Clinical trial NCT02684279
Conditions: Binge Eating Disorder
Sponsor: Sumitomo Pharma America, Inc.
Start date: 2016-02-29; Completion date: 2019-06-24
Enrollment: 533 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Binge Eating Disorder Extension Study.

Detailed description:
This is a Phase 3, 12 month, multicenter, open-label, flexibly-dosed, safety study in adults with Binge Eating Disorder.

Arms: arm 1: 4, 6, 8 mg flexibly dosed
Interventions: intervention 1: Dasotraline
Intervention descriptions: intervention 1: Dasotraline 4, 6, 8 mg flexibly dosed once daily

Protocol documents:
Prot_000.pdf: 
 
Title page
 
 
DASOTRALINE (SEP-225289) 
 
Protocol SEP360-322 
 
An Open-label, Flexibly-dosed, Multicenter, Extension Study of 
Dasotraline to Evaluate Long-term Safety and Tolerability in Adults 
with Binge-eating Disorder 
 
IND No. 125,078 
 
Version 4.00 
Incorporates Amendment 3.00 
13 Jun 2017 
 
 
SUNOVION PHARMACEUTICALS INC. 
84 Waterford Drive 
Marlborough, MA 01752, USA 
(508) 481-6700 
 
CONFIDENTIALITY STATEMENT 
This document contains information confidential and/or of proprietary interest to Sumitomo 
Dainippon Pharma Co. Ltd. and/or Sunovion Pharmaceuticals Inc. (including their 
predecessors, subsidiaries or affiliates). The information cannot be disclosed to any third party 
or 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. 


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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 (SEP-225289) 
Title of Study: An Open-label, Flexibly-dosed, Multicenter, Extension Study of Dasotraline to 
Evaluate Long-term Safety and Tolerability in Adults with Binge-eating Disorder 
Proposed Indication: Binge-eating Disorder 
Study Centers: ~ 61 clinical sites in the United States 
Planned Study Period: 35 months 
Study Objectives: 
Primary: To evaluate the long-term safety and tolerability of flexibly-dosed dasotraline (4, 6, or 
8 mg/day) in adults with binge-eating disorder (BED) who have completed a prior dasotraline study in 
BED by: 
•
The incidence of adverse events (AEs), discontinuations due to AEs, and serious AEs
(SAEs)
•
The frequency and severity of suicidal ideation and suicidal behavior using the
Columbia - Suicide Severity Rating Scale (C-SSRS)
•
Changes in 12-lead electrocardiograms (ECGs), vital signs, body weight, body mass index
(BMI), and clinical laboratory results
Secondary: 
•
To assess potential withdrawal effects of dasotraline 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 Hamilton Anxiety Rating Scale (HAM-A)
− 
Symptoms of depression utilizing the Montgomery-Asberg Depression Rating Scale
(MADRS) 
•
To assess the abuse potential of dasotraline utilizing a comprehensive abuse potential
monitoring plan (APMP)
•
To evaluate the long-term effectiveness of flexibly-dosed dasotraline in the treatment of
adults with BED as measured by the following:
− 
Eating Disorder Examination Questionnaire (EDE-Q) modified
− 
Binge-eating Clinical Global Impressions - Severity (BE-CGI-S)


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− 
Sheehan Disability Scale (SDS) 
• 
To assess subject-reported health status using the Medical Outcomes Study 12-Item Short 
Form Survey Instrument (SF-12)1 
Study Design: This is a Phase 3, 12-month, multicenter, open-label, flexibly-dosed, safety study in 
adults with BED. This study is projected to enroll approximately 500 subjects based on the number of 
subjects expected to complete treatment in the core studies (ie, SEP360-221 or SEP360-321). 
Informed consent will be obtained from all subjects after all procedures from the core study have been 
completed and before any study procedures unique to this study are performed. Safety and tolerability 
will be monitored throughout the study by AE reports, physical and neurological examinations, 12-lead 
ECG, vital signs, body weight, BMI, clinical laboratories (hematology, chemistry, urinalysis, 
hemoglobin A1c, and lipid panel), and C-SSRS. Effectiveness will be evaluated using the BE-CGI-S, 
EDE-Q modified, and SDS. Subject-reported health status will be assessed using the SF-12 (subjects 
from Study SEP360-221 only). Assessment of potential withdrawal effects of dasotraline 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. 
A comprehensive Abuse Potential Monitoring Plan (APMP; see Section 24) 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 including data on 
adverse events (AEs) and serious adverse events (SAEs) at regular intervals. 
Subjects will self-administer study drug on an outpatient basis for 12 months, once a day at 
approximately the same time each morning with or without food, including on the days when clinic 
visits occur. Subjects meeting all inclusion and no exclusion criteria will start taking open-label study 
drug on Day 1, the morning following the OL Baseline visit (ie, Week 12 visit in the core study).  
The total daily dose will remain between 4 mg/day and 8 mg/day for the 12-month treatment period. 
Dasotraline will be dosed at 4 mg/day for the first 2 weeks of the study. At the Week 2 visit, the dose 
may be increased to 6 mg/day. Thereafter the dose may be increased or decreased by 2 mg/day, as 
necessary for effectiveness or tolerability reasons at the discretion of the investigator. A minimum of 
8 days is required between dose increases. Dose decreases may be made at less than 8 day intervals, at 
the investigator’s discretion, for reasons of safety or tolerability. If, in the judgment of the investigator, 
the subject does not tolerate the minimum required dose (4 mg/day), he or she will be discontinued 
from the study. 
All changes in study drug dose will begin the morning after the visit at which the dose change decision 
is made and using the new package of study drug. 
The study will consist of a baseline visit, 12-month open-label treatment period, and 3-week study drug 
withdrawal period as shown in the Study Schematic (Figure 1). During the treatment period, subjects 
will return to the clinic at the end of 2 and 4 weeks for clinical evaluation and thereafter will return to 
the clinic once every 4 weeks during the treatment period for scheduled visits. At the approximate 
midpoint between the scheduled monthly visits (ie, 14 ± 2 days after a visit), the site staff will contact 
the subject via telephone, text, or email in order to monitor for SAEs, AEs, and concomitant 
medications, as well as to remind subjects about adherence to study drug administration, and upcoming 
visits. If necessary, an unscheduled visit can be arranged. 
                                                     
 
 
1 SF-12 collected only for subjects enrolling in this study after completing core Study SEP360-221. 


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Subjects will attend weekly visits during the 3-week study drug withdrawal period. Assessment of 
potential withdrawal effects will be conducted via administration of the CSSA, DESS, HAM-A, and 
MADRS at the end of treatment. Subjects will undergo assessments every other day and weekly as 
follows: the CSSA and DESS will be completed every other day during the 3-week study medication 
withdrawal period. Clinical site staff will call the subject every other day, beginning the second day 
after the last dose of study drug, unless a clinic visit is scheduled for that day. Phone contacts may be 
made up to 3 times per day if the clinical site staff is 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 missed CSSA and DESS, in addition to the current day’s CSSA and 
DESS, as necessary. Clinical site staff will record the responses in the subject’s source information and 
in the CRF with the contact date and time. The CSSA, DESS, HAM-A, and MADRS also will be 
administered at each weekly visit during the withdrawal period. 
A window of ± 1 day will be allowed for each weekly clinic visit and telephone call during the study 
medication withdrawal period. 
After the last withdrawal period visit, all subjects will be referred for follow-up care as determined by 
the investigator. 
Number of Subjects (planned): This study is projected to enroll approximately 500 subjects based on 
the number of subjects expected to complete treatment in the core studies. 
Diagnosis and Main Criteria for Subject Inclusion: 
Inclusion Criteria: 
1. Completion of the treatment period of a dasotraline core study (ie, SEP360-221 or 
SEP360-321) for the treatment of BED. 
2. Subject has agreed to participate by providing written informed consent and is willing and able 
to comply with the protocol, in the opinion of the investigator. 
3. Subject has not taken any medication other than the study drug for the purpose of controlling 
BED symptoms during the core study. 
4. Female subject must have a negative urine pregnancy test at open-label (OL) Baseline; 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. 
5. 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 22, Appendix III) 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. 
6. Subject is judged by the investigator to be suitable for participation in a 12-month clinical trial 
involving open-label dasotraline treatment. 
7. Subject can read well enough to understand the informed consent form and other subject 
materials. 
Exclusion Criteria: 
1. Subject is considered by the investigator to be at imminent risk of suicide, injury to self or to 
others, or damage to property. 
2. Subject is considered a suicide risk in the investigator’s opinion or has any previous history of 
suicide attempt within the past 12 months. 
3. 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 


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the C-SSRS assessment at OL Baseline. Subjects who answer “yes” to this question must be 
referred to the Investigator for follow-up evaluation. 
4. Subject has a clinically significant abnormality including physical examination, vital signs, 
ECG, or laboratory tests that the investigator in consultation with the medical monitor 
considers to be inappropriate to allow participation in the study.  
5. Subject has a positive urine drug screen (UDS) or breath alcohol test at OL Baseline. 
6. Subject is breastfeeding. 
7. Subject is at high risk of non-compliance in the investigator’s opinion. 
Investigational Product, Dosage and Mode of Administration:  
Dasotraline 4 mg, 6 mg, and 8 mg capsules for oral administration will be supplied. Based on the 
flexible dosing schedule, 1 capsule of dasotraline 4 mg, 6 mg, or 8 mg will be taken once daily, at 
approximately the same time each morning with or without for food. Following the initial 2 weeks at 
4 mg, subjects will be flexibly dosed at 4, 6, or 8 mg/day for the duration of the study. 
Dose schedule and adjustment are described above under Study Design. 
Duration of Treatment: 12 months 
Reference Therapy, Dosage and Mode of Administration: Not applicable 
Concomitant Medications: 
Use of certain medications, including but not limited to the following, is prohibited throughout the 
study from open-label baseline through the 3-week study medication withdrawal period: 
• 
psychostimulants  
• 
any medications for the treatment of binge eating or other eating disorders, obesity, or 
weight gain 
• 
antidepressant medications (eg, bupropion, SSRI/SNRI, Monoamine oxidase [MAO] 
inhibitor, tricyclic) and St. John’s Wort 
• 
medications that are CYP2B6 substrates or inhibitors or inducers of CYP2B6, eg, 
bupropion, cyclophosphamide, carbamazepine, etc (see Section 23, Appendix IV) 
• 
medications for the treatment of attention deficit hyperactivity disorder (ADHD) 
• corticosteroids except as noted in Section 10.3.3 and anabolic steroids 
• 
antiepileptic medications 
• 
benzodiazepines except for sleep or anxiety 
• 
mood stabilizers (eg, lithium, anticonvulsants) 
• 
antipsychotic medications 
• 
suvorexant 
• 
any medication that can result in either weight gain or weight loss (eg, insulin, liraglutide, 
diphenhydramine except topical formulations, etc) including over-the-counter and herbal 
products 
Use of concomitant medications permitted during the study include, but are not limited to, sleep aids 
(with some restrictions), anxiety (with some restrictions), oral contraceptives, and limited use of 


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opiates. 
Other Restrictions: Participation in non-pharmacologic therapy such as supportive psychotherapy, 
cognitive behavioral therapy or interpersonal therapy is permitted and should be documented by the 
investigator, to the extent possible. Any participation in a formal weight loss program such as Weight 
Watchers® is prohibited throughout the study. 
See Section 10.3 for complete information on concomitant medications and therapies permitted during 
the study. 
Study Endpoints: 
Safety Endpoints: 
• 
The incidence of overall AEs, serious AEs (SAEs), and AEs (or SAEs) leading to 
discontinuation 
• 
Clinical laboratory evaluations (serum chemistry, hematology, urinalysis) 
• 
Clinical evaluations (vital signs including orthostatic effects, and 12-lead ECGs) 
• 
Frequency and severity of suicidal ideation and suicidal behavior using the C-SSRS 
• 
Change and percent change in body weight and BMI 
• 
Change in fasting lipid panel (triglycerides, total cholesterol, high-density lipoprotein 
[HDL] cholesterol, and low-density lipoprotein [LDL] cholesterol) 
• 
Change in hemoglobin A1c levels 
• 
Change in fasting glucose levels 
• 
Change in the symptoms of withdrawal from dasotraline from Week 52/EOT as measured 
by: 
− 
CSSA total score at Weeks 53, 54, and 55 
− 
DESS total score at Weeks 53, 54, and 55 
− 
HAM-A total score at Weeks 53, 54, and 55 
− 
MADRS total score at Weeks 53, 54, and 55 
Effectiveness Endpoints:  
• 
Change in EDE-Q modified global score and subscale scores (restraint, shape concern, 
weight concern), and Items 4-6 scores 
• 
Change in BE-CGI-S score 
• 
Change in SDS total score and subscale scores (school/work disability, social life 
disability, and family life disability) 


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Subject-reported Health Status Endpoints: 
• 
Change in SF-12 two component scores (physical component, mental health component)2 
Statistical Methods: 
The safety population will include all subjects who receive at least one dose of study medication. A 
total of 2 analysis groups will be formed based on a subject’s previous participation in the core study 
(previously randomized to dasotraline, previously randomized to placebo). A group that combines 
these 2 analysis groups also will be presented. Summary tables, wherever applicable, will be presented 
by analysis group, respectively. Where changes are reported, the reference will be to the pretreatment 
baseline from the core study, and indicated as “DB baseline”. Where relevant, changes from baseline 
for the open-label study, defined as the Week 12 assessment in the double-blind study or the last 
assessment prior to the first dose of study medication in the open-label study, will also be reported, and 
will be referred to as the open-label study baseline or "OL baseline." Continuous variables will be 
summarized using descriptive statistics (N, mean, standard deviation, median, range, 95% confidence 
interval [CI] as needed) and categorical variables will be reported as frequencies and percentages. No 
statistical comparisons will be conducted and no inferential statistics on effectiveness and safety will be 
presented. 
Safety Analyses: The safety data will be analyzed by analysis group based on the safety population for 
the open-label treatment period (for data up to the end of treatment period) and withdrawal period (for 
data collected during the withdrawal period), separately, as appropriate. 
Treatment-emergent adverse event (TEAE) and discontinuation-emergent adverse events (DEAE) will 
be summarized (hereafter TEAE is referred as AE). The incidence of AEs, SAEs, and AEs leading to 
discontinuation due to AEs (or SAEs) will be summarized by analysis group (by presenting the number 
and percentage of subjects with one or more AEs in each category). The number and proportion of 
subjects with one or more AEs within a system organ class (SOC) or by preferred term will be 
presented by analysis group as well. 
For laboratory tests (hematology, chemistry, urinalysis, lipid panel, hemoglobin A1c), weight, BMI, 
vital signs, neurological examination, and ECG parameters, descriptive statistics will be provided for 
observed values and changes from DB baseline and OL baseline for the continuous variables. 
Frequencies and percentages will be reported for categorical variables by study visit and analysis 
group. The markedly abnormal values for selected safety parameters will be summarized, as 
appropriate. 
The number and percentage of subjects with suicidal ideation and/or suicidal behavior, emergence or 
worsening of suicidal ideation or suicidal behavior will be summarized by analysis group for the open-
label treatment period, and the withdrawal period, separately. 
The CSSA total score, DESS total score, MADRS total score, and HAM-A total score will be 
summarized by presenting descriptive statistics of observed values and changes from Week 52/EOT by 
treatment and visit for the withdrawal period. 
Analyses for Effectiveness and Subject-reported Health Status: Descriptive statistics of observed 
values and changes from DB baseline and OL baseline in BE-CGI-S score, EDE-Q modified  global 
and subscale scores (restraint, shape concern, weight concern), EDE-Q modified items 4-6 scores, SDS 
total score and subscale scores (school/work disability, social life disability, and family life disability), 
and SF-12 (subjects from Study SEP360-221) two component scores (physical component, mental 
                                                     
 
 
2 SF-12 collected only for subjects enrolling in this study after completing core Study SEP360-221. 


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health component) will be summarized by visit and analysis group. 
Sample Size: Subjects who complete the double-blind treatment period of the core study, sign the 
informed consent, and meet all entry criteria will be included in this study. The double-blind core study 
SEP360-221 plans to randomize approximately 300 subjects and the double-blind core study 
SEP360-321 plans to randomize approximately 480 subjects. It is estimated that approximately 
500 subjects will be eligible for enrollment in this study based on the number of subjects expected to 
complete treatment in the core studies. 
 


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Table 2: 
Schedule of Assessments 
Procedures 
 
Treatment Period 
 
V1E 
V2E 
V3E 
V4E 
V5E 
V6E 
V7E 
V8E 
V9E 
V10E 
V11E 
OL BSNa 
Week 2 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 28 
Week 32 
Week 36 
Day -1 
Day 
14 ± 3 
Day 
28 ± 3 
Day 
56 ± 3 
Day 
84 ± 3 
Day 
112 ± 3 
Day 
140 ± 3 
Day 
168 ± 3 
Day 
196 ± 3 
Day 
224 ± 3 
Day 
252 ± 3 
Informed Consente 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
Dispense Study Drugc  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Medication 
Accountability 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Between visit contactd 
 
 
At the approximate midpoint between Visits 3E and 4E, Visits 4E and 5E, Visits 5E and 6E, 
Visits 6E and 7E, Visits 7E and 8E, Visits 8E and 9E, Visits 9E and 10E, Visits 10E and 11E, and 
Visits 11E and 12E. 
Demographics 
X  
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X (carried 
over) 
 
 
 
X 
 
 
X 
 
 
 
Neurological 
Examination 
X (carried 
over) 
 
 
 
 
 
 
X 
 
 
 
Prior and Concomitant 
Medications 
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Binge-eating Clinical 
Global Impressions of 
Severity (BE-CGI-S) 
X (carried 
over) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Eating Disorder 
Examination 
Questionnaire (EDE-Q) 
modified 
Xl  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sheehan Disability 
Scale (SDS) 
X (carried 
over) 
 
 
 
X 
 
 
X 
 
 
X 


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Table 2: 
Schedule of Assessments (Continued) 
Procedures 
 
Treatment Period 
 
V1E 
V2E 
V3E 
V4E 
V5E 
V6E 
V7E 
V8E 
V9E 
V10E 
V11E 
OL BSNa 
Week 2 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 28 
Week 32 
Week 36 
Day -1 
Day 
14 ± 3 
Day 
28 ± 3 
Day 
56 ± 3 
Day 
84 ± 3 
Day 
112 ± 3 
Day 
140 ± 3 
Day 
168 ± 3 
Day 
196 ± 3 
Day 
224 ± 3 
Day 
252 ± 3 
Medical Outcomes 
Study 12-Item Short 
Form Survey 
Instrument (SF-12) for 
subjects from Study 
SEP360-221 only 
X (carried 
over) 
 
 
 
X 
 
 
X 
 
 
X 
Vital Sign 
Measurements 
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight and Body Mass 
Index 
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X (carried 
over) 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistryf 
X (carried 
over) 
 
 
 
X 
 
 
X 
 
 
X 
Lipid panelf 
X (carried 
over) 
 
 
 
X 
 
 
X 
 
 
X 
Hemoglobin A1c 
X (carried 
over) 
 
 
 
X 
 
 
X 
 
 
X 
Hematology 
X (carried 
over) 
 
 
 
X 
 
 
X 
 
 
X 
Urinalysis 
X (carried 
over) 
 
 
 
X 
 
 
X 
 
 
X 
Columbia – Suicide 
Severity Rating Scale 
(C-SSRS)g 
X (carried 
over) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Table 2: 
Schedule of Assessments (Continued) 
Procedures 
 
Treatment Period 
 
V1E 
V2E 
V3E 
V4E 
V5E 
V6E 
V7E 
V8E 
V9E 
V10E 
V11E 
OL BSNa 
Week 2 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 28 
Week 32 
Week 36 
Day -1 
Day 
14 ± 3 
Day 
28 ± 3 
Day 
56 ± 3 
Day 
84 ± 3 
Day 
112 ± 3 
Day 
140 ± 3 
Day 
168 ± 3 
Day 
196 ± 3 
Day 
224 ± 3 
Day 
252 ± 3 
Hamilton Anxiety 
Rating Scale (HAM-A)h 
X (carried 
over) 
 
 
 
 
 
 
X 
 
 
 
Montgomery-Asberg 
Depression Rating 
Scale (MADRS)i 
X (carried 
over) 
 
 
 
 
 
 
X 
 
 
 
Cocaine Selective 
Severity Assessment 
(CSSA)j 
 
 
 
 
 
 
 
 
 
 
 
Discontinuation-
Emergent Signs and 
Symptoms (DESS) 
Scalej 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Testk 
(females of child-
bearing potential only) 
X (carried 
over) 
 
X 
 
X 
 
X 
 
X 
 
X 
Urine Drug Screen 
X (carried 
over) 
 
X 
 
X 
 
X 
 
X 
 
X 
Breath Alcohol Test 
X (carried 
over) 
 
X 
 
X 
 
X 
 
X 
 
X 
12-Lead 
Electrocardiogram 
(ECG) 
X (carried 
over) 
 
X 
 
X 
 
 
X 
 
 
X 
 
 


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Table 2: 
Schedule of Assessments (Continued) 
Procedures 
Treatment Period 
Withdrawal Period 
V12E 
V13E 
V14E 
V15E/EOT 
V16E 
V17E 
V18E/EOS 
Week 40 
Week 44 
Week 48 
Week 52b 
Week 53 
Week 54 
Week 55 
Day 
280 ± 3 
Day 
308 ± 3 
Day 
336 ± 3 
Day 
364 ± 1 
Day 
371 ± 1 
Day 
378 ± 1 
Day 
385 ± 1 
Informed Consente 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
 
 
 
 
 
 
Dispense Study Drugc  
X 
X 
X 
 
 
 
 
Study Medication Accountability 
X 
X 
X 
X 
 
 
 
Between visit contactd 
At the approximate midpoint between Visits 12E and 13E, 
Visits 13E and 14E, and Visits 14E and 15E. 
 
 
 
Demographics 
 
 
 
 
 
 
 
Physical Examination 
 
 
 
X 
 
 
X 
Neurological Examination 
 
 
 
X 
 
 
X 
Prior and Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
Binge-eating Clinical Global 
Impressions of Severity 
(BE-CGI-S) 
X 
X 
X 
X 
X 
X 
X 
Eating Disorder Examination 
Questionnaire (EDE-Q) modified 
X 
X 
X 
X 
 
 
 
Sheehan Disability Scale (SDS) 
 
 
 
X 
 
 
X 
Medical Outcomes Study 12-Item 
Short Form Survey Instrument 
(SF-12) for subjects from Study 
SEP360-221 only 
 
 
 
X 
 
 
X 
Vital Sign Measurements 
X 
X 
X 
X 
X 
X 
X 
Weight and Body Mass Index 
X 
X 
X 
X 
X 
X 
X 
Height 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Serum chemistryf 
 
 
 
X 
 
 
X 
Lipid panelf 
 
 
 
X 
 
 
X 
Hemoglobin A1c 
 
 
 
X 
 
 
X 
Hematology 
 
 
 
X 
 
 
X 


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Table 2: 
Schedule of Assessments (Continued) 
Procedures 
Treatment Period 
Withdrawal Period 
V12E 
V13E 
V14E 
V15E/EOT 
V16E 
V17E 
V18E/EOS 
Week 40 
Week 44 
Week 48 
Week 52b 
Week 53 
Week 54 
Week 55 
Day 
280 ± 3 
Day 
308 ± 3 
Day 
336 ± 3 
Day 
364 ± 1 
Day 
371 ± 1 
Day 
378 ± 1 
Day 
385 ± 1 
Urinalysis 
 
 
 
X 
 
 
X 
Columbia – Suicide Severity 
Rating Scale (C-SSRS)g 
X 
X 
X 
X 
X 
X 
X 
Hamilton Anxiety Rating Scale 
(HAM-A)h 
 
 
 
X 
X 
X 
X 
Montgomery-Asberg Depression 
Rating Scale (MADRS)i 
 
 
 
X 
X 
X 
X 
Cocaine Selective Severity 
Assessment (CSSA)j 
 
 
 
X 
X 
X 
X 
Discontinuation-Emergent Signs 
and Symptoms (DESS) Scalej 
 
 
 
X 
X 
X 
X 
Urine Pregnancy Testk (females of 
child-bearing potential only) 
X 
X 
X 
X 
 
 
X 
Urine Drug Screen 
 
X 
 
X 
 
 
X 
Breath Alcohol Test 
 
X 
 
X 
 
 
X 
12-Lead Electrocardiogram 
(ECG) 
 
 
 
X 
X 
X 
X 
Abbreviations: BSN = baseline; EOS = End of Study; EOT = End of Treatment; OL = open label; V = visit  
a Week 12 in core study. Baseline assessments indicated as “carried over” are primarily performed as part of Week 12 visit in the core study and do not need to be repeated; the 
data will be duplicated from Week 12 visit or other visits (such as for height) in the core study.  
b Subjects who discontinue from the study prior to completion of treatment with study drug will be asked to return to the site and complete the EOT assessments within 1 day of 
discontinuation and complete the Withdrawal Period visits and calls. 
c Subjects will take the first dose of study drug in this study on Day 1 (the morning following the baseline visit); there will be no break in study drug treatment between the core 
study and this extension study. All study drug will be administered by the subject once a day at approximately the same time each morning including on the days when clinic 
visits occur. 
d At the approximate midpoint between the scheduled monthly treatment period visits (ie, 14 ± 2 days after a visit), the site staff will contact the subject via telephone, text, or 
email to monitor for SAEs, AEs, and concomitant medications, as well as to remind subjects about adherence to study drug administration and upcoming visits, following which 
an unscheduled visit may be scheduled, if necessary. 
Footnotes continued on the next page. 
 


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e Informed consent will be obtained from all subjects after all procedures from the core study have been completed and before any study procedures unique to this study are 
performed.  
f  Subjects must be fasting for at least 8 hours (may have water) prior to the indicated laboratory tests. Visits should be scheduled in the morning. 
g  The “Since Last Visit” version will be used. 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 any time during the study must be referred to the Investigator for follow up 
evaluation. 
h The Structured Interview Guide for the HAM-A (SIGH-A) will be used for the administration of the HAM-A. 
i The Structured Interview Guide for the MADRS (SIGMA) will be used for the administration of the MADRS. 
j 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, as necessary. 
k Any positive urine β-hCG test should be confirmed by serum β-hCG. 
l Carried over for subjects enrolling in this study from SEP360-321 and collected for subjects enrolling in this study from SEP360-221.


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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 ...............17 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................23 
4. 
INTRODUCTION ......................................................................................................27 
4.1. 
Background .................................................................................................................27 
4.1.1. 
Neurobiology of Binge Eating Disorder .....................................................................28 
4.1.2. 
Pharmacological Management of Binge Eating Disorder ..........................................28 
4.2. 
Study Conduct Rationale ............................................................................................29 
4.3. 
Risk-Benefit Assessment ............................................................................................30 
5. 
STUDY OBJECTIVES ..............................................................................................31 
5.1. 
Primary Objectives .....................................................................................................31 
5.2. 
Secondary Objectives .................................................................................................31 
6. 
STUDY ENDPOINTS ................................................................................................32 
6.1. 
Safety Endpoints .........................................................................................................32 
6.2. 
Effectiveness Endpoints ..............................................................................................32 
6.3. 
Subject-reported Health Status Endpoints ..................................................................33 
7. 
INVESTIGATIONAL PLAN .....................................................................................34 
7.1. 
Overall Study Design ..................................................................................................34 
7.2. 
Treatment Assignment and Blinding ..........................................................................35 
7.3. 
Rationale .....................................................................................................................36 
7.3.1. 
Rationale for the Study Design ...................................................................................36 
7.3.2. 
Rationale for the Dosages ...........................................................................................36 
7.3.3. 
Rationale for the Study Population .............................................................................36 
7.3.4. 
Rationale for the Endpoints ........................................................................................36 
7.3.5. 
Prevention of Missing Data ........................................................................................36 
8. 
SELECTION OF SUBJECTS ....................................................................................37 


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8.1. 
Subject Inclusion Criteria ...........................................................................................37 
8.2. 
Subject Exclusion Criteria ..........................................................................................37 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................39 
9.1. 
Description of Study Drug ..........................................................................................39 
9.2. 
Study Drug Packaging and Labeling ..........................................................................39 
9.2.1. 
Package Description ...................................................................................................39 
9.2.2. 
Labeling Description ..................................................................................................39 
9.3. 
Study Drug Storage .....................................................................................................40 
9.4. 
Dispensing of Study Drug ..........................................................................................40 
9.5. 
Study Drug Accountability .........................................................................................40 
9.6. 
Study Drug Handling and Disposal ............................................................................40 
10. 
TREATMENT OF SUBJECTS ..................................................................................41 
10.1. 
Study Medication ........................................................................................................41 
10.1.1. 
Dose or Dosage for Study Drug..................................................................................41 
10.1.2. 
Dose Adjustment Criteria ...........................................................................................41 
10.2. 
Treatment Compliance ................................................................................................41 
10.3. 
Concomitant Medications and Therapies ...................................................................42 
10.3.1. 
Prohibited Medications ...............................................................................................42 
10.3.2. 
Prohibited Therapies ...................................................................................................42 
10.3.3. 
Permitted Medications ................................................................................................43 
10.3.4. 
Permitted Therapies ....................................................................................................43 
10.3.5. 
Contraception Requirements ......................................................................................43 
10.4. 
Guidance for Overdose ...............................................................................................44 
10.5. 
Cautions ......................................................................................................................44 
11. 
STUDY ASSESSMENTS ..........................................................................................45 
11.1. 
Demographics and Baseline Characteristics ...............................................................45 
11.2. 
Safety Assessments .....................................................................................................46 
11.2.1. 
Adverse Events ...........................................................................................................46 
11.2.2. 
Clinical Laboratory Tests ...........................................................................................46 
11.2.3. 
Vital Signs ..................................................................................................................46 
11.2.4. 
Electrocardiograms (ECGs) ........................................................................................46 
11.2.5. 
Physical and Neurological Examinations ...................................................................47 


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11.2.6. 
Safety Scales ...............................................................................................................47 
11.2.6.1. 
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................................47 
11.2.6.2. 
Cocaine Selective Severity Assessment (CSSA) ........................................................47 
11.2.6.3. 
Discontinuation-Emergent Signs and Symptoms (DESS) Scale ................................48 
11.2.6.4. 
Hamilton Anxiety Rating Scale (HAM-A) .................................................................48 
11.2.6.5. 
Montgomery-Asberg Depression Rating Scale (MADRS) ........................................48 
11.3. 
Effectiveness Assessments .........................................................................................48 
11.3.1. 
Eating Disorder Examination Questionnaire (EDE-Q) Modified ..............................48 
11.3.2. 
Sheehan Disability Scale (SDS) .................................................................................49 
11.3.3. 
Binge-eating Clinical Global Impressions–Severity of Illness (BE-CGI-S) ..............49 
11.4. 
Other Assessments and Scales ....................................................................................49 
11.4.1. 
Short Form-12 Health Survey (SF-12) .......................................................................49 
11.5. 
Study Visits and Assessments ....................................................................................49 
11.5.1. 
Open-label Baseline: Visit 1E (Day -1) ......................................................................49 
11.5.2. 
Treatment Period (Visits 2E – 15E; Weeks 2 – 52) ....................................................50 
11.5.2.1. 
Visit 2E: Week 2 (Day 14 ± 3) ...................................................................................50 
11.5.2.2. 
Visit 3E (Week 4; Day 28 ± 3), Visit 5E (Week 12; Day 84 ± 3), Visit 7E 
(Week 20 Day 140 ± 3), Visit 9E (Week 28; Day 196 ± 3), Visit 11E 
(Week 36; Day 252 ± 3), and Visit 13E (Week 44 Day 308 ± 3)...............................51 
11.5.2.3. 
Visit 4E (Week 8; Day 56 ± 3), Visit 6E (Week 16; Day 112 ± 3), Visit 8E 
(Week 24; Day 168 ± 3), Visit 10E (Week 32; Day 224 ± 3), Visit 12E 
(Week 40; Day 280 ± 3), and Visit 14E (Week 48; Day 336 ± 3) .............................51 
11.5.2.4. 
Visit 15E/End of Treatment (Week 52; Day 364 ± 1) ................................................52 
11.5.3. 
Withdrawal Period ......................................................................................................52 
11.5.3.1. 
Visit 16E (Week 53; Day 371 ± 1, ) and Visit 17E (Week 54; Day 378 ± 1) ............53 
11.5.3.2. 
Visit 18E/End of Study (Week 55; Day 385 ± 1) .......................................................53 
12. 
SAFETY REPORTING ..............................................................................................54 
12.1. 
Definitions ..................................................................................................................54 
12.1.1. 
Adverse Events ...........................................................................................................54 
12.1.2. 
Serious Adverse Events ..............................................................................................54 
12.2. 
Objective Findings ......................................................................................................55 
12.3. 
Collection and Recording of Adverse Events .............................................................56 
12.4. 
Immediately Reportable Events ..................................................................................57 
12.4.1. 
Serious Adverse Event ................................................................................................57 


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12.4.2. 
Pregnancy ...................................................................................................................58 
12.5. 
Data Monitoring Committee/Data and Safety Monitoring Board ..............................59 
13. 
TERMINATION OF SUBJECT FROM STUDY/DISCONTINUATION OF 
STUDY DRUG ...........................................................................................................60 
13.1. 
Criteria for Study Drug Discontinuation ....................................................................60 
13.2. 
Clinical Assessments After Study Drug Discontinuation ...........................................60 
13.3. 
Criteria for Subject Termination from the Withdrawal Period ...................................60 
14. 
STUDY TERMINATION ..........................................................................................62 
15. 
STATISTICS ..............................................................................................................63 
15.1. 
Sample Size ................................................................................................................63 
15.2. 
Analysis Populations ..................................................................................................63 
15.3. 
Data Analysis ..............................................................................................................63 
15.3.1. 
Analysis Group ...........................................................................................................63 
15.3.2. 
Definitions of Assessments.........................................................................................64 
15.3.3. 
Safety Analysis ...........................................................................................................65 
15.3.3.1. 
Adverse Events ...........................................................................................................65 
15.3.3.2. 
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................................65 
15.3.3.3. 
Other Safety Assessments ...........................................................................................66 
15.3.3.4. 
Physical Dependence and Withdrawal Symptoms .....................................................66 
15.3.3.5. 
Concomitant Medications ...........................................................................................66 
15.3.4. 
Analyses for Effectiveness and Subject-Reported Health Status ...............................66 
15.3.5. 
Interim Analysis ..........................................................................................................66 
16. 
PROCEDURE FOR CLINICAL STUDY QUALITY CONTROL /DATA 
COLLECTION, MANAGEMENT, AND QUALITY ASSURANCE ......................67 
16.1. 
Data Collection/Electronic Data Capture (EDC) ........................................................67 
16.2. 
Computerized Systems Used for Source Data ............................................................67 
16.3. 
Study Monitoring ........................................................................................................68 
16.4. 
Audits ..........................................................................................................................68 
16.5. 
Study Documentation .................................................................................................68 
16.6. 
Clinical Laboratory Certification and Normal Values ................................................69 
17. 
ETHICAL AND REGULATORY OBLIGATIONS..................................................70 
17.1. 
Study Conduct ............................................................................................................70 
17.2. 
Institutional Review Board/Independent Ethics Committee ......................................70 


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17.3. 
Informed Consent .......................................................................................................71 
17.4. 
Subject Privacy ...........................................................................................................71 
17.5. 
Protocol Amendments and Emergency Deviations ....................................................72 
17.6. 
Records Retention .......................................................................................................72 
17.7. 
Inspection of Records .................................................................................................72 
17.8. 
Financial Disclosure ...................................................................................................72 
17.9. 
Publication Policy .......................................................................................................73 
18. 
REFERENCES ...........................................................................................................74 
19. 
INVESTIGATOR APPROVAL .................................................................................78 
20. 
APPENDIX I. CARDIAC SAFETY MONITORING (ECG) ....................................79 
21. 
APPENDIX II. CLINICAL LABORATORY TESTS ...............................................80 
22. 
APPENDIX III. ACCEPTABLE CONTRACEPTIVE PROCEDURES FOR 
AND DURING THE STUDY ....................................................................................81 
23. 
APPENDIX IV. CLINICALLY RELEVANT CYP2B6 SUBSTRATES OR 
INDUCERS OR INHIBITORS (GENERIC NAMES) ..............................................82 
24. 
APPENDIX V. ABUSE POTENTIAL MONITORING PLAN ................................83 
 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Schedule of Assessments ............................................................................................11 
Table 3: 
List of Abbreviations ..................................................................................................23 
Table 4: 
Definition of Key Study Terms ..................................................................................26 
Table 5: 
Study Medication ........................................................................................................39 
Table 6: 
Recommended Schedule for Clinical Assessments ....................................................45 
Table 7: 
Computerized Systems Used for Source Data ............................................................67 
Table 8: 
Checklist of Events Subject to Additional Monitoring Terms ...................................85 
 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................35 
 


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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 
AE 
Adverse event 
ADHD 
Attention deficit hyperactivity disorder 
APMP 
Abuse Potential Monitoring Plan 
BE-CGI-S 
Binge-eating Clinical Global Impression-Severity 
BED 
Binge eating disorder 
BMI 
Body mass index  
BN 
Bulimia nervosa 
CAP 
College of American Pathologists 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CR 
Controlled release 
CRF 
Case report form 
CRO 
Clinical research organization 
C-SSRS 
Columbia-suicide severity rating scale 
CSSA 
Cocaine Selective Severity Assessment 
CTM 
Clinical trial material 
DA 
Dopamine 
DAT 
Dopamine transporter 
DB 
Double-blind 
DEA 
Drug Enforcement Agency 
DEAE 
Discontinuation-emergent adverse event 
DESS 
Discontinuation-Emergent Signs and Symptoms 
DHPG 
3,4-dihydroxyphenylglycol 
DMP 
Data Management Plan 
DNRI 
Dopamine and norepinephrine reuptake inhibitor 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition 


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Table 3: 
List of Abbreviations (Continued) 
Abbreviation 
Full Form 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EDE-Q Modified 
Eating Disorder Examination Questionnaire Modified 
EOT 
End of treatment 
ESAM 
Event subject to additional monitoring 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
5-HT 
5-hydroxytryptamine (serotonin) 
HAM-A 
Hamilton Anxiety Rating Scale 
HDL 
High-density lipoprotein (cholesterol) 
HEENT 
Head, ears, eyes, nose and throat 
HR 
Heart rate  
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IXRS 
Interactive Response System 
LDL 
Low-density lipoprotein (cholesterol) 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MAO 
Monoamine oxidase 
MDD 
Major Depressive Disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHI 
Medication Handling Irregularity 
MRI 
Magnetic resonance imaging 
NE 
Norepinephrine 
NET 
Norepinephrine transporter 
OL 
Open-label 
OTC 
Over-the-counter (medications) 


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Table 3: 
List of Abbreviations (Continued) 
Abbreviation 
Full Form 
PET 
Positron emission tomography 
PK 
Pharmacokinetic(s) 
POC 
Point of care 
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 
RR 
RR interval 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDS 
Sheehan disability Scale 
SERT 
Serotonin transporter 
SF-12 
Medical Outcomes Study 12-Item Short Form 
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 
TEAE 
Treatment-emergent adverse event 
tmax 
Time to maximum concentration 
UDS 
Urine drug screen 
US 
United States 
USP 
United States Pharmacopeia 
VAS 
Visual analog scale 
WBC 
White blood cells 
WHO-DD 
World Health Organization Drug Dictionary 


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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. 
Open-label 
Treatment Period 
The period of the study in which the study drug is administered. 
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 excess 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 
adults with BED. 


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4.1.1. 
Neurobiology of Binge Eating Disorder 
Nonclinical 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. 
Nonclinical 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 accumbens 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 
nonclinical 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 
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 higher binge eating scores (Wang-2011). Additional 
PET studies have shown negative correlations between impulsivity and availability of dopamine 
D2/3 receptors in the striatum and midbrain of humans (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 these studies show that a dysregulated dopaminergic driven reward 
circuit is critical to the symptomology associated with BED and suggest that therapies targeting 
this system may be effective interventions for the disorder. 
4.1.2. 
Pharmacological Management of Binge Eating Disorder 
Although cognitive, behavioral and interpersonal psychotherapies improve binge eating 
symptoms, many patients do not respond. Recent studies suggest that pharmacotherapies that 


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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 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 efficacy results supported United States 
Food and Drug Administration (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 
ADHD, blocks pre-synaptic DAT and 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 dopamine and 
norepinephrine reuptake inhibitor (DNRI). Dasotraline has a long time to maximum 
concentration (tmax; reaches maximum concentrations approximately 10 to 12 hours after dosing) 
and mean apparent half-life (47.1 to 77.0 hours). 
A nonclinical 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 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. 
A recently completed clinical study supports dasotraline as a potentially safe and efficacious 
treatment option for adults with ADHD (Koblan-2015). Clinically meaningful and statistically 
significant treatment effects were observed at 8 mg/day. Consistent with DNRI pharmacology, 
the most frequent adverse events reported in the study were insomnia, decreased appetite, and 
dry mouth. In addition, significant dose dependent decreases were observed in appetite and 
weight loss. A review of previously published trials for BED suggests that decreases in appetite 
and weight loss are strongly associated with a reduction in binge eating frequency 
(Appolinario-2003, Grilo-2005, McElroy-2003B, McElroy-2006, McElroy-2007, 
McElroy-2012). Administration in over 1000 adult subjects in completed and ongoing studies 
supports the safety of dasotraline for continued evaluation. 
Use of dasotraline as a potential treatment for BED is supported by research that suggests 
pharmacotherapies that target one or more of the neurotransmitter systems (including dopamine 
and norepinephrine) that have been implicated in the pathogenesis of BED may play a critical 
role in its management. The centrally acting effects of dasotraline on dopamine and 


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norepinephrine uptake combined with the results from the SEP360-201study, and the rat model 
study of binge eating provide further support to evaluate dasotraline as a treatment for BED. 
The initial 12-week study SEP360-221 evaluates dasotraline flexibly dosed at 4, 6, or 8 mg/day 
and the 12-week study SEP360-321 evaluates dasotraline fixed doses of 4 or 6 mg/day as a 
potential treatment for BED. The current study evaluates long term safety and efficacy of 
dasotraline as a treatment for BED and will enroll subjects who complete treatment in Study 
SEP360-221 or Study SEP360-321. 
4.3. 
Risk-Benefit Assessment 
Overall, in previous clinical studies dasotraline was generally safe and well tolerated. The 
pharmacokinetic (PK) and safety profiles observed in adults from completed clinical studies 
support evaluation of dose levels of 4 – 8 mg/day in adults with BED. 
Most adverse events in completed clinical studies were mild to moderate in intensity, and 
included headache, dizziness, insomnia, tachycardia, and nausea. Dose dependent increases in 
the incidence of insomnia and weight loss were observed, consistent with DNRI pharmacology. 
A total of 13 serious adverse events (SAEs) have been reported in 9 subjects receiving 
dasotraline. Across the 8 completed clinical studies evaluating dasotraline, the rate of 
discontinuations as a result of treatment-emergent adverse events (TEAEs) was low. The highest 
rate of discontinuations due to TEAEs was in the SEP360-201 adult ADHD study (11.2% and 
29.7% of subjects treated with dasotraline 4 and 8 mg/day, respectively), primarily due to 
insomnia. In general, the side-effect profile of dasotraline, based on available data, appears 
comparable with other medications used in the treatment of ADHD and suggests it may be well 
tolerated in patients with BED. A flexible dose design to reach the 8 mg dose will be 
implemented in this study to facilitate management of safety and tolerability issues. 
The results from the human abuse liability study indicate dasotraline has minimal abuse potential 
and is unlikely to be recreationally abused. All doses of dasotraline (8, 16, 36 mg) demonstrated 
significantly lower drug liking scores than methylphenidate (40, 80 mg) and were no greater than 
placebo. The most frequently reported abuse potential adverse events were insomnia and 
dizziness in subjects with major depressive disorder (MDD) and insomnia and suicidal ideation 
in adults with ADHD. 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 a comprehensive Abuse Potential 
Monitoring Plan (APMP) for dasotraline designed to detect potential abuse of the compound and 
to more closely monitor adverse events (AEs) consistent with the pharmacology of the 
compound will be implemented for this study (Section 24, Appendix V). 
Additionally, a Data and Safety Monitoring Board (DSMB) will be established for this study. 
The DSMB will review safety data including AEs and SAEs at regular intervals. 
Results from the adult ADHD study and the rat model of binge-eating combined with 
dasotraline’s DNRI pharmacology, and extended PK profile suggest dasotraline may prove safe 
and efficacious in the treatment of patients with BED. Although drugs targeting disturbances in 
dopaminergic transmission may translate to therapeutic benefit in BED, the efficacy and safety 
of dasotraline in this indication is currently being evaluated. 


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5. 
STUDY OBJECTIVES 
5.1. 
Primary Objectives 
The primary objective of the study is to evaluate the long-term safety and tolerability of flexibly-
dosed dasotraline (4, 6, or 8 mg/day) in adults with binge-eating disorder (BED) who have 
completed a prior dasotraline study in BED by: 
• The incidence of AEs, discontinuations due to AEs, and serious AEs (SAEs) 
• The frequency and severity of suicidal ideation and suicidal behavior using the 
Columbia – Suicide Severity Rating Scale (C-SSRS) 
• Changes in 12-lead electrocardiograms (ECGs), vital signs, body weight, body mass 
index (BMI), and clinical laboratory results 
5.2. 
Secondary Objectives 
The secondary objects are: 
• To assess potential withdrawal effects of dasotraline 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 Hamilton Anxiety Rating Scale (HAM-A) 
− Symptoms of depression utilizing the Montgomery-Asberg Depression Rating 
Scale (MADRS) 
• To assess the abuse potential of dasotraline utilizing a comprehensive abuse potential 
monitoring plan (APMP) 
• To evaluate the long-term effectiveness of flexibly-dosed dasotraline in the treatment 
of adults with BED as measured by the following: 
− Eating Disorder Examination Questionnaire (EDE-Q) modified  
− Binge-eating Clinical Global Impressions - Severity (BE-CGI-S) 
− Sheehan Disability Scale (SDS) 
• To assess subject-reported health status using the Medical Outcomes Study 12-Item 
Short Form Survey Instrument (SF-12)3  
                                                     
 
 
3 SF-12 collected only for subjects enrolling in this study after completing core Study SEP360-221. 


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6. 
STUDY ENDPOINTS 
6.1. 
Safety Endpoints 
The safety endpoints include: 
• The incidence of overall AEs, serious AEs, and AEs or SAEs leading to 
discontinuation 
• Clinical laboratory evaluations (serum chemistry, hematology, urinalysis) 
• Clinical evaluations (vital signs including orthostatic effects, and 12-lead ECGs) 
• Frequency and severity of suicidal ideation and suicidal behavior using the C-SSRS 
• Change and percent change in body weight and BMI 
• Change in fasting lipid panel (triglycerides, total cholesterol, high-density lipoprotein 
[HDL] cholesterol, and low-density lipoprotein [LDL] cholesterol) 
• Change in hemoglobin A1c levels 
• Change in fasting glucose levels 
• Change in the symptoms of withdrawal from dasotraline from Week 52/end of 
treatment (EOT) as measured by  
− CSSA total score at Weeks 53, 54, and 55 
− DESS total score at Weeks 53, 54, and 55 
− HAM-A total score at Weeks 53, 54, and 55 
− MADRS total score at Weeks 53, 54, and 55 
6.2. 
Effectiveness Endpoints 
The effectiveness endpoints include: 
• Change in EDE-Q modified global score, subscale scores (restraint, shape concern, 
weight concern),  and Items 4-6 scores 
• Change in BE-CGI-S score 
• Change in SDS total score and subscale scores (school/work disability, social life 
disability, and family life disability) 


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6.3. 
Subject-reported Health Status Endpoints 
The subject-reported health status endpoints include: 
• Change in SF-12 two component scores (physical component, mental health 
component)4 
                                                     
 
 
4 SF-12 collected only for subjects enrolling in this study after completing core Study SEP360-221. 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a Phase 3, 12-month, multicenter, open-label, flexibly-dosed, safety study in adults with 
BED. This study is projected to enroll approximately 500 subjects based on the number of 
subjects expected to complete treatment in the core studies (ie, SEP360-221 or SEP360-321). 
Informed consent will be obtained from all subjects after all procedures from the core study have 
been completed and before any study procedures unique to this study are performed. Safety and 
tolerability will be monitored throughout the study by AE reports, physical and neurological 
examinations, 12-lead ECG, vital signs, body weight, BMI, clinical laboratories (hematology, 
chemistry, urinalysis, hemoglobin A1c, and lipid panel), and C-SSRS. Effectiveness will be 
evaluated using the BE-CGI-S, EDE-Q modified, and SDS. Subject-reported health status will be 
assessed using the SF-12 (subjects from Study SEP360-221 only). Assessment of potential 
withdrawal effects of dasotraline 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. 
A comprehensive Abuse Potential Monitoring Plan (APMP; see Section 24) 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 including 
data on adverse events (AEs) and serious adverse events (SAEs) at regular intervals. 
Subjects will self-administer study drug on an outpatient basis for 12 months, once a day at 
approximately the same time each morning with or without food, including on the days when 
clinic visits occur. Subjects meeting all inclusion and no exclusion criteria will start taking 
open-label study drug on Day 1, the morning following the open-label (OL) Baseline visit (ie, 
Week 12 visit in the core study). 
The total daily dose will remain between 4 mg/day and 8 mg/day for the 12-month treatment 
period. Dasotraline will be dosed at 4 mg/day for the first 2 weeks of the study. At the Week 2 
visit, the dose may be increased to 6 mg/day. Thereafter the dose may be increased or decreased 
by 2 mg/day, as necessary for effectiveness or tolerability reasons at the discretion of the 
investigator. A minimum of 8 days is required between dose increases. Dose decreases may be 
made at less than 8 day intervals, at the investigator’s discretion, for reasons of safety or 
tolerability. If, in the judgment of the investigator, the subject does not tolerate the minimum 
required dose (4 mg/day), he or she will be discontinued from the study. 
All changes in study drug dose will begin the morning after the visit at which the dose change 
decision is made and using the new package of study drug. 
The study will consist of a baseline visit, 12-month open-label treatment period, and 3-week 
study drug withdrawal period as shown in the Study Schematic (Figure 1). During the treatment 
period, subjects will return to the clinic at the end of 2 and 4 weeks for clinical evaluation and 
thereafter will return to the clinic once every 4 weeks during the treatment period for scheduled 
visits. At the approximate midpoint between the scheduled monthly visits (ie, 14 ± 2 days after a 


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visit), the site staff will contact the subject via telephone, text, or email in order to monitor for 
SAEs, AEs, and concomitant medications, as well as to remind subjects about adherence to study 
drug administration, and upcoming visits. If necessary, an unscheduled visit can be arranged. 
Subjects will attend weekly visits during the 3-week study drug withdrawal period. Assessment 
of potential withdrawal effects of dasotraline will be conducted via administration of the CSSA, 
DESS, HAM-A, and MADRS at the end of treatment. Subjects will undergo assessments every 
other day and weekly as follows: The CSSA and DESS will be completed every other day during 
the 3-week study medication withdrawal period. Clinical site staff will call the subject every 
other day, beginning the second day after the last dose of study drug, unless a clinic visit is 
scheduled for that day. Phone contacts may be made 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 missed 
CSSA and DESS, in addition to the current day’s CSSA and DESS, as necessary. 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. The CSSA, DESS, HAM-A, and MADRS also will be 
administered at each weekly visit during the withdrawal period. 
A window of ± 1 day will be allowed for each weekly clinic visit and telephone call during the 
study medication withdrawal period. 
After the last withdrawal period visit, all subjects will be referred for follow-up care as 
determined by the investigator. 
A study schematic is presented in Figure 1. Details of the study assessments and other 
procedures to be performed at each visit are presented in Table 2, Schedule of Assessments, and 
Section 11, Study Assessments. 
If necessary, subjects may return to the clinic at any time for an unscheduled visit. 
 
Figure 1: 
Study Schematic 
Study Schematic 
 
 
 
 
 
 
 
 
 
7.2. 
Treatment Assignment and Blinding 
This is a non-randomized open-label study. All subjects receive flexibly-dosed dasotraline (4, 6, 
or 8 mg/day). 
Dasotraline 4, 6, and 8 mg/day 
(flexibly dosed) 
a There will be no break in study drug treatment between the core study and this extension study. 
12 Months 
Core Study 
Study SEP360-221 
or SEP360-321a 
Study Drug 
Withdrawal 
Period 
3 Weeks 


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7.3. 
Rationale 
7.3.1. 
Rationale for the Study Design 
This is an open-label study to evaluate the long-term safety and effectiveness of flexibly-dosed 
dasotraline consistent with the intended long-term use of the compound in this population. 
7.3.2. 
Rationale for the Dosages 
The dosages to be used in this study (4, 6, or 8 mg/day) are the same as those administered in the 
core study SEP360-221. Doses of 4 and 6 mg are administered in the core study SEP360-321. 
7.3.3. 
Rationale for the Study Population 
Subjects in this study will have met BED eligibility requirements in the core study and not have 
taken any medication other than study drug for the purpose of controlling BED symptoms during 
the core study. 
7.3.4. 
Rationale for the Endpoints 
The safety assessments and their timing are considered appropriate to assess the long-term safety 
of dasotraline, taking into account known pharmacology and adverse events based on previous 
studies. The symptom, functional, and quality of life assessments were selected to assess the 
potential effectiveness of dasotraline on these parameters. 
7.3.5. 
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 2 weeks for the first month, every 4 weeks for the remainder of treatment, and every week 
during the study drug withdrawal period, (ii) during the treatment period a window of ± 3 days 
for each bi-weekly or monthly clinic visit and a window of ± 1 day for each weekly clinic visit 
starting at Week 52, (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, and (iv) monitoring of data collection for adherence 
during the study. 


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8. 
SELECTION OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
A subject who fulfills all of the following criteria may be included in the study. 
1. Completion of the treatment period of a dasotraline core study (ie, SEP360-221 or 
SEP360-321) for the treatment of BED. 
2. Subject has agreed to participate by providing written informed consent and is willing 
and able to comply with the protocol, in the opinion of the investigator. 
3. Subject has not taken any medication other than the study drug for the purpose of 
controlling BED symptoms during the core study. 
4. Female subject must have a negative urine pregnancy test at open-label (OL) Baseline; 
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. 
5. 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 22, Appendix III) 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. 
6. Subject is judged by the investigator to be suitable for participation in a 12-month clinical 
trial involving open-label dasotraline treatment. 
7. Subject can read well enough to understand the informed consent form and other subject 
materials. 
8.2. 
Subject Exclusion Criteria 
A subject who meets any of the following criteria will be excluded in the study. 
1. Subject is considered by the investigator to be at imminent risk of suicide, injury to self 
or to others, or damage to property. 
2. Subject is considered a suicide risk in the investigator’s opinion or has any previous 
history of suicide attempt within the past 12 months. 
3. 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 OL Baseline. Subjects who answer “yes” to this 
question must be referred to the Investigator for follow up evaluation. 
4. Subject has a clinically significant abnormality including physical examination, vital 
signs, ECG, or laboratory tests that the investigator in consultation with the medical 
monitor considers to be inappropriate to allow participation in the study. 
5. Subject has a positive urine drug screen (UDS) or breath alcohol test at OL Baseline. 


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6. Subject is breastfeeding. 
7. Subject is at high risk of non-compliance in the investigator’s opinion. 


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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: 
Study Medication 
Attribute 
Study Medication 
Product name 
Dasotraline 4.0 mg 
Dasotraline 6.0 mg 
Dasotraline 8.0 mg 
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. 
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, 
6 mg, or 8 mg capsules (7 days + 3 extra days). 
9.2.2. 
Labeling Description  
All packaging for the study medication will be labeled with: 
• Protocol number 
• Sponsor’s name and address 
• Content (eg, number of capsules) 
• 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 permitted to 15°C to 30°C (59°F - 86°F) 
but must still be reported to CRO. The subject will be instructed to store the study medication at 
room temperature. 
9.4. 
Dispensing of Study Drug  
An Interactive Response System (IXRS) will be used to manage subject 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 on which medication number to assign 
to a subject. Each subject will be dispensed two or four 10-day blister cards per scheduled visit 
depending on the timing of the next scheduled visit (see Table 2). 
Subjects will self-administer the study drug on an outpatient basis. 
9.5. 
Study Drug Accountability 
The Investigator or designee is responsible for storing the study drug in a secure location and for 
maintaining adequate records of drug disposition that includes 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/ clinical 
research organization (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 or designee on an ongoing basis must maintain a study drug inventory record of 
supplied, received, dispensed, and returned study drug 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 
the study medication. 


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10. 
TREATMENT OF SUBJECTS 
10.1. 
Study Medication 
10.1.1. 
Dose or Dosage for Study Drug 
Dasotraline 4 mg, 6 mg, or 8 mg 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 months. 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. 
10.1.2. 
Dose Adjustment Criteria 
The total daily dose will remain between 4 mg/day and 8 mg/day for the 12-month treatment 
period. Dasotraline will be dosed at 4 mg/day for the first 2 weeks of the study. At the Week 2 
visit, the dose may be increased to 6 mg/day. Thereafter the dose may be increased or decreased 
by 2 mg/day, as necessary for effectiveness or tolerability reasons at the discretion of the 
investigator. A minimum of 8 days is required between dose increases. Dose decreases may be 
made at less than 8 day intervals, at the investigator’s discretion, for reasons of safety or 
tolerability. If, in the judgment of the investigator, the subject does not tolerate the minimum 
required dose (4 mg/day), he or she will be discontinued from the study. 
All changes in study drug dose will begin the morning after the visit at which the dose change 
decision is made and using the new package of study drug. 
10.2. 
Treatment Compliance 
Compliance with study drug will be monitored closely and determined at each visit during 
treatment. Subjects will be instructed to bring all unused study drug 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 
subject, 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 
drug for the effectiveness of treatment and for the successful outcome of the study. 


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10.3. 
Concomitant Medications and Therapies 
The following information on all medication administered between open-label baseline through 
the 3-week study medication withdrawal period or at 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 coding dictionary is provided in the Data Management 
Plan (DMP). All medications will be coded using World Health Organization Drug Dictionary 
(WHO-DD). Information on the concomitant mediations carried over from the core-study will be 
described in the DMP. 
10.3.1. 
Prohibited Medications 
Use of certain medications, including but not limited to the following, is prohibited throughout 
the study from open-label baseline through the 3-week study medication withdrawal period: 
• 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] inhibitor, tricyclic) and St. John’s 
Wort 
• medications that are CYP2B6 substrates or inhibitors or inducers of CYP2B6, eg, 
bupropion, cyclophosphamide, carbamazepine, etc (see Section 23, Appendix IV) 
• medications for the treatment of ADHD 
• corticosteroids except as noted in Section 10.3.3 and anabolic steroids  
• antiepileptic medications  
• benzodiazepines except for sleep or anxiety 
• mood stabilizers (eg, lithium, anticonvulsants) 
• antipsychotic medications 
• suvorexant 
• any medication that can result in either weight gain or weight loss (eg, insulin, 
liraglutide, diphenhydramine except topical formulations, etc) including 
over-the-counter and herbal products 
10.3.2. 
Prohibited Therapies 
Any participation in a formal weight loss program such as Weight Watchers® is prohibited 
throughout the study. 
For permitted therapies, see Section 10.3.4. 


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10.3.3. 
Permitted Medications 
The following medications are permitted during the study, with the restrictions noted: 
• Corticosteroids: Topical and intra-nasal corticosteroids. Other formulations of 
corticosteroid may be permitted following consultation with the Medical Monitor 
• 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 permitted for clinically significant 
anxiety/agitation or as a sedative/hypnotic up to a maximum daily dose of 
6 mg/day. Lorazepam should be used sparingly, when clinically required, per 
investigator judgment 
− 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 
• Medications used for the treatment of anxiety/agitation and insomnia (eg, lorazepam 
and zolpidem) should not be used in close temporal proximity (defined as 
administration within 2 hours of each other) 
• Opiates may be allowed in rare cases for a limited period of time with prior 
authorization from the Medical Monitor 
• Medications for short-term treatment of a medical condition (no more than 10 days) 
are allowed following consultation with the Medical Monitor 
• Subjects who require treatment with more than 1 of the restricted concomitant 
medications (including other antipsychotics or anxiolytics [lorazepam or equivalent 
above protocol-specified limits]) will be discontinued (as appropriate) from the study 
• Contraceptives (see Section 22, Appendix III) 
The date and time of the last dose taken prior to scheduled effectiveness assessments of any sleep 
aid listed above must be recorded at each visit.  
10.3.4. 
Permitted Therapies 
Participation in non-pharmacologic therapy, such as supportive psychotherapy, cognitive 
behavioral therapy or interpersonal therapy is permitted and should be documented by the 
investigator, to the extent possible. 
10.3.5. 
Contraception Requirements 
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, as 


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described in Section 22, Appendix III, from informed consent through the end of the study. Note: 
Continued use of an effective and medically acceptable form of birth control is recommended for 
30 days after study completion or premature discontinuation from the study. 
10.4. 
Guidance for Overdose 
There is no overdose experience with dasotraline in humans. Signs and symptoms of overdose in 
nonclinical 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). 
10.5. 
Cautions 
Dasotraline capsules should not be opened or tampered with in any way; the active ingredient is 
an ocular irritant. 


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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 
EDE-Q modified, BE-CGI-S, MADRS, SDS, HAM-A, CSSA, DESS, and SF-12 rating scales. 
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 
Visits 1E, 2E, 3E, 4E, 5E, 6E, 7E, 8E, 9E, 10E, 
11E, 12E, 13E, and 14E  
(as applicablea) 
Visits 15E/End of Treatment, Visits 16E, 17E, 
and 18E/End of Study 
(as applicablea) 
EDE-Q modified (by subject) 
EDE-Q modified (by subject) 
SDS (by subject) 
SDS (by subject)  
MADRS 
MADRS 
C-SSRS 
C-SSRS 
BE-CGI-S 
BE-CGI-S 
SF-12b (by subject) 
SF-12b (by subject) 
HAM-A 
HAM-A 
 
CSSA 
 
DESS 
a As applicable, see Table 2, schedule of assessments, and Section 11.5. 
b SF-12 collected only for subjects enrolling in this study after completing core Study SEP360-221. 
 
11.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics including date of birth, sex, ethnicity, race, and subject 
ID number from the core study will be collected at the OL Baseline visit. Weight, BMI, physical 
and brief neurological examination results will be carried over from Week 12 in the core studies. 


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11.2. 
Safety Assessments 
11.2.1. 
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 will be monitored throughout the study at all visits including telephone, text, or email 
assessments. 
Information on AEs carried over from the core-study will be described in the DMP. 
11.2.2. 
Clinical Laboratory Tests 
The 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. For detailed instructions regarding clinical laboratory 
procedures, sampling, and shipping guidelines refer to the Central Laboratory Instructions 
Manual. Samples will be processed at a central laboratory to ensure consistency. All clinical 
laboratories will be College of American Pathologists (CAP) and Clinical Laboratory 
Improvement Amendments (CLIA) (or equivalent) certified. 
Any POC (point of care) kits that are performed on site by study personnel rather than in a lab- 
must be CLIA waived and the study center must possess a CLIA certificate of Waiver. 
11.2.3. 
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 sample collection and 
performance of an ECG, whenever possible. 
11.2.4. 
Electrocardiograms (ECGs) 
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 by a centralized cardiac safety 
vendor 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 
interval, and QRS duration. 


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11.2.5. 
Physical and Neurological Examinations 
Clinically significant physical and neurological examination findings, as judged by the 
investigator, after baseline (carried over) 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. 
11.2.6. 
Safety Scales 
11.2.6.1. 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 the “Since Last Visit” version of the C-SSRS. 
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 any time during the study must be referred to the 
Investigator for follow-up evaluation. 
11.2.6.2. 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. 


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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. 
Subjects will be instructed by the site staff regarding the appropriate way to take their pulse. 
11.2.6.3. 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. 
11.2.6.4. 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. 
11.2.6.5. 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. 
Effectiveness Assessments 
11.3.1. 
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. 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). 


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Convergent findings from confirmatory factor analyses of item data 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.  
11.3.2. 
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. 
Binge-eating Clinical Global Impressions–Severity of Illness (BE-CGI-S) 
The BE-CGI-S (Busner & McElroy, 2012; based on Guy-1976) asks the clinician one question: 
“Considering your total clinical experience with the adult Binge Eating Disorder (BED) 
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. 
11.4. 
Other Assessments and Scales 
11.4.1. 
Short Form-12 Health Survey (SF-12) 
The SF-12 is a 12-item self-report questionnaire that is a subset of the SF-36 Health Survey. The 
survey captures physical and mental health. There are 8 subscales including: Physical 
functioning, Role-physical, Bodily pain, General health, Vitality, Social Functioning, 
Role-emotional, Mental health. The responses are reported on a 3 or 5 point Likert scale, 
depending on the question. The SF-12 is collected only for subjects enrolling in this study after 
completing Study SEP360-221. 
11.5. 
Study Visits and Assessments 
11.5.1. 
Open-label Baseline: Visit 1E (Day -1) 
Subjects will be evaluated at the Open-label Baseline Visit to determine their eligibility to enroll 
in the study. The following study-related procedures will be performed at Open-label Baseline: 


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• Obtain informed consent 
• Review inclusion/exclusion criteria 
• Demographics 
• Administer EDE-Q modified (Subjects from Study SEP360-221 only) 
• Dispense study drug (First dose taken the following day on Day 1) 
Results for the following study-related procedures will be carried over from the core study 
Week 12 visit, and do not need to be performed for the Open-label Baseline visit: 
• Physical and neurological examinations 
• Vital signs, weight, and BMI 
• ECG 
• Scales: BE-CGI-S, SDS, SF-12 (Subjects from Study SEP360-221 only), C-SSRS, 
HAM-A, MADRS, and EDE-Q modified (Subjects from Study SEP360-321 only) 
• Clinical laboratories (serum chemistry, lipid panel, hemoglobin A1c, hematology, 
urinalysis), UDS, and urine pregnancy test for females of child bearing potential 
• Breath alcohol test 
AEs and concomitant medications ongoing at the Week 12 visit in the core study will be carried 
over. Other data such as height will be carried over from other visits in the core study. 
Further information on data carried over from the core study will be addressed in the DMP. 
11.5.2. 
Treatment Period (Visits 2E – 15E; Weeks 2 – 52) 
Approximate midpoint between monthly Visits 3E and 4E, Visits 4E and 5E, Visits 5E and 6E, 
Visits 6E and 7E, Visits 7E and 8E, Visits 8E and 9E, Visits 9E and 10E, Visits 10E and 11E, 
Visits 11E and 12E, Visits 12E and 13E, Visits 13E and 14E, and Visits 14E and 15E (ie, 
14 ± 2 days after visit) a member of the study site staff will contact the subject/parent/legal 
guardian via telephone, text, or email between monthly visits according to the timeline in Table 2. 
These contacts will be used to collect AEs, and concomitant medications, as well as to remind 
subjects about adherence to study drug administration and upcoming visits, following which an 
unscheduled visit may be scheduled, if necessary. The date and time of these contacts will be 
documented in the CRF. 
11.5.2.1. Visit 2E: Week 2 (Day 14 ± 3) 
The following study related procedures will be performed: 
• Record concomitant medications 
• Collect vital signs and weight 
• Record AEs 
• Administer C-SSRS 


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• Perform study medication accountability 
• Dispense study medication 
11.5.2.2. Visit 3E (Week 4; Day 28 ± 3), Visit 5E (Week 12; Day 84 ± 3), Visit 7E (Week 20 
Day 140 ± 3), Visit 9E (Week 28; Day 196 ± 3), Visit 11E (Week 36; Day 252 ± 3), 
and Visit 13E (Week 44 Day 308 ± 3) 
The following study related procedures will be performed: 
• Record concomitant medications 
• Collect vital signs and weight 
• Perform physical examination (Visit 5E, Week 12, only) 
• Perform ECG (Visit 3E, Week 4; Visit 5E, Week 12; and Visit 11E, Week 36 only) 
• Record AEs 
• Administer Scales:  
• EDE-Q modified, SDS (Visit 5E, Week 12; and Visit 11E, Week 36, only), C-SSRS, 
BE-CGI-S, and SF-12 (Visit 5E, Week 12; and Visit 11E, Week 36 only; Subjects 
from Study SEP360-221 only) 
• Collect samples for clinical laboratories (serum chemistry, lipid panel, hemoglobin 
A1c, hematology, urinalysis) (Visit 5E, Week 12; and Visit 11E, Week 36 only) 
• Collect samples for UDS and urine pregnancy test for females of child bearing 
potential 
• Perform breath alcohol test 
• Perform study medication accountability 
• Dispense study medication 
11.5.2.3. Visit 4E (Week 8; Day 56 ± 3), Visit 6E (Week 16; Day 112 ± 3), Visit 8E (Week 
24; Day 168 ± 3), Visit 10E (Week 32; Day 224 ± 3), Visit 12E (Week 40; 
Day 280 ± 3), and Visit 14E (Week 48; Day 336 ± 3) 
The following study related procedures will be performed: 
• Record concomitant medications 
• Collect vital signs and weight 
• Perform physical examination (Visit 8E, Week 24, only) 
• Perform neurological examination (Visit 8E, Week 24, only) 
• Perform ECG (Visit 8E, Week 24, only) 
• Record AEs 


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• Administer Scales: SDS (Visit 8E, Week 24, only), EDE-Q modified, C-SSRS, 
BE-CGI-S, SF-12 (Visit 8E, Week 24, only; Subjects from Study SEP360-221 only), 
HAM-A (Visit 8E, Week 24, only), and MADRS (Visit 8E, Week 24, only) 
• Collect samples for clinical laboratories (serum chemistry, lipid panel, hemoglobin 
A1c, hematology, urinalysis) (Visit 8E, Week 24, only) 
• Collect samples for urine pregnancy test for females of child bearing potential 
(Visit 12E, Week 40 and Visit 14E,Week 48 only) 
• Perform study medication accountability 
• Dispense study medication 
11.5.2.4. Visit 15E/End of Treatment (Week 52; Day 364 ± 1) 
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 
• Administer Scales: EDE-Q modified, SDS, MADRS, C-SSRS, BE-CGI-S, SF-12 
(Subjects from Study SEP360-221 only), HAM-A, CSSA, and DESS 
• Collect Samples for clinical laboratories (serum chemistry, lipid panel, hemoglobin 
A1c, hematology, urinalysis), UDS and urine pregnancy test for females of child 
bearing potential 
• Perform breath alcohol test 
• Perform study medication accountability 
11.5.3. 
Withdrawal Period 
All subjects, including those who complete treatment and those who discontinue treatment, will 
complete weekly in-clinic visits during the 3 week study medication withdrawal period. In 
addition to the weekly 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 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 


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retrospectively collect the missed CSSA and DESS, in addition to the current day’s CSSA and 
DESS, as necessary. 
11.5.3.1. Visit 16E (Week 53; Day 371 ± 15) and Visit 17E (Week 54; Day 378 ± 16) 
The following study related procedures will be performed: 
• Record concomitant medications 
• Collect vital signs and weight 
• Perform ECG 
• Record AEs 
• Administer Scales: MADRS, C-SSRS, BE-CGI-S, HAM-A, CSSA, and DESS 
11.5.3.2. Visit 18E/End of Study (Week 55; Day 385 ± 17) 
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 
• Administer Scales: MADRS, C-SSRS, BE-CGI-S, HAM-A, CSSA, DESS, SDS, 
SF-12 (Subjects from Study SEP360-221 only) 
• Collect Samples for clinical laboratories (serum chemistry, lipid panel, hemoglobin 
A1c, hematology, urinalysis), UDS, and urine pregnancy test for females of child 
bearing potential 
• Perform breath alcohol test 
                                                     
 
 
5 For Early terminating subjects 7 days post last dose ± 1 day 
6 For Early Terminating subjects 14 days post last dose ± 1 day 
7 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 AE is any untoward medical occurrence in a study subject administered a medicinal 
(investigational) product and which does not necessarily have a causal relationship with this 
treatment. 
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 the time the informed consent is obtained to the last study visit. 
Lack of effectiveness 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 (ie, a patient is at immediate risk of death at the time of the event, 
not an event where occurrence in a more severe form might have caused death) 
• 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 an 
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. 
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 site. 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 at OL Baseline is indicated as 
clinically significant and is not covered by the inclusion criteria in Section 8.1, 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 at the Follow-up Visit, this should be recorded as an AE and the subject 
will be followed until the test(s) has (have) normalized or stabilized. 
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 ECG that persists 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 AEs must be collected and recorded in the subject’s study records/source documents, in 
accordance with the Investigator’s normal clinical practice, and on the CRF. All AEs will be 
followed up 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 2 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 medication stopped temporarily 
• Drug Withdrawn – Study medication stopped permanently 
• Dose Reduced 
• Dose Increased 
• Dose not Changed 
• Not Applicable 
The outcome of the AE: 
• Recovered/Resolved 
• Recovering/Resolving 
• Not Recovered/Not Resolved 
• Recovered/Resolved with Sequelae 
• Fatal 


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• Unknown 
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-medication 
administration, but could be related to concurrent drugs or underlying disease. 
o Probable - occurred in a reasonable time after study-medication 
administration, is unlikely to be attributable to concurrent drugs or underlying 
disease, and there is a plausible mechanism to implicate the study medication. 
o Definite - occurred in a reasonable time after study-medication administration 
and cannot be explained by concurrent drugs or underlying disease. The AE 
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 
from the time that informed consent is signed 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 medication. 
SAEs occurring from the time of informed consent through 14 days following last dose of the 
study medication also must be recorded on the CRF and the data recorded should match 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 PPD-PVG if considered at least possibly related to the 
study medication. 


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Serious AEs will be followed until resolution, loss to follow-up, stabilization of condition, or the 
event is otherwise explained. 
In addition to the initial 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 site staff becoming aware of the event. The SAE report 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 sites 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 site. 
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. 
If a pregnancy is reported for the study subject’s partner, the Sponsor’s representative will 
provide instructions on how to collect pregnancy information in accordance with local 
requirements. Proper consent to collect the partner’s information will be obtained before the 
collection of any information. 
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 site staff becoming aware of the 
pregnancy. The Sponsor provides the Pregnancy Event Form. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study medication 
may have interfered with the effectiveness of a contraceptive medication or other AEs were 
detected. 


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12.5. 
Data Monitoring Committee/Data and Safety Monitoring Board 
The Data and Safety Monitoring Board (DSMB) will monitor safety throughout the study. 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 effectiveness 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 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. 
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 11.5.2.4), as soon as possible following 
discontinuation of study drug, and complete the study medication withdrawal assessments and 
visits (Section 11.5.3). 
13.3. 
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). 
• Protocol violation (specify). 
• Pregnancy. 
• Withdrawal by subject (specify). 
• Other (specify). 


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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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14. 
STUDY TERMINATION 
The Sponsor reserves the right to discontinue the study at this site or at multiple sites for safety 
or administrative reasons at any time while ensuring that early termination does not compromise 
subjects’ safety or well-being. In particular, a site that does not recruit at an acceptable rate may 
be closed. Should the study be terminated and/or the site 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 after consultation with the Sponsor. 
In the event of study or site termination, subjects who discontinue study medication before 
completion will be asked to return to the site and complete the EOT visit assessments 
(Section 11.5.2.4) as soon as possible after discontinuation of study drug and complete the study 
medication withdrawal visits and calls (Section 11.5.3). 


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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 
Subjects who complete the double-blind treatment period of the core study, sign the consent, and 
meet all entry criteria will be included in this study. The double-blind core study SEP360-221 
plans to randomize approximately 300 subjects and the double-blind core study SEP360-321 
plans to randomize approximately 480 subjects. It is estimated that approximately 500 subjects 
will be eligible for enrollment in this study based on the number of subjects expected to complete 
treatment in the core study. 
15.2. 
Analysis Populations 
Safety Population: The safety population will include all subjects who receive at least one dose 
of study medication. The safety population mainly is used for the data analyses of the safety data 
collected through Week 52 or during the open-label treatment period. 
Withdrawal Population: The withdrawal population includes all subjects who receive at least one 
dose of study medication, and either early terminate from the study drug during the OL treatment 
period or complete the 52-week OL treatment period, and have at least 1 assessment after the last 
study drug administration for any evaluation. The withdrawal population is used to summarize 
the safety and effectiveness assessments collected in the withdrawal period. 
All effectiveness and safety evaluations will be summarized by analysis group based on the 
safety population and withdrawal population separately, when applicable. 
15.3. 
Data Analysis 
Unless otherwise specified, safety data will be presented separately by analysis group for the 
open-label treatment period (for data collected up to the end of open-label treatment period) and 
withdrawal period (for data collected during the withdrawal period), as appropriate. Since this is 
an uncontrolled open-label extension, no statistical comparisons will be conducted and no 
inferential statistics on effectiveness and safety will be presented. 
15.3.1. 
Analysis Group 
A total of 2 analysis groups will be formed based on a subject’s previous participation in the core 
studies (ie, subjects previously randomized to dasotraline and subjects previously randomized to 
placebo). Group “All-Das” that combines these 2 analysis groups will be also presented. 
Summary tables, wherever applicable, will be presented by above analysis group, respectively. 
 Pbo-Das: Subjects previously randomized to placebo in studies SEP360-221 or 
SEP360-321 
 Das-Das: Subjects previously randomized to dasotraline group in studies SEP360-221 or 
SEP360-321 


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 All-Das: all subjects combined 
Subjects continued from Study SEP360-221 will be further grouped into 2 analysis subgroups. In 
summary table they will be labeled as follows (ie, with one additional pooled group: 221-Das):  
 Pbo-Das: previously randomized to placebo  
 Das-Das: previously randomized to dasotraline 4–8 mg/day 
 221-Das: subjects continued from study SEP360-221 
Subjects continued from Study SEP360-321 will be further grouped into 3 analysis subgroups. In 
summary table they will be labeled as follows (ie, with 2 additional pooled groups: All Das-Das 
and 321-Das):  
 Pbo-Das: previously randomized to placebo 
 Das4-Das: previously randomized to dasotraline 4 mg/day 
 Das6-Das: previously randomized to dasotraline 6 mg/day 
 All Das-Das: previously randomized to dasotraline (4 mg/day or 6 mg/day) 
 321-Das: subjects continued from study SEP360-321 
Results will be presented by analysis subgroup as needed for limited analyses, wherever 
applicable. 
15.3.2. 
Definitions of Assessments 
The following definitions will be used for assessments: 
• Double-blind (DB) Baseline (ie, Baseline assessment of the double-blind study [core 
study]): the last assessment made on or before double-blind randomization as 
described in the core protocols; 
• OL Baseline (ie, Endpoint assessment of the double-blind treatment period of core 
study) or Baseline assessment of the open-label study (SEP360-322): the last 
assessment made during the double-blind treatment period, as described in the core 
protocols; 
• Week 52 Endpoint/Withdrawal Baseline: the last post-OL Baseline assessment made 
prior to or at Week 52 visit. 
• Withdrawal Endpoint: the last post-Withdrawal Baseline assessment made prior to or 
at Week 55 visit. 
Continuous variables will be summarized using descriptive statistics (N, mean, standard 
deviation [SD], median, range, 95% confidence interval [CI] as needed). Where changes are 
reported, the reference will be to “DB Baseline”. Where relevant, changes from “OL Baseline” 
will also be reported. 


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15.3.3. 
Safety Analysis 
The CSSA and DESS, which are used to assess physical dependence and withdrawal symptoms, 
are collected only at the Week 52 endpoint and in the withdrawal period; all other safety data are 
to be collected in both treatment period and withdrawal period and will be presented by analysis 
group for the open-label treatment period and withdrawal period, separately, as appropriate. 
15.3.3.1. Adverse Events 
All AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) version 
18.0 or higher. 
Treatment-emergent adverse events (TEAEs) are those reported adverse events with onset data 
on or after the first day of the open-label treatment period through 7 days after study drug 
discontinuation (14 days for serious adverse events and deaths). The start of the open-label 
treatment period is defined as Day 1 for subjects previously randomized to placebo group and the 
OL Baseline visit date for subjects previously randomized to dasotraline groups. 
A discontinuation-emergent adverse event (DEAE) is defined as an AE which has an onset after 
the last dose date of study drug through the Week 55 visit (ie, the last study visit in the 
withdrawal period). 
Table summaries of AEs will be limited to TEAEs and DEAEs. All AE data will be displayed in 
data listings. For the sake of simplicity, hereafter TEAE is referred to 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, study 
drug-related AEs leading to discontinuation, serious AEs leading to discontinuation, and serious 
study drug-related AEs, and serious study drug-related AEs leading to discontinuation will be 
summarized by analysis 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 analysis 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 incidence of AEs of special interest, including but not limited to neuropsychiatric-related 
and cardiovascular-related AEs, will be summarized by analysis group. For time to the earliest 
onset of insomnia, Kaplan-Meier curves will be plotted by analysis group. 
The overall incidence of DEAEs and serious DEAEs will be summarized by analysis group. The 
DEAEs also will be summarized by SOC and PT by presenting the number and percentage of 
subjects with each AE category. 
15.3.3.2. Columbia Suicide Severity Rating Scale (C-SSRS) 
The number and percentage of subjects with suicidal ideation and/or suicidal behavior, 
emergence or worsening of suicidal ideation or suicidal behavior will be summarized by analysis 
group for the open-label treatment period and the withdrawal period, separately. 


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15.3.3.3. Other Safety Assessments 
Other safety assessments, including but not limited to laboratory values, ECG, vital signs, 
weight, BMI, and neurological exam, will be summarized as below. BMI at a study visit will be 
derived per weight assessed at each open-label study visit and the height collected at Screening 
in the core studies. 
Treatment Period 
Descriptive statistics will be provided for observed values and changes from DB baseline and OL 
baseline by study visit and analysis group for continuous variables; for categorical variables. 
Frequencies and percentages by study visit and analysis group will be reported. In addition, for 
selected parameters of laboratory values, ECG, vital signs, and weight, the number and 
percentage of subjects with markedly abnormal values will be presented. 
Withdrawal Period 
Descriptive statistics of continuous variables will be provided for observed values and changes 
from Week 52 Endpoint by study visit and analysis group; for categorical variables, frequencies 
and percentage by study visit and analysis group will be reported. 
15.3.3.4. Physical Dependence and Withdrawal Symptoms 
For continuous data used to assess physical dependence and withdrawal symptoms (ie, CSSA 
total score, DESS total score, MADRS total score, and HAM-A total score), descriptive statistics 
of the observed values and changes from Week 52 Endpoint will be summarized by analysis 
group and visit for the withdrawal period. 
15.3.3.5. Concomitant Medications 
The number and percentage of subjects taking concomitant medication will be summarized by 
anatomical therapeutic chemical (ATC) classification and preferred name by analysis group. 
15.3.4. 
Analyses for Effectiveness and Subject-Reported Health Status 
For BE-CGI-S score, EDE-Q modified global score and subscales scores (restraint, shape concern, 
weight concern), EDE-Q modified items 4-6 scores, SDS total score and subscale scores, and 
SF-12 (subjects from Study SEP360-221 only) physical component and mental health 
component scores, descriptive statistics (N, mean, SD, median, range) of observed values will be 
summarized by analysis group at DB baseline, OL baseline (when applicable), each scheduled 
assessment in the treatment period, and Week 52 Endpoint. In addition, similar summary 
statistics as described above and 95% CI of changes from DB baseline and OL baseline will be 
presented. Confidence intervals will be based on means and standard deviations estimated 
without adjustment for any center or baseline effects. 
For time to early discontinuation, Kaplan-Meier curves will be plotted by analysis group. 
15.3.5. 
Interim Analysis 
No interim analysis is planned. 


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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 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 electronic data capture (EDC) system that is compliant with relevant FDA 
regulatory requirements per 21 CFR Part 11, Medidata Rave®. The SDS, C-SSRS, EDE-Q 
modified, MADRS, BE-CGI-S, HAM-A, CSSA, DESS, and SF-12 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 
Inclusion/Exclusion Criteria 
A 
Dispense Study Drug 
A, D 
Study Medication Accountability 
A 
Between visit contact 
A 
Demographics 
A 
Physical Examination 
A 
Neurological Examination 
A 
Prior and Concomitant Medications 
A 
Binge-eating Clinical Global Impressions of Improvement (BE-CGI-S) 
A 
Eating Disorder Examination Questionnaire (EDE-Q) modified 
A 
Sheehan Disability Scale (SDS) 
A 
Medical Outcomes Study 12-Item Short Form Survey Instrument (SF-12) 
A 
Vital Sign Measurements 
A 
Weight and Body Mass Index 
A 
Height 
A 
Adverse Events 
A 
Serum chemistry 
B 


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Table 7: 
Computerized Systems Used for Source Data (Continued) 
Protocol Step 
Computerized System Type or 
Description 
Lipid panel 
B 
Hemoglobin A1c 
B 
Hematology 
B 
Urinalysis 
B 
Columbia – Suicide Severity Rating Scale (C-SSRS) 
A 
Hamilton Anxiety Rating Scale (HAM-A) 
A 
Montgomery-Asberg Depression Rating Scale 
(MADRS) 
A 
Cocaine Selective Severity Assessment (CSSA) 
A 
Discontinuation-Emergent Signs and Symptoms (DESS) 
Scale 
A 
Urine Pregnancy Test (females of child-bearing 
potential only) 
A 
Urine Drug Screen 
A 
Breath Alcohol Test 
A 
12-Lead Electrocardiogram (ECG) 
C 
Statistical analysis 
SAS®, version 9.1.3 or higher 
 A = EDC (Medidata Rave®); B = LIMS; C = Core Lab Over-read; D = IXRS. 
 Abbreviations: EDC = electronic data capture; IXRS = Interactive Response System; LIMS = laboratory 
information management system. 
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 informed consent form (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. 
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. 


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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). All draft, 
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 
(see Section 19). 
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) will be obtained for all participating 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 approval must be obtained and also forwarded to the Sponsor. The IRB 
must supply the Sponsor a list of the IRB membership, and a statement to confirm that the IRB is 
organized and operates according to ICH GCP, applicable law(s) and regulation(s). 
A copy of written IRB 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 chairman or designee 
identify the IRB 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 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 continued review of the clinical 
research or submitting periodic progress reports, in accordance with applicable regulations, at 


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intervals not to exceed one year or as otherwise specified by the IRB. The Sponsor must be 
supplied with written documentation of continued review of the clinical research. 
The Investigator must promptly inform their IRB 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 before submission to the IRB. 
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 approval. The Sponsor/CRO may submit 
informed consent forms to a central IRB for review and approval or favorable opinion contingent 
upon prior the 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 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 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 and initials 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. 


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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. 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, except 
where necessary to eliminate an apparent immediate hazard to a study subject. 
Emergency deviations or modifications may be initiated without Sponsor or IRB 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 immediately/within five business days of the 
occurrence, or in accordance with applicable regulatory requirements. 
17.6. 
Records Retention 
The Investigator/the site must arrange for retention of study records at the site for at least 
15 years from time of participation in the study or longer in accordance with applicable 
regulations and Sponsor standard operating procedures (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 
site 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, 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 before 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. 


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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 
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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Arnold LM, McElroy SL, Hudson JI, Welge JA, Bennett AJ, et al. A placebo-controlled, 
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Buckholtz JW, Treadway MT, Cowan RL, Woodward ND, Li R, et al. Dopaminergic network 
differences in human impulsivity. Science 2010; 329:532.  
Busner, J. & McElroy, S.L. “Binge Eating Clinical Global Impressions - Severity Scale (BE-
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Carlezon WA, Devine DP, Wise RA. Habit-forming actions of nomifensine in nucleus 
accumbens. Psychopharmacology 1995; 122:194-7. 
Fairburn CG, Beglin SJ. Assessment of eating disorders: interview or self-report questionnaire? 
International Journal of Eating Disorders 1994; 16 (4):363-70. 
Filbey FM, Myers US, DeWitt S. Reward circuit function in high BMI individuals with 
compulsive overeating: similarities with addiction. Neuroimage 2012; 63:1800-6. 
Gold MS, Avena NM. Animal models lead the way to further understanding food addiction as 
well as providing evidence that drugs used successfully in addictions can be successful in 
treating overeating. Biol Psychiat 2013; 74(7):e11. 
Grilo CM, Crosby RD, Peterson CB, Masheb RM, White MA, et al. Factor structure of the eating 
disorder examination interview in patients with binge-eating disorder. Obesity 2010; 18: 977–81. 
Grilo CM, Crosby RD, White MA. Spanish-language Eating Disorder Examination interview: 
Factor structure in Latino/as. Eating Behaviors 2012;13: 410–13. 
Grilo CM, Masheb RM, Salant SL. Cognitive behavioral therapy guided self-help and orlistat for 
the treatment of binge eating disorder: a randomized, double-blind, placebo-controlled trial. Biol 
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Grilo CM, Masheb RM, Wilson GT. A comparison of different methods for assessing the 
features of eating disorders in patients with binge eating disorders. Journal of Consulting and 
Clinical Psychology 2001A; 69(2):317-22. 


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Grilo CM, Masheb RM, Wilson GT. Different methods for assessing the features of eating 
disorders in patients with binge eating disorder: A replication. Obesity Research 2001B; 9(7): 
418-22. 
Grilo CM, Henderson KE, Bell RI, and Crosby RD. Eating Disorder Examination-Questionnaire 
Factor Structure and Construct Validity in Bariatric Surgery. Obes Surg 2013;23:657-62.  
Grilo CM, Reas DL, Hopwood CJ, Crosby RD. Factor structure and construct validity of the 
eating disorder examination-questionnaire in college students: Further support for a modified 
brief version. Int J Eat Disord 2015; 48:284–89. 
Hoebel BG, Hernandez L, Schwartz DH, Mark GP, Hunter GA. Microdialysis studies of brain 
norepinephrine, serotonin, and dopamine release during ingestive behavior. Ann NY Acad Sci 
1989; 575(1):171-93. 
Hrabosky JI, White MA, Masheb RM, Rothschild BS, Burke-Martindale CH, et al. Psychometric 
evaluation of the eating disorder examination-questionnaire for bariatric surgery candidates. 
Obesity 2008; 16: 763–69. 
Hudson JI, Hiripi E, Pope HG, Kessler RC. The prevalence and correlates of eating disorders in 
the national comorbidity survey replication. Biol Psychiat 2007; 61:348-58. 
Hudson JI, McElroy SL, Raymond NC, Crow S, Keck PE, et al. Fluvoxamine in the treatment of 
binge-eating disorder: a multicenter placebo-controlled, double-blind trial. Am J Psychiat 1998; 
155(12):1756-62. 
Hutson PH, Tarazi FI, Madhoo M, Slawecki C, Patkar AA. Preclinical pharmacology of 
amphetamine: implications for the treatment of neuropsychiatric disorders. Pharmacol Therapeut 
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Ikemoto S, Glazier BS, Murphy JM, McBride WJ. Role of dopamine D1 and D2 receptors in the 
nucleus accumbens in mediating reward. J Neurosci 1997; 17(21):8580-7.  
Johnson PM, Kenny PJ. Dopamine D2 receptors in addiction-like reward dysfunction and 
compulsive eating in obese rats. Nat Neurosci 2010; 13:635-41. 
Kampman KM, Volpicelli JR, McGinnis DE, Alterman AI, Weinrieb RM, et al. Reliability and 
validity of the Cocaine Selective Severity Assessment. Addictive Behaviors 1998; 23(4): 449–
61. 
Kessler RC, Berglund PA, Chiu WT, Deitz AC, Hudson JI, et al. The prevalence and correlates 
of binge eating disorder in the WHO World Mental Health Surveys. Biol Psychiat 2013; 
73(9):904-14. 
Koblan KS, Hopkins SC, Sarma K, Jin F, Goldman R, et al. Dasotraline for the treatment of 
attention-deficit/hyperactivity disorder: a randomized, double-blind, placebo-controlled, proof-
of-concept trial in adults. [advance online publication June 3, 2015] Neuropsychopharmacology. 
doi: 10.1038/npp.2015.124. 
Lee B, London ED, Poldrack RA, Farahi J, Nacca A, et al. Striatal dopamine D2/D3 receptor 
availability is reduced in methamphetamine dependence and is linked to impulsivity. J Neurosci 
2009; 29:14734-40. 


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Leombruni P, Piero A, Brustolin A, Mondelli V, Levi M, et al. A 12 to 24 weeks pilot study of 
sertraline treatment in obese women binge eaters. Hum Psychopharm Clin 2006; 21:181-8. 
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 
trial. Am J Psychiat 2003A; 160(2):255-61. 
McElroy SL, Casuto LS, Nelson EB, Lake KA, Soutullo CA, et al. Placebo-controlled trial of 
sertraline in the treatment of binge eating disorder. Am J Psychiat 2000; 157(6):1004-6.  
McElroy SL, Guerdjikova AI, Mori N, O’Melia AM. Pharmacological management of binge 
eating disorder: current and emerging treatment options. Ther Clin Risk Manage 2012; 8:219-41. 
McElroy SL, Hudson JI, Capece JA, Beyers K, Fisher AC, et al. Topiramate for the treatment of 
binge eating disorder associated with obesity: a placebo-controlled study. Biol Psychiat 2007; 
61:1039-48. 
McElroy SL, Hudson JI, Malhotra S, Welge JA, Nelson EB, et al. Citalopram in the treatment of 
binge-eating disorder: a placebo-controlled trial. J Clin Psychiat 2003B; 64:807-13. 
McElroy SL, Kotwal R, Guerdjikova AI, Welge JA, Nelson EB, et al. Zonisamide in the 
treatment of binge eating disorder with obesity: a randomized controlled trial. J Clin Psychiat 
2006; 67(12):1897-1906. 
Minzenberg MJ. Pharmacotherapy for attention-deficit/hyperactivity disorder: from cells to 
circuits. Neurotherapeut 2012; 9:610-21. 
Murray S, Tulloch A, Gold MS, Avena NM. Hormonal and neural mechanisms of food reward, 
eating behavior and obesity. Nat Rev Endocrinol 2014; 10:540-52. 
NCT01718483: SPD489 in adults aged 18-55 years with moderate to severe binge eating 
disorder [Internet]. ClinicalTrials.gov. Accessed 2015 Jan 30. Available from: 
https://clinicaltrials.gov/ct2/show/NCT01718483?term=01718483&rank=1 
NCT01718509: SPD489 in adults aged 18-55 years with moderate to severe binge eating 
disorder [Internet]. ClinicalTrials.gov. Accessed 2015 Jan 30. Available from: 
https://clinicaltrials.gov/ct2/show/NCT01718509?term=01718509&rank=1 
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of 
Suicide Assessment (C-CASA): classification of suicidal events in the FDA's pediatric suicidal 
risk analysis of antidepressants. Am J Psychiatry 2007;164(7):1035-43. 
Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB. Selective Serotonin Reuptake 
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. 
Smith DG, Robbins TW. The neurobiological underpinnings of obesity and binge eating: a 
rationale for adopting the food addiction model. Biol Psychiat 2013; 73:804-10. 
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. 


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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. 
https://www.shire.com/~/media/shire/shireglobal/shirecom/pdffiles/newsroom/2015/january/201
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. 


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19. 
INVESTIGATOR APPROVAL 
I have read the protocol, SEP360-322, Version 4.00, “An Open-label, Flexibly-dosed, 
Multicenter, Extension Study of Dasotraline to Evaluate Long-term Safety and Tolerability in 
Adults with 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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20. 
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, Breath Alcohol Test, Urine Pregnancy Test (in female subjects of child-
bearing potential only), Serum Pregnancy Test (in female subjects with a positive urine 
pregnancy test). 
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. ACCEPTABLE CONTRACEPTIVE 
PROCEDURES FOR AND DURING THE STUDY 
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 
adequate contraception is defined as abstinence or continuous use of 2 barrier methods of 
contraception (eg, spermicidal condom). 
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. 


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23. 
APPENDIX IV. 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 21 April 2014. 


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24. 
APPENDIX V. 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. 


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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 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 


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identified that require similar medical surveillance. Subjects experiencing an event subject to 
additional monitoring may need to be discontinued from the study. 
 
Table 8: 
Checklist of Events Subject to Additional Monitoring Terms 
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 
 
 
Preparation of a Narrative for an Event Subject to Additional Monitoring (ESAM) 


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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 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 1 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 baseline and at various post-baseline 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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SAP_001.pdf: 
                                                                                                             
 
 
Statistical Analysis Plan 
 
   
An Open-label, Flexibly-dosed, Multicenter, Extension Study of 
Dasotraline to Evaluate Long-term Safety and Tolerability in Adults 
with Binge-eating Disorder 
 
 
DASOTRALINE (SEP-225289) 
Protocol SEP360-322 
 
Version Number: Final V 1.0 
Version Date: June 20, 2019 
 
Prepared by Syneos Health  
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-
322 
Final Version 1.0 
2 
 
Authorization Signature Page 
 
AN OPEN-LABEL, FLEXIBLY-DOSED, MULTICENTER, EXTENSION STUDY OF 
DASOTRALINE TO EVALUATE LONG-TERM SAFETY AND TOLERABILITY IN 
ADULTS WITH BINGE-EATING DISORDER 
  
 
Author: 
 
 
 
 
  
Name 
 Date 
Position:   Principal Biostatistician 
  
Company:  Syneos Health 
  
 
  
Approved by: 
 
  
 
 
_______________________________________________ 
 Manager, Biostatistics,  
Syneos Health 
 
 
_________________ 
Date 
 
 
_______________________________________________ 
Sr. Director, Clinical Research,  
Sunovion Pharmaceuticals Inc. 
 
 
_________________ 
Date 
 
 
_______________________________________________ 
Sr. Director, Biostatistics, 
Sunovion Pharmaceuticals Inc. 
 
 
_________________ 
Date 
 
 
_______________________________________________ 
 Executive Director, Biostatistics, 
Sunovion Pharmaceuticals Inc. 
 
 
_________________ 
Date 
 
 
Table of contents 


Statistical Analysis Plan                                                                                                     Sunovion Pharmaceuticals 
Inc.  
                                                                                                                                                                         SEP360-
322 
Final Version 1.0 
3 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................7 
1. 
INTRODUCTION ........................................................................................................9 
2. 
STUDY OBJECTIVES ..............................................................................................10 
2.1. 
Primary Objective .......................................................................................................10 
2.2. 
Secondary Objective ...................................................................................................10 
3. 
STUDY DESIGN .......................................................................................................11 
3.1. 
Determination of Sample Size ....................................................................................12 
3.2. 
Randomization, Stratification and Blinding ...............................................................12 
4. 
CHANGES IN PLANNED ANALYSES ...................................................................13 
5. 
EFFECTIVENESS AND SAFETY VARIABLES ....................................................14 
5.1. 
Effectiveness Variables ..............................................................................................14 
5.1.1. 
Binge-eating Clinical Global Impression-Severity (BE-CGI-S) ................................14 
5.1.2. 
Eating Disorder Examination Questionnaire (EDE-Q) modified and 
Comparison with EDE-Q and EDE-Q Brief Version (EDE-Q7) ...............................14 
5.1.3. 
Sheehan Disability Scale (SDS) .................................................................................16 
5.2. 
Patient-Reported Outcome (PRO) ..............................................................................17 
5.2.1. 
12-Item Short Form Health Survey (SF-12) ...............................................................17 
5.3. 
Safety Assessment ......................................................................................................17 
5.3.1. 
Columbia – Suicide Severity Rating Scale (C-SSRS) ................................................18 
5.3.2. 
Withdrawal Assessment for Physical Dependence and Withdrawal 
Symptoms ...................................................................................................................19 
5.3.2.1. 
Cocaine Selective Severity Assessment (CSSA) ........................................................19 
5.3.2.2. 
Discontinuation-Emergent Signs and Symptoms (DESS) Scale ................................19 
5.3.2.3. 
Montgomery-Asberg Depression Rating Scale (MADRS) ........................................20 
5.3.2.4. 
Hamilton Anxiety Rating Scale (HAM-A) .................................................................20 
6. 
STATISTICAL METHODS .......................................................................................21 
6.1. 
General Analysis Definition .......................................................................................21 
6.1.1. 
Analysis Period and Study Day ..................................................................................21 
6.1.1.1. 
Open-Label Treatment Period (On Treatment) ..........................................................21 
6.1.1.2. 
Withdrawal Period (Off Treatment) ...........................................................................21 
6.1.1.3. 
Overall Study Period ...................................................................................................22 
6.1.2. 
Visit Windows ............................................................................................................22 
6.1.2.1. 
Visit Windows for Visits in Open-Label Treatment Period .......................................22 


Statistical Analysis Plan                                                                                                     Sunovion Pharmaceuticals 
Inc.  
                                                                                                                                                                         SEP360-
322 
Final Version 1.0 
4 
 
6.1.2.2. 
Visit Window for Visits in Withdrawal Period ..........................................................24 
6.1.3. 
Baseline .......................................................................................................................25 
6.1.3.1. 
DB Baseline ................................................................................................................25 
6.1.3.2. 
OL Baseline ................................................................................................................25 
6.1.3.3. 
Withdrawal Baseline ...................................................................................................26 
6.1.4. 
Endpoint ......................................................................................................................26 
6.1.4.1. 
Endpoint ......................................................................................................................26 
6.1.4.2. 
Withdrawal Endpoint ..................................................................................................26 
6.1.5. 
Aggregated Analysis Timepoint .................................................................................26 
6.1.6. 
Pooling Strategy for Analysis of Centers ...................................................................26 
6.1.7. 
Adjustments for Covariates ........................................................................................26 
6.1.8. 
Analysis Populations ..................................................................................................26 
6.1.9. 
Analysis Group and Analysis Subgroup .....................................................................27 
6.1.10. 
Average Dose, Predominant/Modal Dose, Maximum Dose ......................................28 
6.1.11. 
Handling of Dropouts or Missing Data ......................................................................29 
6.1.11.1. 
Unknown or Unconfirmed Last Study Dose Date ......................................................29 
6.1.11.2. 
Composite Score .........................................................................................................29 
6.1.11.3. 
Incomplete/Missing Dates ..........................................................................................29 
6.1.11.3.1.  Start/End Dates for Adverse Event .............................................................................29 
6.1.11.3.2.  Start/End Dates for Prior/Concomitant Medication ...................................................30 
6.1.12. 
Subgroup Analysis ......................................................................................................30 
6.1.13. 
BMI (kg/m2) ................................................................................................................30 
6.1.14. 
EDE-QM Items 4, 5, and 6 .........................................................................................30 
6.2. 
Methods of Analysis ...................................................................................................31 
6.2.1 
General Methodology .................................................................................................31 
6.2.2 
Statistical Hypotheses for Trial Objectives ................................................................31 
6.2.3 
Interim Analysis ..........................................................................................................31 
6.2.4 
Data Monitoring ..........................................................................................................31 
7. 
STATISTICAL ANALYSES .....................................................................................32 
7.1. 
SUBJECT INFORMATION ......................................................................................32 
7.1.1. 
Demographic and Baseline Characteristics ................................................................32 
7.1.2. 
Disposition Information ..............................................................................................33 


Statistical Analysis Plan                                                                                                     Sunovion Pharmaceuticals 
Inc.  
                                                                                                                                                                         SEP360-
322 
Final Version 1.0 
5 
 
7.1.3. 
Treatment Compliance ................................................................................................33 
7.1.4. 
Extent of Exposure .....................................................................................................35 
7.1.5. 
Study Medication and Concomitant Medications .......................................................35 
7.1.5.1. 
Study Medication ........................................................................................................35 
7.1.5.2. 
Concomitant Medications ...........................................................................................36 
7.1.6. 
Psychiatric History and Medical History Prior to DB Phase of Core Study ..............36 
7.1.7. 
Psychotherapy .............................................................................................................37 
7.1.8. 
Protocol Deviations ....................................................................................................37 
7.2. 
Effectiveness Analyses ...............................................................................................37 
7.2.1. 
Definition ....................................................................................................................37 
7.2.2. 
Analysis Methods .......................................................................................................38 
7.3. 
Pharmacokinetics (PK) Analysis ................................................................................38 
7.4. 
Safety ..........................................................................................................................38 
7.4.1. 
Analysis Specifications ...............................................................................................38 
7.4.2. 
Adverse Events ...........................................................................................................39 
7.4.3. 
Laboratory Measurements ..........................................................................................43 
7.4.3.1. 
Treatment Period ........................................................................................................43 
7.4.3.2. 
Withdrawal Period ......................................................................................................45 
7.4.4. 
ECG Evaluations ........................................................................................................45 
7.4.4.1. 
Treatment Period ........................................................................................................46 
7.4.4.2. 
Withdrawal Period ......................................................................................................47 
7.4.5. 
Vital Signs, Weight, and BMI ....................................................................................47 
7.4.5.1. 
Treatment Period ........................................................................................................47 
7.4.5.2. 
Withdrawal Period ......................................................................................................49 
7.4.6. 
Assessments of Withdrawal Effects (CSSA, DESS, HAM-A, and MADRS) ...........49 
7.4.6.1. 
Treatment Period ........................................................................................................49 
7.4.6.2. 
Withdrawal Period ......................................................................................................49 
7.4.7. 
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................................50 
7.4.7.1. 
Treatment Period ........................................................................................................51 
7.4.7.2. 
Withdrawal Period ......................................................................................................52 
7.4.8. 
Other Safety Assessments ...........................................................................................52 
7.4.8.1. 
Breath Alcohol Test ....................................................................................................52 


Statistical Analysis Plan                                                                                                     Sunovion Pharmaceuticals 
Inc.  
                                                                                                                                                                         SEP360-
322 
Final Version 1.0 
6 
 
7.4.8.2. 
Neurological Examination ..........................................................................................52 
7.4.8.3. 
Abuse Potential Monitoring Plan (APMP) .................................................................52 
7.4.8.3.1. 
Medication Handling Irregularities .............................................................................53 
7.4.8.3.2. 
Events Subject to Additional Monitoring (ESAMs) ...................................................53 
 


Statistical Analysis Plan                                                                                                     Sunovion Pharmaceuticals 
Inc.  
                                                                                                                                                                         SEP360-
322 
Final Version 1.0 
7 
 
List of Abbreviations and Definition of Terms 
Abbreviation  
Full Form  
AE  
Adverse event  
ALT  
Alanine aminotransferase  
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  
BSN 
Baseline 
BUN  
Blood urea nitrogen  
CI  
Confidence interval  
CRF  
Case report form  
C-SSRS  
Columbia-suicide severity rating scale  
CSSA  
Cocaine Selective Severity Assessment  
DAS  
Dasotraline  
DB  
Double-blind 
DBL  
Database lock  
DEAE  
Discontinuation-emergent adverse event  
DESS  
Discontinuation-Emergent Signs and Symptoms  
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 
EOS 
End of Study 
EOT  
End of treatment  
FDA  
U.S. Food and Drug Administration  
HAM-A  
Hamilton Anxiety Rating Scale  
HDL  
High-density lipoprotein (cholesterol)  
HR  
Heart rate  
ICF  
Informed consent form  
LDL  
Low-density lipoprotein (cholesterol)  
LOCF  
Last Observation Carried Forward  
MADRS  
Montgomery-Asberg Depression Rating Scale  


Statistical Analysis Plan                                                                                                     Sunovion Pharmaceuticals 
Inc.  
                                                                                                                                                                         SEP360-
322 
Final Version 1.0 
8 
 
Abbreviation  
Full Form  
MALV 
Markedly Abnormal Laboratory Values 
MAVS 
Markedly Abnormal Vital Signs 
MCS 
Mental Component Summary 
NDA 
New Drug Application
OL 
Open Label 
PCS 
Physical Component Summary 
PK  
Pharmacokinetic(s)  
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  
SD  
Standard deviation  
SDS  
Sheehan disability Scale  
SF-12  
Medical Outcomes Study 12-Item Short Form  
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  
ULN  
Upper limit of normal  
VAS  
Visual analog scale  
WBC  
White blood cells  


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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 SEP360-322 for subjects continued from core studies SEP360-221 or SEP360-321.  
Study completion status of the two core studies is given below: both studies were completed. 
Study SEP360-221 clinical database was locked on Nov 15, 2016 and study SEP360-321 clinical 
database was locked on June 25, 2018.   
One full interim analysis was planned to support regulatory filing of New Drug Application 
(NDA) submission for binge eating disorder (BED). The interim analysis was conducted per data 
snapshot with data cut date of Aug 31, 2018. In total there are two separate and independent data 
analyses for study SEP 360-322, one for the interim analysis and the other for final analysis. The 
final database lock will occur when the study is completed and a subsequent final analysis of 
study SEP 360-322 will be performed. 
This SAP is developed based on the version of the study protocol with Amendment 3.0 dated 
June 13, 2017. It outlines analyses to be conducted for the final database lock for data collected 
through the withdrawal period. A separate SAP for the interim analysis was prepared and 
finalized prior to data snapshot for the interim data cut.   
If additional analyses are required to supplement the planned analyses described in this SAP after 
the final database lock, they may be performed and will be identified and documented 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 long-term safety and tolerability of flexibly-
dosed dasotraline (4, 6, or 8 mg/day) in adults with BED who have completed a prior dasotraline 
study in BED by: 
 The incidence of AEs, discontinuations due to AEs, and serious AEs (SAEs)  
 The frequency and severity of suicidal ideation and suicidal behavior using the Columbia 
– Suicide Severity Rating Scale (C-SSRS)  
 Changes in 12-lead electrocardiograms (ECGs), vital signs, body weight, body mass 
index (BMI), and clinical laboratory results 
2.2. 
Secondary Objective 
The secondary objects are:  
 To assess potential withdrawal effects of dasotraline 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 Hamilton Anxiety Rating Scale (HAM-A)  
 Symptoms of depression utilizing the Montgomery-Asberg Depression Rating 
Scale (MADRS)  
 To assess the abuse potential of dasotraline utilizing a comprehensive abuse potential 
monitoring plan (APMP)  
 To evaluate the long-term effectiveness of flexibly-dosed dasotraline in the treatment of 
adults with BED as measured by the following:  
 Eating Disorder Examination Questionnaire (EDE-Q) modified  
 Binge-eating Clinical Global Impressions - Severity (BE-CGI-S)  
 Sheehan Disability Scale (SDS)  
 To assess subject-reported health status using the Medical Outcomes Study 12-Item Short 
Form Survey Instrument (SF-12) (SF-12 collected only for subjects enrolling in this study 
after completing core study SEP360-221). 


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3. 
Study Design 
This is a Phase 3, 12-month, multicenter, open-label, flexibly-dosed, safety study in adults with 
BED. This study is projected to enroll approximately 500 subjects based on the number of 
subjects expected to complete treatment in the core studies (ie, SEP 360-221 or SEP360-321). 
Informed consent is obtained from all subjects after all procedures from the core study have been 
completed and before any study procedures unique to this study are performed. Safety and 
tolerability is monitored throughout the study by AE reports, physical and neurological 
examinations, 12-lead ECG, vital signs, body weight, BMI, clinical laboratories (hematology, 
chemistry, urinalysis, hemoglobin A1c, and lipid panel), and C-SSRS. Effectiveness will be 
evaluated using the BE-CGI-S, EDE-Q modified, and SDS. Subject-reported health status will be 
assessed using the SF-12 (subjects from Study SEP360-221 only). Assessment of potential 
withdrawal effects of dasotraline 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.  
A comprehensive Abuse Potential Monitoring Plan (APMP, see Protocol Section 24) 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) reviews safety data including data 
on adverse events (AEs) and serious adverse events (SAEs) at regular intervals. 
Subjects self-administers study drug on an outpatient basis for 12 months, once a day at 
approximately the same time each morning with or without food, including on the days when 
clinic visits occur. Subjects meeting all inclusion and no exclusion criteria start taking open-label 
study drug on Day 1, the morning following the open-label (OL) Baseline visit (ie, Week 12 visit 
in the core study). 
The total daily dose remains between 4 mg/day and 8 mg/day for the 12-month treatment period. 
Dasotraline is dosed at 4 mg/day for the first 2 weeks of the study. At the Week 2 visit, the dose 
may be increased to 6 mg/day. Thereafter the dose may be increased or decreased by 2 mg/day, 
as necessary for effectiveness or tolerability reasons at the discretion of the investigator. A 
minimum of 8 days is required between dose increases. Dose decreases may be made at less than 
8 day intervals, at the investigator’s discretion, for reasons of safety or tolerability. If, in the 
judgment of the investigator, the subject does not tolerate the minimum required dose (4 mg/day), 
he or she is discontinued from the study. All changes in study drug dose begins the morning after 
the visit at which the dose change decision is made and using the new package of study drug. 
The study consists of a baseline visit, 12-month open-label treatment period, and 3-week study 
drug withdrawal period as shown in the Study Schematic (protocol section 7.1 Figure 1). During 
the treatment period, subjects will return to the clinic at the end of 2 and 4 weeks for clinical 
evaluation and thereafter will return to the clinic once every 4 weeks during the treatment period 


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for scheduled visits. At the approximate midpoint between the scheduled monthly visits (ie, 14 ± 
2 days after a visit), the site staff will contact the subject via telephone, text, or email in order to 
monitor for SAEs, AEs, and concomitant medications, as well as to remind subjects about 
adherence to study drug administration, and upcoming visits. If necessary, an unscheduled visit 
can be arranged. 
Subjects attend weekly visits during the 3-week study drug withdrawal period. Assessment of 
potential withdrawal effects of dasotraline will be conducted via administration of the CSSA, 
DESS, HAM-A, and MADRS at the end of treatment. Subjects will undergo assessments every 
other day and weekly as follows: The CSSA and DESS will be completed every other day during 
the 3-week study medication withdrawal period. Clinical site staff will call the subject every 
other day, beginning the second day after the last dose of study drug, unless a clinic visit is 
scheduled for that day. Phone contacts may be made 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 missed 
CSSA and DESS, in addition to the current day’s CSSA and DESS, as necessary. 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. The CSSA, DESS, HAM-A, and MADRS also will be 
administered at each weekly visit during the withdrawal period. 
A window of ± 1 day is allowed for each weekly clinic visit and telephone call during the study 
medication withdrawal period.  
After the last withdrawal period visit, all subjects will be referred for follow-up care as 
determined by the investigator. 
The schedule of assessments for this study is in Attachment 9.1; also see protocol Section 11.5 
for study visits and assessments detail. 
3.1. 
Determination of Sample Size 
Subjects who complete the double-blind treatment period of the core study, sign the consent, and 
meet all entry criteria are included in this study. The double-blind core study SEP360-221 
planned to randomize approximately 300 subjects and the double-blind core study SEP360-321 
planned to randomize approximately 480 subjects. It is estimated that approximately 500 
subjects are eligible for enrollment in this study based on the number of subjects expected to 
complete treatment in the core studies. 
3.2. 
Randomization, Stratification and Blinding 
This is an open-label extension study, therefore randomization and blinding is not employed. 


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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. 
Effectiveness and Safety Variables  
5.1. 
Effectiveness Variables 
5.1.1. 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 Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52/EOT in the 
open-label treatment period, and at Weeks 53, 54 and 55/EOS for subjects who enter the 
withdrawal period. 
5.1.2. Eating Disorder Examination Questionnaire (EDE-Q) modified and 
Comparison with EDE-Q and EDE-Q Brief Version (EDE-Q7)  
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 an 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 the Eating Disorder Examination Questionnaire Brief Version (EDE-Q7) and EDE-Q 
modified  are shorter versions of the EDE-Q.  
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 and is 
used in this study. 
 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)? 


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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  
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 scores is missing. For EDE-Q, EDE-Q modified, and EDE-Q7, higher scores on 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, EDE-Q7, and EDE-Q modified are all designed to collect the data in the past 28 days.  
For subjects continued from study SEP360-221, EDE-Q modified is collected at open label 
baseline visit; for subjects continued from study SEP360-321, EDE-Q modified is carried over 
from W12/EOT visit in study SEP360-321. In addition, EDE-Q modified is collected at Weeks 4, 
8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52/EOT in the open-label treatment period. 
5.1.3. 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, 
the SDS total score for that visit is also missing. A higher subscale score and total score are 
associated with greater illness severity. 
SDS is collected at Weeks 12, 24, 36, 52/EOT in treatment period, and at Week 55/EOS for 
subjects who enter the withdrawal period. 


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5.2. 
Patient-Reported Outcome (PRO)  
5.2.1. 12-Item Short Form Health Survey (SF-12) 
The SF-12 is a 12-item self-report questionnaire. The survey captures physical and mental 
health. There are 8 subscales including: Physical functioning, Role-physical, Bodily pain, 
General health, Vitality, Social Functioning, Role-emotional, Mental health. The responses are 
reported on a 3 or 5 point Likert scale, depending on the question. The SF-12 uses two items 
each to estimate scores for four of the eight health concepts (physical functioning, role-physical, 
role-emotional, and mental health). Scores for the remaining four health concepts (bodily pain, 
general health, vitality, and social functioning) are estimated using one item each. Physical 
Component Summary (PCS) and Mental Component Summary (MCS) are computed using the 
scores of twelve questions and range from 0 to 100, where a zero score indicates the lowest level 
of health measured by the scales and 100 indicates the highest level of health. 
SF-12 data will be provided by Optum. For details of data derivation, see Attachment 9.2.  
For subjects who continued from study SEP360-221 only, the SF-12 is collected at Weeks 12, 
24, 36 and 52/EOT and at Week 55/EOS for subjects who enter  the withdrawal period. SF-12 is 
not collected for subjects who continue from study SEP360-321. 
5.3. 
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)  
 body weight and body mass index (BMI) 
 concomitant medication reports 
 physical examinations 
 Columbia – Suicide Severity Rating Scale (C-SSRS) 
 
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 


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 Symptoms of depression utilizing the MADRS 
5.3.1. Columbia – Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is an instrument designed to systematically assess and track suicidal behavior and 
suicidal ideation 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’. 
For all study visits, the “Since Last Visit” version of the C-SSRS is administered. 
C-SSRS is collected at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52/EOT in the open-
label treatment period, and at Weeks 53, 54 and 55/EOS for subjects who enter the withdrawal 
period. 


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5.3.2. Withdrawal Assessment for Physical Dependence and Withdrawal 
Symptoms 
Subjects who either are early terminated in the open-label treatment period or complete the 52-
week open-label treatment period 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 52/EOT, then at Weeks 53, 54, and 55/EOS 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. 
5.3.2.1. 
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 Week 52/EOT, and Weeks 53, 54 and 55/EOS for subjects who enter 
the withdrawal period. 
5.3.2.2. 
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 


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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 Week 52/EOT, and Weeks 53, 54 and 55/EOS for subjects who enter 
the withdrawal period. 
5.3.2.3. 
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 Weeks 24, 52/EOT, and Weeks 53, 54 and 55/EOS for subjects who 
enter the withdrawal period. 
5.3.2.4. 
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 Weeks 24, 52/EOT, and Weeks 53, 54 and 55/EOS for subjects who 
enter the withdrawal period. 


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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 study data for the subject.  
6.1.1.1. 
Open-Label Treatment Period (On Treatment) 
The day of the 1st dose date in the extension study will be denoted as study Day 1. All 
measurements at each visit will be assigned a study day relative to this date. All data collected 
on/after Day 1 for subjects previously randomized to placebo group in core study or on/after the 
extension baseline visit for subjects previously randomized to dasotraline groups and up to Week 
52, including the End-of-treatment/Early Withdrawal visit, will be considered within the open-
label treatment phase. That is to say, the start of the open-label treatment period is defined as 
Day 1 for subjects previously randomized to placebo group and the OL Baseline visit date for 
subjects previously randomized to dasotraline groups; the end of the open-label treatment phase 
is defined as the maximum of the last date of administration of study medication and the 
withdrawal/ completion date.  
The start and end of open-label treatment period are given below: 
 Start of treatment period =  
  = Date of the first study medication administration for subjects previously randomized 
to placebo group 
  = Date of the OL Baseline visit for subjects previously randomized to dasotraline; 
 End of treatment period = maximum of the last date of administration of study 
medication and the withdrawal/ completion date (ie, Week 52/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 the first dose date in the extension study.   
 Study Day = Assessment date − the first dose date in the extension study + 1; if 
assessment date ≥ the first dose date in the extension study 
 Study Day = Assessment date − the first dose date in the extension study; if assessment 
date < the first dose date in the extension study 
6.1.1.2. 
Withdrawal Period (Off Treatment) 
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 or ‘unconfirmed’ (eg, lost follow-up 
subjects), start and end days relative to the last study dose 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 (ie, the last study dose 
date). 
 Study Day = Assessment date − the last dose date  if assessment date ≥ the last dose 
date in the extension study 
6.1.1.3. 
Overall Study Period 
Overall study period is defined as a combination of the open-label treatment period and 
withdrawal period. 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 
Open  Label Treatment 
Period 
Day 1* 
EOT a  
Subjects previously randomized to Placebo group  
Baseline 
Visit Date 
EOT a 
Subjects previously randomized to Dasotraline  
Withdrawal Period 
Day 0 ** 
 
EOS b  
Withdrawal Population  
Overall Study Period 
Day 1* 
EOS b 
Subjects previously randomized to Placebo group 
Baseline 
Visit Date 
EOS b 
Subjects previously randomized to Dasotraline group 
Note:   *: the day of the first dose of open-label study medication. 
            a : Week 52 visit/ early withdrawal visit            
           **: the day of the last dose of open-label 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 OL treatment are based on 
the portion of study data that fall in the open-label treatment period. 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. Visit Windows 
6.1.2.1. 
Visit Windows for Visits in Open-Label Treatment Period 
While the Time and Events Schedule of the protocol indicates the visit timing and procedures for 
each visit, the timing of a subject’s actual visit timing may not be exactly as per the protocol 
indicated target day/visit window (note that the protocol does not indicate required visit windows, 
but rather provides clear guidance for visit timing).  Consequently, for the purpose of analysis, 
the conventions outlined below will be used to allocate the data collected at each actual visit to a 
planned protocol visit by defining analysis visit windows. 


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The reference day is study Day 1. Definition of baseline and endpoint is provided in Sections 
6.1.3 - 6.1.4. 
Table 4 summarizes the analysis visit windows for all questionnaires, laboratory, weight, height, 
vital signs, ECG, physical and neurological examination, and other safety variables assessed at 
scheduled visits. 
Table 4. Time Intervals for Analysis Visit Windows in Open-Label Treatment Period 
Scheduled Visit 
(label on output in 
Extension study) 
Target Day (a) 
Time Interval (Day) 
OL Baseline (b) 
−1 
<1
Week 2 
14
1 – 21
Week 4 
28
22 – 35
Week 8 
56
36 - 70
Week 12 
84
71 - 98
Week 16 
112
99 - 126
Week 20 
140
127 - 154
Week 24 
168
155 - 182
Week 28 
196
183 - 210
Week 32 
224
211 - 238
Week 36 
252
239 - 266
Week 40 
280
267 - 294
Week 44 
308
295 - 322
Week 48 
336
323 - 350
Week 52 
364
351 - EOT
(a): Relative to the day of the 1st dose date .  
(b): Also refer Section 6.1.3 for details of definition of Baseline. 
 
If a subject has 2 or more visits in one analysis visit window (scheduled or unscheduled), the 
visit closest to the target day will be used as the study visit for that analysis visit window. The 
other additional visit(s) in the same analysis visit window will not be included in the by-visit 
descriptive summary analyses.   However, measurements from this/these other additional visit(s) 
will be included in the other safety analyses (eg, Potentially Markedly Abnormal Laboratory 
Values or the worst case analysis) to assure all on-treatment measurements are included. If 2 
study visits occur on 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.  
Although all (scheduled and unscheduled) visits will be allocated to an analysis visit window, 
only planned protocol visits for each measurement will be included in the by-visit analyses. All 
tables and figures presenting data by visit will present only those timepoints where the applicable 
assessment was scheduled to be collected, unless otherwise noted below.  Unscheduled and early 
termination data will be included for definition of endpoint or overall assessments (eg, the worst 
case analysis for an assessed period).  Data listings will present all data, regardless of scheduled 
and unscheduled visits.     


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6.1.2.2. 
Visit Window for Visits in Withdrawal Period 
Visits within withdrawal period will be mapped per visit window defined in Table 5.1 below for 
effectiveness and safety data collected in withdrawal period except of the phone contact visits 
used for collecting additional CSSA and DESS information.  
Table 5.1: Visit Window for Clinic Visits in Withdrawal Period  
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 open-label study medication 
b per both 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 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 2 study visits occur 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 5.2 below for CSSA and DESS specifically.  
 
Table 5.2: 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 
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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. 
 
6.1.3. Baseline 
Three types of Baseline will be defined: DB Baseline, OL Baseline, and Withdrawal Baseline.  
6.1.3.1. 
DB Baseline  
DB Baseline (ie, Baseline assessment of the double-blind core studies [SEP 360-221, or SEP 
360-321]) is defined as the last assessment made on or before the 1st dose of double-blind study 
medication as described in the SAPs of the core studies. 
6.1.3.2. 
OL Baseline  
Except for height ( for all subjects), demographics (for all subjects) and EDE-Q modified (for 
subjects continued from SEP360-221), unless otherwise specified, based on the protocol of 
SEP360-322 and the schedule of assessment (Attachment 9.1), OL Baseline values are to be 
carried over from W12/Endpoint in the core studies. The OL Baseline is defined as the last 
assessment made on or before Day 1 of the extension study (ie, Baseline assessment in the open-
label study [SEP 360-322] for demographic (for all subjects) and EDE-Q modified (for subjects 
from SEP360-221), and height at the screening and the Endpoint assessment of the double-blind 
studies [SEP 360-221, or SEP 360-321] (for all subjects), otherwise).  
As indicated in the protocol, height at the screening visit in the core studies will be carried over 
as OL Baseline. For operation convenience, the protocol specified that data collected at the EOT 
visit of the core studies are recorded in core studies only and are not to be saved in the clinical 
database of the extension study. Height at OL Baseline visit will be assigned a value per the 
corresponding Study Data Tabulation Model (SDTM) dataset of core studies directly.  
Unless otherwise specified,  at each study visit of study SEP 360-322, data derivation rule and 
missing imputation method for aggregated parameters that involves multiple individual items 
(eg, total score, subscale score, or composite score), are same as the corresponding ones in 
individual core study SAPs.  DB Baseline is defined same as the Baseline in individual core 
study per core study SAPs.  DB Baseline used in the analysis of study SEP 360-322 will be 
extracted from corresponding Analysis Data Model datasets (ADaM) of the core studies directly. 


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6.1.3.3. 
Withdrawal Baseline  
See Section 6.1.2.2 for the definition of Withdrawal Baseline.  No imputation will be made if the 
Withdrawal Baseline value is missing. 
6.1.4. Endpoint 
6.1.4.1. 
Endpoint 
Endpoint (ie, Week 52 Endpoint) is defined as the last post-OL Baseline assessment during the 
open-label treatment period.  
6.1.4.2. 
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). 
6.1.5. Aggregated Analysis Timepoint 
An aggregated analysis timepoint named as ‘any OL treatment period (treatment emergent)’ will 
be derived for selected safety assessments (eg, the worst case analysis) as below. 
 
Any OL treatment period (treatment emergent): defined as any assessment collected in 
open-label treatment period (see Section 6.1.1.1).   
Specifically, the aggregated analysis timepoint of any OL treatment period (treatment emergent) 
will be applied on the following worst-case analysis:   
 Markedly Abnormal Laboratory Values (MALV) (Section 7.4.3.1, Table 6)  
 Markedly Abnormal Vital Signs (MAVS) (Section 7.4.5.1, Table 9.1)  
 QTc prolongation (Section 7.4.4.1, Table 7)  
 ECG abnormality (Section 7.4.4.1, Table 8).  
 C-SSRS (Section 7.4.7) 
6.1.6. Pooling Strategy for Analysis of Centers 
There will be no pooling of centers in this study. 
6.1.7. Adjustments for Covariates 
Not Applicable. No statistical modeling or inference will be performed, including the ones 
containing baseline as a covariate to adjust baseline.  
6.1.8. Analysis Populations 
The Safety Population: All subjects who receive at least one dose of study medication. The 
safety population mainly is used for the data analyses of the safety data collected through 
Week 52 or during the open-label treatment period.   


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The Withdrawal Population: The withdrawal population includes all subjects who receive at 
least one dose of study medication, and either early terminate from the study drug during the OL 
treatment period or complete the 52-week OL treatment period, and have at least 1 assessment 
after the last study drug for any evaluation. The withdrawal population is used to summarize the 
safety and effectiveness assessments collected in the withdrawal period. Withdrawal analysis 
will be presented by analysis group.  
The ‘Modified’ Withdrawal Population: all subjects in the withdrawal population plus the 
subjects who either are early terminated during the OL treatment period or complete the 52-week 
OL treatment period and do not enter the withdrawal period, but the last study dose dates are at 
least 2 days  prior to their last study visit. The modified withdrawal population will be only used 
for summary of adverse event data which could be retrospectively collected. 
 
6.1.9. Analysis Group and Analysis Subgroup 
For all subjects in Study 360-322, summary tables, wherever applicable, will be presented by 
analysis group per subject’s previous participation in core studies (ie, subjects previously 
randomized to dasotraline, subjects previously randomized to placebo, all subjects combined) as 
described as below  
 Pbo-Das: Subjects previously randomized to placebo in studies SEP360-221 or SEP360-
321 
 Das-Das: Subjects previously randomized to dasotraline group in studies SEP360-221 or 
SEP360-321   
 All-Das: all subjects combined 
For subjects continued from Study SEP360-221, analyses per selected data may be conducted as 
needed; summary of these analyses will be presented per subject’s previous participation in study 
SEP360-221 as described below(hereafter, referred as ‘Analysis Subgroup A’):  
 Pbo-Das: previously randomized to placebo  
 Das-Das: previously randomized to dasotraline 4–8 mg/day   
 221-Das: all subjects continued from study SEP360-221 
For subjects continued from Study SEP360-321, analyses per selected data may be conducted as 
needed; summary of these analyses will be presented per subject’s previous participation in study 
SEP360-321 as described below (hereafter, referred as ‘Analysis Subgroup B’):   
 Pbo-Das: previously randomized to placebo  
 Das4-Das: previously randomized to dasotraline 4 mg/day   
 Das6-Das: previously randomized to dasotraline 6 mg/day 
 AllDas-Das: previously randomized to dasotraline (4 mg/day or 6 mg/day) 


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 321-Das: subjects continued from study SEP360-321 
Subjects in Study SEP360-322 may be further grouped and presented according to their 
predominant dose (alternatively, modal dose, see Section 6.1.10) and the maximum dose during 
the open-label treatment period as below, as needed.  Hereafter, analysis subgroup based on the 
modal dose will be referred as ‘Analysis Subgroup C’ and analysis subgroup based on the 
maximum dose will be referred as ‘Analysis Subgroup D’. 
   Analysis Subgroup C 
 Das4: subjects with modal dose of dasotraline 4 mg/day 
 Das6: subjects with modal dose of dasotraline 6 mg/day  
 Das8: subjects with modal dose of dasotraline 8 mg/day 
 All Das: all subjects combined 
   Analysis Subgroup D 
 Das4: subjects with maximum dose of dasotraline 4 mg/day 
 Das6: subjects with maximum dose of dasotraline 6 mg/day  
 Das8: subjects with maximum dose of dasotraline 8 mg/day 
 All Das: all subjects combined 
 
For limited analyses, wherever applicable, results may be presented by modal dose group and 
maximum dose group as needed. 
6.1.10. 
Average Dose, Predominant/Modal Dose, Maximum Dose 
The predominant dose (or, equivalently, modal dose, used interchangeably hereafter in this 
document) duration in the open-label treatment period is defined as the dasotraline dose to which 
the subject was exposed for the greatest duration during the treatment period. If a subject has 2 or 
more doses with the great duration, the one with higher dosage will be selected as predominant 
treatment. 
The average total daily dose during the open-label treatment phase will be calculated as the sum 
of the total daily dose divided the treatment duration (see Section 7.1.5.1). The average total 
daily dose during a visit period is defined in a similar way. 
For any study 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), average total daily dose at the visit will not be derived 
and will be set as missing.  For an assessment period that involves multiple study visits (eg, the 
open-label treatment period), if at some visit(s) the drug usage information is incomplete, then 


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the other visits with complete information of kit usage will be used to derive the average daily 
dose, predominant dose, and maximum dose,  accordingly.  
 
6.1.11. 
Handling of Dropouts or Missing Data  
6.1.11.1. 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 date of the disposition date 
(ie, date of the last contact with subject) and 7 days from the date of the last medication kit  
dispensed if the last contact visit is either V1E (OL baseline), or V2E (Week 2), and 14 days 
from the date of the last medication kit dispensed if the last contact visit  is V3E (Week 4) or 
after.  
6.1.11.2. 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. EDE-Q modified global score and 3 subscale scores, SDS total score and 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.   
Since a vendor generates for the SF-12, two component scores and subdomain scores using 
standard software, missing data is imputed by default algorithm provided by the vendor, which is 
provided on Attachment 9.2. 
For analyses of the change from baseline for a given effectiveness parameter, only subjects who 
have both baseline and at least one post-baseline measurement are included.  
6.1.11.3. Incomplete/Missing Dates 
6.1.11.3.1. 
Start/End Dates for Adverse Event 
Treatment-emergent adverse events (TEAEs) are those reported adverse events with an onset 
date on or after the first day of the open-label treatment period (See Section 6.1.1.1 for definition 
of the OL treatment period)), through 7 days after study drug discontinuation (14 days for serious 
adverse events and deaths). 
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 to be done to calculate AE duration.  


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6.1.11.3.2. 
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 open-label treatment phase, the medication 
is considered as a concomitant medication).  
6.1.12. 
Subgroup Analysis  
For a limited number of descriptive analyses, data will be presented for analysis group by 
subgroup below as needed:  
 Age group at OL Baseline (years): “< 40 years”, “≥ 40 years”  
 Gender: Male, Female 
 Race: White, Non-white 
 BMI at OL Baseline: Non-obese (ie, Normal & Overweight), Obese class I/II, Obese 
class III 
6.1.13. 
BMI (kg/m2)  
BMI is calculated at each visit using the following formula:  
         BMI = weight (kg)/(height(m)*height(m)) 
Height is per measurement at Screening visit in core studies.  
 
6.1.14. 
EDE-QM Items 4, 5, and 6  
EDE-QM items 4, 5, and 6 are expected to collect numeric type of data. Due to the data fields 
were set as character type in clinical database, total 11 records (6 cases for item 4, 3 cases for 
item 5, and 2 cases for item 6), which were collected at early stage of the study, had a range type 
of data   (ie, 1-2, 8-10 etc.) instead of a single integer value. For such cases, the higher value (ie, 
the worse value) are to be used in EDE-QM related summary analyses (eg, mean actual value 
and change from baseline). In addition, for a few records with character value of 
‘NO’,’NONE’,’NA’, and ‘N/A’, zero will be used instead in terms of analysis purpose. The 
original data will be displayed in data listing.   
 


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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 (CI) will be calculated whenever appropriate. All 
data will be summarized by analysis group (or analysis subgroup) and visit as appropriate. All 
subject data will be presented in data listings by subject. 
6.2.2 Statistical Hypotheses for Trial Objectives 
Because of the nature of an open-labeled study, no hypotheses are planned and to be tested. 
6.2.3 Interim Analysis 
One interim analysis was planned to support regulatory filing of BED NDA submission and a 
separate SAP was developed for the interim analysis. 
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.  


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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 will include all enrolled subjects in the database. In 
general, the subject listings will be sorted by analysis 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 analysis group and analysis 
subgroup, as needed (see Section 6.1.9) for the safety population.   
7.1.1. Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by analysis group and analysis 
subgroup based on the safety population. 
Baseline descriptive statistics (N, mean, SD, median, and range) of demographic characteristics 
will be provided by analysis group and analysis subgroup 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 analysis 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;  
Baseline summary statistics (N, mean, SD, median, and range) of disease characteristics will be 
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 DB Baseline and OL Baseline of BE-CGI-S score 
 DB Baseline and OL Baseline of EDE-Q modified global score and subscale scores 
7.1.2. Disposition Information 
Subject disposition of open-label treatment period for all enrolled subjects will be summarized 
by analysis group and analysis subgroup using the following categories: 
 Subjects who entered the extension study; 
 Subjects who entered the extension study, but not dosed; 
 Subjects in the Safety population; 
 Subjects in the Safety who completed the study; 
 Subjects who discontinued during the treatment period. 
Subject disposition of withdrawal period for subjects in withdrawal population will be 
summarized by analysis group and analysis subgroup as below: 
 Subjects in withdrawal population; 
 Subjects who completed the withdrawal period; 
 Subjects who discontinued during the withdrawal period. 
For subjects who are consented and discontinue from the study, the corresponding reasons for 
discontinuation will be summarized.  
Kaplan-Meier plot of the time to early discontinuation will be presented by analysis group and 
subgroup. 
7.1.3. Treatment Compliance 
At each post OL-baseline (Weeks 2 – 52) visit, prior to dispensing study medication, previously 
dispensed study medication will be retrieved and assessed by tablet count.  Compliance in the 
open-label treatment phase will be calculated for each post-OL 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. 


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For any study 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), compliance rate at the visit will not be derived and will 
be set as missing.   
For an assessment period that involves multiple study visits (ie, the open-label 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 proportion of 
medication kits with incomplete usage information at each dispensed visit and the overall open-
label treatment period will be summarized by treatment for categories below. 
 incomplete kit usage of Dasotraline 4 mg kit 
 incomplete kit usage of Dasotraline 6 mg kit 
 incomplete kit usage of Dasotraline 8 mg kit 
 incomplete kit usage of any Dasotraline kit 
Specifically, for each subject, overall rate (percentage) of medication kits with incomplete usage 
information during the open-label treatment period will be calculated as the total number of 
medication kits with incomplete usage information divided by total number of medication kits 
dispensed in the treatment period. Summary statistics (n, mean, median, range) of overall rate of 
incomplete medication kit usage will be presented by treatment group.  
In addition, number and percentage of subjects with at least one of incomplete medication kit 
usage information for each dispensed visit and the number and percentage of subjects for 
categories below for the overall open-label treatment period will be summarized by treatment 
group. 
 With <=4 incomplete kit usage 
− With 1 incomplete kit usage ONLY,  
− With 2 incomplete kit usage ONLY,  
− With 3 incomplete kit usage ONLY,  
− With 4 incomplete kit usage ONLY,  
 With 5-12 incomplete kit usage 
 With >=13 incomplete kit usage 
                  
 Missing at 1 study visit only; 
 Missing at 2 study visits only; 
 Missing at 3 study visits only;  


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 Missing at >=4 visits 
 
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 analysis group 
for percent compliance by study visit and overall open-label treatment period. In addition, the 
number and percentage of subjects in the categories of the following variables will also be 
summarized by analysis group for open-label treatment period: 
 Compliant;  
 Non-compliant (<75% or >125%); 
 Non-compliant: <75%;  
 Non-complaint: >125%. 
 
7.1.4. 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 
day. See Section 6.1.11.1 for imputation rule if the end date of the medication intake is unknown 
or ‘unconfirmed’.   
Descriptive statistics (N, mean, standard deviation, median, and range) will be presented by 
analysis group and analysis subgroup for treatment duration. Number of subjects with duration in 
each of following categories (days): ≥ 1, ≥ 14, ≥ 28,  ≥ 56, ≥84, ≥112, ≥140, ≥168, ≥183, ≥196,  
≥252,  ≥308, and ≥364; 1-13, 14-27, 28-55, 56-83, 84-111, 112-139,140-167,168-195, 196-251, 
252-307, 308-363, ≥364 days will also be presented. Return of the blister card at any given visit 
is not a prerequisite for inclusion in exposure summary statistics if corresponding dose start and 
end dates are reported. 
7.1.5. Study Medication and Concomitant Medications 
7.1.5.1. 
Study Medication 
Descriptive summary statistics (N, mean, median) for the mean daily dose will be provided by 
analysis group at each post-baseline visit, endpoint, and overall treatment period.  Mean daily 
dose for an assessed period (eg, overall treatment period) will be calculated as the sum of the 
total daily dose divided by the total exposure (ie, last dose day – first dose day+1) in the assessed 
period. 
In addition, frequency distribution of the following dose information will be summarized: 


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 predominant dose(ie, modal dose) during the open-label treatment period 
 maximum daily dose during the open-label treatment period  
See Section 6.1.10 for definition of the predominant daily dose during the OL treatment period. 
In addition, frequency distribution of the all dispensed medication (regardless the kit return 
status) by study visit and number and percentage of subjects who have modified the dosing 
schedule since last visit will be summarized by visit.  
Return of the blister card at any given visit is not a prerequisite for inclusion in average daily 
dose summary statistics or predominant dose summary statistics if corresponding dose start and 
end dates and amount are reported. 
7.1.5.2. 
Concomitant Medications 
Concomitant medications during the open-label treatment period (see Section 6.1.1.1) (ie, 
medications taken during the OL treatment period) are coded using World Health Organization 
(WHO) Drug Dictionary and Anatomical Therapeutic Chemical (ATC) codes.  
Number and percentage of subjects taking concomitant medications will be provided by level 3 
ATC classification and preferred name by analysis group based on the safety population. Since 
medications are coded to ATC classification by indication, preferred names may appear under 
multiple ATC classifications. Concomitant medications started prior to and on/after the first day 
of the open-label treatment period will be summarized separately in a similar way.  
Number and percentage of subjects taking medications after last dose of study drug will be 
summarized based on the withdrawal population.  
 Summary of concomitant usage of sleep aids 
As specified in the study protocol, during the course of the study, subjects are permitted to 
receive sleep aids with some restrictions. The full list of sleep aids used in the study will be 
obtained through medical review prior to the final database lock and the definition of sleep aids 
is provided in Attachment 9.6. The number and percentage of subjects receiving any sleep aid 
during the open-label treatment period will be summarized by preferred term based on the Safety 
population. In addition, percentage of subjects with usage of sleep aids over time will be 
presented graphically by study day, where the percentage is calculated as number of subjects 
with usage of any sleep aid on the day divided by number of subjects remaining on the treatment 
period at that time point. 
All medication data will be included in the prior and concomitant medication listing. 
7.1.6. Psychiatric History and Medical History Prior to DB Phase of Core Study 
Psychiatric history and medical history data will be extracted from the corresponding ADaM 
datasets of core studies directly. The number and percentage of subjects with medical pre-


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condition will be summarized by system organ class (SOC) and preferred term for each analysis 
group. 
Psychiatric history information prior to DB phase of core studies will be summarized in a same 
way as for core studies by analysis group. See Section 7.1.2 of SEP360-221 and SEP360-321 
SAP for details. It should be noted that at study level, study SEP360-321 was coded using 
MedDRA 19.0 while study SEP360-221 was coded using MedDRA 18.0. For table summary of 
study SEP360-322, medical history will be summarized based on MedDRA Version 19.0 (ie, 
corresponding data from study SEP360-221 will be re-coded at programming level and summary 
output will be generated accordingly). 
7.1.7. Psychotherapy 
A listing of CRF collected psychotherapy will be provided for all safety subjects. 
 
7.1.8. Protocol Deviations 
Protocol deviations will be 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 the final 
database lock.  
A summary of  protocol deviations will be provided as the number (%) of subjects with at least 
one protocol major deviation and the number (%) of subjects with a major deviation in each 
category for the safety population. A listing will be provided containing all protocol deviations. 
7.2. 
 Effectiveness Analyses  
7.2.1. Definition 
The effectiveness endpoints of interest are:  
 Change in BE-CGI-S score 
 Change in EDE-Q modified global score and 3 subscale scores (dietary restraint, shape 
concern, weight concern ) 
 Change in values of items 4, 5, and 6 of EDE-Q modified (ie, number of times of 
unusually large amount of food, number of times of having lost control eating, number of 
days of overeating episodes) 
 Change in SDS total score and subscale scores (school/work disability, social life 
disability, and family life disability)  
The subject-reported health status endpoint for subjects continued from SEP360-221 only is:  
 Change in SF-12 two component scores (physical component, mental health component) 


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7.2.2. Analysis Methods 
No inferential statistics on effectiveness will be presented. For all continuous effectiveness 
assessments, descriptive summary statistics (N, mean, standard deviation, median, range, and a 
95% confidence interval) will be presented by analysis group, at DB baseline, OL baseline, each 
of post-OL visit, and endpoint in the open-label treatment period. All analyses for the scheduled 
assessments will be based on observed cases (OC). In addition, for all effectiveness evaluations, 
changes from DB baseline and changes from OL baseline will be presented in a similar way 
using summary statistics as described above.  
In addition, the number and percentage of subjects in the following categories for the number of 
days of overeating episodes per Item 6 of EDE-Q Modified will be summarized by analysis 
group and at DB Baseline (for subjects from SEP360-321 only) or DB Screening (for subjects 
from SEP360-221 only), OL Baseline, post-OL Baseline visit, and endpoint: 
 0 day  
 1 day  
 >1 to ≤4 days  
 >4 to ≤8 days  
 >8 to ≤12 days  
 >12 to ≤ 20 days  
 >20 days  
Frequency distribution of BE-CGI-S score over time will be summarized similarly. Plots of the 
mean actual value, mean change from DB Baseline as well as mean change from OL Baseline in 
all effectiveness assessments over time by analysis group will be presented for the safety 
population. 
7.3. 
Pharmacokinetics (PK) Analysis  
Not applicable. 
7.4. 
Safety  
7.4.1. Analysis Specifications 
All safety analyses and summaries will be based on the safety analysis population. 
Unless otherwise specified, safety data will be presented separately by analysis group for the 
open-label treatment period (for data collected up to the end of open-label treatment period) and 
withdrawal period (for data collected during the withdrawal period), as appropriate. The CSSA 
and DESS, which are used to assess physical dependence and withdrawal symptoms, are 
collected only at the Week 52/EOT and in the withdrawal period; all other safety data are to be 


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collected in both treatment period and withdrawal period and will be presented by analysis group 
for the open-label treatment period and withdrawal period, separately, as appropriate. 
For continuous data collected in the OL treatment period, actual observed value and change form 
baseline will be summarized using descriptive statistics (N, mean, standard deviation [SD], 
median, range, 95% confidence interval [CI] as needed). Where changes are reported, the 
reference will be to “DB Baseline”. Where relevant, changes from “OL Baseline” will also be 
reported.  
For continuous data collected in the withdrawal period, the actual value, changes from DB and 
OL baseline (when applicable), and change from withdrawal baseline will be summarized by 
analysis group at study visits (ie, DB Baseline, OL Baseline, Withdrawal Baseline,  and other 
post-withdrawal baseline visits and  withdrawal endpoint). 
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 19.0 
or higher. 
Treatment-Emergent Adverse Event (TEAE) 
Treatment-emergent adverse events (TEAEs) are those reported adverse events with onset data 
on or after the first day of the open-label treatment period through 7 days after study drug 
discontinuation (14 days for serious adverse events and deaths). The start of the open-label 
treatment period is defined as Day 1 for subjects previously randomized to placebo group and the 
OL Baseline visit date for subjects previously randomized to dasotraline groups. 
AEs with a start date prior to the first day of the OL treatment period 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 first day of the 
OL treatment period are considered as TEAEs. 
Discontinuation-emergent adverse events (DEAEs) are defined as AEs which have an onset after 
the last dose date of study drug through the Week 55 visit (ie, the last study visit in the 
withdrawal period). 
Table summary of AEs will be limited to TEAEs and DEAEs. All AE data will be displayed in 
data listings. For the sake of simplicity, hereafter TEAE is referred to as AE.  
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, study 
drug-related AEs leading to discontinuation, serious AEs leading to discontinuation, and serious 


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study drug-related AEs, and serious study drug-related AEs leading to discontinuation will be 
summarized by analysis 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 analysis 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 by 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) during the extension study will be presented by analysis group. Time to the first onset (in 
days) is defined as the earliest onset date of insomnia – start date of OL 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.  
Prevalence rate of insomnia (combined term) at a study day in the open-label treatment period is 
defined as number of subjects experiencing insomnia on the day divided by number of subjects 
remaining on open-label study 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 
summarized and presented graphically by analysis 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  


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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 of Special Interest (AESI) 
A list of preferred terms that are to be combined for assessment of each of pre-specified adverse 
events category as below are provided in Attachment 9.3.  
 cardiovascular-related AEs 
− Cardiac arrhythmias 
− Vital signs-related  
 metabolic-related AEs 
− Weight-related  
− Metabolic-Related (excluding weight)  
 Neuropsychiatric-related AEs,  
− Neuropsychiatric AEs 
− Psychosis or Mania 
− Psychosis   
− Mania 
 Combined insomnia 
 Suicide and self-injury related AEs 
 Spontaneous abortion /miscarriage (for female subjects only).   
 Drug abuse and dependence (for AEs onset on/prior to the last study dose) 
 Potential drug abuse (for AEs onset on/prior to the last study dose) 
 Drug withdrawal related AEs (for AEs onset after the last study dose) 
Definition of above AESI categories were initially provided in the integrated statistical analysis 
plan (ISAP) of the Integrated Summary of Safety (ISS) of Dasotraline BED NDA (NDA number: 
213025). For final analysis of study SEP360-322, definitions of AESIs, including  cardiac 


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arrhythmias, combined insomnia, psychosis, mania, suicide and self-injury, spontaneous abortion 
/miscarriage, drug abuse and dependence,  drug withdrawal, and potential drug abuse,  are 
exactly same as what were defined in the ISAP, since their definitions are either directly based 
on standard SMQs or from other standard terms.  
For other AESI categories, including vital signs-related AEs, weight-related AEs, metabolic-
related (excluding weight) related AEs, and neuropsychiatric AEs, their AE preferred terms are 
determined and verified by medical review of coded AE terms during data review and finalized 
prior to the final database lock.  Definitions of these AESIs were obtained per medical review 
from the accumulative database of dasotraline clinical program. Since more data are obtained 
from study SEP360-322 after the BED NDA submission, additional AE preferred terms might be 
identified and added to preferred lists  of definition. AE preferred terms that had been already 
identified in ISS ISAP of BED NDA will be kept as they are.  
Except of category of drug withdrawal related AEs, the incidence of TEAEs with special interest 
by AESI category and PT will be summarized by analysis group, by severity, by the action taken 
regarding the study medication, as well as by the outcome based on the safety population. For 
“Spontaneous abortion /miscarriage” related AEs, the incidence will calculated based on the 
number of female subjects in each analysis group as denominator.  
Listings will also be generated for deaths, SAEs, AESI, and discontinuations due to AEs. All 
adverse events regardless of treatment emergent status will be provided in the AE data listing. 
 
 
AEs by Exposure  
The TEAEs will be summarized by exposure to study drug using time intervals beginning with 
the earliest concurrent exposure to study drug for following AE summary as needed. 
Denominators for exposure intervals will be based on the number of subjects who were exposed 
as of the first day of the interval; for cases where events meet the treatment-emergent definition 
but start after the last dose, the exposure interval for the event will be considered the interval of 
the last day of exposure to study medication. 
 AEs by SOC and PT, Serious AEs by SOC and PT, and AEs leading to discontinuation 
by SOC and PT (sorted alphabetically by SOC and PT within SOC). 
 AEs by PT, AEs with special interest by PT (sorted by descending order per frequency 
count) 
Exposure categories to be summarized are given below: 
 Exposure categories : 1-13 days, 14-27 days, 28-83 days, 84-167 days, ≥168 days.  
AEs by Subgroup  
The TEAEs will be summarized by SOC, PT for subgroups (see Section 6.1.12) below: 


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 Age group at OL Baseline (years): < 40 years, ≥ 40 years  
 Gender: Male, Female 
 Race: White, Non-white 
 BMI at OL Baseline: Non-obese , Obese class I/II, Obese class III 
 
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 6.1.8), 
which includes all subjects in the withdrawal population plus the subjects who do not enter 
withdrawal period, but their last study dose dates are at least 2 days earlier than their last study 
visit (ie, Week 52/EOT visit). The rationale of defining ‘modified’ withdrawal population is that 
the AE information after the last study dose is expected to be continuously collected till the last 
study visit    
The overall incidence of DEAEs and serious DEAEs will be summarized by analysis group. The 
DEAEs also will be summarized by SOC and PT, and by PT of each analysis 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 9.4.1. 
7.4.3.1. 
Treatment Period 
Descriptive statistics (N, mean, standard deviation, median, and range) will be reported for each 
continuous laboratory analyte at DB baseline, OL baseline, each post-OL baseline time point, 
and endpoint for observed actual value as well as change from DB baseline and OL baseline, 
respectively. Categorical results (eg, urinalysis tests) will be summarized at DB baseline, OL 
baseline, each post-OL baseline visit, and endpoint by analysis group using frequency and 
percentage. 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 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 DB baseline and shift from 


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OL baseline over time will be produced by analysis group to show the percentage of subjects 
with laboratory test values below, within, and above the normal range. Criteria for Markedly 
Abnormal Laboratory Values (MALV) per International System of Units (SI) unit of selected 
laboratory parameters can be found in Table 6. Equivalent MALV criteria for conventional unit 
are provided in Attachment 9.4.2. The criterion of MALV is satisfied if a value falls into the 
markedly abnormal range at an assessed visit or if subjects have experienced at least once 
MALV in the open-label treatment period. The number and percentage of subjects with a 
particular MALV at each OL visit, endpoint, and during the open-label treatment period 
(treatment emergent, up to and including endpoint), will be presented by analysis group. 
Table 6: – Criteria for Markedly Abnormal Laboratory Values (MALV)  (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 
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 


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Laboratory Test 
Criteria for Markedly Abnormal Status 
Low 
High 
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 MALV during the open-
label treatment period will be generated. Urine drug screen results will be presented for each 
parameter by DB baseline, OL baseline, post-OL baseline visit, and endpoint. Number and 
percentage of positive and negative results will be displayed. Summary statistics of laboratory 
outputs will be generated per conventional unit and SI unit, separately. 
7.4.3.2. 
Withdrawal Period 
Laboratory data will be summarized by presenting descriptive statistics of actual values, change 
from DB baseline and OL baseline, and changes from withdrawal baseline by visit and analysis 
group. 
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). 


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7.4.4.1. 
Treatment Period 
Descriptive statistics (eg, mean, SD, median, range, 95% CI) for observed actual value at the DB 
baseline, OL baseline, each post-OL baseline visit, and endpoint and changes from DB baseline 
and OL baseline, respectively will be displayed for continuous variables (ie, HR, QRS, QTcF, 
etc) by analysis group.  
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 OL baseline and 
Shifts from DB baseline over time will be produced by analysis group. 
Bazett and Fridericia corrected QTc values will be classified as having QTc prolongation 
according to Table 7. 
Table 7: – QTc Prolongation  
QTc Prolongation 
> 450 msec for males 
> 470 msec for females 
> 480 msec  
> 500 msec 
Increase from OL baseline QTc ≥ 30 msec 
Increase from DB baseline QTc ≥ 30 msec 
Increase from OL baseline QTc ≥ 60 msec 
Increase from DB baseline QTc ≥ 60 msec  
 
The number and percentage of subjects having a QTc prolongation using Fridericia correction 
method for DB baseline, OL baseline, post-OL baseline visit, endpoint, and any open-label 
treatment period (treatment emergent, the worst case), will be summarized by analysis 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 8. For abnormal ECG parameter reporting, counts and percentages of subjects 
will be presented for DB baseline, OL baseline, each post-OL baseline visit, endpoint, and any 
open-label treatment period (treatment emergent) by analysis group. 
Table 8: – Definition of Abnormal ECG Values by Parameter 
 ECG parameter (unit) 
Abnormally Low 
Abnormally High 
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 
 


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7.4.4.2. 
Withdrawal Period 
ECG data will be summarized by presenting descriptive statistics of observed values, change 
from DB baseline and OL baseline, and changes from withdrawal baseline by visit and analysis 
group. 
7.4.5. Vital Signs, Weight, and BMI 
7.4.5.1. 
Treatment Period 
Descriptive statistics (mean, SD etc.) will be provided for observed at the DB baseline, OL 
baseline, post-OL baseline visit, and endpoint, and change from DB baseline and OL baseline 
values, respectively of each vital sign parameters, weight,  and BMI listed below:  
 Systolic blood pressure (SBP) in supine and standing positions 
 Diastolic blood pressure (DBP) in supine and standing positions 
 pulse rate in supine and standing positions 
 Orthostatic change in SBP 
 Orthostatic change in DBP 
 Orthostatic change in pulse rate 
 Respiratory rate  
 Temperature 
 Body weight and BMI, 
Percent change from DB baseline and OL baseline values in weight and BMI will be 
summarized in a similar way. 
The number and percentage of subjects with Markedly Abnormal Vital Signs (MAVS), defined 
in Table 9.1, will be presented by analysis group at DB baseline and OL baseline, post-OL 
baseline visits, endpoint, and any  open-label treatment period (treatment-emergent, the worst 
case). 
A listing of subject data for those who satisfy MAVS during the open-label treatment period will 
be presented.  
Table 9.1: – Criteria for Markedly Abnormal 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 
baseline 
≥120 and increased >15 from 
baseline  
Weight (kg) 
≥ 7% decrease from baseline  
≥ 7% increase from baseline  
Temperature (˚C) 
N/A 
Value ≥ 38.3°C and ≥0.8°C  


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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 9.2 and as underweight/normal, overweight, obesity class I, 
obesity class II, and obesity class III using Table 9.3.  
Shifts from OL baseline and shifts from DB baseline to endpoint for weight status categories 
(Tables 9.3) will be summarized by analysis group to show the number and percentage of 
subjects that fall into each 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 analysis group. 
           
Table 9.2: – 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 9.3: – 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 
 


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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 DB baseline and OL baseline, and changes from withdrawal baseline by visit and 
analysis group. 
7.4.6. Assessments of Withdrawal Effects (CSSA, DESS, HAM-A, and MADRS) 
7.4.6.1. 
Treatment Period 
MADRS total score, HAM-A total score, and the individual scores collected in the OL treatment 
period will be summarized by presenting descriptive statistics (N, mean, median, and range) of 
observed values and change from DB baseline and OL baseline over time by analysis group  for 
safety population. 
7.4.6.2. 
Withdrawal Period 
MADRS total score,  HAM-A total score, and each of the individual item scores in the 
withdrawal period will be summarized by presenting descriptive statistics (N, mean, median, and 
range) of observed values and change from DB baseline, OL baseline, and withdrawal baseline 
by analysis group and visit; a similar analysis will be performed by gender as well. 
CSSA total score, DESS total score, and the individual scores will be summarized by presenting 
descriptive statistics (N, mean, median, and range) of observed values and change from 
withdrawal baseline by analysis group and visits based on the withdrawal population; the visits 
will be displayed  in an order defined as follow: withdrawal Baseline, day 1-2, day 3-4, day 5-6, 
day 7-8, withdrawal Week 1, day 9-10, day 11-12, day 13-14, withdrawal Week 2, day 15-16, 
day 17-18, day 19-20, day 21-22, withdrawal Week 3. See Section 6.1.2.2 for details about how 
to define these analysis visits per both clinic and non-clinic visits. A similar analysis will be 
performed by gender as well. Number and percentage of subjects with a new symptom or worsen 
old symptom for each DESS individual score (ie, each individual score of DESS with value of 1) 
by study visit and the worst case during the withdrawal period will be summarized based on the 
withdrawal population as well. 
The number and percentage of subjects in each of the following breakdown will be summarized 
by study visit during the withdrawal period. 
 CSSA total score: 0-7, 8-15, 16-30, 31-45, 46-60, >60; 
 DESS total score category 1: 0-2, 3-5, 6-10, 11-15,16-20;  
 DESS total score category 2: 0-10, 11-20, 21-30, 31-43.  
In addition, the number and percentage of subjects with change in DESS total score from 
withdrawal baseline by withdrawal visit and during any time point of the withdrawal period (per 
the worst case value) will be summarized in each of the following categories: ≤0, +1, +2, +3, 
≥+4. 
 
 


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7.4.7. Columbia Suicide Severity Rating Scale (C-SSRS) 
According to FDA draft guidance for suicidal ideation and behavior ([2]), 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 analysis group for one 
analysis time point ‘Any extension (treatment emergent)’, whose definition is given in Table 10.  
The analysis time point is applied to suicidal ideation score and ideation intensity total score. 
Table 10: Definition of Analysis Timepoint 
Analysis Timepoint 
eCRF Visit(s) to be 
Involved 
C-SSRS Version 
/Assessment 
Period 
Derivation Rule 
Any extension visit 
(treatment emergent)(a) 
all visits in the open-
label treatment period  
(up to EOT) 
Since last visit 
Most severe value  
Any withdrawal visit  
all visits after the last 
study dose 
Since last visit 
Most severe value  
(a): including all visits in open-label treatment period (see Section 6.1.1.1). 
 
At each analysis time point, 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. 


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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 11.  
 
Table 11: Comparative Endpoint of C-SSRS Relative to DB Baseline 
Comparative 
Endpoints  
Analysis  
Time Points Involved 
Derivation Rule 
Emergence of 
Suicidal Ideation 
DB Baseline(a) 
Any extension visit 
(treatment emergent) (b)  
 
No suicidal ideation at DB Baseline, and any type of 
suicidal ideation in ‘any extension visit (treatment 
emergent)’ 
Emergence of Serious 
Suicidal Ideation 
No suicidal ideation at DB Baseline, and any serious 
suicidal ideation [ideation score of 4 or 5] in ‘any 
extension visit (treatment emergent)’  
Emergence of 
Suicidal Behavior  
No suicidal behavior at DB Baseline, and any type of 
suicidal behavior in ‘any extension visit (treatment 
emergent)’ 
Emergence of 
Suicidality 
No suicidality at DB Baseline, and any suicidality in 
‘any extension visit (treatment emergent)’ 
Worsening of 
Suicidal Ideation 
Most severe suicidal ideation in ‘any extension visit 
(treatment emergent)’ is more severe than the most 
severe value at DB Baseline 
(a): Definition of DB Baseline: see Table 12 in SEP360-221 SAP and Table 12 in SEP360-321 SAP;  
(b): see Table 10. 
 
7.4.7.1. 
Treatment Period 
The number and percentage of subjects with following categories will be summarized by 
analysis group for any extension visit (treatment emergent). 
 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 
In addition, for any extension visit (treatment emergent), the number and percentage of subjects 
with following categories will be also summarized by analysis group. 


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 emergence of suicidal ideation,  
 emergence of serious suicidal ideation,  
 worsening of suicidal ideation,  
 emergence of suicidal behavior, 
 emergence of suicidality 
Shifts from DB baseline and OL baseline to any post-OL baseline visit (ie, the worst case) in 
suicidal ideation score will be presented by analysis group, 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 DB baseline, OL baseline, each post-OL baseline visit, and endpoint for observed 
value as well as change from DB and OL 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 
analysis group for any withdrawal visit 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 analysis 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 
analysis group at each visit. A shift table of each assessment for DB and OL baseline to endpoint 
and the worst case during open-label treatment period will also be presented by analysis group.  
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 


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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 analysis 
group. Instances of medication handling irregularity will be listed for all enrolled 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 
9.5. AEs identified as ESAMs will be summarized by ESAM type and PT by analysis group for 
safety population (OL treatment period) and withdrawal population (withdrawal period), 
respectively.  ESAMs will also be listed for all enrolled subjects.