Analysis Definition 
6.1.1. Analysis Period and Study Day 
Two scopes of data for a subject are considered in this study. Each scope of data consists of a 
specific portion (subset) of all study data for that subject.  
6.1.1.1. 
Double-Blind Treatment Period (On Treatment) 
The double-blind treatment period will begin with the day when the first dose of double-blind 
study medication is taken, which will be denoted as study Day 1. The end of the double blind 
phase is defined as the maximum of the last date of administration of study medication and the 
withdrawal completion date of the treatment period (ie, Week 12/EOT visit date). If the end date 
of the medication intake is unknown (eg, subject is lost to follow-up), the end of the double blind 
period is defined as the withdrawal date provided by investigator site. If a subject does not take 
any study medication, start and end of the treatment period are set to missing.  
The start and end of treatment period are given below: 
 Start of treatment period = Date/time of the first study medication administration 
during the double-blind treatment period 
 End of treatment period = maximum of the last date of administration of study 
medication and the withdrawal/ completion date (ie, Week 12/EOT visit date) 
Each subject’s assessment at each visit in pre-treatment and treatment period will be assigned a 
study day with respect to start date of the treatment period. 
 Study Day = Assessment date − start date of the treatment period + 1;  if assessment date 
≥ start date of the study period 
 Study Day = Assessment date − start date of the treatment period; if assessment date < 
start date of the study period 
6.1.1.2. 
Withdrawal Period (Off Treatment) 
For subjects who either are early terminated from DB period or complete DB period but do not 
enter the extension, withdrawal period analyses will be generated; no withdrawal period analyses 
will be produced for subjects entering the extension study. 
The withdrawal period will begin with immediately after the last study dose. Study day relative 
to the last study dose date will be denoted as Day 0. The end of the withdrawal period is defined 
as the maximum of last study visit (scheduled or unscheduled) and last phone contact after the 


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last study dose. If the last study dose date is missing (eg, lost follow-up subjects), start and end 
days will be set as missing. 
Each subject’s assessment at each visit (site or phone contact) in the withdrawal period will be 
assigned a study day with respect to start date of the withdrawal period. 
 Study Day = Assessment date − start date of the withdrawal period if assessment date 
≥ start date of the withdrawal period 
6.1.1.3. 
Overall Study Period 
Overall study period is defined as treatment period for subjects who complete the 12-week 
treatment period and enter the extension study, and a combination of treatment and withdrawal 
periods for subjects who either are early terminated during the treatment period or complete the 
12-week treatment period but do not enter into extension study. See Table 3 below for summary 
of definition of all analysis periods and study day used for this study. 
Table 3: Definition of Analysis Study Period 
Analysis Study 
Period 
Start 
Date 
End 
Date 
Applicable Scope 
Double-Blind 
Treatment Period 
Day 1* 
EOT a  
All subjects 
Withdrawal Period 
Day 0 ** 
 
EOS b  
Subjects who either are early terminated in treatment 
period or complete 12-week treatment period but do not 
enter into extension study 
Overall Study Period 
Day 1* of 
treatment 
period 
 
EOT 
Subjects who complete 12-week treatment period and 
enter extension study. 
EOS 
Subjects who either are early terminated in treatment 
period or complete 12-week treatment period but do not 
enter into extension study 
Note:   *: the day of the first dose of double-blind study medication. 
            a : Week 12 visit/ early withdrawal visit            
           **: the day of the last dose of double-blind study medication. 
           b : last scheduled or unscheduled (site/phone contact) visit in withdrawal period  
 
Except for adverse event data, summaries and analyses of all data on double-blind treatment are 
based on the portion of study data that fall in the treatment period (defined in Section 6.1.1.1). 
For adverse events, see Section 7.4.2 for how a study subject is considered to be on treatment 
during the treatment period (ie, last study medication administration + 7 days for AE or +14 days 
for Serious AE).  
6.1.2  Baseline 
Two types of Baseline will be defined: DB Baseline and Withdrawal Baseline. DB baseline is 
also referred as Baseline by default in this document. 


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6.1.2.1 
DB Baseline for Assessment Based on Diary Data 
See Section 5.1.1 for definition of Baseline for eating diary based data. 
6.1.2.2 
DB Baseline for Other Data 
Baseline is defined as the pre-dosing measure on Day 1. If it is missing, unless otherwise 
specified, it will be imputed by the latest non-missing measurement prior to Day 1. 
6.1.2.3 
Withdrawal Baseline for Assessment Based on Diary Data 
Withdrawal Baseline is defined as the derived value at Week 12/EOT. See Section 5.1.1 
6.1.2.4 
Withdrawal Baseline for Other Data 
See Section 6.1.4.2 for the definition of Withdrawal Baseline.  No imputation will be made if the 
withdrawal Baseline value is missing. 
6.1.3 Endpoint 
6.1.3.1 
Week 12 Endpoint 
Week 12 Endpoint is defined as the last post-baseline non-missing assessment in the treatment 
period. Hereafter, for the sake of simplicity, Week 12 Endpoint will be referred as Endpoint by 
default. 
6.1.3.2 
Withdrawal Endpoint 
Withdrawal Endpoint is defined as the last non-missing post-withdrawal baseline assessment in 
the withdrawal period (regardless of clinic or non-clinic visits). 
6.1.4 Visit Windows 
6.1.4.1 
Early Termination (ET) Visit in Double-Blind Treatment Period 
All data are organized and analyzed according to the scheduled times as outlined in the protocol 
and by the visit denoted on the electronic case report form (eCRF), except for early termination 
(ET) visits during the treatment period.  If a subject terminates early during the DB treatment 
period, the early termination visit (ie, EOT visit) will be re-mapped using the study day of the 
visit in Table 4, which applies on both efficacy  and safety data per a specific rule associated 
with that measurements except of the variables derived from binge eating diary. Table 5 
describes the remapping rules applied to diary data at ET visits. 
 
 


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Table 4: Visit Window for Early Termination Visit in Treatment Period for Non-Binge 
Eating Diary Data  
Last Scheduled Visit 
Time Interval (Day)a 
Analysis Visit 
(label on output) 
Baseline * 
≥ DLSV+1  
Week 1 
Week 1 
≥ DLSV+1 
Week 2 
Week 2 
≥ DLSV+1  
Week 3 
Week 3 
≥DLSV+1  
Week 4 
Week 4 
≥ DLSV+1 
Week 6 
Week 6 
≥ DLSV+1 
Week 8 
Week 8 
≥ DLSV+1 
Week 10 
Week 10 
DLSV+1   EOT 
Week 12 
a Relative to the day of the first dose of double-blind study medication 
DLSV=study day of last scheduled visit relative to the first dose of study medication 
*: for the study day of the ET visit > Day1 
Note: Applicable scope of Table 4: vital sign, weight and BMI, C-SSRS, HAM-A, MADRS, EDE-QM, lab, 
ECG, PK, neurological exam, and breath alcohol test. 
BE-CGI-S and Y-BOCS-BE:  if the last scheduled visit is Baseline or Week 1, the ET visit will be mapped to 
Week 2; if the last scheduled visit is Week 2 or Week 3, the ET visit will be mapped to Week 4; if the last 
scheduled visit is Week 4 or after, the ET visit will be mapped same as Table 4 
SDS: if the last scheduled visit is prior to Week 6, the ET visit will be mapped to Week 6; if the last scheduled 
visit is at/after Week 6, the ET visit will be mapped to Week 12. 
 
Only protocol planned visits for each measurement (ie, Baseline, Weeks 1, 2, 3, 4, 6, 8, 10, and 
12 as appropriate) are included in the by-visit analyses. That is to say, the unscheduled visits will 
not be included in the by-visit summary; however, measurements from this/these additional 
visit(s) will be included in the safety analyses (eg, markedly abnormal value in treatment period, 
the worst case analysis etc.) to assure all on-treatment measurements are included.  
Table 5: Visit Window for Early Termination Visit in Treatment Period for Binge Eating 
Diary Data 
Last Scheduled Visit 
Time Interval (Day)a 
Analysis Visit  
(label on output) 
Baseline * 
DLSV   DLSV+30 
Week 1 
Week 1 
DLSV   DLSV+30 
Week 2 
Week 2 
DLSV   DLSV+30 
Week 3 
Week 3 
DLSV   DLSV+30 
Week 4 
Week 4 
DLSV   DLSV+40 
Week 6 


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Week 6 
DLSV   DLSV+40 
Week 8 
Week 8 
DLSV   DLSV+40 
Week 10 
Week 10 
DLSV   DLSV+40 
Week 12 
a Relative to the day of the first dose of double-blind study medication 
DLSV=study day of last scheduled visit relative to the first dose of study medication 
*: for the study day of the ET visit > Day 1 
6.1.4.2 
Visit Window for Visits in Withdrawal Period 
Visits within withdrawal period will be mapped per visit window defined in Table 6.1 below for 
efficacy and safety data collected in withdrawal period except of binge eating diary data. For 
diary data, see Section 5.1.1 for data derivation rule. 
 
Table 6.1: Visit Window for Clinic Visits in Withdrawal Period for Non-Binge Eating 
Diary Data 
Variables to be Applied 
Time Interval  
(Day)a 
Target Time Point  
( Day) 
Analysis Visit 
(label on output) 
CSSA, DESS 
5 to 1 (b) 
0 
Withdrawal Baseline 
2  10 (c) 
7 
Withdrawal Week 1 
11  17(c) 
14 
Withdrawal Week 2 
18  EOS(c) 
21 
Withdrawal Week 3 
Other 
5 to 3 
0 
Withdrawal Baseline 
4  10 
7 
Withdrawal Week 1 
11  17 
14 
Withdrawal Week 2 
18  EOS 
21 
Withdrawal Week 3 
a Relative to the day of the last dose of double-blind study medication 
b per phone contacts or clinic visits 
c for clinic visits only. 
If a subject has 2 or more visits in one analysis visit window, the visit closest to the targeted day 
will be used as the study visit for that analysis visit window. The other additional visit(s) will be 
denoted as an unscheduled visit and not included in the by-visit descriptive summary analyses.  
However, measurements from this/these other additional visit(s) may be included in the other 
safety analyses to assure all off-treatment measurements are included. If the 2 study visits occur 
with the same number of days from the target day within the same visit window, the later one 
will be considered as the study visit for that target day. 
Non-clinic phone contact visits within withdrawal period will be mapped per visit window 
defined in Table 6.2 below for CSSA and DESS specifically.  


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Table 6.2: Visit Window for Non-Clinic/Phone Contact Visits in Withdrawal Period  
Variables to be Applied 
Time Interval  
(Day)a 
Target Time Point  
( Day) 
Analysis Visit 
(label on output) 
CSSA, DESS 
1  2 
1 
Day 1-2 
3  4 
3 
Day 3-4 
5  6 
5 
Day 5-6 
7  8 
7 
Day 7-8 
9  10 
9 
Day 9-10 
11  12 
11 
Day 11-12 
13  14 
13 
Day 13-14 
15  16 
15 
Day 15-16 
17  18 
17 
Day 17-18 
19  20 
19 
Day 19-20 
21  22 
21 
Day 21-22 
23  24 
23 
Day 23-24 
25  EOS(b) 
25 
≥ Day 25  
a Relative to the day of the last dose of open-label study medication 
b per phone contacts visits only. 
6.1.5 Protocol Amendment for Region Stratification  
6.1.5.1 
Stratification Error of ‘Region’  
The original protocol (version 1.0) and amendment 1 (version 2.0) stated that the randomization 
was to be balanced using permuted blocks with 2 stratification criteria: (1) baseline number of 
binge eating days per week and (2) regions in the United States, which were defined in the 
Interactive Response Technology System (IRT) User Requirements Specification and is provided 
in Attachment 9.2.2. For sake of convenience, hereafter in this document, terms of IXRS and 
IRT are used interchangeably. 
In total 50 sites participated in this study. The study team noticed on July 20, 2017 that 
stratification by region was not implemented as planned, that is to say, the initiated sites in IXRS 
were linked to incorrect regions. As of July 20, 2017, a total of 44 sites were screening subjects 
and 137 subjects from 35 sites had already been randomized. A full investigation was 
immediately requested by Sponsor to IRT vendor (Oracle).  According to the incident report 
(Incident Number: INC000004665171 ) provided by Oracle,  the root cause of this mistake was 
with a third party software tool used to develop the IXRS system; more specifically, the mistake 
was caused by  the software’s component related to a dropdown list for “region” selection .  
Region field should have been populated with the set of initial sites that Sponsor provided to 
Oracle and then should have been populated by Sponsor for all other sites. Once a site was 
added, the “region” selection should have been disabled. Due to the unexpected behavior of the 
software component, the “region” value was sometimes overwritten.  Based on this investigation 


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report, in one scenario, a consistent pattern for region selection was identified: when a new site 
was added in “Manage Sites”, the “region” dropdown was loaded as a blank value, and 
eventually the “region” value assignment would be moved up by one row in the database. In 
other scenarios, a consistent pattern for region selection was not identified. IXRS vendor noted 
that there was no way for them to reproduce how the data was assigned in this trial. 
 
6.1.5.2 
IXRS Update  
Although unexpected region assignment of sites may not be truly random in a statistical sense, 
region allocation appears inconsistent and no clear pattern was found. To minimize the impact of 
the region strata error on data interpretation, the study team decided to amend the IXRS and 
study protocol to remove the regional stratification factor due to the following considerations.  
(1) Once a site was initiated in the IXRS system, its associated region was determined and 
could not be changed. When the mistake was found, 44 of the 50 planned sites had been 
incorrectly linked to incorrect regions; by the time that IXRS eventually could have been 
fixed, 47 out the 50 sites would have been linked to incorrect regions. This means that about 
85%~90% randomized subjects were to have been linked to incorrect region. Therefore, the 
regional stratification of subjects would no longer have been meaningful. 
(2) Incorrectly linked regions of the study sites show no overall consistent patterns according to 
the investigation report issued by the IXRS vendor. Two-dimensional distribution of sites 
by initial planned region in IRT User Requirements Specifications (URS) vs. the region 
actually assigned by IXRS (see Attachment 9.2.3) seems to support that regions were 
assigned nearly randomly before IXRS amendment.  
(3) Initial purpose of stratification by region was solely to balance the treatment allocation 
within a region for this United States study.  Differences in treatment response among US 
regions were not expected, nor was the sponsor’s intention to detect potential US regional 
differences. The stratification strategy was chosen for optimization purposes and should not 
be treated as necessary.  
 
IXRS URS was amended and signed off on Aug 09, 2017 (V7.0). The updated IXRS went alive 
on Aug 23, 2017. By removing the stratification factor ‘Region’, study SEP360-321 essentially 
adopted the same stratification criterion as study SEP360-221. Data analysis methods in protocol 
amendment 2 (V3.0) of this study are similar to what was planned and performed for study SEP 
360-221. 
 
 


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6.1.6 Pooling Strategy for Analysis of Centers  
Study SEP360-321 is a multicenter study conducted in the United States. In principle, all centers 
with 18 or fewer subjects are pooled based on geographic proximity if necessary, with the 
intention that no pooled center contains more than 36 randomized subjects.  The list of pooled 
centers for the study based on the pooling strategy described above is provided in Attachment 
9.2.1 and finalized prior to database lock of the study. 
Similarly, planned region and actual region (defined in Section 6.1.7) will be pooled based on 
geographic proximity as well if a region has 18 or fewer subjects. The list of pooled regions is 
provided Table 6.3 in Section 6.1.7.  
6.1.7 Definition of Planned Region Group and Actual Region Group (‘Modified’ 
Region Strata)  
To assess the robustness of primary and key efficacy analyses, two region-related exploratory 
efficacy analyses for primary and key secondary endpoints will be conducted. For each 
randomized subject, two region variables are defined as below: 
 Planned region group: unless otherwise specified, it is defined per URS of original IRT 
(see Attachment 9.2.2). 
 Actual region group (or equivalently, ‘Modified’ region strata): defined as 
Case 1: for subjects randomized PRIOR to the IXRS update:   
Actual region is equal to the region strata value.  
 
 Case 2: for subjects randomized AFTER the IXRS update and from an ‘old’ site, where an 
old site is defined as the one with at least one subject randomized prior to the IXRS            
update (see Attachment 9.2.3):  
Actual region is same as the corresponding region strata value of the site per IXRS data. 
 
Case 3: for subjects randomized AFTER the IXRS update and from a ‘new’ site, where a 
new site is defined as the one without any subject randomized prior to the IXRS update but 
having at least one subject randomized after the IXRS update (see Attachment 9.2.3):  
Actual region will be assigned with the corresponding planned region value per URS of 
original IXRS if location of the new site (ie, State) was listed in the URS of original 
IXRS (see Attachment 9.2.2); otherwise, the planned region and actual region will be 
assigned as ‘Undefined’ since the new site is not listed in URS of original IXRS. 
 
Numbers of subjects within each planned and actual region are listed in Table 6.3 as below. As 
of the completion of study enrollment, there is one site (site 067), which has 3 randomized 
subjects, from a location that was not listed in original URS of IXRS. In addition, the actual 


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region ‘Central 2’ is small and has only 3 subjects. To make sure exploratory analyses related to 
the planned region and actual region are feasible, small planned and actual regions will be pooled 
for analysis purposes. Specifically, for planned region, site ‘067’ will be pooled with the initial 
planned region ‘Central 1’ to generate a pooled planned region still named as ‘Central 1’; no 
pooling is needed for other planned regions; for actual region, site ‘067’ and initial actual region 
‘Central 2’ will be pooled with the initial actual region ‘Central 1’ to generate a pooled actual 
region named as ‘Central1/Central 2’; no pooling is needed for other actual regions. Numbers of 
subjects within each pooled planned and actual region are listed in Table 6.3 as well and are 
finalized prior to database lock of the study. The exploratory efficacy analyses are to be 
performed as needed by replacing term of ‘pooled center’ with pooled actual region or pooled 
planned region group in the corresponding statistical analysis to further corroborate primary and 
key secondary efficacy results.  
 
 
Table 6.3 Pooled Planned and Actual Region Groups Used for Exploratory Efficacy Analyses 
Planned Region  
Group 
Pooled Planned  
Region Group 
Actual Region  
Group 
Pooled Actual Region 
Group 
Region 
Name 
Number 
of 
Subjects 
Region 
Name 
Number 
of 
Subjects 
Region 
Name 
Number 
of 
Subjects 
Region 
Name 
Number 
of 
Subjects 
Northeast 
59 
Northeast 
59 
Northeast 
127 
Northeast 
127 
East 
75 
East 
75 
East 
37  
East 
37  
Central 1 
50 
Central 1 (a) 
53 
Central 1 
138  
Central 1 
/Central 2(b) 
144 
Central 2 
69 
Central 2 
69 
Central 2 
3  
 
 
Southeast 1 
55 
Southeast 1 
55 
Southeast 1 
62  
Southeast 1 
62  
Southeast 2 
22 
Southeast 2 
22 
Southeast 2 
17  
Southeast 2 
17  
West 1 
88 
West 1 
88 
West 1 
24  
West 1 
24  
West 2 
70 
West 2 
70 
West 2 
80  
West 2 
80  
Undefined 
3 
 
 
Undefined 
3  
 
 
Note:   (a): Site 067 from Michigan (undefined in URS of IXRS) is pooled with initial region ‘Central 1’.  
            (b): Site 067 and actual region ‘Central 2’ are pooled with actual region ‘Central 1’. 
 
 
6.1.8 Adjustments for Covariates 
MMRM model and ANCOVA model contain baseline as a covariate to adjust baseline.  Other 
covariates may be included for modeling purposes, as specified. 


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6.1.9 Analysis Populations 
The Intent-to-Treat (ITT) Population: All randomized subjects who receive at least one dose of 
study medication and have at least 1 post-baseline result in any efficacy evaluation. The ITT 
population is the primary population for efficacy analyses, ie, unless otherwise specified, all 
efficacy analyses are based on ITT population.  
The Per Protocol (PP) Population: All ITT subjects who have no major protocol violations that 
may affect the interpretation of the primary efficacy endpoint. The PP population will be used to 
assess robustness of the primary efficacy analysis. Major protocol violations and the PP 
population will be determined through a blinded data review meeting (BDRM) and identified 
prior to the database lock. 
Subjects in the ITT and PP populations will be analyzed based on the treatment to which they are 
randomized. 
The Double-blind (DB) Safety Population: All randomized subjects who receive at least one 
dose of study medication. The DB safety population mainly is used for the data analyses of the 
safety data collected through Week 12 or during the treatment period. Subjects are analyzed 
based on the actual treatment received; specifically, for subjects who are randomized to 
dasotraline 6 mg group and dosed with dasotraline 4 mg but never titrated to dasotraline 6 mg 
(ie, early terminated on or prior to Week 2 visit), the actual dose will be dasotraline 4 mg; 
otherwise, actual dose will be set as dasotraline 6 mg; In the event that a subject receives a 
treatment other than the one to which he/she is randomized or expected, the actual treatment is 
defined as the treatment to which the subject is exposed for the greatest duration during the 
treatment period. The actual treatment is generally the same as the randomized treatment group, 
unless the subject takes incorrect/unexpected dose  during the entire study. Hereafter, DB safety 
population will be referred as safety population by default.   
The Withdrawal  Population: The withdrawal population includes all randomized subjects who 
receive at least one dose of study medication, and either discontinues the study drug during the 
treatment period before the Week 12 visit or completes the 12-week treatment period but do not 
enter the extension study (Study SEP360-322), and have at least 1 assessment after the last study 
drug for any safety or efficacy evaluation. The withdrawal population mainly is used to 
summarize the safety/efficacy assessments collected in the withdrawal period except of adverse 
event data.  
The Modified Withdrawal Population: all subjects in the withdrawal population plus the 
subjects who do not enter the extension study and do not enter the withdrawal period, but the last 
study dose dates are at least 2 days earlier than the last study visit. The modified withdrawal 
population will be mainly used for adverse event that could be retrospectively collected. 
Withdrawal analyses will be presented by planned treatment group for efficacy data and by 
actual treatment group for safety data. 


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Pharmacokinetics (PK) Population: The PK population is defined as all subjects who are 
randomized, receive at least 1 dose of study drug, and have any post-baseline plasma 
concentrations sample collection of dasotraline. 
6.1.10 Stratification Factor ‘Baseline Number of Binge Days’ vs. Baseline Number 
of Binge Days Group  
Group of Baseline number of binge days is defined as: Baseline number of binge days  4, 
Baseline number of binge days >4; this group should be essentially equivalent to the 
stratification factor unless there is a subject stratified into the incorrect stratum. The stratification 
factor (ie, Baseline binge days category) will be consistently used in the statistical models, when 
applicable, for efficacy analysis as described in this document. Compared with the stratification 
factor, group of Baseline number of binge days will be used in the other scenarios, including the 
statistical models based analyses for safety variables.  
6.1.11 Handling of Dropouts or Missing Data  
6.1.11.1 Missing Diary Entry 
Missing diary on certain assessed days in an assessment period will not be imputed, see Section 
5.1.1.1. 
6.1.11.2 Unknown or Unconfirmed Last Study Dose Date 
If the end date of the medication intake is unknown or ‘unconfirmed’ (including but not limited 
to, eg, subject is lost to follow-up),  it will be imputed as the earlier of the disposition date (ie, 
date of the last contact with subject) and 7 days from the date that the last medication kit is 
dispensed. 
6.1.11.3 Composite Score 
Unless otherwise specified, any individual missing item in any scale won’t be imputed. When 
calculating a total score, subscale score, composite score, or any assessment with more than one 
item (e.g. Y-BOCS-BE total score and 2 subscale scores, EDE-Q global score and 4 subscale 
scores, EDE-QM global score and 3 subscale scores, SDS total score and 3 subscale scores, 
MADRS total score, HAM-A total score, CSSA total score, DESS total score), if one or more 
items are missing at a visit, then the associated score (ie, total score or subscale score) will be set 
to missing.   
In the event of missing data at Week 12 for efficacy variables, the last post-baseline observation 
carried forward (LOCF) approach is used to impute missing values in the ITT LOCF efficacy 
analyses. Unscheduled visits are included in the imputation.  
For analyses of the change from baseline for a given efficacy parameter, only subjects who have 
both baseline and at least one post-baseline measurement are included.  


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6.1.11.4 Incomplete/Missing Dates 
6.1.11.4.1 Start/End Dates for Adverse Event 
Treatment-emergent adverse events (TEAEs) are those events with an onset date on or after the 
start of double-blind study medication, through 7 days after study drug discontinuation (14 days 
for serious adverse events and deaths) for subjects who complete or discontinue this study but do 
not enter into the extension study), or through the last study day of the double-blind treatment 
period for subjects continuing into the extension study. A conservative approach will be used to 
handle the missing dates for AE onset date and end date to identify the treatment-emergent AE 
(ie, if the available incomplete date cannot determine treatment emergent status, the AE will be 
considered as a treatment-emergent AE). No imputation is done to calculate AE duration.  
6.1.11.4.2 Start/End Dates for Prior/Concomitant Medication 
Partial dates of non-study medication start/end date need to be imputed in order to classify the 
medications as prior or concomitant medications, or post-treatment medication (ie, medication 
initiated after the last dose of study medication). A conservative approach will be used to handle 
the incomplete date(s) for medication start/end date (ie, if the available incomplete date(s) cannot 
determine the concomitant relationship relative to the double-blind phase, the medication is 
considered as a concomitant medication).  
6.1.11.4.3 Psychotherapy Dates /Psychiatric History Dates 
Partial dates of initial symptoms of BED, initial diagnosis of BED, and psychotherapy will be 
imputed as follows: (1) If year and month are known, and if the year or month is previous to 
Screening, use the 15th of the month; otherwise, if the month is the month of Screening, use the 
1st of the month. (2) If only year is known, and it is previous to the year of Screening, use June 
30th of that year; If only year is known and it is same as the year of Screening, use Jan 1.  This 
imputation rule will be applied to calculation of duration of initial symptoms of BED, initial 
diagnosis of BED, and psychotherapy. 
6.1.11.4.4 Lab Data 
Where applicable, the upper limit of quantification (ULOQ) will be imputed for chemistry, 
hematology, urinalysis, and urine microscopic values that are greater than the ULOQ. Similarly, 
if the value is below the lower limit of quantification (LLOQ), then the LLOQ will be imputed.  
6.2. 
Methods of Analysis  
6.2.1 General Methodology 
All statistical inference analyses will be performed with 2-sided tests at a significance level of 
0.05, and 2-sided 95% confidence intervals (CIs) will be calculated whenever appropriate. All 


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data will be summarized by treatment group and visit as appropriate. All subject data will be 
presented in data listings by subject. 
Data for unscheduled assessments will be included when deriving baseline values and the worst 
case analysis during an assessed period. Unscheduled visits will also be included in treatment 
endpoint (Week 12 LOCF), which is the last available non-missing treatment endpoint carried 
forward to Week 12. 
6.2.2 Statistical Hypotheses for Trial Objectives 
6.2.2.1 
Hypotheses for Primary Objective   
In adults with moderate to severe BED, after 12 weeks of treatment, 
 Dasotraline 6 mg/day reduces change from baseline in the number of binge days per 
week relative to placebo 
 Dasotraline 4 mg/day reduces change from baseline in the number of binge days per 
week relative to placebo  
  
6.2.2.2 
Hypotheses for Key Secondary Objectives 
In adults with moderate to severe BED, after 12 weeks of treatment, 6 mg/day dasotraline or both 
doses of dasotraline:
 Reduce change from baseline in BE-CGI-S score relative to placebo  
 Provide a greater proportion of subjects with a 4-week cessation from binge eating at 
Week 12 relative to placebo  
 Reduce change from baseline in Y-BOCS-BE total score relative to placebo 
6.2.3 Interim Analysis 
Not Applicable. 
6.2.4 Data Monitoring  
Data and Safety Monitoring Board (DSMB) meetings are planned to be held at regular intervals. 
Data to be presented to the DSMB are described in its charter.  
6.2.5 Multiple Comparisons/Multiplicity  
To control the overall type I error rate strongly at 5% for the primary and key secondary 
endpoints, for the hypotheses to be tested, a sequential testing strategy will be used. Following 
the fixed sequence closed testing procedure in Figure 1, testing will only proceed conditional on 
the statistical significance of the test(s) of prior level(s) at a 2-sided 5% significance level.  
 


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Figure 1: Fixed Sequence of Hypothesis Testing for Primary and Key Secondary Efficacy 
Endpoints 
1
H : Number of binge days per week, 
dasotraline 6 mg/day vs placebo 
α = 0.050  
↓ 
2
H : Number of binge days per week, 
dasotraline 4 mg/day vs placebo 
↓ 
3
H : BE-CGI-S score, 
dasotraline 6 mg/day vs placebo 
↓ 
4
H : Subjects with a 4-week cessation, 
dasotraline 6 mg/day vs placebo 
↓ 
5
H : Y-BOCS-BE total score, 
dasotraline 6 mg/day vs placebo 
↓ 
6
H : BE-CGI-S score, 
dasotraline 4 mg/day vs placebo 
↓ 
7
H : Subjects with a 4-week cessation, 
dasotraline 4 mg/day vs placebo 
↓ 
8
H : Y-BOCS-BE total score, 
dasotraline 4 mg/day vs placebo 
 
Denote raw p-values associated with hypotheses 
1
H  to 
8
H  as 
1p  to 
8p . Adjusted p-value of  
raw p-value of each testing hypothesis is calculated as below. 
    
 
,
1
_
1
p
p
adj 
 
    
 
8
...,
,2
),
,
max(
_
1
_



i
p
p
p
adj
i
i
adj
i
 
 


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7. 
Statistical Analyses 
All analyses and summaries will be produced using SAS® version 9.3 (or higher) for windows. 
Unless otherwise specified, continuous variables will be summarized with descriptive statistics 
including: the number of observations (n), mean, standard deviation (SD), median, range 
(minimum and maximum values). For change from baseline, 95% CI will be calculated 
whenever appropriate. All categorical data will be presented using frequency counts and 
percentages. Shift tables will be produced for some assessments that contain counts and 
percentages of subjects in each cross-classification level of baseline versus post-baseline 
assessment. The by-visit summary of continuous and categorical data will be displayed at 
protocol planned visits (weeks) and endpoint. Data for unscheduled assessments will be included 
when determining baseline values, selecting worst result for shift analyses, and for summary of 
normal/abnormal values. The listings, except for a listing for screen failures, will include all 
randomized subjects in the database. In general, the subject listings will be sorted by randomized 
treatment group, subject number and assessment visit and date (and time, if applicable). 
7.1 
Subject Information  
Unless otherwise specified, subject information will be presented by treatment group for the ITT 
population. The treatment groups will include all Dasotraline (ie, pool two dasotraline groups 
together) and overall (ie, pooled three treatment groups together).  If the safety population differs 
from the ITT population, similar descriptive statistics will be provided by treatment group, all 
Dasotraline, and overall for the safety population.  
7.1.1 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment group, and overall 
for the ITT and PP populations, respectively. 
Baseline descriptive statistics (N, mean, SD, median, and range) of demographic characteristics 
will be provided by treatment group for age at study entry (in years), body weight, height, body 
mass index (BMI, calculated as weight (kg)/ [height (m)2]), and waist circumference.  
The number and percentage of subjects in each of the following categories (and sub-categories) 
at baseline will also be summarized by treatment group: 
 Age group: <40,  ≥40 years old; 
 Gender: Male, Female;  
 Race: white, black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Islander, Other; 
 Ethnicity: Hispanic or Latino, Not Hispanic or Latino; 
 Baseline BMI category: Underweight/Normal (<25), Overweight (25 to <30), Obesity 
Class I (30 to <35), Obesity Class II (35 to <40), and Obesity Class III ( ≥ 40) kg/m2;  
 


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Baseline descriptive statistics (N, mean, SD, median, and range) of disease characteristics will be 
provided by treatment group for number of binge eating days per weeks, number of binge eating 
episodes per weeks, BE-CGI-S, and Y-BOCE-BE total score.  
The number and percentage of subjects in each of the following categories (and sub-categories) 
at baseline will also be summarized by treatment group: 
 Baseline number of binge eating days category: 3-4, > 4 to 5, >5 to 6, >6 to 7; 
 Baseline severity of BED (number of episodes/week): Mild (3), Moderate (4-7), Severe 
(8-13), Extreme (≥14) 
7.1.2 Psychiatric History  
Descriptive statistics (N, mean, SD, median, and range) of baseline disease characteristics will be 
provided by treatment group, and overall for both the ITT and PP populations for 
 Age at the first onset of initial symptoms of BED (years);  
 Duration of initial onset of initial symptoms of BED to screening (in years); 
 Age at the first onset of initial diagnosis of BED (years);  
 Duration of initial onset of initial diagnosis of BED to screening (in years); 
 the average number of binge eating days per week in the preceding six months  
 the least number of binge eating days per week in the preceding six months 
 the maximum number of binge eating days per week in the preceding six months 
 the average number of binge episodes per week in the preceding six months 
Frequency distribution of the following variables will be summarized by treatment 
 the least number of binge eating days per week in the preceding six months 
 the maximum number of binge eating days per week in the preceding six months 
 
The number and percentage of subjects in each of the following categories (and sub-categories) 
at baseline will also be summarized by treatment group 
 the average number of binge eating days per week in the preceding six months: 2 to <3, 3 
to < 4, 4 to <5, 5 to <6, and 6 to 7; 
 the average number of binge episodes per week in the preceding six months: 2 to <4, >=4 
to <=7, >7 to <14, and >=14.  
Summaries of any other current psychiatric disorders present at screening include DSM-V codes 
for the ITT and PP populations. If a subject had 1 or more history events more than once, the 
subject will be counted only once under any given DSM-V code. 
 


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7.1.2.1 
Psychiatric Family History  
The number and percentage of subjects whose biological relatives (mother, father, siblings, 
children, extended family) have/had each of pre-specified psychiatric history will be summarized 
by treatment group for both the ITT and PP populations. 
Listings of psychiatric history and psychiatric family history are provided for all randomized 
subjects. 
7.1.3 Disposition Information 
Subject disposition for all randomized subjects will be summarized by treatment group using the 
following categories: 
 Subjects who are randomized; 
 Subjects who are randomized, but not dosed; 
 Subjects in the ITT population; 
 Subjects in the Safety population; 
 Subjects in the PP population;  
 Subjects in the ITT who complete the Week 12 visit; 
 Subjects in the ITT who complete the Week 12 visit and enter into the open-label 
extension study; 
 Subjects who discontinue during the DB period. 
 
 Subjects in the withdrawal population; 
 Subjects who complete the withdrawal period; 
 Subjects who discontinue during the withdrawal period 
 
For subjects who discontinue from the study after randomization, the corresponding reasons for 
discontinuation will be summarized for DB period and withdrawal period, respectively. For 
subjects who are excluded from the PP population, the corresponding reasons will be 
summarized by treatment.  
For subjects who consented but were not randomized (eg, screen failures) the corresponding 
reasons for discontinuation will be summarized.  
Kaplan-Meier plot of the time to early discontinuation in the DB period will be presented by 
treatment group. Subjects who complete 12-weeks DB treatment period will have their time to 
treatment discontinuation censored on the study day of end of the treatment period.  
7.1.4 Treatment Compliance 
At each post-baseline (Weeks 1 − 12) visit, prior to dispensing study medication, previously 
dispensed study medication will be retrieved and assessed by tablet count.  


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Unless otherwise specified, compliance in the double-blind phase will be calculated for each 
post-baseline visit and overall as follows: 
 
 Percent compliance = (number of tablets taken / number of tablets should have taken) x 
100. 
 Number of tablets taken = number of tablets dispensed – number of tablets returned. 
 Number of tablets should have taken = (number of tablets supposed to take in a day) x 
(number of exposure days). 
 Number of exposure days = last dose date – first dose date + 1. 
 
For each post-baseline visit, if medication kit usage information is incomplete (ie, meet one of 
following conditions: any dispensed medication kit at the visit has missing number of tables 
returned, or has missing dosing start or ending date), the corresponding compliance will not be 
derived and will be set as missing.  
For an assessment period that involves multiple study visits (ie, overall double-blind treatment 
period), if at some visit(s) the drug usage information is incomplete, then the other visits with 
complete information of kit usage will be used to derive the compliance rate. Number and 
percentage of subjects with incomplete medicate kit usage information will be summarized by 
study visit and treatment group.  
Non-compliance is defined as less than 75% or more than 125% non-missing compliance with 
the study medication. Subjects with missing compliance will not be classified as non-compliant.  
Descriptive summary statistics (N, mean, median, and range) will be provided by treatment 
group and overall for percent compliance. In addition, the number and percentage of subjects in 
the categories of the following variables will also be summarized by treatment group through the 
Week 12 visit: 
 Compliant;  
 Non-compliant (<75% or >125%); 
 Non-compliant: <75%;  
 Non-complaint: >125%; 
 Complete and Incomplete medication kit usage information: complete, incomplete for 1-2 
weeks, 3-4 weeks, and > 4 weeks visit period.  
7.1.5 Extent of Exposure 
Treatment duration is defined as the amount of elapsed time between the first and the last day 
that study medication was taken (inclusive). It will be calculated (in days) in terms of the 
difference in relative study days between the last and first dose of study medication, plus one 


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day. See Section 6.1.9.2 for imputation rule if the end date of the medication intake is unknown 
or ‘confirmed’. 
Descriptive statistics (N, mean, standard deviation, median, and range) will be presented by 
treatment group for treatment duration. Number of subjects with duration in each of following 
categories: ≥ 7, ≥ 14, ≥ 21, ≥ 28, ≥ 42, ≥56, ≥70, and ≥ 83 days;1-6, 7-13, 14-20, 21-27, 28-41, 
42-55, 56-69, 70-82, and ≥ 83 days will also be presented by treatment group and overall. Return 
of the blister card at any given visit will not be a prerequisite for inclusion in exposure summary 
statistics if corresponding dose start and end dates are reported. 
Note that exposure will be shown only up through the Week 12 visit or, for subjects with 
premature discontinuation, the last day of dosing of double-blind study drug for the subject. 
7.1.6 Protocol Deviations  
Deviations from the protocol, as adjudicated by Medical Monitor review, may have an impact on 
the efficacy analysis.   
Protocol deviations that may impact on efficacy analysis include, but will not be limited to the 
following: 
 Subject received any incorrect study treatment or was not dosed in DB period 
 Overall missing diary rate in double-blind treatment period is > 5%  
 Subject does not have a baseline efficacy measurement  or at least one post-baseline 
efficacy measurement for primary efficacy variable 
 Subject was unblinded during the double-blind treatment period 
 Subject does not have 28 days or more of exposure 
 Subject that does NOT belong to  one of the following 2 cases:  
Case 1: there is no medication kit usage with incomplete information, and overall 
medication compliance is between 75% and 125%;  
Case 2: if there is 1 or 2 medication kits with incomplete usage information, overall 
medication compliance per the worst case imputation is between 75% and 125%,  
 Subject violated inclusion/exclusion criteria which have any potential impact on 
efficacy results 
 Subject took >1 dose of a prohibited medication or more than one day of a prohibited 
dose of an allowed medication or received prohibited psychotherapy during the 
double-blind treatment period, that were judged to have a potential impact on the 
primary efficacy analysis based upon blinded medical review. 


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 If the subject tests positive for substance of abuse at any post-baseline visit during the 
double-blind period (through 10 days after the Early Termination Visit for subjects 
who discontinue prematurely or for subjects who complete the study but do not 
continue into the extension study; and, through the Week 12 Visit date for subjects 
continuing into the extension study), without a verified prescription for use of a drug 
that could have caused a positive test result (confirmed by medical review) 
A complete list of subjects who met with at least one of above protocol deviation criteria, will be 
identified prior to database lock.  
Subjects in ITT population regarded as protocol deviators per above criteria will not be included 
in the PP population. A summary of all these protocol deviations will be presented by treatment 
group and overall for all randomized subjects. Subjects will be counted once within each 
deviation category, regardless of how many deviations they have in that category. A listing of 
protocol deviations will be provided for all randomized subjects. A listing will also be provided 
for subjects who take any incorrect study drug.  
In addition, regardless of potential efficacy impact, protocol deviations are collected during 
monitoring visits. Protocol deviations will be placed into the following categories: concomitant 
medications, dosing, enrollment criteria, laboratory, non-compliance, visit schedule, 
visit/procedure requirement, and other. Each instance of a protocol deviation will be reviewed 
and determined to be major or minor prior to database lock of the study.  
Number and percentage of subjects with at least one major protocol deviation of each deviation 
category will be summarized by treatment group. A listing that presents all protocol deviations 
will be also provided. 
 
7.1.7 Study Medication and Prior and Concomitant Medications 
7.1.7.1 
Prior and Concomitant Medications 
Prior (ie, medications taken before initiation) and concomitant medications (ie, medications 
taken on or after initiation of double-blind study medication that were either started prior or after 
initiation of double-blind study medication) will be coded using World Health Organization 
(WHO) Drug Dictionary and Anatomical Therapeutic Chemical (ATC) codes. 
Number and percentage of subjects taking prior and concomitant medications will be provided 
by level 3 ATC classification and preferred name by treatment group and overall. Since 
medications are coded to ATC classification by indication, preferred names may appear under 
multiple ATC classifications. Medications started after last dose of study drug will be included in 
the prior and concomitant medication listing only. 


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7.1.8 Medical History 
Events reported on the medical history page of the eCRF at the Screening visit will be coded 
according to MedDRA®. The number and percentage of subjects having each system organ class 
(SOC) and preferred term will be summarized by treatment group and overall.  
7.1.9 Psychotherapy 
A listing of CRF collected psychotherapy will be provided for all safety subjects. 
7.2 
 Efficacy  
The primary efficacy analysis will be performed based on the ITT population (Section 6.1.7) 
Assessment of the primary efficacy endpoint on the PP population will be conducted as 
supportive analyses. 
7.2.1 Analysis Specifications 
7.2.1.1 
Level of Significance 
Unless otherwise specified, all statistical tests will be interpreted at a 2-sided significance level 
of 5% and all confidence intervals (CIs) will be presented at a 2-sided confidence level of 95%.  
The overall type I error rate for testing dasotraline 6 mg/day group versus placebo and 
dasotraline 4 mg/day group versus placebo will be strongly controlled at the 5% level across the 
primary endpoint and key secondary endpoints, which is detailed in Section 6.2.5.  
7.2.2 Presentation of Analysis Result from Statistical Model 
Whenever MMRM or ANCOVA analysis are conducted, LS mean of treatment differences, 
associated 95% CIs and p-values (raw) will be generated per corresponding statistical model.  
For each efficacy variable, effect sizes for within-group and between-group are presented at each 
post-baseline visit using a same approach in Section 7.2.3.2.1.  
7.2.3 Primary Efficacy Endpoint 
7.2.3.1 
Definition 
The primary efficacy endpoint is the change from baseline in the number of binge days per week 
at Week 12. See Section 5.1.1 for details of data definition and derivation at each assessed time 
point.  


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7.2.3.2 
Analysis Methods 
7.2.3.2.1 Primary Efficacy Analysis  
The primary efficacy analyses of primary efficacy endpoint (the change from baseline in the 
number of binge days per week at Week 12) will be performed using a likelihood-based mixed 
model for repeated measures (MMRM). The response (dependent) variable is the change from 
baseline in the number of binge days per week assessed at Weeks 1, 2, 3, 4, 6, 8, 10, and 12. 
Specifically, the MMRM model includes fixed effects terms for treatment, visit (as a categorical 
variable), pooled center, baseline binge days category (stratification factor), the number of binge 
days per week at baseline, and treatment-by-visit interaction. Restricted maximum likelihood 
estimation method will be applied using unstructured covariance model. The Kenward Roger 
approximation will be used to estimate denominator degrees of freedom. In case of a failure of 
convergence with the unstructured covariance, the following structures may be assessed in a 
sequential order: heterogeneous Toeplitz, Toeplitz, and spatial exponential covariance pattern 
model. Of the above 3 covariance structures, the first covariance structure yielding convergence 
in the MMRM model will be used for the MMRM analysis. The spatial exponential model is 
selected for the analysis of data with unequally spaced time points. The LS mean treatment 
differences (each dasotraline group minus placebo group) of change from baseline at Week 12, 
their 2-sided 95% CIs, and the associated p-values will be calculated based on this model. At 
each post-baseline visit, effect size for within-group and between-group will be presented. 
Within-group effect size is calculated as mean change from baseline divided by the SD. Based on 
the MMRM, between-group effect size at a visit is calculated as the LS mean difference from 
placebo divided by the model estimate of the pooled SD at the visit, which is obtained from the 
square root of the diagonal element, associated at the visit, from the covariance matrix. 
In addition, descriptive statistics (mean, SD, 95% CI) will be provided for the number of binge 
days per week and change from baseline by study visit for each treatment group. The likelihood 
based mixed effects model can accommodate incomplete data under the assumption of ignorable 
attrition.  
The primary efficacy analysis will be repeated for the PP population to examine the impact of 
premature dropouts and/or protocol deviations.  
7.2.3.2.2 Assessment of Model Assumptions in the Primary Efficacy Analysis  
The normality and homoscedasticity assumptions underlying the primary MMRM model will be 
assessed graphically. Conditional studentized and scaled residuals will be plotted against the 
predicted values, respectively, and Q-Q (quantile-quantile) plots of these residuals versus the 
expected quantiles of the standard normal distribution will be presented to provide a graphical 
view of similarity and difference in the two distributions. Cumulative distribution function 
(CDF) of the primary endpoint will be also provided by treatment group. Considering that the 
validity of likelihood-based analyses also hinge on correct specification of the correlation 


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structure, an unstructured correlation matrix for modelling the within-patient errors is used (see 
Section 7.2.3.2.1) as a means of avoiding misspecification. However, this approach does not 
guarantee validity. If unstructured fails to converge, a more parsimonious model is likely 
necessary, but not necessarily correct; for such case, MMRM based on structures more general 
than unstructured one, ie, separate unstructured matrices by treatment, will be checked. 
If there are evidences of deviations from the model assumption(s), the degree and nature of such 
deviation(s) will be explored to better understand the potential impact on interpretation of the 
primary efficacy analysis.  
7.2.3.2.3 Supportive Analysis  
The primary efficacy endpoint will be analyzed using an analysis of covariance (ANCOVA) 
model and the LOCF approach, as a supportive analysis. The model include terms for treatment,  
pooled center, and baseline binge days category (stratification factor) as factors, and the number 
of binge days per week at baseline as covariates. The LS mean of treatment differences (each 
dasotraline group minus placebo group), their 2-sided 95% CIs, and the associated p-values will 
be obtained from the model. 
Effect sizes for within-group and between-group will be presented at each post-baseline visit. 
Within-group effect size is calculated as mean change from baseline divided by the SD. Based on 
the ANCOVA model, between-group effect size is calculated as the LS mean difference from 
placebo divided by the model estimate of the pooled SD, which is calculated as the SE of the LS 
mean difference divided by the square root of the sum of inverse treatment group sizes.   
 
7.2.3.2.4 Sensitivity Analyses  
To address early dropouts under the assumption of missing not at random (MNAR), a pattern-
mixture model (PMM) using a placebo-based multiple imputation method (Attachment 9.3.1) 
and a pattern mixture model using multiple imputations with penalties (ie, tipping point analysis 
by deflating the individually estimated treatment effect size by known factors) (Attachment 
9.3.2) will be performed as sensitivity analyses to explore the robustness of the MMRM results 
for the primary analysis based on the ITT population.   
The PMM using a placebo-based multiple imputation method is a method based on methodology 
proposed by Ratitch and O’Kelly ([5]). The assumption that efficacy profiles of dropouts after 
discontinuation are similar to those of placebo subjects is considered very conservative because 
this methodology tends to minimize the difference between each dasotraline group and placebo 
group. 
The PMM using multiple imputations with penalties by deflating the individually estimated 
treatment effect size by known factors provides a way to assess plausible deviations from MAR 
[8]. The tipping point, which is defined as the value of the factor where statistical significance of 


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treatment effect is lost, will be evaluated. If the tipping point is unrealistically high, treatment 
effect is robust. This approach will generate a serial of conservative estimates and provide the 
extent of robustness of primary efficacy result in a stepwise way. 
In case of a deviation from the assumptions required for the primary analysis (Section 7.2.3.2.2), 
to confirm the robustness of the primary analysis result, two additional sensitivity analyses, 
permutation test and Generalized Linear Mixed Model (GLMM) analysis (Attachment 9.3.3)   
will be performed. 
Permutation test is to fit a large number of datasets (ie, 10000) based on a same MMRM for the 
primary analysis with randomly assigning pseudo-treatment group designations. The empirical p-
value will be obtained from the permutation test. The non-parametric based permutation test 
provides a conservative way to assess the primary efficacy endpoint. 
GLMM analysis will fit count data over time (ie, number of binge days among number of 
assessed days at each visit period) based on a binomial distribution. This approach may better 
address the potential unequal variances assumption among subjects due to different number of 
assessed days (either because of assessment schedule, early dropout, or missing diary) among 
subjects and therefore is expected to better reflect the true distribution of the primary efficacy 
endpoint.  
7.2.3.2.5 Exploratory Analyses Related to Planned Region and Actual Region Group 
For primary efficacy variable, following exploratory analyses will be performed using the same 
predictor terms as described above (Sections 7.2.3.2.1, 7.2.3.2.3, and 7.2.3.2.4) by replacing the 
fixed term ‘pooled center’ with either the planned region or actual region group (pooled ones 
when applicable), respectively, to evaluate the impact of mis-stratification of region on treatment 
effect and further corroborate the primary efficacy result. 
 the MMRM model,  
 the ANCOVA model 
 the PMM using a placebo-based multiple imputation method,  
 the PMM using multiple imputations with penalties by deflating treatment effect size, 
 
7.2.3.2.6 Assessment of Dropout and Dropout Profiles  
To assess the impact of the drop-outs on the primary efficacy variable, a plot of cumulative 
distribution of the primary efficacy endpoint (change from baseline in number of binge days per 
week at Week 12) will be presented by treatment using the worst imputation for dropouts (i.e., 
missing value at a visit will be imputed by the most extreme increase in binge days at the visit 
per treatment group). 


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Subjects will be grouped by the visit group at which they have their last number of binge days 
per week. This will result in five categories for subjects discontinuing: Weeks 1/2 dropouts, 
Weeks 3/4 dropouts, Weeks 6/8 dropouts, Weeks 10/12 dropouts, and Completers. Specifically, 
for an example, subjects who discontinue after Week 2 visit but prior to or at Week 4 visit will 
be classified as Weeks 3/4 dropouts.  The means change from baseline in number of binge days 
per week and BE-CGI-S score over time will be plotted by dropout category for each treatment 
(prior to and including the termination visit).  
A similar plot will be generated using the grouped termination reasons defined in Table 7 as 
below.  Summaries involving dropout category and termination reason will be based on the ITT 
population. The reason of withdrawal by subject will be reviewed prior to DBL to better 
understand the sub-category it belongs (due to efficacy, due to adverse reaction, due to other). 
Table 7 Reasons for Discontinuation and Mapping for Termination Reason 
eCRF Term 
Grouped Term 
Adverse event 
Adverse event 
Lack of efficacy 
Lack of efficacy 
Lost to follow-up 
Lost to follow-up or withdrew consent 
 
Withdrawal by subject 
Non-compliance with study drug 
Non-compliance and other 
Protocol Violation 
Pregnancy 
Other 
7.2.3.2.7  Missingness of Diary Entry  
Summary statistics (ie, N, mean, median, range) of number of days with missing diary entries and 
missing diary rate (calculated as 100*the number of days with missing diary divided by the total 
number of days in the assessed visit period), as well as number and percentage of subjects of each 
missing entries category (ie, missing 1 days only, 2 days only, 3 days only,  4 days only, and >4 
days) will be summarized by visit and overall DB treatment period for each treatment. A listing 
of missing diary entry by subject will be provided as well.  
7.2.4 Key Secondary Endpoints Analyses 
7.2.4.1 
Definition 
The key secondary efficacy endpoints involved in the hypothesis testing of each dasotraline dose 
(4 mg/day and 6 mg/day) versus placebo include change from baseline at Week 12 in BE-CGI-S 
score and Y-BOCS-BE total score, and percent of subjects with a 4-week cessation from binge 
eating prior to Week 12/EOT. See Section 5.1.1.4 for details.  
 


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7.2.4.2 
Analysis Methods 
Change in BE-CGI-S score and Y-BOCS-BE total score 
Continuous key secondary variables (ie, change in BE-CGI-S score and Y-BOCS-BE total score) 
will be analyzed with an MMRM model similar to the primary efficacy analysis 
(Section 7.2.3.2.1) by adjusting the corresponding baseline. The LS mean treatment differences 
(each dasotraline group minus placebo group) of change from baseline at Week 12, their 2-sided 
95% CIs, and the associated p-values will be calculated based on the model. Effect sizes for 
within-group and between-group will be presented at each post-baseline visit using a same 
approach in Section 7.2.3.2.1. 
As a supportive analysis of the above MMRM analyses, the change from baseline in BE-CGI-S 
and Y-BOCS-BE total score at Week 12 will be analyzed using an ANCOVA model and the 
LOCF approach for the ITT population, which includes terms for treatment,  pooled center, 
baseline binge days category (stratification factor), and corresponding baseline score as 
covariate; Effect sizes for within-group and between-group will be presented at each post-
baseline visit by a similar approach described in Section 7.2.3.2.3. 
To address early dropouts or potential deviation from the model assumption(s), sensitivity 
analyses similar to Section 7.2.3.2.4, including PMM using a placebo-based multiple imputation 
method, PMM using multiple imputations with penalties by deflating the individually estimated 
treatment effect size, and permutation test may be conducted for the key secondary endpoint for 
BE-CGI-S; PMM using a placebo-based multiple imputation method  may be conducted  for 
Y-BOCS-BE total score.  
For above key secondary efficacy variables,  following exploratory analyses will be performed 
using the same predictor terms described above by replacing the fixed term ‘pooled center’ with 
the planned region or actual region group (pooled one when applicable), respectively, to evaluate 
the impact of mis-stratification of region on treatment effect and further corroborate these key 
secondary efficacy result. 
 the MMRM model  
 the PMM using a placebo-based multiple imputation method  
 the PMM using multiple imputations with penalties by deflating treatment effect size  
(for BE-CGI-S only) 
 
Percent of subjects with a 4-week cessation from binge eating 
The categorical key secondary efficacy endpoint of percent of subjects with a 4-week cessation 
from binge eating will be analyzed using a logistic regression model with treatment, baseline 
binge days category (stratification factor), and baseline number of binge days per week as 
covariate using a LOCF approach based on ITT population. The odds ratios, their 2-sided 95% 


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CIs, and the associated p-values for each dasotraline group over the placebo group will be 
derived from the model. 
As a supportive analysis, percent of subjects with a 4-week cessation from binge eating will be 
analyzed by an inverse probability weighting (IPW) model; See Attachment 9.3.4 for details 
about IPW method ([6]).   A sensitivity analysis per quasi-likelihood approach will be conducted 
by fitting same fixed terms as listed above with random-residual based on binary distribution 
with logit link, which will effectively lift the constraints of the model parameter. The above 
approach will be implemented using GLIMMIX procedure in SAS.  
 
For above logistic regression model, two exploratory analyses will be performed using same 
predictor terms with an additional fixed term of planned or actual region group (pooled one when 
applicable), respectively, to evaluate the impact of mis-stratification of region on treatment effect 
and further corroborate key secondary efficacy results. 
7.2.5 Multiplicity Adjustment  
To control the overall type I error rate strongly at 5% for the primary and key secondary 
endpoints, for the hypotheses to be tested, a sequential testing strategy will be used. Following 
the fixed sequence closed testing procedure in Figure 1, testing will only proceed conditional on 
the statistical significance of the test(s) of prior level(s) at a 2-sided 5% significance level.  See 
Section 6.2.5 for details. 
7.2.6 Other Secondary Endpoints Analyses 
7.2.6.1 
Definition 
The other secondary endpoints of interest are:  
 Change from baseline in number of binge days per week at Weeks 1, 2, 3, 4, 6, 8, and 10 
 Change from baseline in number of binge episodes per week at Weeks 1, 2, 3, 4, 6, 8, 10, 
and 12  
 Change from baseline in BE-CGI-S score at Weeks 2, 4, 6, 8, and 10 
 Change from baseline in Y-BOCS-BE total score at Weeks 2, 4, 6, 8, and 10 and subscale 
scores (obsessions and compulsions) at Weeks 2, 4, 6, 8, 10, and 12 
 Change from baseline in MADRS total score at Week 12 
 Change from baseline in HAM-A total score at Week 12 
 Change from baseline in SDS total score and subscale scores (school/work disability, 
social life disability, and family life disability) at Weeks 6 and 12 
 Proportion of binge eating responders (ie, ≥ 75% reduction in the number of binge eating 
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 Change from baseline in EDE-Q modified including EDE-Q modified global score and 
3 subscale scores (dietary restraint, shape/weight overvaluation, and body dissatisfaction) 
at Week 12 
7.2.6.2 
Analysis Methods 
The analyses of continuous variables associated with the primary efficacy endpoint and the key 
secondary endpoints (ie, the change from baseline in number of binge days per week, BE-CGI-S 
score and Y-BOCS-BE total score) have been described on Sections 7.2.3 and 7.2.4 of this SAP. 
Continuous variables related to change in number of binge episodes per week, Y-BOCS-BE 
subscale scores , and SDS-total score and subscale scores will be analyzed using an MMRM 
model similar to the primary efficacy analysis (Section 7.2.3.2.1 ) with adjusting the 
corresponding baseline; other continuous variables with one scheduled post-baseline assessment 
(ie, change in MADRS total score, HAM-A total score, EDE-QM global score and subscale 
scores) will be analyzed using an ANCOVA model similar to the supportive analysis for the 
primary efficacy endpoint (Section 7.2.3.2.3) with adjusting the corresponding baseline as a 
covariate. The treatment differences and 95% CIs for each dasotraline group relative to placebo 
in the change from baseline will be obtained from this model.  
The proportion of binge eating responders at Week 12 will be analyzed using a logistic 
regression model and LOCF approach with factors of treatment, pooled center, baseline binge 
days category (stratification factor), and baseline number of binge episodes per week as 
covariate. For subjects who are discontinued, binge eating responders at Week 12 LOCF is 
defined per the last post-baseline time period during the treatment period that binge diary is 
assessed. To ensure that the logistic regression model is feasible, pooled region may be removed 
from the analysis model if some pooled center has no responder either because there is a small 
number of subjects in the pooled center or subjects experience little change (for example, no 
subject achieving at least 75% reduction in number of binge episodes per week). In addition, for 
each dasotraline group (vs. Placebo), effect size and the number needed to treat (NNT) will be 
presented as well. The effect size will be calculated as log(odds ratio)*sqrt(3)/, where odds ratio 
is based on 2 by 2 contingency table and the NNT is derived as 1/Risk Reduction, where Risk 
Reduction (RR) = (each dasotraline response rate – placebo response rate). The 95% CI of NNT 
will be obtained similarly by using the 95% CI of the RR when both lower and upper confidence 
limits are positive. The NNT and 95% CI results will be provided in whole number format as any 
fractional values are rounded up to the nearest whole number (the lower confidence limit is 
rounded down and the upper confidence limit is rounded up.) 
As a supportive analysis, the proportion of binge eating responders for achieving 75% reduction 
over time will be analyzed, respectively, by an inverse probability weighting (IPW) Generalized 
Estimating Equations (GEE) model. See Attachment 9.3.4 ([6]) for details. 


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In addition, the number and percentage of subjects in the following categories for reduction in 
the number of binge eating episodes from baseline will be summarized by treatment and by visit: 
 cessation (defined as 100% reduction)  
 99% to 75% reduction 
 74% to 50% reduction 
 other 
At each assessment time point, for each of above continuous secondary efficacy variables, 
summary statistics (N, mean, standard deviation, median, and range) will be presented for the 
actual values and the changes from baseline. The 95% CIs of the changes from baseline will also 
be presented.  
Plots of the mean actual values as well as MMRM LS means (SE) of change in number of 
binge days over time by treatment group will be presented for the ITT and PP populations; plot 
for ANCOVA LS means (SE) of change will be also presented over time including Week 12 
LOCF endpoint. Similar plots of the key secondary endpoints such as BE-CGI-S score, 
Y-BOCS-BE total score, and number of binge episodes over time will also be provided based on 
the ITT population. 
7.2.7 Subgroup Analysis 
The primary efficacy variable (change from baseline in number of binge days per week at Week 
12) and key secondary variable (change from baseline in BE-CGI-S at Week 12) will be 
examined to explore the consistency of the treatment effect across certain subgroups listed below 
(if there are at least 45 subjects in the subgroup).  
The subgroup analysis will be conducted based on a similar MMRM model to the corresponding 
primary efficacy analysis with three additional terms: subgroup, treatment-by-subgroup 
interaction, and 3-way interaction of treatment*subgroup*visit. 
Descriptive statistics (N, mean, standard deviation), LS Means and SE, the treatment differences 
vs. placebo and 95% CIs at Week 12 from the MMRM model will be provided for each category 
of the subgroups by treatment group:  
 Gender: male or female 
 Race group: White, Non-white 
 Age group: <40,  ≥40 years old 
 Ethnicity: Hispanic, non-Hispanic 
 Baseline BMI (kg/m2): Non-obese (<30), Obese (≥30 kg/m2) 
 Baseline severity (number of episodes/week): Moderate (<=7), Severe (>7) 
P-value for treatment-by-subgroup interaction at Week 12 from the MMRM model will be 
provided. For each category of above subgroups and for overall subjects, LS mean differences 
(vs. placebo) and their 95% CIs in the change from baseline at week 12 in the number of binge 


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days/week will be plotted on a same forest plot. A similar forest plot will be provided for BE-
CGI-S as well. 
All subgroup analyses will be based on the ITT population. 
7.3 
Pharmacokinetics (PK) Analysis  
Plasma concentrations for dasotraline will be summarized at Week 2, 6, and 12 by the most 
recent dasotraline dose level for the PK population.  The descriptive statistics (n, mean, SD, 
coefficient of variation [CV%], median, range) will be provided by most recent dasotraline dose 
group.  A listing of PK concentration for all samples will be provided. 
7.4 
Safety  
7.4.1 Analysis Specifications 
Safety reporting includes all safety data reported during the 12-weeks double-blind treatment 
period, as well as the all safety data reported in post-treatment withdrawal period, if a subject 
does not enter the extension study. 
The safety data will be analyzed by treatment group based on the safety population for data up to 
the end of treatment period and on the withdrawal population for data collected during the 
withdrawal period, separately, as appropriate. Specifically, the data, which are used to assess 
physical dependence and withdrawal symptoms, will be analyzed by treatment for data collected 
in the withdrawal period based on the modified withdrawal population for AE, CSSA and DESS, 
and based on withdrawal population for MADRS and HAM-A, respectively. Unless otherwise 
specified, for continuous data collected in the treatment period, the actual value and change from 
baseline (ie, DB baseline) will be summarized by treatment and visit; for continuous data 
collected in the withdrawal period, the actual value, change from DB baseline (when applicable), 
and change from withdrawal baseline  will be summarized by treatment and visit. 
There will be no imputation of missing values for clinical laboratory test results, vital sign 
measurements, and ECG evaluations in the by-visit analyses. All analyses of safety data are 
descriptive. No inferential analyses of safety data are performed. 
7.4.2 Adverse Events 
All AEs are coded using Medical Dictionary for Regulatory Activities (MedDRA) version 18.0 
or higher. 
Treatment-Emergent Adverse Event (TEAE) 
A treatment-emergent adverse event (TEAE) is defined as an AE with a start date on or after the 
date of first dose through 7 days after study drug discontinuation (14 days for serious adverse 
events and deaths) for subjects who complete or discontinue this study but do not enter into the 
extension study), or through the last study day of the double-blind treatment period for subjects 


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continuing into the extension study (ie, subjects in safety population). AEs with a start date prior 
to initiation of double-blind study medication which are reported to have an increase in intensity, 
or which are reported to have a attribution in relationship to study medication (ie, attribution to 
possible related, probably related, related) after the initiation of double-blind study medication 
are considered as TEAEs. 
Discontinuation-emergent adverse event (DEAE) is defined as an AE with a start date after the 
last dose day of study medication through the last study visit in the withdrawal period. 
Table summary of overall AEs (and SAEs) will be limited to TEAEs and DEAEs. All AE data 
will be displayed in data listings. For sake of simplicity, hereafter TEAE is referred as AE in this 
section.  
The overall incidence (ie, number and percent of subjects with one or more AE in each category) 
of AEs, serious AEs, deaths, AEs leading to discontinuation, study drug-related AEs, serious 
study drug-related AEs, study drug-related AEs leading to discontinuation, and serious AEs 
leading to discontinuation, serious study drug-related AEs, will be summarized by treatment 
group. 
The AEs also will be summarized by system organ class (SOC) and preferred term (PT) by 
presenting the number and percentage of subjects with each AE category. The incidence of AEs 
(by preferred term, grouped by SOC, and presented by treatment group) will also be summarized 
by severity, by the relationship to study medication, by the action taken regarding the study 
medication, as well as by the outcome. If a subject has the same AE on multiple occasions, the 
highest severity (severe, moderate, mild) recorded for the event and the highest drug relationship 
(unrelated, unlikely to be related, possibly related, probably related, and definitely related) will 
be presented, respectively. The relationship to study medication will be presented by 2 
categories: related (which includes possibly related, probably related, and related, as determined 
by investigators), and not related (which includes unrelated and unlikely to be related, as 
determined by investigators). Furthermore, for AE summary by SOC and PT or PT only, the 
following combined preferred terms will be summarized as well:  
 
Insomnia: Insomnia, Initial insomnia, Middle insomnia, Terminal insomnia. 
 
Hallucination: Hallucination; Hallucination, auditory; Hallucination, gustatory; 
Hallucination, olfactory; Hallucination, synaesthetic; Hallucination, tactile; Hallucination, 
visual; Hallucinations, mixed; Hypnagogic hallucination; Hypnopompic hallucination; 
Somatic hallucination. 
A Kaplan-Meier plot of the time to the first onset of treatment emergent insomnia (combined 
term) will be presented by treatment group. Time to the first onset (in days) is defined as the 
earliest onset date of insomnia – start date of DB treatment period + 1. Subjects who do not 
experience any insomnia on or before the last dose date will be censored on the day of last dose. 


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Prevalence rate of insomnia (combined term) at a study day in the DB treatment period is defined 
as number of subjects experiencing insomnia on the day divided by number of subjects 
remaining on DB treatment period at that time point. It is notable that subjects may experience 
multiple insomnia episodes during the study. Prevalence rate over time will be presented 
graphically by treatment group. 
     AE maximum relationship  
Each AE will be classified as ‘related’, ‘not related’, and ‘not specified’. TEAEs with a missing 
AE relationship will be classified as ‘not specified’. AE summary by the relationship to the study 
medication will be based on the highest relationship within an SOC and PT. Response values will 
be ranked in order from minimum to maximum as ‘not specified’ < ‘not related’ < ‘related’. 
     AE maximum severity  
AEs with a missing severity will be classified as ‘not specified’. AE summary by the severity 
will be based on the maximum severity within an SOC and PT. Response severity values will be 
ranked in order from minimum to maximum as ‘not specified’ < ‘mild’ < ‘moderate’ < ‘severe’. 
     AE maximum action taken 
AEs with a missing action taken will be classified as ‘unknown’. AE summary by the action 
taken will be based on the maximum action taken within an SOC and PT. Response action values 
will be ranked in order from minimum to maximum as ‘not applicable’< ‘unknown’ < ‘dose 
increased’ < ‘unchanged’< ‘dose reduced’ < ’drug interrupted’< ’drug withdrawn’. 
     AE maximum outcome  
AEs with a missing outcome will be classified as ‘unknown’’. AE summary by the outcome will 
be based on the maximum outcome within an SOC and PT. Response outcome values will be 
ranked in order from minimum to maximum as ‘unknown’ < ‘recovered/resolved’ < 
‘recovered/resolved with sequelae’ < ‘recovering/resolving’ < ’not recovered/not resolved’< 
’fatal’. 
     AEs with Special Interest  
A list of preferred terms that are to be combined for the assessment of each of the pre-specified 
adverse events (including cardiovascular-related AEs, metabolic related AEs, neuropsychiatric-
related AEs, and suicide and self-injury related AEs) is provided in Attachment 9.4. These AE 
preferred terms are determined and verified by medical review of coded AE terms during BDRM 
and finalized prior to database lock.  The incidence of cardiovascular-related AEs, metabolic 
related AEs (weight-related and non-weight-related), neuropsychiatric-related AEs (including a 
defined subset of psychosis and mania-related AEs) and suicide and self-injury related AEs will 
be summarized by treatment, respectively.  


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Listings will also be generated for deaths, SAEs, and discontinuations due to AEs. All adverse 
events regardless of treatment emergent status will be provided in the AE data listing.      
Discontinuation-Emergent Adverse Event (DEAE) (ie, AEs Onset After Last Study Dose) 
All summary of DEAEs will be based on a ‘modified’ withdrawal population (see Section 6.1.7).   
The overall incidence of DEAEs, DEAEs by SOC and PT (by presenting the number and 
percentage of subjects with each AE category), and DEAEs by PT will be summarized by 
treatment group.  
In addition, incidence of DEAEs by SOC and PT will be also summarized using time intervals 
beginning with the earliest AE concurrent withdrawal duration in the withdrawal period, where 
denominators in percentage calculation for withdrawal duration intervals (in days) will be based 
on the number of subjects whose withdrawal duration are no less than the first day of the 
interval. Withdrawal duration (in days) will be derived as the last withdrawal visit date minus the 
last dose date +1 and withdrawal duration categories to be assessed are 1-7 days, 8-14 days, and 
≥ 15 days.  
7.4.3  Laboratory Measurements 
Laboratory data will be summarized for each laboratory test listed in Attachment 9.5.1. 
7.4.3.1 
Treatment Period 
Descriptive statistics (N, mean, standard deviation, median, and range) will be reported for each 
continuous laboratory analyte at baseline, each scheduled post-baseline time point, and endpoint 
for observed value as well as change from baseline. Categorical results (eg, urinalysis tests) will 
be summarized at each visit by treatment group using frequency and percentage. If a subject has 
more than one measurement at any time point, the one closest to the scheduled visit will be used 
in the by-visit analysis. All lab values will be presented in the data listings. 
Results for glucose and lipid tests (HDL cholesterol, LDL cholesterol, total cholesterol, and 
triglycerides) will be presented separately by fasting status, which includes fasting only and 
overall (fasting, non-fasting, or unknown).  The change from baseline value at endpoint for these 
selected laboratory parameters (ie, lipid tests, glucose, HbA1c, and insulin), will be evaluated 
using a nonparametric rank ANCOVA.  For the comparison of each dasotraline group versus 
placebo group, the change from baseline at endpoint and baseline value is ranked.  A linear 
regression will be conducted on the change from baseline ranks and baseline value rank as 
independent variable to produce regression residuals. Using the values of the residuals as scores, 
Mantel-Haenszel row mean score tests will be produced for each dasotraline group versus 
placebo group. 
In addition, the change from baseline value at Weeks 6, 12, and endpoint for these selected 
laboratory parameters (ie, lipid tests, glucose, HbA1c, and insulin), will be further evaluated 


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using an ANCOVA model which includes terms for treatment, baseline binge days group, and 
the corresponding baseline as covariate. The LS means of treatment differences (each dasotraline 
group minus placebo group) and 2-sided 95% CIs will be obtained from the model. 
The normal reference ranges for laboratory tests will be used to determine whether the laboratory 
test value is below, within, or above the normal range. Shifts from baseline to endpoint will be 
produced by treatment group to show the percentage of subjects with laboratory test values 
below, within, and above the normal range. 
Criteria for Markedly Abnormal Post-baseline Laboratory Values (MAPLV) per International 
System of Units (SI) of selected laboratory parameters can be found in Table 8. Equivalent 
MAPLV criteria for conventional unit are provided in Attachment 9.5.2.   The criterion of 
MAPLV is satisfied if a value falls into the markedly abnormal range at an assessed visit  or if 
subjects have experienced at least once MAPLV in the study period. The number and percentage 
of subjects with a particular MAPLV at each post-baseline visit, endpoint, and during the post-
baseline double-blind phase (up to and including endpoint), regardless of baseline value, will be 
presented by treatment group. 
Table 8  Criteria for Markedly Abnormal Post-baseline Laboratory Values (MAPLV)  
(SI Unit) 
Laboratory Test 
Criteria for Markedly Abnormal Status 
Low 
High 
Hematology 
Hematocrit 
Male: ≤ 0.37 
Female: ≤ 0.32 
Male: ≥ 0.60 
Female: ≥ 0.54 
Hemoglobin 
Male: ≤ 115 g/L 
Female: ≤ 95 g/L 
Male: ≥ 190 g/L 
Female: ≥ 175 g/L 
RBC 
≤ 3.5 x1012/L 
≥ 6.4 x 1012/L 
Total WBC Count 
≤ 2.8 x109/L 
≥ 16 x109/L 
Basophils 
N/A 
≥ 10 % 
≥ 1.6 x109/L 
Eosinophils 
N/A 
≥ 10 % 
≥ 1.6 x109/L 
Lymphocytes 
N/A 
≥ 75 % 
≥ 12.0 x109/L 
Monocytes 
N/A 
≥ 15 % 
≥ 2.4 x109/L 
Neutrophils 
≤ 15 % 
≤ 0.42 x109/L 
≥ 85 % 
≥ 13.6 x109/L 
Platelet Count 
≤ 75 x109/L 
≥ 700 x109/L 
Chemistry  
Albumin 
≤ 25 g/L 
N/A 
ALP 
N/A 
≥ 3 x ULN 
AST 
N/A 
≥ 3 x ULN 


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Laboratory Test 
Criteria for Markedly Abnormal Status 
Low 
High 
ALT 
N/A 
≥ 3 x ULN 
Bicarbonate 
≤ 16 mmol/L 
≥ 35 mmol/L 
Calcium 
≤ 2.05 mmol/L 
≥ 2.99 mmol/L 
Chloride 
≤ 90 mmol/L 
≥ 118 mmol/L 
Creatinine 
N/A 
≥ 176.8 µmol/L 
Glucose (fasting) 
 
≤ 2.22 mmol/L 
≥ 9.71 mmol/L 
Inorganic Phosphorus 
≤ 0.5 mmol/L 
≥ 1.7 mmol/L 
Magnesium 
≤ 0.6 mmol/L 
≥ 1.15 mmol/L 
Potassium 
≤ 3 mmol/L 
≥ 6 mmol/L 
Sodium 
≤ 126 mmol/L 
≥ 156 mmol/L 
Total Bilirubin 
N/A 
≥ 34.2 µmol/L 
Total Protein 
≤ 45 g/L 
≥ 100 g/L 
Uric Acid 
Male: N/A 
Female: N/A 
Male: ≥ 625 µmol/L 
Female: ≥ 506 µmol/L 
Urea (BUN) 
 
N/A 
≥ 11 mmol/L 
Lipids panel 
    Total Cholesterol (fasting) 
N/A 
≥7.77 mmol/L  
    LDL Cholesterol (fasting) 
N/A 
≥5.18 mmol/L  
    HDL (fasting) 
  1.036 mmol/L 
N/A 
    Triglycerides (fasting) 
N/A 
≥ 3.39 mmol/L  
 
 
 
 HbA1c 
N/A 
≥ 7.5% 
 
 
 
Urinalysis  
    Urine Blood 
N/A 
≥ 1+ 
    Urine Glucose 
N/A 
≥ 3+ 
    Urine Ketones 
N/A 
≥ 2+ 
    Urine Protein 
N/A 
≥ 2+ 
Note:  ULN = Upper Limit of Normal; N/A = Not Applicable 
A listing of subject data for those who have experienced at least once post-baseline MAPLV 
during the double-blind treatment period will be generated. Urine drug screen results will be 
presented for each parameter by visit and at endpoint. Number and percentage of positive and 
negative results will be displayed. Summary statistics of laboratory outputs will be generated per 
conventional units and International System of Units (SI), separately. 
7.4.3.2 
Withdrawal Period 
Laboratory data will be summarized by presenting descriptive statistics of actual values, change 
from baseline, and changes from withdrawal baseline by visit and treatment. 


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7.4.4  ECG Evaluations 
As a part of each ECG, heart rate (HR), axis, and the following intervals will be measured:  RR, 
PR, QRS, and QT. Corrected QT intervals (QTcB and QTcF) values are based on the following 
formula: 
 
Bazett: QTcB (msec) = QT (msec) / (RR/1000)1/2 
 
Fridericia: QTcF (msec) = QT (msec) / (RR/1000)1/3  
where RR will be reported in milliseconds (msec). 
7.4.4.1 
Treatment Period 
Descriptive statistics (eg, mean, SD, median, range) for observed value and change from baseline 
values by visit and endpoint will be displayed for continuous variables (ie, HR, QRS, QTcF, etc). 
In addition, 95% CIs of the mean change from baseline value will be provided for post-baseline 
visits. 
The overall ECG assessment is conducted by central reading and a determination is made 
whether the reading is normal (or absent if applicable) or abnormal). Shifts from baseline to post-
baseline visit and endpoint will be produced by treatment group. 
Bazett and Fridericia corrected QTc values will be classified as having QTc prolongation 
according to Table 9. 
Table 9: – QTc Prolongation  
QTc Prolongation 
> 450 msec for males 
> 470 msec for females 
> 480 msec  
> 500 msec 
Increase from baseline QTc ≥ 30 msec
Increase from baseline QTc ≥ 60 msec 
 
The number and percentage of subjects having a QTc prolongation using any of the two 
correction methods (Bazett, Fridericia) by baseline, post-baseline visits, endpoint, and any post-
baseline measurement (ie, the worst case in DB period) will be summarized by treatment group. 
A listing of ECG data for subjects with at least one prolonged QTc will also be produced. 
For other ECG parameters, subjects are classified as normal or abnormal using the limits 
specified in Table 10. For abnormal ECG parameter reporting, counts and percentages of 
subjects will be presented for baseline, each post-baseline visit, endpoint, and any post-baseline 
DB visit (the worst case) by treatment group. 
Table 10: – Definition of Abnormal ECG Values by Parameter 
 ECG parameter 
Abnormally Low 
Abnormally High 


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(unit) 
HR (bpm) 
≤50  
 
≥100 
PR interval (msec) 
N/A 
≥210  
QRS interval (msec) 
N/A 
≥120  
QT interval (msec) 
N/A 
> 500  
Note:  N/A = Not Applicable 
7.4.4.2 
Withdrawal Period 
ECG data will be summarized by presenting descriptive statistics of observed values, change 
from baseline, and changes from withdrawal baseline by visit and treatment. 
7.4.5 Vital Signs, Weight, and BMI 
7.4.5.1 
Treatment Period 
At each visit and endpoint, descriptive statistics (mean, SD etc.) will be provided by treatment 
group for 
 Observed and change from baseline values of each vital sign parameter, including 
orthostatic changes in systolic blood pressure, diastolic blood pressure, and pulse rate; 
 Observed and change, and percent change from baseline values in weight and BMI.  
A similar MMRM model for the primary efficacy variable by using corresponding baseline will 
be applied for the following variables at the specified time points. 
 Change and percent change from baseline in body weight (kg) at Weeks 1, 2, 3, 4, 6, 8, 
10, and 12. 
 Change and percent change from baseline in BMI at Weeks 1, 2, 3, 4, 6, 8, 10, and 12. 
The number and percentage of subjects with Markedly Abnormal Post-baseline Vital Signs 
(MAPVS), defined in Table 11.1, will be presented by visit, endpoint, or study period and by 
treatment group. Included are subjects having experienced at least once post-baseline MAPVS 
during the double-blind phase, up to and including endpoint. 
Table 11.1: – Criteria for Markedly Abnormal Post-Baseline Vital Signs and Weight  
Parameter (unit) 
Markedly Low 
Markedly High 
SBP (supine, standing) 
(mmHg) 
<90 
≥180 
Value ≤ 90 and ≥ 20 decrease from 
baseline 
Value ≥ 180 and ≥ 20 increase 
from baseline 
DBP (supine, standing) 
(mmHg) 
<50 
≥105 
Value ≤ 50 and ≥ 15 decrease from 
baseline 
Value ≥ 105 and ≥ 15 increase 
from baseline 
Pulse rate (supine, 
standing) (bpm) 
<50 
≥120 
Value ≤ 50 and ≥ 15 decrease from 
≥120 and increased >15 from 


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baseline 
baseline  
 
Weight (kg) 
≥ 7% decrease from baseline  
≥ 7% increase from baseline  
Temperature (˚C) 
N/A 
Value ≥ 38.3°C and ≥0.8°C  
increase from baseline 
Orthostatic Criteria 
SBP orthostatic criteria 
(mmHg) 
≥ 20 mmHg reduction from supine to 
standing position  
N/A 
DBP orthostatic criteria 
(mmHg) 
 ≥ 10 mmHg reduction from supine 
to standing position  
N/A 
Orthostatic tachycardia 
(bpm) 
 
N/A 
≥ 20 bpm increase from supine to 
standing position in pulse rate  
. 
BMI measurements will be used to classify a subject’s weight status as underweight, normal, 
overweight or obese using Table 11.2 (Category 1) and as underweight/normal, overweight, 
obesity class I, obesity class II, and obesity class III using Table 11.3 (Category 2). Shifts from 
Baseline to Week 12 Endpoint will be produced by treatment group for the number and 
percentage of subjects that fall into each BMI category. In addition, the number and percentage 
of subjects with 3%, 5%, 7%, and 10% reduction in body weight will be presented by visit and 
treatment group for overall safety population as well as by baseline BMI groups (Category 2).           
Table 11.2: – BMI Weight Status Category 1 
BMI (kg/m2) 
Weight Status 
< 18.5 
Underweight
18.5 ≤  BMI < 25.0 
Normal
25.0 ≤ BMI < 30 
Overweight
≥ 30.0  
Obese
 
Table 11.3: – BMI Weight Status Category 2 
BMI (kg/m2) 
Weight Status 
BMI < 25 
Underweight/ Normal
25 ≤ BMI < 30 
Overweight
30  ≤ BMI < 35 
Obesity Class I
35  ≤ BMI < 40 
Obesity Class II
40  ≤ BMI  
Obesity Class III
 
A listing of subject data for those who satisfy MAPVS at least once post-baseline visit in the 
double-blind treatment period will be presented.  


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7.4.5.2 
Withdrawal Period 
Vital sign data will be summarized by presenting descriptive statistics of observed values, 
change from baseline, and changes from withdrawal baseline by visit and treatment. 
7.4.6 Assessments of Withdrawal Effects (CSSA, DESS, HAM-A, and MADRS) 
CSSA total score, DESS total score, MADRS total score, and HAM-A total score will be 
summarized by presenting descriptive statistics (N, mean, median, and range) of observed values 
and change from withdrawal baseline by treatment and visit (ie, both clinic and non-clinic visits) 
for the withdrawal period. 
A similar analysis will be performed by gender as well. 
7.4.7 Columbia Suicide Severity Rating Scale (C-SSRS) 
According to FDA draft guidance for suicidal ideation and behavior ([7]), the following C-SSRS 
outcomes, which have binary responses (yes/no), will be re-ordered and numbered to facilitate 
the further definitions of the composite endpoint and comparative endpoint of C-SSRS as below. 
Category 1 – Wish to be Dead 
Category 2 – Non-specific Active Suicidal Thoughts 
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Category 5 – Active Suicidal Ideation with Specific Plan and Intent 
 
Category 6 – Preparatory Acts or Behavior 
Category 7 – Aborted Attempt 
Category 8 – Interrupted Attempt 
Category 9 – Actual Attempt  
Category 10 – Completed Suicide 
Category 11– Self-injurious behavior without suicidal intent 
Unless otherwise specified, C-SSRS table outputs will be presented by treatment for following 
analysis time points: lifetime (when applicable), baseline, any post-baseline in DB period, and 
any post-withdrawal Baseline. Definitions of these analysis time points are given in Table 12. 
The analysis time point is applied to suicidal ideation score and ideation intensity total score. 
Table 12: Definition of Analysis Timepoint 
Analysis Timepoints 
eCRF Visit(s) Used 
C-SSRS Version 
Derivation Rule 
Baseline 
Screening 
 
1 month prior to 
screening 
Most severe value  
Baseline 
Since last visit 


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Any post-baseline in DB 
period 
Post-baseline visits 
up to and including 
Week 12/EOT  
Since last visit 
Most severe value  
Any post- withdrawal 
Baseline visit 
Post-withdrawal 
baseline visits up to 
and including 
Week15/EOS 
Since last visit 
Most severe value 
 
At each analysis time points, the following binary variables will be derived. 
 Any Suicidal Ideation (Categories 1-5) 
 Any Suicidal Behavior (Categories 6-10) 
 Any Suicidality (Categories 1-10) 
 Individual Item for Category 6-11, respectively. 
 
Comparative endpoints for ‘Emergence’ (outcomes that include events that first emerge) and 
‘Worsen’ (outcomes that include events that worsen) will be derived as below. See Table 13.  
Table 13: Comparative Endpoint of C-SSRS in DB Treatment Period 
Comparative Endpoints  
(Relative to DB Baseline) 
Derivation Rule  
Emergence of Suicidal Ideation 
No suicidal ideation at Baseline, and any type of suicidal ideation 
in any post-baseline in DB period 
Emergence of Serious Suicidal Ideation 
No suicidal ideation at baseline, and any serious suicidal ideation 
[ideation score of 4 or 5] in any post-baseline in DB period 
Emergence of Suicidal Behavior  
No suicidal behavior at baseline, and any type of suicidal behavior 
in any post-baseline in DB period 
Emergence of Suicidality 
No suicidality at baseline, and any suicidality in any post-baseline 
in DB period 
Worsening of Suicidal Ideation 
Most severe suicidal ideation in any post-baseline in DB period is 
more severe than the most severe value at baseline  
7.4.7.1 
Treatment Period 
The number and percentage of subjects with following categories will be summarized by 
treatment for lifetime, baseline and any post-baseline in DB period, respectively. 
 each type of suicidal ideation,  
 any suicidal ideation,  
 each type of suicidal behavior, 
 any suicidal behavior,  
 any having self-injurious behavior without suicidal intent, 
 any suicidality 
 


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At any post-baseline visit in DB period, comparisons between each dasotraline group and 
placebo group for suicidality will be conducted using Fisher’s exact test. 
In addition, the number and percentage of subjects with following categories will also be 
summarized by treatment for any post-baseline in DB period. 
 emergence of suicidal ideation,  
 emergence of serious suicidal ideation,  
 worsening of suicidal ideation,  
 emergence of suicidal behavior, 
 emergence of suicidality 
Shift from baseline to any post-baseline in DB period in suicidal ideation score will be presented 
by treatment to show the percentage of subjects with values 0 (’No ideation present’) to 5 
(’Active ideation with plan and intent’).  Descriptive statistics (N, mean, standard deviation, 
median, and range) will be reported for Ideation intensity total score at baseline, each scheduled 
post-baseline time point, and endpoint for observed value as well as change from baseline. Data 
collected on actual suicide attempts (lethality of actual attempts and potential lethality of 
attempts) will be presented in a data listing.  
All summaries pertaining to the C-SSRS will be based on subjects in the safety population. 
7.4.7.2 
Withdrawal Period 
The number and percentage of subjects with following categories will be summarized by 
treatment for any post-withdrawal baseline for withdrawal population.  
 each type of suicidal ideation,  
 any suicidal ideation,  
 each type of suicidal behavior, 
 any suicidal behavior,  
 any having self-injurious behavior without suicidal intent, 
 any suicidality 
7.4.8 Other Safety Assessments 
7.4.8.1 
Breath Alcohol Test 
The number and percentage of subjects at each assessment (negative/positive) will be 
summarized at each visit by treatment group. 
7.4.8.2 
Neurological Examination 
Frequency distribution of each category of assessment (ie, Cranial Nerves, Motor System, 
sensory System, Reflexes, Coordination, Gait and Rhomberg’s test) will be summarized by 


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treatment at each visit. A shift table of each assessment for baseline to the worst case during 
treatment period will also be presented by treatment.  
7.4.8.3 
Abuse Potential Monitoring Plan (APMP) 
The Abuse Potential Monitoring Plan (APMP) for dasotraline has been designed to detect 
potential abuse of the compound and to more closely monitor AEs consistent with the 
pharmacology. The plan detects irregularities in the handling of dasotraline in clinical trials and 
identifies the misuse of dasotraline or other psychoactive substances. Moreover, the APMP 
provides a process by which events subject to additional monitoring are identified, processed, 
and reviewed. Events subject to additional monitoring are identified based on the pharmacology 
of dasotraline, as well as adverse event profiles of compounds with similar mechanisms of 
action. 
APMP results will be provided by sites before DBL and provided in a listing. 
7.4.8.3.1 Medication Handling Irregularities 
Medication handling irregularities will be summarized using the following categories: 
 Drug accounting errors, not involving suspected abuse or diversion by subject 
 Non-compliance with study procedures, not involving suspected abuse or diversion by 
subject 
 Other cases not involving suspected abuse or diversion by subject 
 Suspected or known abuse or diversion of study drug 
 Suspected abuse (nonmedical use) of alcohol, illicit substances, OTC drugs or 
prescription drugs obtained outside the study protocol 
Instances that meet the threshold criteria for a medication handling irregularity will be 
summarized descriptively. Both the number of instances and the number (%) of subjects 
experiencing medical drug irregularities will be provided for each category and by treatment. 
Instances of medication handling irregularity will be listed for all randomized subjects. 
7.4.8.3.2 Events Subject to Additional Monitoring (ESAMs) 
In addition to monitoring for irregularities in medication handling, AEs that may be suggestive 
of a developing abuse potential, will receive special attention. The adverse experiences or related 
signs and symptoms that will require additional monitoring (ESAMs) are listed in Attachment 
9.6. AEs identified as ESAMs will be summarized by ESAM type and PT by treatment for safety 
population (treatment period) and withdrawal population (withdrawal period), respectively.  
ESAMs will also be listed for all randomized subjects. 
 


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