Clinical trial NCT02969382
Conditions: Schizophrenia
Keywords: Schizophrenia
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Start date: 2016-12-05; Completion date: 2018-07-31
Enrollment: 245 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A study to evaluate the efficacy and safety of an experimental drug (SEP-363856) in acutely psychotic adults with schizophrenia

Detailed description:
This is a multicenter, randomized, double-blind, parallel-group, flexibly-dosed, study evaluating the efficacy and safety of SEP-363856 in acutely psychotic adult subjects with schizophrenia using SEP-363856 (50 or 75 mg/day \[ie, once daily\]) versus placebo over a 4-week treatment period. Primary hypoathesis to be tested: H0: μSEP = μPBO versus H1: μSEP ≠ μPBO, where μSEP and μPBO are the mean changes from Baseline at Week 4 in PANSS total score for the SEP-363856 and placebo arms, respectively. Subjects who complete study SEP361-201 may be eligible to enroll in the open-label extension study SEP361-202.

Arms: arm 1: SEP-363856 capsule (50 mg or 75 mg) once daily arm 2: Placebo capsule once daily
Interventions: intervention 1: SEP-363856 intervention 2: Placebo - Cap
Intervention descriptions: intervention 1: One SEP-363856 capsule (50 mg or 75 mg) daily for four weeks intervention 2: One Placebo capsule daily for 4 weeks

Protocol documents:
Prot_000.pdf: 
Titlepage 
SEP-363856 
Clinical Study Protocol SEP361-201 
A 4-Week, Randomized, Double-blind, Parallel-group, Placebo-
controlled, Flexibly-dosed, Multicenter Study to Evaluate the 
Efficacy and Safety of SEP-363856 in Acutely Psychotic Adult 
Subjects With Schizophrenia
EudraCT No. 2016-001555-41 
Clintrials.gov Identifier: NCT02969382 
Version 3.01 
17 August 2017 
Incorporates Nonsubstantial amendment 1.00 
SUNOVION PHARMACEUTICALS INC. 
84 Waterford Drive 
Marlborough, MA 01752, USA 
(508) 481-6700 


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


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EMERGENCY CONTACTS 
Table 1: Emergency Contact Information 
Role in Study 
Name 
Contact Information 
Responsible Physician 
Telephone: 
 Email: 
Medical Monitor 
Office:  
Mobile: 
Email:  
SAE/Pregnancy Reporting  
Hotline Number: 
 Fax: 
Email:  


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1. 
SYNOPSIS 
Name of Sponsor/Company: Sunovion Pharmaceuticals, Inc. 
Name of Investigational Product: SEP-363856 
Title of Study: A 4-Week, Randomized, Double-blind, Parallel-group, Placebo-controlled, Flexibly-
dosed, Multicenter Study to Evaluate the Efficacy and Safety of SEP-363856 in Acutely Psychotic 
Adult Subjects With Schizophrenia 
Proposed Indication: Schizophrenia 
Study Centers: Approximately 35 centers globally  
Phase of Development: 2 
Study Objectives: 
Primary: To evaluate the efficacy of flexibly dosed SEP-363856 (50 or 75 mg/day) compared with 
placebo in acutely psychotic adult subjects with schizophrenia as measured by the Positive and 
Negative Syndrome Scale (PANSS). 
Secondary: 
• 
To evaluate the efficacy of flexibly-dosed SEP-363856 (50 or 75 mg/day) compared with 
placebo in acutely psychotic adult subjects with schizophrenia as measured by: 
− 
Clinical Global Impression-Severity (CGI-S) 
− 
PANSS subscale scores (positive, negative, and general psychopathology) 
− 
Brief Negative Symptom Scale (BNSS) 
− 
Montgomery-Asberg Depression Rating Scale (MADRS) 
• 
To evaluate the safety and tolerability of SEP-363856 (50 or 75 mg/day) using 
− 
physical examinations (PE) 
− 
12-lead electrocardiograms (ECG) 
− 
vital signs 
− 
adverse event (AE) reports 
− 
clinical laboratory results 
− 
body weight and body mass index (BMI) 
− 
Columbia – Suicide Severity Rating Scale (C-SSRS) 
Other: 
• 
To assess whether SEP-363856 is associated with extrapyramidal symptoms as measured 
by the Barnes Akathisia Rating Scale (BARS), the Abnormal Involuntary Movement Scale 
(AIMS), and the Simpson-Angus Scale (SAS). 
• 
To characterize the effects of SEP-363856 as measured by the Drug Effects Questionnaire 
(DEQ). 
• 
To characterize the subjective effects of SEP-363856 on sleep as measured by the 
Pittsburgh Sleep Quality Index (PSQI). 
• 
To assess the effects of SEP-363856 on cognition based on the CogState Brief Battery 
(CBB). 


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• 
To perform population pharmacokinetic (POPPK) analysis using plasma SEP-363856 
concentrations 
• 
To explore the relationship between PANSS total score and plasma SEP-363856 exposure 
using population PK/pharmacodynamics (PD) methods. 
• 
To explore the impact of cytochrome (CYP) P450 CYP2D6 metabolizer status on 
SEP-363856 plasma exposure. 
Study Design: 
This is a multicenter, randomized, double-blind, parallel-group, flexibly-dosed, study evaluating the 
efficacy and safety of SEP-363856 in acutely psychotic adult subjects with schizophrenia using 
SEP-363856 (50 or 75 mg/day [ie, once daily]) versus placebo over a 4-week treatment period. This 
study is projected to randomize at least 240 subjects to 2 treatment groups (SEP-363856 or placebo) in 
a 1:1 ratio. The treatment assignment will be balanced within each clinical site. Subjects randomized to 
placebo will receive placebo treatment throughout the study. Study drug will be taken at the same time 
each evening before bed time and may be taken with or without food. 
The study will consist of 3 periods: Screening/Washout (up to 14 days), Treatment (4 weeks in-
patient), and a Follow-up visit (7 days after last study drug dose for subjects who discontinue prior to 
Visit 7 or who complete the study but do not elect to enroll in the open-label extension study 
[SEP361-202]) as shown in Figure 1. 
Screening/Washout Period (up to 14 days):  
Informed consent will be obtained from each subject before any study procedures are performed. 
Subjects will be evaluated for eligibility during a screening phase of up to 14 days, during which they 
will be tapered off all psychotropic medications (except as noted in the protocol) in a manner that is 
consistent with labeling recommendations and conventional medical practice. Subjects will remain 
hospitalized for the duration of the screening/washout period. 
 
Double-Blind Treatment Period (4 weeks):  
During the double-blind phase, subjects will be in-patient through Week 4. Subjects will be eligible for 
hospital discharge after the Week 4 visit (Day 29). 
Randomization/Treatment: At double-blind Baseline (Day 1), subjects who have successfully 
completed the washout of prior medication (see Section 10.3.1) and have met the randomization 
criteria (see below) will be randomly assigned via interactive web/voice response system (in a 
1:1 ratio) to one of two treatment arms: SEP-363856 or placebo. Study drug dosing will initiate the 
evening of the Baseline visit. Treatment will continue once-daily at night for the remainder of study 
during which procedures outlined in Table 2 will be conducted. 
Subjects will receive SEP-363856 50 mg/day on Day 1 through 3. On Day 4, subjects are permitted 
(but not required) to titrate up to a dose of 75 mg/day. Thereafter, if a dose increase is necessary to 
optimize efficacy it should occur at regular scheduled study visits/weekly intervals starting from Visit 4 
based on Investigator judgement. A dose reduction for tolerability purposes is permitted to occur more 
frequently than at weekly intervals. Subject can be flexibly dosed up until Visit 6, but no dose 
adjustments are allowed thereafter. 
End of Double-Blind Period: 
Subjects who complete the 4-week double-blind treatment phase will be eligible to participate in a 
separate open-label 26-week extension study (Study SEP361-202). Subjects who discontinue early 
from the study or complete the study and do not enter the 6-month extension study will be required to 
complete the follow-up visit 7 days (± 2 days) post last dose of study drug. 


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Upon completion or early discontinuation from the study, hospitalization will be allowed for up to an 
additional 7 days to stabilize the subject, if necessary. Prior authorization for the hospitalization must 
be approved by the Medical Monitor. After completion of the follow-up visit or upon study 
discontinuation, all subjects will be referred for appropriate continued treatment and follow-up care as 
determined by the Investigator. 
Efficacy, Safety, and Pharmacokinetic Evaluations 
Efficacy will be evaluated using the PANSS total and subscale scores, as well as CGI-S, BNSS, and 
MADRS scores. Effect of SEP-363856 on cognition will be assessed by the CBB. 
Safety and tolerability will be monitored throughout the study by collection of physical examination 
(PE) results, ECGs, vital signs, AEs, clinical laboratory parameters, C-SSRS, body weight, and BMI. 
Subjects who have significant findings for suicidal ideation upon completion of the C-SSRS at any 
time during the study must be referred to the investigator for follow-up evaluation. 
Subjects will provide information on subjective drug effects via administration of the DEQ. In addition, 
effects on movement disorders will be measured using the AIMS, BARS and SAS scales. Subjective 
effects on sleep will be measured by the PSQI scale. 
Blood samples for plasma SEP-363856 and SEP-363854 concentrations will be collected on Day 1 
(predose) and Day 29. POPPK analysis will be performed using plasma SEP-363856 concentrations; 
the results of which will be reported separately. The relationship between PANSS total score and 
plasma SEP-363856 exposure using population PK/pharmacodynamics (PD) methods exposure will be 
explored and reported separately. The impact of cytochrome (CYP) P450 CYP2D6 metabolizer status 
on plasma SEP-363856 exposure will be explored and reported separately. 
Diagnosis and Main Criteria for Subject Inclusion:  
See Section 8 of full protocol for the complete list of inclusion and exclusion criteria information. 
Inclusion criteria (not all inclusive): 
To qualify for participation, subjects must meet all of the following inclusion criteria: 
1. Male or female subject between 18 to 40 years of age (inclusive) at the time of consent. 
2. Subject meets DSM-5 criteria for schizophrenia as established by clinical interview (using the 
DSM-5 as a reference and confirmed using the SCID-CT). The duration of the subject's illness 
whether treated or untreated must be ≥ 6 months. 
3. Subject must have a CGI-S score ≥ 4 (moderate or greater) at screening and Baseline (Day 1). 
4. Subject must have a PANSS total score ≥ 80 and a PANSS item score ≥ 4 (moderate) on 2 or 
more of the following PANSS items: delusions, conceptual disorganization, hallucinations, and 
unusual thought content at screening and Baseline (Day 1). 
5. Subject has an acute exacerbation of psychotic symptoms (no longer than 2 months). 
• 
Subject has marked deterioration of functioning in one or more areas, such as occupational, 
social, or personal care or hygiene. 
• 
Subject requires hospitalization for an acute psychotic exacerbation at the time of 
screening or has been hospitalized for the purpose of treating an acute psychotic 
exacerbation for no more than 2 consecutive weeks immediately before screening. 
Subjects who have been hospitalized for more than 2 weeks for reasons unrelated to acute 
psychotic exacerbation may be included if such a hospitalization was for a condition other 
than an acute psychotic relapse. For example, subjects in a long-term hospital setting who 
have an acute exacerbation and are transferred to an acute unit are eligible for the study.  
6. Subject has had no more than 2 prior hospitalizations for the treatment of an acute exacerbation 


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of schizophrenia (not including the current hospitalization). This history must be confirmed 
based on report by a reliable informant (eg. caregiver or family member) or medical records 
available at the time of screening. 
7. At Baseline, subject must have a total score < 5 on the SAS.  
Exclusion Criteria (not all inclusive): 
To qualify for participation, subjects must not meet any of the following exclusion criteria: 
1. 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 or during the Screening period (ie, in the past one month) and/or 
at Baseline (ie, since last visit). 
2. Subject has previously received SEP-363856. 
3. Subject has a lifelong history or presence of symptoms consistent with a major psychiatric 
disorder other than schizophrenia as defined by DSM-5. Exclusionary disorders include but are 
not limited to alcohol use disorder (within past 12 months), substance (other than nicotine or 
caffeine) use disorder within past 12 months, major depressive disorder, bipolar depression, 
mania, schizoaffective disorder, obsessive compulsive disorder, posttraumatic stress disorder. 
Previous or current symptoms of mild to moderate mood dysphoria or anxiety are allowed so 
long as these symptoms have not been a focus of primary treatment. 
4. Subject is at significant risk of harming self, others, or objects based on Investigator’s 
judgment. 
5. Subject has attempted suicide within 3 months prior to screening. 
6. Subject is involuntarily hospitalized. 
7. Subject is receiving a total dose of antipsychotic medication equivalent to≥ 12.0 mg/day of 
haloperidol at Screening (see Section 22, Appendix III for table of haloperidol dose 
equivalents). Subject may be eligible if such treatment is less than 2 weeks in duration after 
consultation with the Medical Monitor. 
8. Subject has received electroconvulsive therapy treatment within the 6 months prior to 
screening or is expected to require ECT during the study. 
9. Subject is judged to be resistant to antipsychotic treatment by the Investigator, based on failure 
to respond to 2 or more marketed antipsychotic agents, given at adequate dose for at least 
4 weeks within a 1 year period prior to Screening. 
10. Subject has a history of treatment with clozapine for refractory psychosis and/or subject has 
been treated with clozapine (for any reason) within 4 months of Screening. 
11. Subject is currently participating, or has participated in, a study with an investigational or 
marketed compound or device within 6 months prior to signing the informed consent, or has 
participated in 2 or more studies within 24 months prior to signing informed consent. 
Randomization Criteria 
To qualify for randomization, subjects must meet all of the following randomization criteria: 
1. Subject must have a PANSS total score ≥ 80 at Baseline (Day 1). 
2. Subject must have a PANSS item score ≥ 4 on 2 or more of the following PANSS items: 
delusions, conceptual disorganization, hallucinations, and unusual thought content at Baseline 
(Day 1). 


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3. Subject must not demonstrate a decrease (improvement) of ≥ 20% in the PANSS total score 
between Screening and Baseline visits (see Section 26, Appendix VII for calculation of 
PANSS total score improvement) , or the PANSS total score falls below 80 at Baseline 
(Day 1). 
4. Subject must have a CGI-S score ≥ 4 at Baseline (Day 1). 
5. Subject must have a total score < 5 on the SAS at Baseline (Day 1). 
6. Subject must not 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 Baseline (ie, since last visit). 
7. Subject must meet all other inclusion and none of the exclusion criteria at Baseline (Day 1). 
Investigational Product, Dosage and Mode of Administration:  
SEP-363856 treatment will be size 0, Swedish-orange capsules (50 mg or 75 mg) administered orally 
once daily. Study drug will be taken at the same time each evening before bed time and may be taken 
with or without food. 
Subjects will receive SEP-363856 50 mg/day on Day 1 through 3. On Day 4, subjects are permitted 
(but not required) to titrate up to a dose of 75 mg/day. Thereafter, if a dose increase is necessary to 
optimize efficacy it should occur at regular scheduled study visits/weekly intervals starting from Visit 4 
based on Investigator judgement. A dose reduction for tolerability purposes is permitted to occur more 
frequently than at weekly intervals. Subject can be flexibly dosed up until Visit 6, with no dose 
adjustments allowed thereafter. 
Duration of Treatment: 4 weeks 
Reference Therapy, Dosage and Mode of Administration: 
Matching placebo treatment will be size 0, Swedish-orange capsules administered orally once daily. 
Study drug will be taken at the same time each evening before bed time and may be taken with or 
without food. 
Subjects randomized to placebo will receive placebo throughout the study. 
Concomitant Medications: 
Concomitant Non-psychotropic Medications: 
Medications for short-term treatment of an acute medical condition are allowed after consultation with 
the Medical Monitor. Non-psychotropic medications used to treat mild, chronic medical conditions 
may be used during screening and after randomization if the dose and regimen have been stable 
(± 25%) for at least 30 days prior to screening. The dose for the concomitant medication may change, 
as needed, after randomization (or be discontinued). β-adrenergic antagonists used to treat stable 
hypertension may be continued through the screening phase and post-randomization. In addition, use of 
over-the-counter non-prescription pain medications (eg, aspirin, acetaminophen) are allowed during all 
phases of the study provided these medications do not have a propensity for psychotropic effects and 
do not interfere with the evaluation of study drug. Female subjects may use oral, patch, or IUD 
hormonal contraceptives, or progestin implant or injection (detailed information on allowed 
contraceptives is defined in Section 21 of the full protocol). 
Prior Medications: 
Prior treatment with antipsychotic agents must be discontinued in a manner consistent with general 
medical practice during the screening period for at least 3 days. Depot neuroleptics must be 
discontinued at least one treatment cycle or at least 30 days (whichever is longer) prior to the screening 
visit. 


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Prior treatment with antidepressants must be discontinued as tolerated and clinically appropriate as 
follows: 
• 
MAO inhibitors – at least 14 days prior to baseline (Day 1) 
• 
Fluoxetine hydrochloride – at least 28 days prior to baseline (Day 1) 
• 
Clozapine – at least 120 days prior to screening 
Prior treatment with mood stabilizers (eg, lithium, divalproex/valproic acid, carbamazepine, etc.) must 
be discontinued as tolerated and clinically appropriate at least 7 days prior to double-blind Baseline. 
All other psychotropic medication (except as described in this section), including antipsychotic 
medication, must be discontinued, as tolerated and clinically appropriate, prior to randomization in a 
manner that is consistent with labeling recommendations and conventional medical practice. 
Concomitant Psychotropic Medications: 
All antidepressants and mood stabilizers (eg, lithium, divalproex/valproic acid, carbamazepine, etc.) 
are not allowed during the study. Treatment with benztropine (benzotropine outside the United States 
[US]) up to 6 mg/day will be permitted, as needed, for movement disorders. In cases where benztropine 
is not available or a subject has had an inadequate response or intolerability to benztropine treatment, 
the following medications may be used to treat acute extrapyramidal symptoms (EPS): biperiden (up to 
16 mg/day) or trihexyphenidyl (up to 15 mg/day) or diphenhydramine (up to 100 mg/day). Treatment 
with propranolol (up to 120 mg/day) will be permitted as needed for akathisia. 
Medications used to treat movement disorders should not be given prophylactically. 
Concomitant use of lorazepam, temazepam, eszopiclone, zaleplon, zolpidem and zolpidem CR 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. 
Intramuscular lorazepam is permitted up to 4 mg/day for acute anxiety/agitation, as clinically 
indicated. Lorazepam should be used sparingly, when clinically required, per investigator 
judgment. 
• 
temazepam (≤ 30 mg/day), eszopiclone (≤ 3 mg/day), zopiclone (≤ 7.5 mg/day), zaleplon 
(≤ 20 mg/day), zolpidem (≤ 10 mg/day for males; ≤ 5 mg/day for females), and zolpidem CR 
(≤ 12.5 mg/day for males; ≤ 6.25 mg/day for females) may be administered at bedtime for 
insomnia, as needed. 
• 
hypnotic agents should be administered no more than once nightly and should not be used in 
combination. 
The date and time of the last dose taken prior to scheduled efficacy assessments must be recorded at 
each visit. Subjects should be encouraged to avoid taking these concomitant medications within 
8 hours of scheduled efficacy assessments. 
Opioids may be allowed for a limited period of time with prior authorization from the Medical 
Monitor. 
See Section 10.3 of full protocol for the complete list of concomitant medications and restrictions. 
Study Endpoints: 
Primary Endpoint: 
• 
Change from Baseline in PANSS total score at Week 4. 
Secondary Endpoints: 
• 
Change from Baseline in CGI-S score at Week 4. 
• 
Change from Baseline in PANSS subscale scores at Week 4. 


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• 
Change from Baseline in BNSS total score at Week 4 
• 
Change from Baseline in MADRS total score at Week 4. 
• 
Proportion of subjects who achieve a response, defined as a 20% or greater improvement 
from Baseline in PANSS total score at Week 4.  
• 
The incidence of overall AEs, serious AEs (SAEs) and AEs (or SAEs) leading to 
discontinuation. 
• 
Absolute values and changes from Baseline in clinical laboratory tests (hematology, serum 
chemistry, urinalysis), and clinical evaluations (vital signs, body weight, BMI, blood 
pressure [supine and standing], heart rate [supine and standing], 12-lead ECGs). 
• 
Frequency of subjects with suicidal ideation or suicidal behavior using the C-SSRS. 
Other Endpoints:  
• 
Change from Baseline in BARS, AIMS and SAS scores at Week 4. 
• 
Absolute visual analogue scale (VAS) scores of the DEQ. 
• 
Change from Baseline in PSQI score at Week 4. 
• 
Change from Baseline in CBB total score at Week 4. 
Statistical Methods:  
The analysis of efficacy will be based on the modified Intent-to-Treat (mITT) population, which 
includes all subjects who are randomized, have received at least one dose of study drug, and have a 
Baseline and at least one post-Baseline efficacy measurement in PANSS or CGI-S. The safety 
assessments will use the Safety population, which includes all subjects who are randomized and have 
received at least one dose of study drug. 
The primary efficacy variable is the change from Baseline in PANSS total score at Week 4 for testing 
superiority of SEP-363856 compared to placebo. The primary efficacy variable will be analyzed using 
a Mixed Model for Repeated Measures (MMRM). The MMRM model will include factors for 
treatment, visit (Day 4, Weeks 1, 2, 3, and 4; as a categorical variable), pooled center, and treatment-
by-visit interaction, and include Baseline PANSS total score as a covariate. An unstructured covariance 
matrix will be used for the within-subject correlation and the Kenward-Rogers approximation will be 
used to calculate the denominator degree of freedom. 
Sensitivity analyses will be conducted to assess the robustness of the MMRM analysis result of the 
primary endpoint. The methods will include the random effects pattern-mixture model and the pattern-
mixture model with placebo-based multiple imputation. 
The secondary efficacy variables of change from Baseline at Week 4 in CGI-S score, PANSS subscale 
scores, BNSS total score, and MADRS total score will be analyzed similarly to the primary variable. 
The subjects who achieve a response are defined as subjects having a 20% or greater improvement in 
PANSS total score from Baseline at the last observation carried forward (LOCF) endpoint. A logistic 
regression will be performed with the responder indicator as the dependent variable, and include 
treatment and geographic region as fixed factors, and Baseline PANSS total score as a covariate. 
Safety data including AEs, laboratory values, clinical evaluations, and C-SSRS, will be summarized. 
Adverse events, AEs leading to discontinuation, and serious AEs will be summarized by presenting, for 
each treatment group, the number and percentage of subjects with any AEs, and AEs by system organ 
class and preferred term. Adverse events will be further summarized by severity and by relationship to 
study drug. The summary of AEs will include any AE occurring on or after the first dose of study drug. 
A nonparametric rank analysis of covariance (ANCOVA) will be applied to prolactin, HbA1c, lipids, 
and glucose levels, as well as body weight and BMI in order to compare changes from Baseline 


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between treatment groups with adjustments for Baseline value. 
Sample Size: 
A sample size of 100 subjects per treatment group (SEP-363856 and placebo) will provide 80% power 
to detect a treatment effect size of 0.4 in change from Baseline in PANSS total score at Week 4 for 
SEP-363856 versus placebo, using a two independent sample t-test method with 2-sided significant 
level of 0.05. A clinically meaningful effect size of 0.4 was estimated based on review of published 
studies of other antipsychotics for the short-term treatment of schizophrenia. It is anticipated that 17% 
of all randomized subjects will discontinue early from the study. An upward adjustment of the sample 
size is thus used to compensate for missing data from subjects who are randomized and discontinue 
from the study. The total sample size will be 240 randomized subjects (or 120 subjects per treatment 
group). 
 


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Table 2: Schedule of Assessments 
Study Visit Number 
Study Visit Week 
 
Visit 1 
Screeninga 
Visit 2 
Baseline 
Visit 3 
Day 4 
Visit 4 
Week 1 
Visit 5 
Week 2 
Visit 6 
Week 3 
Visit 7 
Week 4 
or ETb 
Visit 8 
Week 5 
Study Visit Day  
-14 to -1 
1 
4 
8 
15 
22 
29 
7 ± 2days 
after Last Dose 
Study Visit Type 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
follow-upc 
Obtain informed consent 
X 
 
 
 
 
 
 
 
Review inclusion/exclusion criteria  
X 
X 
 
 
 
 
 
 
Review randomization criteria 
 
X 
 
 
 
 
 
 
Prior/concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
Randomize (IXRS) to treatment  
 
X 
 
 
 
 
 
 
Administration of study drugd 
 
X 
X 
X 
X 
X 
 
 
Study drug accountability 
 
 
X 
X 
X 
X 
X 
 
Clinical and Laboratory Evaluations 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Psychiatric history/mental status 
X 
 
 
 
 
 
 
 
SCID-CTe 
X 
 
 
 
 
 
 
 
Physical and neurological examination 
X 
 
 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
Vital signsf 
X 
X 
X 
X 
X 
X 
X 
 
Weight (including BMI)g 
X 
X 
 
 
X 
 
X 
 
Waist circumference 
 
X 
 
 
 
 
X 
 
Electrocardiogram (ECG) 
X 
X 
 
 
 
 
X 
 
Hematology, chemistry, and urinalysis  
X 
X 
 
 
 
 
X 
 
Serum prolactin 
X 
X 
 
 
 
 
X 
 
Glycosylated hemoglobin (HbA1c) 
X 
 
 
 
 
 
X 
 


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Table 2: 
Schedule of Assessments (Continued) 
Study Visit Number 
Study Visit Week 
 
Visit 1 
Screeninga 
Visit 2 
Baseline 
Visit 3 
Day 4 
Visit 4 
Week 1 
Visit 5 
Week 2 
Visit 6 
Week 3 
Visit 7 
Week 4 
or ETb 
Visit 8 
Week 5 
Study Visit Day  
-14 to -1 
1 
4 
8 
15 
22 
29 
7 ± 2days 
after Last Dose 
Study Visit Type 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
follow-upc 
Glucose and Lipid panelh 
X 
X 
 
 
 
 
X 
 
Serum follicle stimulating hormone (FSH)i 
X 
 
 
 
 
 
 
 
Serum human chorionic gonadotropin (β-hCG)  
X 
 
 
 
 
 
 
 
Blood sample for pharmacogenomics 
(CYPP450 2D6) 
 
X 
 
 
 
 
 
 
Blood sample for Population PKj 
 
X 
 
 
 
 
X 
 
Urine drug screenk 
X 
X 
 
 
 
 
X 
 
Urine β-hCGl 
 
X 
 
 
 
 
X 
 
Positive and Negative Syndrome Scale 
(PANSS) 
X 
X 
X 
X 
X 
X 
X 
 
Clinical Global Impression – Severity (CGI-S) 
X 
X 
X 
X 
X 
X 
X 
 
Brief Negative Symptom Scale (BNSS) 
X 
X 
X 
X 
X 
X 
X 
 
Montgomery-Asberg Depression Rating Scale 
(MADRS) 
 
X 
X 
X 
X 
X 
X 
 
Columbia Suicide Severity Rating Scale 
(C-SSRS)  
X 
X 
X 
X 
X 
X 
X 
X 
Barnes Akathisia Rating Scale (BARS)m 
X 
X 
X 
X 
X 
X 
X 
 
Abnormal Involuntary Movement Scale 
(AIMS)m 
X 
X 
X 
X 
X 
X 
X 
 
Simpson-Angus Scale (SAS)m 
X 
X 
X 
X 
X 
X 
X 
 
Drug Effects Questionnaire (DEQ) 
 
X 
 
 
 
 
X 
 
Pittsburg Sleep Quality Index (PSQI) 
 
X 
 
 
 
 
X 
 
CogState Brief Battery (CBB) 
 
X 
 
 
 
 
X 
 


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Table 2: 
Schedule of Assessments (Continued) 
Study Visit Number 
Study Visit Week 
 
Visit 1 
Screeninga 
Visit 2 
Baseline 
Visit 3 
Day 4 
Visit 4 
Week 1 
Visit 5 
Week 2 
Visit 6 
Week 3 
Visit 7 
Week 4 
or ETb 
Visit 8 
Week 5 
Study Visit Day  
-14 to -1 
1 
4 
8 
15 
22 
29 
7 ± 2days 
after Last 
Dose 
Study Visit Type 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
follow-upc 
Pretreatment event monitoring 
X 
 
 
 
 
 
 
 
Adverse events (AE) monitoring 
 
X 
X 
X 
X 
X 
X 
X 
Duplicate Subject Checkn 
X 
 
 
 
 
 
X 
X 
Abbreviations: AE = adverse event; BARS = Barnes Akathisia Rating Scale; β-hCG = human chorionic gonadotropin; BMI = Body Mass Index; BNNS = Brief Negative Symptom 
Scale; C-SSRS = Columbia Suicide Severity Rating Scale; ET = early termination; FSH = Follicle stimulating hormone; IXRS = interactive response technology; 
MADRS = Montgomery-Asberg Depression Rating Scale; SAS = Simpson-Angus Scale; PANSS = Positive and Negative Syndrome Scale; PSQI = Pittsburg Sleep Quality 
Index; PK = pharmacokinetic; SCID-CT = Structured Clinical Interview for DSM-5, Clinical Trials Version. 
a Subjects who screen fail may be re-screened up to two times, if judged appropriate by the Investigator. 
b If a subject discontinues from the study, all Visit 7 procedures should be performed at the ET visit, within 48 hours of last study dose. All procedures and assessments scheduled 
for Visit 7 (Week 4) will be utilized as the Baseline procedures and assessments for the open-label extension study (SEP361-202). 
c All subjects will have an inpatient/outpatient safety follow-up prior to discharge (7 [± 2]) days after their last dose of study drug. 
d All study drug will be taken once daily in the evening by mouth.  
e The SCID-CT will be used to support the DSM-5 diagnosis and must be administered by a qualified rater listed on Form 1572 with at least 2 years' experience with the 
population under study. 
f Vital signs will include supine and standing measurements of blood pressure; and heart rate, respiratory rate, and oral body temperature. 
g BMI will be calculated and recorded in the eCRF at the clinical site at Screening for other visits, BMI will be calculated during statistical analysis. 
h Subjects must be fasted (no food or drink except water at least 8 hours prior to specified blood tests). Blood samples should be drawn in the morning followed by a snack or 
meal. 
i Blood samples for follicle stimulating hormone (FSH) will be collected if menopause is suspected. 
j Blood samples for determination of plasma SEP-363856 and SEP-363854 concentrations will be collected predose (prior to administration of the first dose) on Day 1; one 
postdose sample will be collected on Day 29. The time and date of the 3 previous doses of study drug, time, and date of sampling must be recorded. Time and date of food intake 
must be recorded on Day 29 when blood samples are collected for determination of SEP-363856 and SEP-363854 concentrations. 
k If a subject is issued a day pass, an unscheduled urine drug screen will be performed upon returning to the site. Urine drug screen may be ordered at other visits as deemed 
clinically appropriate. These results should be discussed with the Medical Monitor. 
l Any positive urine β-hCG test should be confirmed by a serum β-hCG test. 
m Unscheduled BARS, AIMS, and SAS scales should be administered if a subject develops extrapyramidal symptoms (EPS) requiring treatment. See Section 10.3. 
n Following the last contact with a subject, the duplicate enrollment system should be updated, as appropriate (US sites only). 
Note: With the exception of SCID-CT and DEQ, all rating assessments will be performed by the rater using a tablet. In the event that a tablet is not available, the rating 
assessments will be performed by the rater using a paper version of the assessment. 


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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 ...............15 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................21 
4. 
INTRODUCTION ......................................................................................................25 
4.1. 
Background .................................................................................................................25 
4.2. 
Study Conduct Rationale ............................................................................................25 
4.3. 
Risk-Benefit Assessment ............................................................................................27 
4.4. 
Hypothesis ..................................................................................................................27 
4.4.1. 
Primary Hypothesis ....................................................................................................27 
5. 
STUDY OBJECTIVES ..............................................................................................28 
5.1. 
Primary Objective .......................................................................................................28 
5.2. 
Secondary Objectives .................................................................................................28 
5.3. 
Other Objectives .........................................................................................................28 
6. 
STUDY ENDPOINTS ................................................................................................30 
6.1. 
Primary Endpoint ........................................................................................................30 
6.2. 
Secondary Endpoints ..................................................................................................30 
6.3. 
Other Endpoints ..........................................................................................................30 
7. 
INVESTIGATIONAL PLAN .....................................................................................31 
7.1. 
Overall Study Design ..................................................................................................31 
7.2. 
Treatment Assignment and Blinding ..........................................................................33 
7.2.1. 
Treatment Assignment ................................................................................................33 
7.2.2. 
Blinding ......................................................................................................................33 
7.2.3. 
Emergency Unblinding Procedures ............................................................................34 
7.3. 
Rationale .....................................................................................................................34 
7.3.1. 
Rationale for the Study Design ...................................................................................34 
7.3.2. 
Rationale for the Dosages ...........................................................................................34 
7.4. 
Prevention of Missing Data ........................................................................................34 


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8. 
SELECTION OF SUBJECTS ....................................................................................35 
8.1. 
Subject Inclusion Criteria ...........................................................................................35 
8.2. 
Subject Exclusion Criteria ..........................................................................................36 
8.3. 
Randomization Criteria ...............................................................................................39 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................40 
9.1. 
Description of Study Drug ..........................................................................................40 
9.2. 
Study Drug Packaging and Labeling ..........................................................................40 
9.2.1. 
Package Description ...................................................................................................40 
9.2.2. 
Labeling Description ..................................................................................................40 
9.3. 
Study Drug Storage .....................................................................................................41 
9.4. 
Dispensing of Study Drug ..........................................................................................41 
9.5. 
Study Drug Accountability .........................................................................................41 
9.6. 
Study Drug Handling and Disposal ............................................................................42 
10. 
TREATMENT OF SUBJECTS ..................................................................................43 
10.1. 
Study Drug ..................................................................................................................43 
10.1.1. 
Dosage Adjustment Criteria .......................................................................................43 
10.2. 
Treatment Compliance ................................................................................................43 
10.3. 
Concomitant Medications ...........................................................................................43 
10.3.1. 
Prior Medications ........................................................................................................44 
10.3.2. 
Concomitant Nonpsychotropic Medications ..............................................................45 
10.3.3. 
Concomitant Psychotropic Medications .....................................................................45 
10.3.4. 
Prohibited Medications ...............................................................................................46 
10.3.5. 
Restricted Therapies ...................................................................................................46 
10.4. 
Other Restrictions .......................................................................................................46 
10.5. 
Description of Study Periods, Hospital Discharge, and Day Passes ..........................46 
10.5.1. 
Description of Study Periods ......................................................................................46 
10.5.2. 
Hospital Discharge During the Study .........................................................................47 
10.5.3. 
Emergency Day Passes ...............................................................................................47 
10.6. 
Guidance for Overdose ...............................................................................................48 
10.7. 
Dietary Guidelines ......................................................................................................48 
11. 
STUDY ASSESSMENTS ..........................................................................................49 
11.1. 
Demographics and Baseline Characteristics ...............................................................49 
11.2. 
Prior and Concomitant Medication Review ...............................................................49 


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11.3. 
Structured Clinical Interview for DSM-5 Axis I Disorders-Clinical Trials 
version (SCID-CT) .....................................................................................................49 
11.4. 
Efficacy Assessments .................................................................................................50 
11.4.1. 
Positive and Negative Syndrome Scale (PANSS) ......................................................50 
11.4.2. 
Brief Negative Symptom Scale (BNSS) .....................................................................50 
11.4.3. 
Montgomery-Asberg Depression Rating Scale (MADRS) ........................................50 
11.4.4. 
Clinical Global Impressions – Severity Scale (CGI-S) ..............................................50 
11.4.5. 
CogState Brief Battery (CBB) ....................................................................................51 
11.5. 
Safety Assessments .....................................................................................................51 
11.5.1. 
Adverse Events ...........................................................................................................51 
11.5.2. 
Clinical Laboratory Tests ...........................................................................................51 
11.5.3. 
Vital Signs ..................................................................................................................51 
11.5.4. 
Electrocardiograms (ECGs) ........................................................................................52 
11.5.5. 
Physical and Neurological Examination .....................................................................52 
11.5.6. 
Height, Weight, and BMI ...........................................................................................52 
11.5.7. 
Safety Scales ...............................................................................................................53 
11.5.7.1. 
Abnormal Involuntary Movement Scale (AIMS) .......................................................53 
11.5.7.2. 
Barnes Akathisia Rating Scale (BARS) .....................................................................53 
11.5.7.3. 
Simpson-Angus Scale (SAS) ......................................................................................53 
11.5.7.4. 
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................................53 
11.5.7.5. 
Drug Effects Questionnaire (DEQ) ............................................................................53 
11.5.7.6. 
Pittsburg Sleep Quality Index (PSQI).........................................................................54 
11.6. 
Population Pharmacokinetic Assessments ..................................................................54 
11.7. 
Pharmacogenomic Assessments .................................................................................54 
11.8. 
Study Visits and Assessments ....................................................................................54 
11.8.1. 
Screening: Visit 1 (Day -14 to -1);Inpatient ...............................................................54 
11.8.2. 
Baseline: Visit 2 (Day 1); Inpatient ............................................................................56 
11.8.3. 
Visit 3 (Day 4); Inpatient ............................................................................................57 
11.8.4. 
Visit 4 (Week 1; Day 8), Visit 5 (Week 2; Day 15), and Visit 6 (Week 3; 
Day 22); Inpatient .......................................................................................................58 
11.8.5. 
Visit 7 (Week 4; Day 29/Early Termination); Inpatient .............................................58 
11.8.6. 
Visit 8 (+ 7 days); Inpatient Follow-up ......................................................................59 
12. 
SAFETY REPORTING ..............................................................................................60 


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12.1. 
Definitions ..................................................................................................................60 
12.1.1. 
Adverse Events ...........................................................................................................60 
12.1.2. 
Serious Adverse Events ..............................................................................................60 
12.2. 
Objective Findings ......................................................................................................61 
12.3. 
Collection and Recording of Adverse Events .............................................................61 
12.4. 
Immediately Reportable Events ..................................................................................63 
12.4.1. 
Serious Adverse Event ................................................................................................63 
12.4.2. 
Pregnancy ...................................................................................................................64 
13. 
TERMINATION OF SUBJECT FROM STUDY/DISCONTINUATION OF 
STUDY DRUG ...........................................................................................................65 
13.1. 
Criteria for Study Drug Discontinuation ....................................................................65 
13.2. 
Clinical Assessments After Study Drug Discontinuation ...........................................65 
14. 
STUDY TERMINATION ..........................................................................................66 
15. 
STATISTICS ..............................................................................................................67 
15.1. 
Sample Size ................................................................................................................67 
15.2. 
Analysis Populations ..................................................................................................67 
15.2.1. 
Modified Intention-to-Treat Population .....................................................................67 
15.2.2. 
Per Protocol Population ..............................................................................................67 
15.2.3. 
Safety Population ........................................................................................................67 
15.3. 
Data Analysis ..............................................................................................................68 
15.3.1. 
Subject Disposition .....................................................................................................68 
15.3.2. 
Drug Exposure and Compliance .................................................................................68 
15.3.3. 
Important Protocol Deviations ....................................................................................68 
15.3.4. 
Demographic and Baseline Characteristics ................................................................68 
15.3.5. 
Efficacy Analyses .......................................................................................................69 
15.3.5.1. 
Primary Efficacy Endpoint Analysis ..........................................................................69 
15.3.5.2. 
Secondary Efficacy Endpoint Analysis ......................................................................69 
15.3.5.3. 
Other Efficacy Endpoint Analysis ..............................................................................70 
15.3.5.4. 
Adjustment for Multiplicity ........................................................................................70 
15.3.5.5. 
Subgroup Analysis ......................................................................................................71 
15.3.6. 
Safety Analyses ..........................................................................................................71 
15.3.6.1. 
Adverse Events ...........................................................................................................71 
15.3.6.2. 
Clinical Laboratory Assessments ...............................................................................72 


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15.3.6.3. 
ECGs/Centrally-read ECG/Holter Monitor ................................................................72 
15.3.6.4. 
Vital Signs ..................................................................................................................72 
15.3.6.5. 
Physical/Neurological Examination ...........................................................................72 
15.3.6.6. 
Concomitant Medications ...........................................................................................72 
15.3.6.7. 
Suicidality Measure ....................................................................................................73 
15.3.6.8. 
Movement Disorder Measures ....................................................................................73 
15.3.6.9. 
Drug Effects Questionnaire ........................................................................................73 
15.3.6.10. Pittsburgh Sleep Quality Index ...................................................................................73 
15.3.6.11. Subgroup Analysis ......................................................................................................73 
15.3.7. 
Population Pharmacokinetic Analysis ........................................................................73 
15.3.8. 
Pharmacodynamic Analysis........................................................................................73 
15.3.9. 
Pharmacogenomic Analysis........................................................................................74 
15.3.10. 
Interim Analysis ..........................................................................................................74 
15.3.11. 
Treatment of Missing Data .........................................................................................74 
15.3.12. 
Sensitivity Analyses ....................................................................................................74 
16. 
PROCEDURE FOR CLINICAL STUDY QUALITY CONTROL /DATA 
COLLECTION, MANAGEMENT, AND QUALITY ASSURANCE ......................75 
16.1. 
Data Collection/Electronic Data Capture (EDC) ........................................................75 
16.2. 
Computerized Systems Used for Source Data ............................................................75 
16.3. 
Study Monitoring ........................................................................................................76 
16.4. 
Audits ..........................................................................................................................77 
16.5. 
Study Documentation .................................................................................................77 
16.6. 
Clinical Laboratory Certification and Normal Values ................................................77 
17. 
ETHICAL AND REGULATORY OBLIGATIONS..................................................78 
17.1. 
Study Conduct ............................................................................................................78 
17.2. 
Institutional Review Board/Independent Ethics Committee ......................................78 
17.3. 
Informed Consent .......................................................................................................78 
17.4. 
Subject Privacy ...........................................................................................................79 
17.5. 
Protocol Amendments and Emergency Deviations ....................................................79 
17.6. 
Records Retention .......................................................................................................80 
17.7. 
Inspection of Records .................................................................................................80 
17.8. 
Publication Policy .......................................................................................................80 
18. 
REFERENCES ...........................................................................................................81 


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19. 
INVESTIGATOR APPROVAL .................................................................................84 
20. 
APPENDIX I. CARDIAC SAFETY MONITORING (ECG) ....................................85 
21. 
APPENDIX II. HIGHLY EFFECTIVE CONTRACEPTIVE 
PROCEDURES FOR AND DURING THE STUDY ................................................86 
22. 
APPENDIX III. HALOPERIDOL EQUIVALENT DOSES .....................................87 
23. 
APPENDIX IV. CLINICAL LABORATORY TESTS ..............................................88 
24. 
APPENDIX V. PHARMACOKINETIC SAMPLING AND SAMPLE 
HANDLING GUIDELINE .........................................................................................89 
25. 
APPENDIX VI. SAMPLE COLLECTION AND HANDLING 
GUIDELINES FOR PHARMACOGENOMICS ASSESSMENT .............................90 
26. 
APPENDIX VII. MINIMUM PANSS TOTAL SCORE CRITERIA AT 
BASELINE .................................................................................................................91 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Schedule of Assessments ............................................................................................12 
Table 3: 
List of Abbreviations ..................................................................................................21 
Table 4: 
Definition of Key Study Terms ..................................................................................24 
Table 5: 
Investigational Product ...............................................................................................40 
Table 6: 
Concomitant Medications/Therapies: Use During Study ...........................................44 
Table 7: 
Description of Study Periods ......................................................................................46 
Table 8: 
Computerized Systems Used for Source Data ............................................................75 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................31 
 


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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 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BARS 
Barnes Akathisia Rating Scale 
BMI 
Body mass index  
BNSS 
Brief Negative Symptom Scale 
BOLD 
Blood oxygen level dependent 
BUN 
Blood urea nitrogen 
CDR 
Clinical data repository 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical global impression - improvement 
CGI-S 
Clinical global impression - severity 
CLIA 
Clinical Laboratory Improvement Amendments 
CNS 
Central nervous system 
CRF 
Case report form 
CRO 
Contract research organization 
CS 
Clinically significant 
C-SSRS 
Columbia – Suicide Severity Rating Scale 
CYP 
cytochrome 
DEQ 
Drug Effects Questionnaire 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EEG 
Electroencephalogram 
ET 
Early termination 
 


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Table 3: 
List of Abbreviations (Continued) 
Abbreviation 
Full Form 
FDA 
U.S. Food and Drug Administration 
fMRI 
functional magnetic resonance imaging (fMRI) 
GCP 
Good Clinical Practice 
5-HT 
5-hydroxytryptamine (serotonin) 
HIV 
Human immunodeficiency virus  
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee  
IND 
Investigational New Drug 
IPD 
Important protocol deviation 
IRB 
Institutional Review Board 
IXRS 
Interactive voice/web response system 
LOCF 
Last Observation Carried Forward 
LIMS 
Laboratory information management system 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MID 
Monetary incentive delay 
mITT 
Modified Intention-to-Treat 
MMRM 
Mixed-effects Models Repeated Measures 
MoA 
Mechanism of action 
SAS 
Simpson-Angus Scale 
MTD 
Maximum tolerated dose 
N2 
NREM sleep stage 2 
N3 
NREM sleep stage 3 
NCS 
Not clinically significant 
NREM 
Non-rapid eye movement sleep 
PANSS 
Positive and negative syndrome scale 
PD 
Pharmacodynamic(s) 
PE 
Physical examination 
PGx 
Pharmacogenomic(s) 
PK 
Pharmacokinetic(s) 
POPPK 
Population pharmacokinetics 
 


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Table 3: 
List of Abbreviations (Continued) 
Abbreviation 
Full Form 
PR 
Time between P wave and QRS in electrocardiography 
PSG 
polysomnography 
PSQI 
Pittsburgh Sleep Quality Index 
PT 
Preferred term 
QD 
Once daily 
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 
REM 
Rapid eye movement 
RR 
Respiration rate 
SAD 
single ascending dose 
SAE 
Serious adverse event 
SCID-CT 
Structured Clinical Interview for DSM-5, Clinical Trials Version 
SOC 
System organ class 
TAAR1 
trace amine associated 1 receptors 
US, USA 
United States, United States of America 
USP 
United States Pharmacopeia 
VAS 
Visual analogue scale 
WBC 
White blood cells 
WHO 
World Health Organization 


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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. 
Screened Subject 
Any subject who signed the study specific informed consent and 
completed at least one study related procedure. 
Screen Failures 
Any subject who signed the study specific informed consent but 
either failed to meet study requirements during screening or met 
study requirements at screening but was not enrolled/randomized. 
Study Drug (or 
Study medication) or 
Investigational 
Product 
Term to cover investigational drug and placebo. 
Treatment Period 
The period of the study in which the study drug is administered. 
Randomized Subject 
Any subject who was randomized into the treatment period of the 
study and was assigned a randomization number. 
Enrolled Subject 
Any subject who was successfully screened and enrolled into the 
pre-randomization period of the study. 
Randomization 
Failures 
Any subject who was enrolled but not randomized. 
Completed Subject 
Any subject who participated throughout the duration of the 
study, up to and including the last in-clinic visit. 
Early Termination 
Subject 
Any subject who was successfully screened and randomized into 
the treatment period of the study, but did not complete the study. 
End of Treatment 
The day that the subject receives protocol-defined last dose of the 
study drug. This may or may not include a taper period.  
End of Study 
The day that the subject completes the study per the study design. 
 


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4. 
INTRODUCTION 
4.1. 
Background 
Schizophrenia is a chronic and disabling neurodegenerative disorder characterized by a mixture 
of positive symptoms (eg, hallucinations, delusions, and thought and movement disorders), 
negative symptoms (eg, flat affect, anhedonia, alogia, and avolition), and cognitive deficits (eg, 
impaired memory, attention, and planning/organizing). Mood symptoms such as depression, 
anxiety, hostility, and excitement can also be present in patients with schizophrenia (Patel-2007; 
NIMH-2010). Despite scientific advances, schizophrenia remains one of the most challenging 
diseases to treat due to its variable nature, the heterogeneity of clinical response, the side effects 
of treatment, and its association with high morbidity and mortality (Lehman-2004; Tandon-2008; 
NIMH-2010). 
Schizophrenia has an estimated population prevalence of approximately 1% (estimated 
2.4 million adults), with a diagnosed prevalence of 0.51% in the United States (Narrow-2002; 
Wu-2006). It affects both genders equally (NIMH-2010) typically first manifesting in young 
adults, with the peak ages of onset in the early to mid 20s in men and late 20s in women 
(APA-2000). It is believed to be caused by a combination of genetic and environmental factors 
(Minzenberg-2008). Dopaminergic, serotonergic and glutamatergic systems are believed to play 
a role in schizophrenia (Kuroki-2008; Kim-2009). 
The current standard of care for the treatment of schizophrenia is the use of second generation 
antipsychotics or “atypical antipsychotics” (Lehman-2004; Kreyenbuhl-2009; NIMH-2010; 
Meltzer-2011; Nakamura-2009). These “atypicals” are thought to have fewer extrapyramidal 
side effects compared to first generation antipsychotics or “typical antipsychotics” (eg, 
haloperidol) (Leucht-2009; Naber-2009). However some patients respond poorly to both atypical 
and typical antipsychotics and some continue to have symptoms and substantial 
functional/cognitive impairment (Keefe-2006; Webber-2008). Very few patients return to 
Baseline (pre-psychosis) function (Schultz-1999; Pearlson-2000; Kapur-2001). In addition, some 
atypical agents have a variety of other side effects, including weight gain, metabolic syndrome, 
sedation, QTc prolongation, extrapyramidal symptoms and tardive dyskinesia (Davis-2004; 
Lieberman-2005; Newcomer-2007; Leucht-2009), which may lead to significant medical 
problems as well as contribute to poor compliance and treatment discontinuation. The large scale 
NIMH-CATIE schizophrenia study found that 70% to 80% of outpatients discontinue 
medications because of lack of efficacy or occurrence of side effects (Lieberman-2005) often 
leading to relapse of symptoms and need for rehospitalization (Ascher-Svanum-2010; 
Munro-2011; Morken-2008). Clearly, an unmet need exists for new, effective, and well-tolerated 
treatments. 
4.2. 
Study Conduct Rationale 
SEP-363856 is a CNS-active compound, which shows broad efficacy in animal models of 
schizophrenia (positive and negative symptoms), cognition and depression. The molecular target 
responsible for the profile effects has not been completely elucidated, but may include actions at 
5-HT1A and trace amine associated 1 (TAAR1) receptors. Rat electroencephalogram (EEG) 


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studies showed that SEP-363856 suppressed rapid eye movement (REM) sleep in a dose 
dependent manner. In nonhuman primate functional magnetic resonance imaging (fMRI) 
experiments, similar to risperidone, pretreatment with SEP-363856 also reduced the ketamine 
brain fMRI response in rhesus monkey supporting an antipsychotic-like profile. Taken together, 
these data demonstrate that SEP-363856 exhibits clear, functional CNS PD signals in rats and 
nonhuman primates. 
To date, 210 subjects have received oral doses of SEP-363856 in six Phase 1 clinical studies. 
Five Phase 1 studies have been completed (SEP361-101, SEP361-103, SEP361-105, 
SEP361-106, and SEP361-108). One Phase 1 study has been clinically completed (SEP361-104). 
The first in human clinical study, a single ascending dose study (SAD; Study SEP361-101), was 
designed to determine the safety, tolerability, maximum tolerated dose (MTD), and PK of a 
single oral dose of SEP-363856 in normal, healthy, adult male subjects. 
Study SEP361-103 was a randomized, double-blind, placebo-controlled, crossover 
polysomnography (PSG) study that investigated the effect of a single oral dose (50 mg and 
10 mg) of SEP-363856 on REM sleep suppression and PK in healthy adult male subjects. A 
single 50 mg oral dose of SEP-363856 suppressed REM sleep in all subjects (increased latency 
to REM sleep and reduced time spent in REM sleep) and increased NREM sleep stage 2 (N2), 
and NREM sleep stage 3 (N3) (deep or slow wave sleep). A single oral 10 mg dose of 
SEP-363856 also increased latency to REM sleep to a lesser extent, but did not reduce time spent 
in REM sleep. Taken together, results from these 2 studies in healthy adult male subjects 
demonstrated acceptable safety profile as well as robust CNS effect. 
Study SEP361-105 was a randomized, single-blind, placebo-controlled, SAD study assessing the 
safety, tolerability, and PK of SEP-363856 in male and female subjects with schizophrenia. 
Study SEP361-106 was a 2-part, randomized, single-blind, placebo-controlled, multiple 
ascending oral dose (MAD) and open-label study in male and female schizophrenic patients 
assessing the safety, tolerability, and PK of SEP-363856 in the target patient population. Results 
from this study demonstrates an acceptable safety and tolerability profile of SEP-363856 up to 
28 days in schizophrenia patients. Additionally, in Part 2, treatment with SEP-363856 at 
75 mg/day for 28 days demonstrated improvement in efficacy measures (PANSS total score, 
CGI-S) compared with Baseline. Furthermore, ad hoc subgroup analyses showed a significantly 
greater decrease from Baseline in PANSS total scores at the end of the 28 day treatment period 
in subjects who had less frequent hospitalizations per year of illness compared with subjects who 
had more frequent hospitalizations per year of illness. 
Study SEP361-104 was a randomized, double-blind, placebo-controlled, single dose study of the 
effects of SEP-363856 (50 mg) and amisulpride (400 mg) on BOLD-fMRI signal in healthy adult 
male and female subjects with high or low schizotype characteristics. Subjects with high 
schizotype characteristics and patients with schizophrenia share many similar features including 
positive, cognitive, negative and anhedonia symptoms, although in high schizotypes the features 
present in an attenuated form. In this study, fMRI was used in combination with a validated 
monetary incentive delay (MID) task to examine the single dose effects SEP-363856 on changes 
in reward processing. During the anticipation/motivational phase of the task, SEP-363856 
modulated striatum, insula and orbitofrontal cortex brain activity, and fMRI effects of 
SEP-363856 were similar to those observed with the D2 antagonist amisulpride. During the 
outcome/hedonic phase of the task, SEP-363856 generally increased brain activity in core reward 


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areas (striatum, insula), whereas amisulpride decreased brain activity in these same regions. 
Taken together the overall pattern of activity during MID task performance support specific 
hypotheses for the potential of SEP-363856, a novel MoA molecule, to improve positive and 
negative symptoms of schizophrenia. Overall, the known molecular pharmacology profile, 
animal model evidence, and clinical experience in healthy adult male and female subjects, adult 
male and female subjects with high and low schizotype characteristics, and patients with 
schizophrenia provide further support to evaluate SEP-363856 as a potential treatment for 
schizophrenia. 
The present study is designed to evaluate efficacy and safety of SEP-363856 50 and 75 mg/day 
for 4 weeks in adult male and female subjects with an acute exacerbation of schizophrenia. 
4.3. 
Risk-Benefit Assessment 
Overall, in previous clinical studies SEP-363856 was generally well-tolerated. The PK and safety 
profiles observed in adult subjects from completed Phase 1 clinical studies supports the 
evaluation of SEP-363856 50 to 75 mg/day in adults with schizophrenia. 
Schizophrenia is a life-long disorder and despite advances in drug treatment many patients 
continue to experience symptoms with impaired quality of life. SEP-363856 has a different and 
novel mechanism of action not related to direct antagonism of the D2 receptor. If proven 
effective and safe, it may provide a s major advance in the treatment of patients with 
schizophrenia. 
4.4. 
Hypothesis 
4.4.1. 
Primary Hypothesis 
Treatment with SEP-363856 in subjects with schizophrenia will result in a significant reduction 
in the PANSS total score at Week 4 when compared to placebo. 
Let μSEP and μPBO represent the mean changes from Baseline at Week 4 in PANSS total score for 
the SEP-363856 and placebo arms, respectively. The following hypothesis will be tested to 
compare the mean change values between the SEP-363856 group and placebo group at Week 4: 
H0: μSEP = μPBO versus H1: μSEP ≠ μPBO 


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5. 
STUDY OBJECTIVES 
5.1. 
Primary Objective 
To evaluate the efficacy of flexibly dosed SEP-363856 (50 or 75 mg/day) compared with 
placebo in acutely psychotic adult subjects with schizophrenia as measured by the Positive and 
Negative Syndrome Scale (PANSS). 
5.2. 
Secondary Objectives 
• To evaluate the efficacy of flexibly dosed SEP-363856 (50 or 75 mg/day) compared 
with placebo in acutely psychotic adult subjects with schizophrenia as measured by: 
− Clinical Global Impression-Severity (CGI-S) 
− PANSS subscale scores (positive, negative, and general psychopathology) 
− Brief Negative Symptom Scale (BNSS) 
− Montgomery-Asberg Depression Rating Scale (MADRS) 
• To evaluate the safety and tolerability of flexibly dosed SEP-363856 
(50 or 75 mg/day) using: 
− physical examinations (PE) 
− 12-lead electrocardiograms (ECG) 
− vital signs 
− adverse event (AE) reports 
− clinical laboratory results 
− body weight and body mass index (BMI) 
− Columbia – Suicide Severity Rating Scale (C-SSRS) 
5.3. 
Other Objectives 
• To assess whether SEP-363856 is associated with extrapyramidal symptoms as 
measured by the Barnes Akathisia Rating Scale (BARS), the Abnormal Involuntary 
Movement Scale (AIMS), and the Simpson-Angus Scale (SAS). 
• To characterize the effects of SEP-363856 as measured by the Drug Effects 
Questionnaire (DEQ). 
• To explore the subjective effects of SEP-363856 on sleep as measured by the 
Pittsburgh Sleep Quality Index (PSQI). 
• To assess the effects of SEP-363856 on cognition based on the CogState Brief 
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• To perform population pharmacokinetic (POPPK) analysis using plasma SEP-363856 
concentrations. 
• To characterize the relationship between PANSS total score and plasma SEP-363856 
exposure using population PK/pharmacodynamics (PD) methods. 
• To explore the impact of cytochrome (CYP) P450 CYP2D6 metabolizer status on 
SEP-363856 plasma exposure. 


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6. 
STUDY ENDPOINTS 
6.1. 
Primary Endpoint 
Change from Baseline in PANSS total score at Week 4 
 
6.2. 
Secondary Endpoints 
• Change from Baseline in CGI-S score at Week 4. 
• Change from Baseline in PANSS subscale scores at Week 4. 
• Change from Baseline in BNSS total score at Week 4 
• Change from Baseline in MADRS total score at Week 4. 
• Proportion of subjects who achieve a response, defined as a 20% or greater 
improvement from Baseline in PANSS total score at Week 4. 
• The incidence of overall AEs, serious AEs (SAEs) and AEs (or SAEs) leading to 
discontinuation. 
• Absolute values and changes from Baseline in clinical laboratory tests (hematology, 
serum chemistry, urinalysis), and clinical evaluations (vital signs, body weight, BMI, 
blood pressure [supine and standing], heart rate [supine and standing], 12-lead 
ECGs). 
• Frequency of subjects with suicidal ideation or suicidal behavior using the C-SSRS. 
6.3. 
Other Endpoints 
• Change from Baseline in BARS, AIMS and SAS scores at Week 4. 
• Absolute visual analogue scale (VAS) scores of the DEQ. 
• Change from Baseline in PSQI score at Week 4. 
• Change from Baseline in the CBB total score at Week 4. 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a multicenter, randomized, double-blind, parallel-group, flexibly-dosed, study evaluating 
the efficacy and safety of SEP-363856 in acutely psychotic adult subjects with schizophrenia 
using SEP-363856 (50 or 75 mg/day [ie, once daily]) versus placebo over a 4-week treatment 
period. This study is projected to randomize at least 240 subjects to 2 treatment groups 
(SEP-363856 or placebo) in a 1:1 ratio. Treatment assignment will be balanced within each 
clinical site. Subjects randomized to placebo will receive placebo treatment throughout the study. 
Study drug will be dosed at bed time with or without food. 
The study will consist of 3 periods: Screening/Washout (up to 14 days), Treatment (4 weeks in-
patient), and a Follow-up visit (7 days after last study drug dose for subjects who discontinue 
prior to Visit 7 or who complete the study but do not elect to enroll in the open-label extension 
study [SEP361-202]). 
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 
 
 
* 
Screening/washout period will be up to 14 days. 
** Follow-up visit 7 ± 2 days after last dose only for subjects not continuing in to open-label extension study SEP361-202. 
Hospitalization will be allowed for up to an additional 7 days to stabilize the subject, if necessary 
 


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Screening/Washout Period (up to 14 days) 
Informed consent will be obtained from each subject before any study procedures are performed. 
Subjects will be evaluated for eligibility during a screening phase of up to 14 days, during which 
they will be tapered off all psychotropic medications (except as noted in the protocol) in a 
manner that is consistent with labeling recommendations and conventional medical practices.  
Subjects will remain hospitalized for the duration of the screening/washout period. 
 
Double-Blind Treatment Period (4 weeks) 
During the double-blind phase, subjects will be in-patient through Week 4. Subjects will be 
eligible for hospital discharge after the Week 4 visit (Day 29). 
 
Randomization/Treatment: At double-blind Baseline (Day 1), subjects who have successfully 
completed the washout of prior medication (see Section 10.3.1) and have met the randomization 
criteria (see below) will be randomly assigned via interactive web/voice response system (in a 
1:1 ratio) to one of two treatment arms: SEP-363856 or placebo. Study drug dosing will initiate 
the evening of the Baseline visit. Treatment will continue once-daily at night for the remainder of 
study during which procedures outlined in Table 2 will be conducted. 
Subjects will receive SEP-363856 50 mg/day on Day 1 through 3. On Day 4, subjects are 
permitted (but not required) to titrate up to a dose of 75 mg/day. Thereafter, if a dose increase is 
necessary to optimize efficacy it should occur at regular scheduled study visits/weekly intervals 
starting from Visit 4 based on Investigator judgement. A dose reduction for tolerability purposes 
is permitted to occur more frequently than at weekly intervals. Subject can be flexibly dosed up 
until Visit 6, but no dose adjustments are allowed thereafter. 
 
End of Double-Blind Period: 
Subjects who complete the 4-week double-blind treatment phase will be eligible to participate in 
a separate open-label 26-week extension study (Study SEP361-202). Subjects who discontinue 
early from the study or complete the study and do not enter the 6-month extension study will be 
required to complete the follow-up visit 7 days (± 2 days) post last dose of study drug.  
Upon completion or early discontinuation from the study, hospitalization will be allowed for up 
to an additional 7 days to stabilize the subject, if necessary. Prior authorization for the 
hospitalization must be approved by the Medical Monitor. After completion of the follow-up 
visit or upon study discontinuation, all subjects will be referred for appropriate continued 
treatment and follow-up care as determined by the Investigator. 
 


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Efficacy, Safety, and Pharmacokinetic Evaluations 
Efficacy will be evaluated using the PANSS total and subscale scores, as well as CGI-S, BNSS, 
and MADRS scores. Effect of SEP-363856 on cognition will be assessed by the CBB. 
Safety and tolerability will be monitored throughout the study by collection of PE results, ECGs, 
vital signs, AEs, clinical laboratory parameters, C-SSRS, body weight, and BMI. Subjects who 
have significant findings for suicidal ideation upon completion of the C-SSRS at any time during 
the study must be referred to the investigator for follow-up evaluation. 
Subjects will provide information on subjective drug effects via administration of the DEQ. In 
addition, effects on movement disorders will be measured using the AIMS, BARS and SAS 
scales. Subjective effects on sleep will be measured by the PSQI scale. 
Blood samples for plasma SEP-363856 and SEP-363854 concentrations will be collected on 
Day 1 (predose) and Day 29. POPPK analysis will be performed using plasma SEP-363856 
concentrations; the results of which will be reported separately. The relationship between 
PANSS total score and plasma SEP-363856 exposure using population PK/pharmacodynamics 
(PD) methods exposure will be explored and reported separately. The impact of cytochrome 
(CYP) P450 CYP2D6 metabolizer status on plasma SEP-363856 exposure will be explored and 
reported separately. 
7.2. 
Treatment Assignment and Blinding 
7.2.1. 
Treatment Assignment 
The randomization schedule will be generated by a non-study biostatistician. Once a subject is 
deemed eligible to be randomized at Day 1 (Visit 2), an IXRS will perform treatment 
assignment. Subjects will be randomized to one of the following treatment groups in a 1:1 ratio 
and balanced within each clinical site: 
• SEP-363856 (50 or 75 mg/day flexible dosing for 4 weeks) 
• Placebo (once daily for 4 weeks) 
Once a randomization number has been assigned, it cannot be reused. 
7.2.2. 
Blinding 
Subjects, Investigator staff, persons performing the assessments, clinical operations personnel, 
data analysts, and personnel at central laboratories (including imaging) will remain blind to the 
identity of the treatment from the time of randomization until database lock and unblinding, 
using the following methods; (1) randomization data are kept strictly confidential until the time 
of unblinding, and will not be accessible by anyone else involved in the study with the exception 
of bioanalytical personnel involved in the analysis of PK samples; (2) the identity of the 
treatments will be concealed by the use of study drugs that are all identical in packaging, 
labeling, schedule of administration and appearance. 
Actual subject identity for plasma concentrations of SEP-363856 and SEP-363854 will not be 
disclosed before the database lock and the unblinding of the double-blind treatment phase. 


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7.2.3. 
Emergency Unblinding Procedures 
In the case of a medical emergency, where knowledge of study drug by the Investigator or an 
authorized delegate is essential for immediate medical management, a 24-hour code-break 
service will be available via the IXRS. The date and reason for unblinding are to be documented 
in the source documents. Any subject for whom the treatment assignment was unblinded is to be 
discontinued from further study participation. The subject should return for a final study 
assessment as described in Section 11.8.6. 
7.3. 
Rationale 
7.3.1. 
Rationale for the Study Design 
This is a multiregional, randomized, double-blind, parallel-group, flexibly-dosed study 
evaluating the efficacy and safety of SEP-363856 in acutely psychotic adult subjects with 
schizophrenia using SEP-363856 (50 or 75 mg/day) versus placebo over a 4-week treatment 
period. The 4-week study duration will provide an adequate timeframe within which to evaluate 
the effects of SEP-363856 compared to placebo in this subject population. 
7.3.2. 
Rationale for the Dosages 
Dosing of SEP-363856 50 or 75 mg mg/day for 28 days will be utilized in this study. Selection 
of these dose levels was guided by the maximum tolerated dose (MTD) determined for single 
doses of SEP-363856 administered to healthy adult male subjects in Study SEP361-101 (50 mg); 
the MTD determined for single doses administered to adult male and female subjects with 
schizophrenia in Study SEP361-105 (100 mg); by the single doses administered to healthy adult 
male subjects (Studies SEP361-103 and SEP361-104 [50 mg]) in which SEP-363856 was found 
to have robust CNS activity). In addition, dose selection is supported by acceptable safety and 
tolerability data from the 7-day (10 - 75 mg) and open label 28-day (75 mg) MAD study 
(Study SEP361-106, Parts 1 and 2) in adult male and female subjects with schizophrenia.  
7.4. 
Prevention of Missing Data 
In an effort to minimize the number of subjects who are terminated from the study prior to study 
completion, the following study design and conduct elements are implemented: 
• allowance of a dose reduction (from 75 to 50 mg/day) for drug tolerability purposes 
• allowance of some concomitant psychotropic medications during study participation 
• use of study centers with a good track record of enrolling and following eligible subjects 
• train the study centers 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 
• monitor data collection at the site level for adherence during the study 
Please see Section 15.3 for statistical considerations related to missing data. 


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8. 
SELECTION OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
To qualify for participation, subjects must meet all of the following inclusion criteria: 
1. Subject must give written informed consent and privacy authorization prior to 
participation in the study. Separate consent will be obtained from a caregiver or legal 
guardian if required by local law. 
2. Subject must be willing and able to comply with the study procedures and visit schedules, 
including required hospitalization for the washout period and the double-blind treatment 
period, and must be able to understand and follow verbal and written instructions. 
3. Male or female subject between 18 to 40 years of age (inclusive) at the time of consent. 
4. Subject meets DSM-5 criteria for schizophrenia as established by clinical interview 
(using the DSM-5 as a reference and confirmed using the SCID-CT). The duration of the 
subject's illness whether treated or untreated must be ≥ 6 months. 
5. Subject must have a CGI-S score ≥ 4 (moderate or greater) at screening and Baseline 
(Day 1). 
6. Subject must have a PANSS total score ≥ 80 and a PANSS item score ≥ 4 (moderate) on 
2 or more of the following PANSS items: delusions, conceptual disorganization, 
hallucinations, and unusual thought content at screening and Baseline (Day 1). 
7. Subject has an acute exacerbation of psychotic symptoms (no longer than 2 months). 
• Subject has marked deterioration of functioning in one or more areas, such as 
occupational, social, or personal care or hygiene. 
• Subject requires hospitalization for an acute psychotic exacerbation at the time of 
screening or has been hospitalized for the purpose of treating an acute psychotic 
exacerbation for no more than 2 consecutive weeks immediately before screening. 
Subjects who have been hospitalized for more than 2 weeks for reasons unrelated to an 
acute psychotic exacerbation may be included if such a hospitalization was for a 
condition other than an acute psychotic relapse. For example, subjects in a long-term 
hospital setting who have an acute exacerbation and are transferred to an acute unit are 
eligible for the study. 
8. Subject has had no more than 2 prior hospitalizations for the treatment of an acute 
exacerbation of schizophrenia (not including the current hospitalization) This history 
must be confirmed based on report by a reliable informant (eg., caregiver or family 
member) or medical records available at the time of screening. 
9. Subject’s BMI must be at least 18 kg/m2 but no more than 35 kg/m2. 
10. Female subject must have a negative serum pregnancy test at screening. 
11. Female subject of reproductive potential agrees to remain abstinent or use highly 
effective and reliable contraception throughout the study and for at least 30 days after the 
last dose of study drug has been taken (See Section 21 Appendix II Highly Effective 


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Contraceptive procedures). In the Investigator's judgment, the subject will adhere to this 
requirement. 
12. Male subjects with female partner(s) of childbearing potential must agree to avoid 
fathering a child and use highly effective methods of birth control (outlined in 
Section 21) from screening until at least 30 days after the last study drug administration. 
13. Subject must be able and agree to remain off prior antipsychotic medication for the 
duration of the study. 
14. Subject must have a total score < 5 on the SAS at Baseline (Day 1). 
15. Subject is, in the opinion of the Investigator, generally healthy based on screening 
medical history, PE, neurological examination, vital signs, clinical laboratory values 
(hematology, serum chemistry, urinalysis, lipid panel, coagulation panel, thyroid panel, 
and serum prolactin). 
16. Subject has had a stable living arrangement at the time of screening and agrees to return 
to a similar living arrangement after discharge. This criterion is not meant to exclude 
subjects who have temporarily left a stable living arrangement (eg, due to psychosis). 
Such subjects remain eligible to participate in this protocol. Chronically homeless 
subjects should not be enrolled.  
17. Subject must agree to comply with all restrictions for the required length of time 
(see Concomitant Medications and Restrictions in Section 10.3). 
8.2. 
Subject Exclusion Criteria 
To qualify for participation, subjects must not meet any of the following exclusion criteria: 
1. 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 or during the Screening period (ie, in the past 
one month) and/or at Baseline (ie, since last visit). 
2. Subject does not tolerate venipuncture or has poor venous access that would cause 
difficulty for collecting blood samples. 
3. Subject is currently participating, or has participated in, a study with an investigational or 
marketed compound or device within 6 months prior to signing the informed consent, or 
has participated in 2 or more studies within 24 months prior to signing informed consent. 
4. Subject has previously received SEP-363856. 
5. Subject has any clinically significant unstable medical condition or any clinically 
significant chronic disease that in the opinion of the Investigator, would limit the 
subject’s ability to complete and/or participate in the study: 
a. Hematological (including deep vein thrombosis) or bleeding disorder, renal, 
metabolic, endocrine, pulmonary, gastrointestinal, urological, cardiovascular, hepatic, 
neurologic, or allergic disease that is clinically significant or unstable (except for 
untreated, asymptomatic, seasonal allergies at time of dosing). 
b. Subject has a history of neuroleptic malignant syndrome. 


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c. Subject has a history of malignancy within 5 years prior to the Screening visit, except 
for adequately treated basal cell or squamous cell skin cancer or in situ cervical 
cancer. Pituitary tumors of any duration are excluded. 
d. Disorder or history of a condition, or previous gastrointestinal surgery 
(eg, cholecystectomy, vagotomy, bowel resection, or any surgical procedure) that 
may interfere with drug absorption, distribution, metabolism, excretion, 
gastrointestinal motility, or pH, or a clinically significant abnormality of the hepatic 
or renal system, or a history of malabsorption. 
e. Subject has Alcohol or Substance Abuse Disorder (DSM-5 criteria). The only 
exceptions include caffeine or nicotine.  
f. Subject has a clinically significant abnormal 12-lead ECG that may jeopardize the 
subject’s ability to complete the study or a screening 12-lead ECG demonstrating any 
one of the following: heart rate > 100 beats per minute, QRS > 120 ms, QT interval 
corrected for heart rate using Fridericia’s formula (QTcF) > 450 ms (males), 
QTcF > 470 ms (females), or PR > 220 ms. 
g. Subjects with known history of human immunodeficiency virus (HIV) seropositivity. 
6. Female subject who is pregnant or lactating. 
7. Subject who has a lifelong history or presence of symptoms consistent with a major 
psychiatric disorder other than schizophrenia as defined by DSM-5. Exclusionary 
disorders include but are not limited to alcohol use disorder (within past 12 months), 
substance (other than nicotine or caffeine) use disorder within past 12 months, major 
depressive disorder, bipolar depression, mania, schizoaffective disorder, obsessive 
compulsive disorder, posttraumatic stress disorder. Previous or current symptoms of mild 
to moderate mood dysphoria or anxiety are allowed so long as these symptoms have not 
been a focus of primary treatment. 
8. Subject tests positive for drugs of abuse at screening, however, a positive test for 
amphetamines, barbiturates, opiates, benzodiazepines may not result in exclusion of 
subjects if the investigator determines that the positive test is as a result of prescription 
medicine(s). In the event a subject tests positive for cannabinoids (tetrahydrocannabinol), 
the Investigator will evaluate the subject’s ability to abstain from using this substance 
during the study. This information will be discussed with the Medical Monitor prior to 
study enrollment. 
9. Subject is at significant risk of harming self, others or objects based on the Investigator’s 
judgment. 
10. Subject has attempted suicide within 3 months prior to screening. 
11. Subject is involuntarily hospitalized. 
12. Subject has received depot antipsychotics unless the last injection was at least one 
treatment cycle or at least 30 days (whichever is longer), prior to the screening phase. 
13. Subject is judged to be resistant to antipsychotic treatment by the Investigator, based on 
failure to respond to 2 or more marketed antipsychotic agents, given at adequate dose for 
at least 4 weeks within a 1 year period prior to Screening. 


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14. Subject has a history of treatment with clozapine for refractory psychosis and/or subject 
has been treated with clozapine (for any reason) within 4 months of Screening. 
15. Subject is receiving a total dose of antipsychotic medication equivalent to > 12.0 mg/day 
of haloperidol at Screening (see Section 22, Appendix III for table of haloperidol dose 
equivalents). Subject may be eligible if such treatment is less than 2 weeks in duration 
after consultation with the Medical Monitor. 
16. Subject has received electroconvulsive therapy treatment within the 3 months prior to 
screening or is expected to require ECT during the study. 
17. Subject takes or has taken other disallowed recent or concomitant medications (see 
Section 10.3). Subjects must taper off antipsychotic medications by Day -1. 
18. Subject has a history of allergic reaction or suspected sensitivity to any substance that is 
contained in the formulation (gelatin). 
19. Subject has any clinically significant abnormal laboratory values (hematology, serum 
chemistry, urinalysis, lipid panel, coagulation panel, thyroid panel, and serum prolactin 
(Note: abnormal findings that may be clinically significant or of questionable 
significance will be discussed with the Medical Monitor prior to including subject). 
20.  Subject demonstrates evidence of acute hepatitis, clinically significant chronic hepatitis, 
or evidence of clinically significant impaired hepatic function through clinical and 
laboratory evaluation. 
Note: Subjects with serum alanine transaminase (ALT) or aspartate transaminase (AST) 
levels ≥ 3 times the upper limit of the reference ranges provided by the central laboratory 
require retesting. If on retesting, the laboratory value remains ≥ 3 times the upper limit, 
the subject will be excluded. 
21. Subject has a serum blood urea nitrogen (BUN) or serum creatinine (Cr) value 
≥ 1.5 times the upper limit of normal for the reference range. 
22. Subject has experienced significant blood loss (≥ 473 mL) or donated blood within 
60 days prior to first dose of study drug; has donated plasma within 72 hours prior to the 
first dose of study drug or intends to donate plasma or blood or undergo elective surgery 
during study participation or within 60 days after the last study visit. 
23. Subject has used disallowed prescription or disallowed nonprescription drugs, vitamins, 
or dietary or herbal supplements within 14 days prior to dosing or anticipates the need for 
any disallowed medication during their participation in this study [exception: female 
subjects who are taking oral, patch, or intrauterine device (IUD) hormonal contraceptives, 
or progestin implant or injection]. 
24. Subject is a staff member or the relative of a staff member. 
25. Subjects with a fasting blood glucose at screening ≥ 126 mg/dL (7.0 mmol/L) or HbA1c 
≥ 6.5% will be excluded. 
26. Subject has a prolactin concentration > 100 ng/mL at screening or has a history of 
pituitary adenoma. NOTE: Subjects with prolactin levels > 100 ng/mL and ≤ 200 ng/mL 


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at the Screening visit are permitted to enroll after discussion with the Medical Monitor to 
ensure exclusion of non-psychotropic drug-related causes of elevated prolactin levels. 
27. .Subject is in the opinion of the Investigator, unsuitable in any other way to participate in 
this study. 
8.3. 
Randomization Criteria 
To qualify for randomization, subjects must meet all of the following randomization criteria: 
1. Subject must have a PANSS total score ≥ 80 at Baseline (Day 1). 
2. Subject must have a PANSS item score ≥ 4 on 2 or more of the following PANSS items: 
delusions, conceptual disorganization, hallucinations, and unusual thought content at 
Baseline (Day 1).  
3. Subject must not demonstrate a decrease (improvement) of ≥ 20% in the PANSS total 
score between Screening and Baseline visits (see Section 26 , Appendix VII for 
calculation of PANSS total score improvement), or the PANSS total score falls below 80 
at Baseline (Day 1). 
4. Subject must have a CGI-S score ≥ 4 at Baseline (Day 1). 
5. Subject must have a total score < 5 on the SAS at Baseline (Day 1). 
6. Subject must not 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 Baseline (ie, since last visit). 
7. Subject must meet all other inclusion and none of the exclusion criteria at Baseline 
(Day 1). 


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9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
9.1. 
Description of Study Drug 
Table 5: 
Investigational Product 
Attribute 
Investigational Product 
Product name 
SEP-363856 
SEP-363856 
Placebo  
Dosage form 
Capsule 
Capsule 
Capsule 
Unit dose 
50 mg 
75 mg 
NA 
Route of 
administration 
Oral 
Oral 
Oral 
Physical description 
Size #0, Swedish Orange 
Capsule 
Size #0, Swedish 
Orange Capsule 
Size #0, Swedish Orange 
Capsule 
Excipients  
None 
None 
Microcrystalline cellulose 
 
9.2. 
Study Drug Packaging and Labeling 
9.2.1. 
Package Description 
Study drug will be provided in one-week blister cards containing 9 capsules of SEP-363856 
50 mg, 75 mg or Placebo capsules (7 days + 2 extra days). 
9.2.2. 
Labeling Description  
All packaging for the study drugs will be labeled with: 
• Protocol number 
• Sponsor’s name and address 
• Compound/Code or name of investigational drug and dosage form 
• Contents (eg number of capsules) 
• Investigational Drug/caution statement 
• Instructions for use and storage 
• Batch number 
• Blank space to record visit number 
• Blank space for subject identifiers 
• Period of use (as required) 
• Unique medication/kit ID number  


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• Investigator information (if needed) 
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 and 77°F); excursions are permitted from 15°C to 30°C 
(59°F to 86°F). 
9.4. 
Dispensing of Study Drug  
An Interactive Response System (IXRS) will be used to manage subject screening and 
randomization. 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 for which study medication unit/number 
to assign to a subject. 
Study drug will be administered to the subjects on an in-patient basis. Subjects will take one 
capsule of study drug per day at approximately the same time each evening at bed-time. Study 
drug may be taken without regard for food. 
Study drug should be maintained under the strict control of qualified site staff at all times. 
Appropriate guidelines should be followed in proper dispensation to the study participant. Proper 
handling and storage should be followed. IXRS drug dispensing guidelines should be followed 
for dispensing study drug to the subject, in addition to all accountability records where required. 
Specific User Manuals will be supplied. 
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/contract 
research organization (CRO). 
Upon receipt of study drug, the Investigator or designee will inventory the supplies and verify 
receipt of supplies. The site will perform an acknowledgement of receipt via the IXRS, 
confirming the date of receipt, inventory and condition of study drug received. 
The Clinical Inventory Management System (CIMS) will be used for the accountability of the 
study drug at the clinical site. The Investigator or designee will maintain the inventory for 
accountability within CIMS, including study drug dispensation, return and availability of study 
drug received. The Investigator or designee will collect and document all used and unused study 
drug from study subjects at appropriate study visits. 


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9.6. 
Study Drug Handling and Disposal 
Study drug 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 unused the study drug to the Sponsor or 
designee as instructed The Investigator or designee is required to maintain copies of study drug 
shipping receipts, drug accountability records, and records of return or final disposal of the study 
drug in accordance with local regulatory requirements. 


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10. 
TREATMENT OF SUBJECTS 
10.1. 
Study Drug  
All study drug doses will consist of capsule(s) containing either SEP-363856 or placebo (in order 
to maintain blinding) administered orally once daily. 
Subjects may take study drug without regard for food at approximately the same time each 
evening at bed-time. 
The date and clock time of food intake must be recorded on Day 29 when blood samples are 
collected for determination of plasma SEP-363856 and SEP-363854 concentrations. 
10.1.1. 
Dosage Adjustment Criteria 
Subjects randomized to placebo will receive placebo treatment throughout the study. 
Subjects will receive SEP-363856 50 mg/day on Day 1 through Day 3. On Day 4, subjects are 
permitted (but not required) to titrate up to a dose of 75 mg/day. Thereafter, if a dose increase is 
necessary to optimize efficacy it should occur at regular scheduled study visits/weekly intervals 
starting from Visit 4 based on Investigator judgement. A dose reduction for tolerability purposes 
is permitted to occur more frequently than at weekly intervals. Subject can be flexibly dosed up 
until Visit 6, but no dose adjustments are allowed thereafter. 
10.2. 
Treatment Compliance 
The Investigator will record the dose of the study drug and the dates of the initial and final 
administration for each dose.  
Compliance must be monitored closely and determined at 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. 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. 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 
Clinical Research Associate (CRA) and/or Medical Monitor. 
10.3. 
Concomitant Medications 
The following information on all medication administered between Visit 1 (screening) and 
Visit 8 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). 
 


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Table 6: 
Concomitant Medications/Therapies: Use During Study 
Type of Drug 
From 
Screening to 
Washout 
Phase 
During Washout 
Phase 
During  
Double-blind 
Treatment 
Phase 
Antipsychotic drugs other than study drug 
Taper 
Not Permitted 
Not Permitted 
Mood stabilizers, antidepressants, or antiepileptic drugs 
Taper 
Not Permitted 
Not Permitted 
Fluoxetine or MAO inhibitors 
Not Permitted 
Not Permitted 
Not Permitted 
Clozapine 
Not Permitted 
Not Permitted 
Not Permitted 
Investigational products for other clinical or 
post-marketing studies 
Not Permitted 
Not Permitted 
Not Permitted 
Electroconvulsive therapy 
Not Permitted 
Not Permitted 
Not Permitted 
Antiparkinsonian drugs 
Permitteda 
Permitteda 
Permitteda 
Anti-anxiety and sedative hypnotic agents 
Permitteda 
Permitteda 
Permitteda 
Drugs for acute or  mild, chronic medical conditions 
Permitteda 
Permitteda 
Permitteda 
Non-prescription pain medications 
Permitted 
Permitted 
Permitted 
Herbal supplements  
Taper 
Not Permitted 
Not Permitted 
Abbreviations: MAO = Monoamine oxidase. 
a Permitted doses of these medications are specified in Section 10.3.2 and Section 10.3.3. 
 
10.3.1. 
Prior Medications 
Prior treatment with antipsychotic agents must be discontinued in a manner consistent with 
general medical practice during the screening period for at least 3 days. Depot neuroleptics must 
be discontinued at least one treatment cycle or at least 30 days (whichever is longer) prior to the 
screening visit. 
Prior treatment with antidepressants must be discontinued as tolerated and clinically appropriate 
as follows:  
• MAO inhibitors – at least 14 days prior to baseline (Day 1) 
• Fluoxetine hydrochloride – at least 28 days prior to baseline (Day 1) 
• Clozapine – at least 120 days prior to screening 
Prior treatment with mood stabilizers (eg, lithium, divalproex/valproic acid, carbamazepine, etc.) 
must be discontinued as tolerated and clinically appropriate at least 7 days prior to double-blind 
Baseline. All other psychotropic medication (except as described in this section), including 
antipsychotic medication, must be discontinued, as tolerated and clinically appropriate, prior to 
randomization in a manner that is consistent with labeling recommendations and conventional 
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10.3.2. 
Concomitant Nonpsychotropic Medications 
Medications for short-term treatment of an acute medical condition are allowed after consultation 
with the Medical Monitor. Non-psychotropic medications used to treat mild, chronic medical 
conditions may be used during screening and after randomization if the dose and regimen have 
been stable (± 25%) for at least 30 days prior to screening. The concomitant medication dose 
may change, as needed, after randomization (or be discontinued). β-adrenergic antagonists used 
to treat stable hypertension may be continued through the screening phase and post-
randomization. In addition, use of non-prescription pain medications (eg, aspirin, 
acetaminophen) are allowed during all phases of the study provided these medications do not 
have a propensity for psychotropic effects and do not interfere with the evaluation of study drug. 
Female subjects may use oral, patch, or intrauterine device [IUD] hormonal contraceptives, or 
progestin implant or injection (detailed information on allowed contraceptives will be defined in 
Section 21). 
10.3.3. 
Concomitant Psychotropic Medications 
All antidepressants and mood stabilizers (eg, lithium, divalproex/valproic acid, carbamazepine, 
etc.) are not allowed during the study.  
Treatment with benztropine (benzotropine outside the US) up to 6 mg/day will be permitted, as 
needed, for movement disorders. In cases where benztropine is not available or a subject has had 
an inadequate response or intolerability to benztropine treatment, the following medications may 
be used to treat acute extrapyramidal symptoms (EPS): biperiden (up to 16 mg/day) or 
trihexyphenidyl (up to 15 mg/day) or diphenhydramine (up to 100 mg/day). Treatment with 
propranolol (up to 120 mg/day) will be permitted as needed for akathisia. 
Medications used to treat movement disorders should not be given prophylactically. 
Concomitant use of lorazepam, temazepam, eszopiclone, zopiclone, zaleplon, zolpidem and 
zolpidem CR 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. 
Intramuscular lorazepam is permitted up to 4 mg/day for acute anxiety/agitation, as 
clinically indicated. Lorazepam should be used sparingly, when clinically required, 
per investigator judgment. 
• temazepam (≤ 30 mg/day), eszopiclone (≤ 3 mg/day), zopiclone (≤ 7.5 mg/day), 
zaleplon (≤ 20 mg/day), zolpidem (≤ 10 mg/day for males; ≤ 5 mg/day for females), 
and zolpidem CR (≤ 12.5 mg/day for males; ≤ 6.25 mg/day for females) may be 
administered at bedtime for insomnia, as needed. 
• hypnotic agents should be administered no more than once nightly and should not be 
used in combination. 
The date and clock time of the last dose of any concomitant psychotropic medication(s) taken 
prior to scheduled efficacy assessments must be recorded at each visit. Subjects should be 
encouraged to avoid taking these medications within 8 hours of scheduled assessments. 
Opioids may be allowed in rare cases for a limited period of time with prior authorization from 
the Medical Monitor. 


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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). In regions that do not have the specified drugs available, similar drugs at 
equivalent dosages will be permitted as described in the Operations Manual or in consultation 
with the Medical Monitor. 
Subjects who require treatment with one or more 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. 
10.3.4. 
Prohibited Medications 
All antipsychotics (except for study drug treatment), antidepressants and mood stabilizers (eg, 
lithium, divalproex/valproic acid, carbamazepine, lamotrigine, etc.) are not permitted during the 
study.  
Subjects who require treatment with one or more of prohibited concomitant medications 
(including antipsychotics [other than study drug treatment] or anxiolytics [lorazepam or 
equivalent above protocol-specified limits]) will be discontinued (as appropriate) from the study. 
Limited use of these medications immediately prior to study discontinuation is permitted and 
will not constitute a protocol deviation. 
10.3.5. 
Restricted Therapies 
Subjects must not receive electroconvulsive therapy treatment within the 3 months prior to 
screening or is expected to require ECT during the study. 
10.4. 
Other Restrictions 
Subjects must abstain from alcohol from clinic admission through the end of the study. 
10.5. 
Description of Study Periods, Hospital Discharge, and Day Passes 
10.5.1. 
Description of Study Periods 
The periods of the study, their duration, and subject status are provided below in Table 7. 
Table 7: 
Description of Study Periods 
Study Period 
Visit Number 
Study Day 
Inpatient/Outpatient 
Screening/Washout 
Visit 1 
-14 to -1 
Inpatient  
Double-blind Baseline 
Visit 2 
1 
Inpatient 
Double-blind 
Visit 3 
4 
Inpatient 
Double-blind 
Visit 4 
8 
Inpatient  
Double-blind 
Visit 5 
15 
Inpatient 
Double-blind 
Visit 6 
22 
Inpatient 
Double-blind 
Visit 7 
29 
Inpatient (Subject may be discharged 
starting this visit) 


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Table 7: 
Description of Study Periods (Continued) 
Study Period 
Visit Number 
Study Day 
Inpatient/Outpatient 
Follow-up 
Visit 8 
7 days after last dose 
(subjects who 
discontinue early or 
do not elect to enroll 
in Study 
SEP361-202) 
Inpatient optional (Investigator 
discretion) 
10.5.2. 
Hospital Discharge During the Study 
To facilitate enrollment of acutely ill subjects and to optimize treatment compliance, 
hospitalization period is mandated during screening and the double-blind phases. Subjects are 
eligible for hospital discharge beginning on study Visit 7 (Day 29) or upon early termination if 
they meet all of the following criteria:  
1. The subject is considered by the Investigator to be clinically stable and appropriate for 
discharge to an outpatient or community setting. 
2. There is no evidence of imminent danger to self or others. 
3. Subject answers “no” to “Suicidal Ideation” Item 4 (active suicidal ideation with some 
intent to act, without specific plan) and Item 5 (active suicidal ideation with specific plan 
and intent) on the C-SSRS at time of evaluation.  
4. An outpatient environment is available that ensures continued safety for the subject and 
continued contact with the treatment team for the remainder of the protocol. 
Discharge under these conditions is permitted after completion of all assessments at Visit 7 
(Day 29). Subjects may participate in day-hospital or outpatient programs after hospital 
discharge. If the subject does not meet the discharge criteria at Visit 7 or early termination; 
hospitalization will be allowed for up to an additional 7 days to stabilize the subject, if necessary. 
Prior authorization for the hospitalization must be approved by the Medical Monitor. After 
completion of the follow-up visit or upon study discontinuation, all subjects will be referred for 
appropriate continued treatment and follow-up care as determined by the Investigator. 
10.5.3. 
Emergency Day Passes 
Day pass may be granted during the study due to emergency unavoidable personal reasons with 
prior approval from the Medical Monitor. The pass must be of limited duration, and the subject 
must be accompanied by a staff member, family member, or caregiver. The subject must be 
considered by the Investigator to be clinically stable and Investigators should follow standard 
local facility or institutional procedures to ensure subject safety during the pass. The reason for 
and duration of the day pass as well as Medical Monitor approval must be documented. Subjects 
will receive an unscheduled urine drug screen upon return to site. 


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10.6. 
Guidance for Overdose 
Potential overdose to SEP-363856 has not been evaluated. Appropriate supportive measures 
should be instituted and close medical supervision and monitoring should continue until the 
subject recovers. Consider the possibility of multiple-drug overdose. 
10.7. 
Dietary Guidelines 
While subjects are confined to the clinic, meals and snacks will be provided at the discretion of 
the clinical site. The date and clock time of food intake will be recorded. 


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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. 
11.1. 
Demographics and Baseline Characteristics 
Demographics (date of birth, sex, ethnicity, race), prior and current medications, and medical and 
psychiatric history will be collected. 
A medical history will be obtained by the Investigator or qualified designee as listed on the Form 
FDA 1572. If the subject’s historical medical care was provided at another institution or location, 
documented efforts must be made to obtain these outside records to verify that the subject meets 
all inclusion and none of the exclusion criteria. This must be accomplished during the screening 
period. Alcohol and substance abuse history should also be obtained and documented in the 
subject’s study chart. The Medical History will subsequently be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). 
For US sites only. At screening subjects will be checked for multiple study enrollment by clinical 
site staff using available registries of subjects participating in clinical trials. US sites will be 
provided training. 
11.2. 
Prior and Concomitant Medication Review 
See Section 10.3 for a complete description of medications permitted during the study. Site study 
staff will record all medications used to treat schizophrenia taken within 1 month prior to 
screening visit in the eCRF. Also, the following parameters will be recorded for all concomitant 
medications: drug name, route of administration, total daily dose, unit, frequency, start/stop 
dates, indication, and whether the medication was started after last dose of study medication. The 
prior and concomitant medications will subsequently be coded using the World Health 
Organization Drug Dictionary (WHO-DD). 
 
11.3. 
Structured Clinical Interview for DSM-5 Axis I Disorders-Clinical 
Trials version (SCID-CT) 
The SCID-5-CT is a modified version of the SCID developed for use in clinical trials. It is a 
semi-structured interview for the purpose of making a DSM-5 diagnosis (First-2015). Clinicians 
administering the SCID should be familiar with the DSM-5 classification and diagnostic criteria. 
The SCID-5-CT will be administered by a qualified rater at the research site listed on Form 
FDA 1572 with at least 2 years of experience with the population under study. The 
administration time is approximately 30 - 40 minutes. 


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11.4. 
Efficacy Assessments 
11.4.1. 
Positive and Negative Syndrome Scale (PANSS) 
The PANSS is an interview-based measure of the severity of psychopathology in adults with 
psychotic disorders. The measure is comprised of 30 items and 3 scales: the Positive scale 
assesses hallucinations, delusions, and related symptoms; the Negative scale assesses emotional 
withdrawal, lack of motivation, and similar symptoms; and the General Psychopathology scale 
addresses other symptoms such as anxiety, somatic concern, and disorientation. An anchored 
Likert scale from 1 - 7, where values of 2 and above indicate the presence of progressively more 
severe symptoms, is used to score each item. Individual items are then summed to determine 
scores for the 3 scales, as well as a total score. A Composite scale score (Positive scale score 
minus Negative scale score) can also be calculated to show the relative valence of positive and 
negative symptoms. Total time required for the PANSS interview and scoring is approximately 
30 - 40 minutes (Kay-1994, Opler-1992; Perkins-2000). PANSS raters will be required to meet 
specific training and education criteria before they are certified to rate for this study. In addition, 
raters will receive specific training and education regarding all of the assessments prior to study 
initiation. 
11.4.2. 
Brief Negative Symptom Scale (BNSS) 
The BNSS is a rating scale to measure the current level of severity of negative symptoms in 
schizophrenia and schizoaffective disorder. The measure is comprised of 13 individual items and 
5 domain scores (blunted affect, alogia, avolition, anhedonia, and asociality). The 5 domain 
scores provide a summary score and the 13 individual items provide a composite total score 
(ranging from 0 to 78). Each of the items are scored on a Likert-type 7-point scale from 0 - 6, 
where values of 0 indicates symptom is absent and a value of 6 means the symptom is a severe 
form. The number of items varies per domain. BNSS raters will be required to meet specific 
training and education criteria before they are certified to rate for this study. In addition, raters 
will receive specific training and education regarding all of the assessments prior to study 
initiation. 
11.4.3. 
Montgomery-Asberg Depression Rating Scale (MADRS) 
The MADRS is a 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) 
(Williams-2008) will be used for the administration of the MADRS assessment. The MADRS 
will be administered by a qualified rater at the site. 
11.4.4. 
Clinical Global Impressions – Severity Scale (CGI-S) 
The CGI-S is a clinician-rated assessment of the subject’s current illness state on a 7-point scale, 
where a higher score is associated with greater illness severity. Following a clinical interview, 
the CGI-S can be completed in 1 to 2 minutes. The CGI-S will be administered by a qualified 
rater at the site. 


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11.4.5. 
CogState Brief Battery (CBB) 
The CBB scale assesses four domains. The Detection test (Attention Domain) measures speed of 
performance. The mean of the log10 transformed reaction times for correct responses are utilized 
to determine the score. Lower scores correspond to better performance. The Identification test 
(Information Processing Domain) also measures speed of performance. The mean of the log10 
transformed reaction times for correct responses are utilized to determine the score. Lower scores 
correspond to better performance. The One Card Learning test (Visual Learning Domain) 
measures accuracy of performance. Arcsine transformation of the proportion of correct responses 
are utilized to determine the domain score. Higher scores correspond to better performance. The 
One-back Memory test (Working Memory Domain) measures Arcsine transformation of the 
proportion of correct responses are utilized to determine the domain score. Higher scores 
correspond to better performance. 
11.5. 
Safety Assessments 
The Investigator or appropriate designee will review results of safety assessments on a regular 
basis and the Sponsor must be kept fully informed of any clinically significant findings either at 
Screening or subsequently during study conduct. 
11.5.1. 
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. 
Pretreatment events will be monitored at Visit 1. 
AEs and SAEs will be monitored from Visit 2 onward. 
11.5.2. 
Clinical Laboratory Tests 
The clinical laboratory tests required by protocol are listed in Section 23, Appendix VI. 
Blood and urine samples will be collected for clinical laboratory tests. 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), Clinical 
Laboratory Improvement Amendments (CLIA) and/or other laboratory certifications or 
equivalent accreditation documents.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. 
11.5.3. 
Vital Signs 
Supine systolic and diastolic blood pressures, respiratory rate, pulse rate, and oral temperature 
will be measured following 5 minutes of seated rest. 
Blood pressure and pulse rate should first be taken with the subject in the supine position after 
resting for ≥ 5 minutes. Blood pressure and pulse rate will be taken again after standing for 2 to 
4 minutes. The same arm should be used during each assessment of blood pressure and pulse rate 


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throughout the study. If a subject develops symptoms consistent with orthostatic hypotension 
(light-headedness, dizziness, or changes in sensorium upon standing) at any point, his or her 
supine and standing blood pressure and pulse rate should be collected at that time in the manner 
described above. Vital signs will be obtained prior to clinical laboratory collection and 
performance of an ECG.  
11.5.4. 
Electrocardiograms (ECGs) 
All ECGs will be obtained in the supine position, after the subject has been resting supine for at 
least 5 minutes. ECGs will be 12-lead with a 10-second rhythm strip. ECGs should be obtained 
prior to drawing blood samples. All attempts should be made to use the same ECG recorder for 
all visits within individual subjects. Refer to Section 20 Appendix I for additional information. 
ECG parameters to be collected include ventricular heart rate (beats/min), QT interval (msec), 
PR interval (msec), QRS interval (msec), RR interval (msec), and overall ECG interpretation 
(Normal, Abnormal NCS, Abnormal CS). 
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 subjects’ 
eligibility for or continuance in the study. Abnormalities require comment as NCS or CS. 
Typically, CS designated events will be reported as adverse events. 
ECGs will be reviewed, signed and dated by the Investigator after each ECG collection. The 
same physician should review all ECG reports for a given subject whenever possible. 
The original ECG tracing will be kept with subject’s source documentation. A copy may be 
collected by the Sponsor. 
11.5.5. 
Physical and Neurological Examination 
A full PE as well as a neurological will be performed. The PE includes an assessment of general 
appearance and a review of systems (dermatologic, head, eyes, ears, nose, mouth/throat/neck, 
thyroid, lymph nodes, respiratory, cardiovascular, gastrointestinal, extremities, musculoskeletal, 
neurologic, and psychiatric systems).  
All PE and neurological exam findings at screening will be captured in the medical history in the 
CRF. Any clinically significant changes from screening, as determined by the Investigator, will 
be noted as AEs in the CRF. 
11.5.6. 
Height, Weight, and BMI 
Weight will be measured in kilograms at Visit 1 (Screening), Visit 2 (Baseline), Visit 5 (Day 15), 
and Visit 7 (Day 29). Height in meters will be recorded only at Visit 1 (Screening).  
Height will be measured without shoes. 
Weight will be measured in street clothes, without shoes and coat/jacket. 
BMI will be calculated by site staff using the equation BMI = weight [kg]/height [m]² at 
Screening (Visit 1) only. BMI for all other visits will be derived within the Electronic Data 
Capture (EDC) system. 
Waist circumference will be measured in inches or centimeters and recorded in the eCRF. 


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11.5.7. 
Safety Scales 
11.5.7.1. Abnormal Involuntary Movement Scale (AIMS) 
The AIMS is a clinician-rated assessment of abnormal movements consisting of unobtrusive 
observation of the subject at rest (with shoes removed) and several questions or instructions 
directed toward the subject. Using a severity scale ranging from 0 (none) to 4 (severe), clinicians 
rate dyskinesia in several body regions, including the facial area, extremities, and trunk. There 
are two items related to dental status, as well as three global impression items assessing overall 
severity, incapacitation, and the subject’s awareness of abnormal movements (Guy-1976; 
Munetz-1988). The AIMS raters will be required to meet specific credential and educational 
criteria before they are certified to rate for this study. The AIMS will be administered by a 
qualified rater at the site. 
11.5.7.2. Barnes Akathisia Rating Scale (BARS) 
The BARS is a rating scale geared toward assessment of neuroleptic-induced akathisia, though it 
can be used to measure akathisia associated with other drugs as well. The BARS consists of four 
items, including one item assessing objective restlessness, two items targeting subjective 
restlessness (awareness and related distress), and one global clinical assessment item. All items 
are anchored and utilize a 4-point scale, except for the global rating which has a 6-point scale 
(from absence of akathisia through severe akathisia). The subjective and objective items are 
summed to yield a total score. The BARS can be administered in about 10 minutes 
(Barnes-1989; Barnes-2003). The BARS will be administered by a qualified rater at the site. 
11.5.7.3. Simpson-Angus Scale (SAS) 
The SAS is a clinician-rated assessment of neuroleptic-induced Parkinsonism consisting of 
10 items. Items are anchor-based, rated on a 5-point scale of severity, and address rigidity, gait 
(bradykinesia), tremor, akathisia, shoulder shaking, glabellar tap, and salivation (Siddiqui-2009; 
Simpson-1970). The SAS will be administered by a qualified rater at the site. 
11.5.7.4. Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a tool designed to systematically assess and track suicidal adverse events 
(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 scale takes approximately 5 minutes to 
administer. The C-SSRS will be administered by a trained rater at the site. Subjects with Type 4 
or Type 5 suicidal ideation during the study will be discontinued from the study and referred to a 
mental health professional (Posner-2007). At screening visit, “Baseline/Screening” version of 
C-SSRS will be used. For all visits from Visit 2 onward, the “Since Last Visit” version of the 
C-SSRS will be used. 
11.5.7.5. Drug Effects Questionnaire (DEQ) 
A Drug Effects Questionnaire designed to assess subjective effects will be completed by the 
subject. The DEQ consist of 3 questions scored on a visual analog scale (VAS). 


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11.5.7.6. Pittsburg Sleep Quality Index (PSQI) 
The Pittsburgh Sleep Quality Index (PSQI) consists of 19 self-rated questions used to measure 
the quality and patterns of sleep in adults. It differentiates “poor” from “good” sleep quality by 
measuring seven areas (components): subjective sleep quality, sleep latency, sleep duration, 
habitual sleep efficiency, sleep disturbances, use of sleeping medications, and daytime 
dysfunction over the last month (Buysse-1989). 
11.6. 
Population Pharmacokinetic Assessments 
All blood samples for determination of plasma SEP-363856 and SEP-363854 concentrations will 
be obtained at the same time that other blood samples are taken whenever possible. Placebo 
samples will not be analyzed. The time and date of the 3 previous doses of study drug, date, and 
clock time of sampling must be recorded. Date and clock time of food intake must be recorded 
on Day 29 when blood samples are collected for determination of plasma SEP-363856 and 
SEP-363854 concentrations. Plasma SEP-363856 and SEP-363854 concentrations will be 
determined by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) 
method. POPPK analysis will be performed using plasma SEP-363856 concentrations; the results 
of which will be reported separately. The relationship between PANSS total score and plasma 
SEP-363856 exposure will be explored using population PK/pharmacodynamics (PD) methods, 
and reported separately. The impact of cytochrome (CYP) P450 CYP2D6 metabolizer status on 
SEP-363856 plasma exposure will be explored and reported separately. See Section 24, 
Appendix V for details including instructions of processing blood samples for determination of 
plasma SEP-363856 and SEP-363854 concentrations. 
11.7. 
Pharmacogenomic Assessments 
If a subject has consented to have a deoxyribo nucleic acid (DNA) sample taken for genetic 
analysis (and is eligible for randomization), a blood sample (approximately 4 mL) for 
pharmacogenetic (PGx) analysis will be taken at Visit 2 (Baseline). Samples should not be 
collected if the subject has not consented to PGx sampling. If samples are collected for analysis, 
this analysis must be performed. The timing of the analysis may be following completion of this 
study and as such can be reported separately. Blood samples will be shipped to the central 
laboratory where they will be stored frozen until shipment to the PGx laboratory (contact details 
provided in the general study information section of the protocol). Following shipment, DNA 
will be extracted and the PGx laboratory will remain blinded to the identity of the subject, but 
will have access to information relating to demographics of the subject (ethnic origin and 
gender). See Section 25 Appendix VI for details including instructions of PGx sample handling. 
11.8. 
Study Visits and Assessments 
See Table 2 Schedule of Assessments, for a summary of procedures at each study visit. See 
Section 11.1 to Section 11.5 for detailed information on conducting assessments. 
11.8.1. 
Screening: Visit 1 (Day -14 to -1);Inpatient 
A unique screening number will be assigned to each subject. 


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The subject’s eligibility assessment will be reviewed by the contract research organization’s 
(CRO) oversight quality team along with the sponsor based on protocol specified inclusion and 
exclusion criteria. The sponsor will participate in the eligibility review process with the CRO to 
ascertain the subject’s eligibility and will be copied on all communications between the CRO and 
the site. In the event the CRO/sponsor and site do not agree on a subject’s eligibility then the 
subject will not be enrolled. 
Subjects will be evaluated at the screening visit (1 to 14 days before the first dose of study drug) 
to determine their eligibility for the study. The following procedures will be conducted during 
this visit: 
• Obtain signed informed consent and privacy authorization from the subject before 
conducting any other visit procedures. 
• Inclusion and exclusion criteria 
• Obtain demographic information 
• Prior/concomitant medications 
• Pretreatment events 
• Medical history 
• Psychiatric history/mental status 
• SCID-CT 
• Physical and neurological examination including height and weight; clinical site staff 
to calculate and record BMI 
• Vital sign measurements (prior to ECG) 
• Perform ECG 
• Fasted blood samples for clinical laboratory evaluation (hematology, serum 
chemistry, serum prolactin, glycosylated hemoglobin [HbA1c], glucose panel, and 
lipid panel). 
• Blood samples for serum pregnancy test (serum human chorionic gonadotropin 
[β-hcG]) for female subjects and serum follicle stimulating hormone (FSH) for 
female subjects if menopause is suspected. 
• Urine sample for urinalysis and urine drug screen (UDS) 
• Duplicate subject check 
• PANSS 
• BNSS 
• C-SSRS 
• CGI-S 
• AIMS 


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• BARS 
• SAS 
 
Procedures should be completed in the following sequence. 
Screening Visit 
Visits 2 through Visit 8 
1. SCID-CT (study center rater) 
1. PANSS (study center rater) 
2. PANSS (study center rater) 
2. BNSS (study center rater) 
3. BNSS (study center rater) 
3. MADRS (study center rater) 
4. C-SSRS (study center rater) 
4. C-SSRS (study center rater) 
5. CGI-S (study center rater) 
5. CGI-S 
 
6. AIMS/BARS/SAS 
 
7. PSQI 
 
8. DEQ 
 
9. CBB 
Note: With the exception of SCID-CT and DEQ, all rating assessments will be performed by the rater using a tablet. 
In the event that a tablet is not available, the rating assessments will be performed by the rater using a paper version 
of the assessment. 
Subjects found to be ineligible during Visit 1 will not be required to complete all the Visit 1 
assessments and will not be followed up on leaving the study. 
Subjects who screen fail may be re-screened up to two times, if judged appropriate by the 
Investigator. 
Re-screened subjects will be re-consented and all Visit 1 procedures will be repeated. 
11.8.2. 
Baseline: Visit 2 (Day 1); Inpatient 
The following procedures will be conducted during this visit: 
• Review inclusion and exclusion criteria and randomization criteria. 
• Prior/concomitant medications. 
• Randomize to treatment 
• Blood sample for determination of plasma SEP-363856 and SEP-363854 (pre-dose) 
• Vital sign measurements (prior to ECG) 
• Weight and waist circumference 
• Perform standard 12-lead ECG. 
• Fasted blood samples for clinical laboratory evaluation (hematology, serum 
chemistry, serum prolactin, glucose panel and lipid panel). 


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• If subject signed separate genetic informed consent, collect blood samples for 
pharmacogenomics (CYPP450 2D6) 
• Urine sample for urinalysis, UDS, and β-hcG (for female subjects). 
• PANSS 
• BNSS 
• MADRS 
• C-SSRS 
• CGI-S 
• AIMS 
• BARS 
• SAS 
• PSQI 
• DEQ 
• CBB 
• Administer study drug  
• Adverse events 
11.8.3. 
Visit 3 (Day 4); Inpatient 
The following procedures will be conducted during this visit: 
• Concomitant medications. 
• Perform study drug accountability 
• Vital sign measurements 
• PANSS 
• BNSS 
• MADRS 
• C-SSRS 
• CGI-S 
• AIMS 
• BARS 
• SAS 
• Administer study drug 
• Adverse events 


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11.8.4. 
Visit 4 (Week 1; Day 8), Visit 5 (Week 2; Day 15), and Visit 6 (Week 3; Day 22); 
Inpatient 
The following procedures will be conducted during each visit (unless otherwise specified): 
• Concomitant medications. 
• Perform study drug accountability 
• Vital sign measurements 
• PANSS 
• BNSS 
• MADRS 
• C-SSRS 
• CGI-S 
• AIMS 
• BARS 
• SAS 
• Administer study drug 
• Adverse events 
11.8.5. 
Visit 7 (Week 4; Day 29/Early Termination); Inpatient 
The following procedures will be conducted during this visit: 
• Concomitant medications 
• Study drug accountability 
• Physical and neurological examination including 
• Weight and waist circumference 
• Vital sign measurements (prior to ECG). 
• Perform standard 12-lead ECG. 
• Fasted blood samples for clinical laboratory evaluation (hematology, serum 
chemistry, serum prolactin, glycosylated hemoglobin [HbA1c], glucose panel, and 
lipid panel). 
• Blood sample for determination of plasma SEP-363856 and SEP-363854 
concentration (post dose) 
• Urine sample for urinalysis, UDS, and β-hcG (for female subjects). 
• PANSS 
• BNSS 


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• MADRS 
• C-SSRS 
• CGI-S 
• AIMS 
• BARS 
• SAS 
• PSQI 
• DEQ 
• CBB 
• Adverse events 
• Duplicate subject check 
At this visit, subjects who have completed treatment will have the option to enroll and continue 
treatment for an additional 26 weeks in an open-label extension study (Study SEP361-202). For 
subjects entering the extension study, Week 4 in this study will be Baseline for the extension 
study and subjects will not need to return for further visits in this study. 
Subjects who do not enter the extension study will complete the inpatient follow-up period. 
11.8.6. 
Visit 8 (+ 7 days); Inpatient Follow-up 
All subjects who discontinue early or do not elect to enroll in the open-label extension study 
(Study SEP361-202) will have an inpatient/outpatient safety follow-up prior to discharge 
(7 ± 2 days) after their last dose of study drug. The following procedures will be conducted 
during this visit: 
• Concomitant medications 
• C-SSRS 
• Adverse events 
• Duplicate subject check 


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


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result of a SAE. However, if the event/condition worsens during the study, it should be reported 
as an AE (or SAE, if the event/condition results in a serious outcome such as prolongation of 
hospitalization). 
Life-threatening means that the subject was, in the view of the Investigator, at immediate risk of 
death from the event as it occurred. This definition does not include an event that had it occurred 
in a more severe form might have caused death. 
SAE criteria information will be captured on the CRF. 
12.2. 
Objective Findings 
Clinically significant abnormal objective findings (eg, clinical laboratory value, ECG value, and 
physical examination observation) will also be recorded as AEs. 
When a clear diagnosis is available that explains the objective findings, this diagnosis will be 
recorded as the AE, and not the abnormal objective finding (eg, viral hepatitis will be recorded as 
the AE, not transaminase elevation). If a definite diagnosis is not available, then record the sign 
(eg, clinically significant elevation of transaminase levels) or symptom (eg, abdominal pain) as 
the AE. 
Clinical laboratory test results will be reviewed by the Investigator. The Investigator must 
determine the clinical significance of all out of range values. Clinical laboratory test with 
possibly drug-related or clinically relevant abnormal values of uncertain causality may be 
repeated. Any abnormal values that persist should be followed at the discretion of the 
Investigator. Laboratory reports will be initialed and dated on all pages by the Investigator. 
Clinical Laboratory Tests Outside the Normal Range: Any value outside the normal range will be 
flagged for the attention of the Investigator or appropriate designee at the study center. The 
Investigator or appropriate designee will indicate whether or not the value is of clinical 
significance. If the result of any test (or repeat test, if done) from the samples taken during 
Screening is indicated as clinically significant and is not covered by the inclusion 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) normalised or stabilised. 
All on-site ECG tracings and ECG over-read reports will be reviewed by the Investigator. The 
Investigator must determine the clinical significance of all abnormal ECGs. ECG with possibly 
drug-related or clinically relevant abnormal findings of uncertain causality may be repeated. Any 
abnormal ECGs that persist should be followed at the discretion of the Investigator. ECG 
tracings will be initialed and dated on all pages by the Investigator. 
12.3. 
Collection and Recording of Adverse Events 
All pre-treatment events and AEs must be recorded in the subject’s study records/source 
documents in accordance with the Investigator’s normal clinical practice. All pre-treatment 
events and AEs/all AEs must be recorded on the CRF. 
All AEs will be followed until resolution, stabilization of the condition, the event is otherwise 
explained, or the subject is lost to follow-up. 


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Each AE is to be evaluated for duration, severity, frequency, seriousness, action taken with the 
study treatment, outcome, and causal relationship to the study treatment. Definitions for severity, 
frequency, action taken with the study treatment, outcome, and causal relationship to the study 
treatment are presented below. 
The severity of AE: 
• Mild - Ordinarily transient symptoms that do not influence performance of subject’s 
daily activities. Other treatment is not ordinarily indicated. 
• Moderate - Marked symptoms sufficient to make the subject uncomfortable. 
Moderate influence on performance of subject’s daily activities. Other treatment may 
be necessary. 
• Severe - Symptoms cause considerable discomfort. Substantial influence on subject’s 
daily activities. May be unable to continue the study, and other treatment may be 
necessary. 
The frequency of AE: 
• Once – an isolated episode. 
• Intermittent – occurs on two or more separate occasions. 
• Continuous – does not abate from date of onset to date of resolution. 
The action taken with the study treatment: 
• Drug Interrupted – Study drug stopped temporarily. 
• Drug Withdrawn – Study drug stopped permanently. 
• Dose Reduced. 
• Dose Increased. 
• Dose Not Changed 
• Not Applicable. 
• Unknown 
The outcome of the AE: 
• Recovered/Resolved 
• Recovering/Resolving 
• Not Recovered/Not Resolved 
• Recovered/Resolved with Sequelae 
• Fatal 
• Unknown 
The causal relationship of the AE to the study treatment: 
• Not related 


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o  Not related - Improbable temporal relationship and is plausibly related to 
other drugs or underlying disease. 
• Related 
o Possible - occurred in a reasonable time after study drug administration, but 
could be related to concurrent drugs or underlying disease. 
o Probable - occurred in a reasonable time after study drug administration, is 
unlikely to be attributable to concurrent drugs or underlying disease, and there 
is a plausible mechanism to implicate the study drug. 
o Definite - occurred in a reasonable time after study drug administration and 
cannot be explained by concurrent drugs or underlying disease. The adverse 
event should respond to dechallenge/rechallenge, however, this is not 
mandatory before assigning a definite causality. 
The Medical Monitor is the initial contact person for protocol related questions or discussion of 
AEs. The contact information for the Medical Monitor as well as other emergency contact 
information can be found in Table 1 of this protocol. 
12.4. 
Immediately Reportable Events 
The following medical events must be immediately reported to the Sponsor: 
• SAE 
• Pregnancy 
Emergency contact information can be found in Table 1. 
12.4.1. 
Serious Adverse Event 
If the Investigator or study center staff becomes aware of a SAE that occurs in a study subject 
after first administration of study drug through 30 days following the last dose of the study drug, 
this must be reported immediately to the Sponsor whether considered related or unrelated to the 
study drug. SAEs must be recorded on the CRF and the data recorded should agree with that on 
the SAE form. 
Following the end of subject participation in the study, the Investigator or an authorized delegate 
should report SAEs “spontaneously” to PPD-PVG if considered at least possibly related to the 
study drug. 
SAEs will be followed until resolution, loss to follow-up, stabilization of condition, or the event 
is otherwise explained. 
In addition to the initial telephone notification, an initial SAE form as applicable must be 
completed and signed and sent via fax or email (see Table 1) to PPD-PVG within 24 hours of the 
Investigator or study center staff becoming aware of the event. The SAE form must be signed by 
the Investigator or appropriate designee. PPD-PVG provides the SAE form used to report SAEs. 
The Sponsor or designee will promptly notify all study centers and Investigators of a SAE that is 
determined to be expedited to the Regulatory Authorities in accordance with applicable law(s) 
and regulation(s). These SAEs must be promptly reported to the Institutional Review Board 


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(IRB) or Independent Ethics Committee (IEC) by the Investigator or the appropriate person at 
the study center if required per IRB/IEC guidelines. 
For the UK, the appropriate Pharmacovigilance (PVG) group must be contacted immediately 
upon first knowledge of the incident. The immediate report should be made by the Investigator 
within a very short period of time and under no circumstances should this exceed 24 hours 
following knowledge of the serious adverse event or pregnancy. 
12.4.2. 
Pregnancy 
Pregnancies that occur from the time that informed consent is signed through 90 days following 
the last dose of the study drug 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 commence 
discontinuation of the study drug. Further, the subject (or female partner of male subject) will be 
instructed to return promptly/within 48 hours of the first notification of pregnancy to the study 
center and undergo a serum/urine pregnancy test, as confirmation of pregnancy. If positive, the 
female pregnant subject will no longer receive any additional study drug. All pregnancies, 
whether or not the subject received any additional study drug, will be followed until resolution 
(ie, termination [voluntary or spontaneous] or birth). 
To report a pregnancy, the Pregnancy Event Form must be completed and sent via fax to 
PPD-PVG within 24 hours of the Investigator or study center staff becoming aware of the 
pregnancy. The Sponsor provides the Pregnancy Event Form. 
If the subject received blinded study drug, unblinding of the study drug will be offered to the 
subject when knowledge of such treatment may have an impact on further treatment decisions. 
Otherwise, information regarding to what treatment the subject was assigned may be provided 
when the study has ended. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study drug may have 
interfered with the effectiveness of a contraceptive medication or other AEs were detected. 


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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 for any of the following reasons: 
• Adverse event (specify) 
• Lack of efficacy (specify) 
• Withdrawal by subject (specify) 
• Non-compliance with study drug (specify) 
• Protocol deviation (specify) 
• Death 
• Progressive disease 
• Pregnancy 
• Other (specify) 
If at any time during the course of the study, 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 on the epoch 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 have not received study drug will not be followed up on leaving the study. 
For subjects who have received study drug and who prematurely discontinue from the study 
treatment (ie, do not complete through Visit 7), every effort should be made to complete the final 
evaluation procedures, in accordance with the early termination (ET) visit described in 
Section 11.8.5. 
Subjects who complete the study but do not elect to enroll in the open-label extension study 
(Study SEP361-202) and those subjects who discontinue the study early will complete a follow 
up visit 7 (±2) days after the last visit to assess any post study discontinuation adverse effects as 
described in Section 11.8.6. 
 


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14. 
STUDY TERMINATION 
The Sponsor reserves the right to discontinue the study at this study center or at multiple centers 
for safety or administrative reasons at any time while safeguarding that early termination does 
not compromise subjects’ safety or well-being. In particular, a study center that does not recruit 
at an acceptable rate may be closed. Should the study be terminated and/or the study center 
closed for whatever reason, all documentation and study drugs 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 will undergo final evaluation procedures, in 
accordance with the early termination (ET) visit described in Section 11.8.5 and safety follow-up 
visit as described in Section 11.8.6. 


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15. 
STATISTICS 
15.1. 
Sample Size  
A sample size of 100 subjects per treatment group (SEP-363856 and placebo) will provide 80% 
power to detect a treatment effect size of 0.4 in change from Baseline in PANSS total score at 
Week 4 for SEP-363856 versus placebo, using a two independent sample t-test method with 
2-sided significant level of 0.05. A clinically meaningful effect size of 0.4 was estimated based 
on review of published studies of other antipsychotics for the short-term treatment of 
schizophrenia. It is anticipated that 17% of all randomized subjects will discontinue early from 
the study. An upward adjustment of the sample size is thus used to compensate for missing data 
from subjects who are randomized and discontinue from the study. The total sample size will be 
240 randomized subjects (or 120 subjects per treatment group). 
15.2. 
Analysis Populations 
15.2.1. 
Modified Intention-to-Treat Population 
The modified intention-to-treat (mITT) population will consist of all subjects who are 
randomized, have received at least one dose of study drug, and have a Baseline and at least one 
post-Baseline efficacy measurement in PANSS or CGI-S. Subjects will be included in the mITT 
population regardless of any protocol deviation. The mITT population will be the primary 
population for the efficacy analyses. Subjects will be analysed according to randomised 
treatment group. 
15.2.2. 
Per Protocol Population 
The per protocol (PP) population will consist of all mITT population subjects who satisfy the 
following conditions: 
• Received assigned study medication as randomized 
• Have 14 days or more continuous exposure 
• Have 75%-125% compliance, both limit values inclusive 
• Have no major protocol violations, determined by a blinded data review prior to 
database lock 
Selected efficacy endpoints will be analyzed using the PP population. 
15.2.3. 
Safety Population 
The safety population will consist of all subjects who are randomized and have received at least 
one dose of study drug. Safety population will be the primary population for the safety analyses. 
Subjects will be analysed according to the actual treatment received (ie, placebo vs 
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15.3. 
Data Analysis 
15.3.1. 
Subject Disposition  
Subject disposition will be summarized by the randomized treatment group (if applicable) and 
overall for all subjects. The number and percentage of subjects who are screened, screen-failed, 
randomized, and completed or discontinued the study (including reasons for discontinuation) will 
be presented. In addition, the number and percentage of subjects who will rollover to the open-
label extension study (SEP361-202) in each treatment group and overall will be presented. 
15.3.2. 
Drug Exposure and Compliance 
Drug exposure and compliance will be summarized by treatment for the safety population. 
Drug exposure (in days) will be calculated as: last dose date - first dose date + 1. Exposure will 
be summarized both as a continuous variable for the double-blind period (i.e. mean days), and 
categorically: 
• 
Number and percentage of subjects with drug exposure ≥ 4, ≥ 7, ≥ 14, ≥ 21, and 
≥ 28 days; 
• 
Number and percentage of subjects with drug exposure for 1 - 3, 4 - 6, 7 - 13, 14 - 20, 
21 - 27, and ≥ 28 days 
Percent compliance will be calculated by visit and overall for the double-blind period as: 
(number of capsules taken / number of capsules should have been taken) × 100%. Non-
compliance is defined as less than 75% or more than 125% non-missing compliance for the 
double-blind period. Subjects with missing compliance will not be classified as non-compliant. 
Compliance will be summarized both as a continuous variable (i.e. mean percentage) and 
categorically (i.e. number and percentage of subjects who are compliant vs. non-compliant, or 
with compliance < 75%, 75% - 125%, > 125%, and missing). 
15.3.3. 
Important Protocol Deviations 
Important protocol deviations (IPDs) will be identified and documented based on a review of 
potentially IPDs. The potentially IPDs will be identified through programmatic checks of study 
data, as well as through review of selected data listings. The potentially IPDs to be reviewed 
include, but are not limited to, subjects who: 
• Did not meet inclusion/exclusion criteria. 
• Received any disallowed concomitant medication. 
• Have overall double-blind compliance rate < 75% or > 125%. 
Individual IPDs will be presented for all randomized subjects in a data listing. The number and 
percentage of subjects in the mITT population with IPDs will be summarized by the type of 
deviation and the randomized treatment group. 
15.3.4. 
Demographic and Baseline Characteristics 
Basic demographics (e.g. age, gender, race, ethnicity, etc.) will be summarized for all screened 
subjects by randomization status (i.e. randomized vs. not randomized). Demographic and 
Baseline characteristics will be summarized for the mITT population and safety population. 


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Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
version 18.1 or higher, and will be summarized by treatment for the safety population by 
presenting the number and percentage of subjects with at least one condition in each system 
organ class (SOC) and preferred term (PT). 
15.3.5. 
Efficacy Analyses 
15.3.5.1. Primary Efficacy Endpoint Analysis 
This section describes the primary analysis for the primary efficacy endpoint. Sensitivity analysis 
of this endpoint is described in Section 15.3.12. 
The primary efficacy variable is the change from Baseline in PANSS total score at Week 4, for 
testing superiority of the SEP-363856 treatment group over the placebo group. This variable will 
be analyzed using a Mixed Model for Repeated Measures (MMRM), with change from Baseline 
in PANSS total score at each visit as the response variable. The MMRM model will include 
factors for treatment, visit (Day 4, Weeks 1, 2, 3, and 4; as a categorical variable), pooled center, 
and treatment-by-visit interaction, and include Baseline PANSS total score as a covariate. An 
unstructured covariance matrix will be used for the within-subject correlation. Kenward-Rogers 
approximation will be used to calculate the denominator degrees of freedom. Pooled centers will 
be generated by country. 
In case the model above fails to converge, a spatial exponential covariance structure and a spatial 
power covariance structure will be assumed sequentially. The first covariance structure to yield 
convergence will be used in the analysis.  
The primary analysis for the primary efficacy endpoint will be based on the observed data only. 
Missing observations will not be imputed. 
15.3.5.2. Secondary Efficacy Endpoint Analysis 
CGI-S score 
The primary analysis for this endpoint is described here. Sensitivity analysis of this endpoint is 
described in Section 15.3.12. 
Change from Baseline in CGI-S score at Week 4 will be analyzed using an MMRM model 
similar to that of the primary efficacy variable, with change from Baseline in CGI-S score at 
each visit as the response variable and Baseline CGI-S score as a covariate.  
The primary analysis for this endpoint is based on the observed data only. Missing observations 
will not be imputed. 
PANSS subscale scores 
Change from Baseline in each PANSS subscale (positive, negative, and general 
psychopathology) score at Week 4 will be analyzed using an MMRM model similar to that of the 
primary efficacy variable, with the respective PANSS subscale score at Baseline as the covariate. 
In addition, as a supportive analysis, missing PANSS subscale data at Week 4 will be imputed 
using the last observation carried forward (LOCF) method, and the resulting efficacy variables 
will be change from Baseline in PANSS subscale scores at the Week 4 LOCF endpoint. These 


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variables will be analyzed using the analysis of covariance (ANCOVA) model which includes 
treatment and pooled center as fixed factors and the respective Baseline value as a covariate. 
BNSS total score 
Change from Baseline in BNSS total score at Week 4 will be analyzed using an MMRM model 
similar to that of the primary efficacy variable, with Baseline BNSS total score as the covariate. 
As an additional, supportive analysis, missing BNSS data at Week 4 will be imputed using the 
LOCF method and the resulting efficacy variable will be the change from Baseline in BNSS total 
score at the Week 4 LOCF endpoint. This variable will be analyzed using an ANCOVA model 
similar to the one above, including Baseline BNSS total score as a covariate. 
MADRS total score 
Change from Baseline in MADRS total score at Week 4 will be analyzed using an MMRM 
model similar to that of the primary efficacy variable, with Baseline MADRS total score as the 
covariate. As an additional, supportive analysis, missing MADRS data at Week 4 will be 
imputed using the LOCF method and the resulting efficacy variable is change from Baseline in 
MADRS total score at the Week 4 LOCF endpoint. This variable will be analyzed using an 
ANCOVA model similar to the one above, including Baseline MADRS total score as a covariate. 
PANSS responders 
Subjects who achieve a response are defined as those having a 20% or greater improvement in 
PANSS total score from Baseline at the Week 4 LOCF endpoint (i.e. missing PANSS data at 
Week 4 being imputed by the LOCF method). The percent improvement in PANSS total score 
from Baseline will be calculated by: 
 
PANSS total score at Week 4 LOCF endpoint - PANSS total score at Baseline
PANSS total score at Baseline - 30
× 100% 
For each subject, the responder indicator will be set to 1 if the percent change is negative and the 
magnitude is equal to or greater than 20%. The indicator will be set to 0 if the percentage is 
negative but the magnitude is less than 20% or if the percentage is non-negative. The indicator 
will be set to missing if the percentage is missing. 
PANSS responders will be analyzed using a logistic regression model with responder indicator 
as the dependent variable, and include treatment and geographic region as fixed factors and 
Baseline PANSS total score as a covariate. 
15.3.5.3. Other Efficacy Endpoint Analysis 
Change from Baseline in the CBB composite score at Week 4 will be analyzed using an 
ANCOVA model with treatment and pooled center as fixed factors and Baseline CBB composite 
score as a covariate. In addition, the LOCF ANCOVA analysis as described in Section 15.3.5.2 
will be performed as a supportive analysis. 
15.3.5.4. Adjustment for Multiplicity 
No multiplicity adjustment will be performed in the testing of the efficacy endpoints. 


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15.3.5.5. Subgroup Analysis 
Exploratory analyses will be performed on certain subgroups of interest for the primary efficacy 
endpoint of change from Baseline in PANSS score at Week 4 and the secondary endpoint of 
change from Baseline in CGI-S score at Week 4. The subgroup factors of interest will include: 
categorized age, gender, race, number of prior hospitalizations for treatment of schizophrenia, 
geographic region or country. Details of the subgroup analyses will be described in the SAP. 
Summary statistics and MMRM analysis results will be provided by treatment for each subgroup. 
In addition, inferential analysis of treatment-by-subgroup interaction will be performed for each 
subgroup factor using the MMRM method on the two efficacy variables described above. The 
model will include treatment, visit (as a categorical variable), subgroup, pooled center, Baseline 
value, and treatment-by-visit, treatment-by-subgroup, subgroup-by-visit, and treatment-by-
subgroup-by-visit interactions. Details of the subgroup analysis of efficacy data will be provided 
in SAP. 
15.3.6. 
Safety Analyses 
15.3.6.1. Adverse Events 
All AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
version 18.1 or higher. AEs are untoward medical occurrences: 
• that occurred on or after the first dose of study drug, 
• with a missing start date and a stop date on or after the first dose of study drug, or 
• with both a missing start and stop date. 
AEs will be summarized by treatment and by MedDRA system organ class (SOC) and Preferred 
Term (PT). 
The following AEs will be summarized and presented by treatment and by MedDRA SOC and 
PT for the Safety population: 
• All AEs (including number of events and subject incidence). 
• AEs by severity (mild, moderate, severe). 
• AEs by relationship to the study treatment (related, or not related). 
The following conventions will be followed in summarizing AEs: 
• For subject incidence summaries, each subject will be counted only once within each 
SOC and within each preferred term. 
• If a subject reports more than one AE within a preferred term and/or a body system, 
the AE with the highest known severity within each body system and within each 
preferred term will be included in the summaries by severity. 
• For summaries by relationship to the study drug, AEs will be grouped as “related” or 
“not related.” AEs assessed as “possible,” “probable,” or “definite,” will be grouped 
as “related.” If a subject reports more than one AE within the same treatment 
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Summaries of SAEs and AEs leading to discontinuation will also be provided. A listing of AEs, 
as well as a listing of deaths, SAEs, or AEs leading to discontinuation, will be presented. 
15.3.6.2. Clinical Laboratory Assessments 
Clinical laboratory parameters will be summarized by presenting shift tables, and by presenting 
summary statistics for the absolute values as well as the change from Baseline values by 
treatment. For laboratory parameters with categorical outcomes, the number and percentage of 
subjects with each outcome will be presented. The data listings will flag values outside the 
reference range. 
The change from Baseline values will be analyzed by nonparametric rank ANCOVA to compare 
between the SEP-363856 and placebo treatments for: serum lipid (total cholesterol, LDL 
cholesterol, HDL cholesterol, and triglycerides), glucose, HbA1c and prolactin levels. Details of 
the rank ANCOVA analysis will be provided in the SAP. 
15.3.6.3. ECGs/Centrally-read ECG/Holter Monitor 
Absolute values and changes from Baseline in ECG parameters will be summarized by 
treatment. In addition, the number and percentage of subjects with elevated QTc intervals 
(> 450 msec, > 480 msec, and > 500 msec) and changes in QTc intervals ≥ 30 msec and 
≥ 60 msec will be summarized by treatment. Fridericia’s correction (QTcF) and Bazett’s 
correction (QTcB) will be used for QT interval correction. 
15.3.6.4. Vital Signs 
Vital sign parameters, as well as weight and BMI, will be summarized by presenting summary 
statistics for the absolute values and the change from Baseline values by treatment. The change 
from Baseline values for weight and BMI will also be analyzed by nonparametric rank 
ANCOVA to compare between the SEP-363856 and placebo treatments.  
15.3.6.5. Physical/Neurological Examination 
All physical and neurological exam findings at screening will be captured in the medical history 
and summarized together with the other medical history events. Clinically significant changes 
from the screening visit will be captured as AEs as appropriate, and summarized together with 
the other AEs. 
15.3.6.6. Concomitant Medications 
All medications will be coded to indication-specific ATC (Anatomical Therapeutic Chemical) 
classification (i.e. ATC level 3) and preferred name using the World Health Organization Drug 
Dictionary (WHO-DD).  
Any medications taken during the course of the study, with a start date on or after the date of the 
first dose of study drug and on or before the date of the last dose of study drug; or with a start 
date prior to, and an end date on or after, the date of the first dose of study drug, or marked as 
ongoing, will be considered concomitant medications. Medications that ended prior to the date of 
the first dose of study drug will be considered prior medications. Medications that started after 
the date of the last dose of study drug will not be considered concomitant, but will be considered 
post-treatment. Prior and Concomitant medications will be summarized for the number and 


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percentage of subjects using each medication by treatment and by the drug class and preferred 
name for the safety population.  
15.3.6.7. Suicidality Measure 
Frequency and severity of suicidal ideation and suicidal behavior as measured by the C-SSRS 
scale will be summarized by treatment for each visit. 
15.3.6.8. Movement Disorder Measures 
Movement disorder measures include AIMS, BARS, and SAS. Change from baseline at Week 4 
in the total score of AIMS, BARS, or SAS will be analyzed using an MMRM model similar to 
that described in the primary analysis for the primary efficacy endpoint (Section 15.3.5.1), with 
the respective baseline values as covariate. 
In addition, as a supportive analysis, missing AIMS (or BARS, SAS) data at the Week 4 visit 
will be imputed using the LOCF method. The resulting efficacy variable will be the change from 
baseline in AIMS (or BARS, SAS) total score at the Week 4 LOCF endpoint. This variable will 
be analyzed using an ANCOVA model similar to that described in Section 15.3.5.2, with the 
respective baseline values as covariate. 
15.3.6.9. Drug Effects Questionnaire 
Data from the DEQ questionnaire will be summarized for the safety population by treatment at 
each visit. 
15.3.6.10. Pittsburgh Sleep Quality Index 
Data from the PSQI scale will be summarized for the safety population by treatment at each visit. 
Change from baseline in the PSQI global score at Week 4 will be analyzed using an ANCOVA 
model similar to that described in Section 15.3.5.3). 
15.3.6.11. Subgroup Analysis 
Selected safety data will be presented by geographic region/country or by gender subgroups. 
Details of subgroup analysis of the safety data will be provided in SAP.  
15.3.7. 
Population Pharmacokinetic Analysis 
All concentrations will be presented in data listings. POP PK analysis will be performed using 
plasma SEP-363856 concentrations; the results of which will be reported separately. 
 
15.3.8. 
Pharmacodynamic Analysis 
The relationship between PANSS total score and plasma SEP-363856 exposure using population 
PK/pharmacodynamics (PD) methods will be explored, the results of which will be reported 
separately. 


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15.3.9. 
Pharmacogenomic Analysis 
The impact of cytochrome (CYP) P450 CYP2D6 metabolizer status on plasma SEP-363856 
exposure will be explored; the results of which will be reported separately. 
15.3.10. 
Interim Analysis 
No interim analysis is planned. 
15.3.11. 
Treatment of Missing Data 
For rating scales with more than one item, such as PANSS and MADRS, if any item score 
contributing to the total/subscale score is missing, then the total/subscale score will be set to 
missing. 
Missing data at the Week 4 visit will be imputed using the last observation carried forward 
(LOCF) approach for the ANCOVA models, where specified. For the MMRM models, no 
imputation for missing data will be applied unless otherwise specified. 
15.3.12. 
Sensitivity Analyses 
This section describes the sensitivity analyses for the efficacy data. 
As a supportive analysis for the efficacy endpoints of change from Baseline in PANSS total 
score or CGI-S score at Week 4, missing data at Week 4 in PANSS total score and CGI-S score 
will be imputed using the LOCF method, and the data will be analyzed using an ANCOVA 
model. The respective response variable for the model will be: change from Baseline in PANSS 
total score at the Week 4 LOCF endpoint and change from Baseline in CGI-S score at the 
Week 4 LOCF endpoint. The ANCOVA model will include treatment and pooled center as fixed 
factors and include Baseline PANSS total score (or CGI-S score) as a covariate. 
Subjects will be grouped by the visit at which they had their last PANSS total score (or CGI-S 
score) measured. This will result in six categories of subject discontinuation: Day 4 dropouts, 
Week 1 dropouts, Week 2 dropouts, Week 3 dropouts, Week 4 dropouts, and Completers. Mean 
change from Baseline in PANSS total score and mean change from Baseline in CGI-S score will 
be plotted by the dropout category and by reason of discontinuation, in order to assess whether 
these two efficacy measures appear to be correlated with study dropout. 
The mechanisms that cause missing data may or may not be at random. The MMRM model used 
in the primary analysis of the two efficacy endpoints above relies on the assumption of missing 
at random (MAR). In order to explore the robustness of the primary analyses, sensitivity 
analyses, such as a random effects pattern mixture model and a pattern mixture model with 
placebo-based multiple imputation, will be performed for these two efficacy endpoints. Details 
of these analyses will be provided in the SAP. 


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16. 
PROCEDURE FOR CLINICAL STUDY QUALITY CONTROL 
/DATA COLLECTION, MANAGEMENT, AND QUALITY 
ASSURANCE 
16.1. 
Data Collection/Electronic Data Capture (EDC) 
The results from Screening and data collected during the study (except clinical laboratory test 
results) will be recorded in the subject’s electronic CRF. Data will be entered into source 
documents prior to being transcribed into the CRF. This transcribing will be done once a subject 
has passed screening (Visit 1). Data for screen failures will not be collected. The study centers 
will use an EDC system that is compliant with relevant FDA regulatory requirements per 21 
Code of Federal Regulations (CFR) Part 11. 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 or delegate. 
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 8: 
Computerized Systems Used for Source Data 
Protocol Step  
Computerized System Type or 
Description 
Obtain informed consent 
A 
Review inclusion/exclusion criteria 
A 
Demographics 
A 
Prior/concomitant medication review 
A 
Randomize (IXRS) to treatment 
E 
Dispense study drug 
A, E 
Study drug accountability 
A 
Medical history 
A 
Psychiatric history/mental status 
A 
SCID-CT 
A 
Physical examination 
A 
Height 
A 
Vital sign measurements 
A 
Weight 
A 
Waist circumference 
A 
Electrocardiogram (ECG) 
C 
Hematology, chemistry, and urinalysis  
B 


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Table 8: 
Computerized Systems Used for Source Data (Continued) 
Protocol Step  
Computerized System Type or 
Description 
Serum prolactin 
B 
Glycosylated hemoglobin (HbA1c) 
B 
Glucose and Lipid panel  
B 
Serum follicle stimulating hormone (FSH) 
B 
Serum human chorionic gonadotropin (β-hCG) 
B 
Blood sample for pharmacogenomics (CYPP450 2D6) 
D 
Blood sample for SEP-363856 PK 
D 
Urine drug screen 
B 
Urine β-hCG (local) 
A 
Urine drug screen (central) 
B 
Positive and Negative Syndrome Scale (PANSS) – Total 
Score 
F 
Clinical Global Impression – Severity (CGI-S) 
F 
Montgomery-Asberg Depression Rating Scale (MADRS) 
F 
Columbia Suicide Severity Rating Scale (C-SSRS)  
F 
Drug Effects Questionnaire (DEQ) 
A 
Abnormal Involuntary Movement Scale (AIMS) 
F 
Barnes Akathisia Rating Scale (BARS) 
F 
Simpson-Angus Scale (SAS) 
F 
Brief Negative Symptoms Scale (BNSS) 
F 
Pittsburg Sleep Quality Index (PSQI) 
F 
CogState Brief Battery (CBB) 
G 
Pretreatment event monitoring 
A 
Adverse events (AE) monitoring 
A 
Provide meals 
A 
Statistical analysis 
SAS®, version 9.2 or higher 
 A = EDC (MediData RAVE); B = LIMS; C = Core Lab Over-read; D = LIMS/ASCII; E = IXRS; F = Bracket; 
G = CogState.  
 Abbreviations: EDC = electronic data capture; CDR = clinical data repository; CIMS = Clinical Inventory 
Management System; IXRS = interactive response technology; IVRS = interactive voice recognition 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 ICH 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. 


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16.4. 
Audits 
The study may be subject to audit by the Sponsor/designee. If such an audit occurs, the 
Investigator must agree to allow access to required subject records. This is dependent on the 
subject granting consent by signing the ICF. By signing this protocol, the Investigator grants 
permission to personnel from the Sponsor or its representatives for on-site monitoring and 
auditing of all appropriate study documentation, as well as on-site review of the procedures 
employed in CRF generation, where clinically appropriate. 
In accordance with ICH GCP the Sponsor may select this study for audit. During the audit the 
Sponsor representative will carry out an inspection of centre facilities (eg, pharmacy, drug 
storage areas, laboratory) and review study related records in order to evaluate the study 
compliance with the Sponsor/centre SOPs, protocol, ICH GCP and local regulations. The 
Investigator or appropriate designee must also agree to inspection of all study documents by the 
regulatory authorities and the IEC. Should the Investigator or appropriate designee be notified of 
a regulatory inspection involving this study they should notify the Sponsor immediately. 
16.5. 
Study Documentation 
Study records are comprised of source documents, CRFs, and all other administrative 
documents, eg, IRB/IEC correspondence, clinical study materials and supplies shipment 
manifests, monitoring logs, Sponsor and CRO correspondence, etc. A study specific binder will 
be provided with instructions for the maintenance of study records. 
Source document is defined as any hand written or computer generated document that contains 
medical information or test results that have been collected for or are in support of the protocol 
specifications, eg, clinical laboratory reports, clinic notes, drug disbursement log, subject sign in 
sheets, subject completed questionnaires if applicable, telephone logs, ECGs, etc. All draft, 
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. 
A local laboratory may optionally be used for analysis of serum pregnancy at Visit 2 in this 
study. The local laboratory/site personnel will provide Sponsor/P1vital with laboratory 
certification(s) and a current dated copy of normal range values for the local clinical laboratory 
selected to analyse clinical specimens. 


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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 Good 
Clinical Practice (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. 
17.2. 
Institutional Review Board/Independent Ethics Committee 
Documented approval for conducting the study from appropriate Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) will be obtained for all participating study centers 
prior to initiation of the study, according to ICH GCP, applicable local law(s) and regulation(s). 
When necessary, an extension, amendment or renewal of the IRB/IEC approval must be obtained 
and also forwarded to the Sponsor. The IRB/IEC must supply the Sponsor a list of the IRB/IEC 
membership, and a statement to confirm that the IRB/IEC is organized and operates according to 
ICH GCP, applicable law(s) and regulation(s). 
A copy of written IRB/IEC approval or favorable opinion of the protocol, informed consent form 
and subject recruitment material (if applicable) must be provided to Sponsor/CRO prior to start 
of the study. The approval or favorable opinion letter must be signed by the IRB/IEC chairman 
or designee identify the IRB/IEC name and address, identify the clinical protocol by title and/or 
protocol number, and include the date that approval or favorable opinion was granted. The letter 
must also contain a statement that the IRB/IEC complies with the requirements in 21 CFR 
Part 56 for a study conducted under a US investigation new drug (IND) or ICH GCP, as 
applicable. 
The Investigator/CRO is responsible for obtaining from the IRB/IEC continued review of the 
clinical research or submitting periodic progress reports, in accordance with applicable 
regulations, at intervals not to exceed one year and (if applicable) as otherwise additionally 
specified by the IRB/IEC. The Sponsor must be supplied with written documentation of 
continued review of the clinical research. 
The Investigator must promptly inform their IRB/IEC of all SAEs reported by subjects enrolled 
in the study or other safety information reported from Sponsor/CRO in accordance with 
applicable law(s) and regulation(s). 
17.3. 
Informed Consent 
The informed consent form will be approved by the Sponsor/CRO prior to submission to the 
IRB/IEC. All informed consent forms must contain the minimum elements as mandated by ICH 


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GCP, applicable local law(s) and regulations and will be subject to Sponsor/CRO approval as 
well as IRB/IEC approval. 
Before recruitment and enrollment, each prospective subject will be given a full explanation of 
the study, allowed to read the approved informed consent form and be provided ample time and 
the opportunity to ask any questions that may arise. Once all questions have been answered and 
the Investigator is assured that the prospective subject understands the implications of 
participating in the study, the prospective subject will be asked to give consent to participate in 
the study by signing the informed consent form. As part of the consent process, each prospective 
subject must consent to direct access to his/her medical records for study-related monitoring, 
auditing, IRB/IEC review, and regulatory inspection. It should be clearly explained to each 
prospective subject that participation in each and every clinical visit and assessment is expected. 
The subject may be discontinued from study drug, but that does not necessarily negate the 
expectation that the subject will continue to participate in the study through the final 
visit/assessment. The Investigator will provide a copy of the signed informed consent form to 
each subject, and will record the date of the informed consent on the CRF. 
If an amendment to the protocol changes the subject participation schedule in scope or activity, 
or if important new information becomes available that may be relevant to the subject’s consent, 
the informed consent form must be revised, submitted to the IRB/IEC for review and approval or 
favorable opinion. The revised informed consent form must be used to obtain consent from a 
subject currently enrolled in the study if he or she is affected by the amendment. The revised 
informed consent form must be used to obtain consent from any new subjects who are enrolled 
into the study after the date of the approval or favorable opinion of the protocol amendment. 
17.4. 
Subject Privacy 
The Sponsor (or Sponsor representative) or any designees affirm uphold the subjects 
confidentiality. The subject will be identified by unique code only; full names will be masked 
prior to transmission to the Sponsor. The confidentiality of the subject’s personal data shall be 
protected in accordance with appropriate laws and regulations. 
If any cases are identified where the subject’s confidentiality has been breached, this must be 
rectified immediately. All subject identifiable information should be removed and the Sponsor 
notified. 
17.5. 
Protocol Amendments and Emergency Deviations 
All revisions and/or amendments to this protocol must be approved in writing by the Sponsor 
and the appropriate IRB/IEC. The Investigator will not make any changes to the conduct of the 
study or the protocol without first obtaining written approval from the Sponsor and the IRB/IEC, 
except where necessary to eliminate an apparent immediate hazard to a study subject. 
Emergency deviations or modifications may be initiated without Sponsor or IRB/IEC approval or 
favorable opinion, only in cases where the deviation or modification is necessary to eliminate or 
avoid an immediate apparent hazard to subjects. Emergency deviations or modifications must be 
reported to the Sponsor/CRO and the IRB/IEC immediately/within five business days of the 
occurrence, or in accordance with applicable regulatory requirements. 


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17.6. 
Records Retention 
The Investigator/the study center must arrange for retention of study records at the study center 
for at least 25 years from time of participation in the study or longer in accordance with 
applicable regulations and Sponsor SOPs. The Investigator/site should take measures to prevent 
accidental or premature destruction of these documents. Documents cannot be destroyed without 
written Sponsor authorization. The Sponsor will inform the Investigator/the study center when 
the destruction of documents is permitted. 
17.7. 
Inspection of Records 
In the event of an inspection, the Investigator agrees to allow representatives of the Sponsor and 
its representative and, the regulatory authorities’ access to all study records. The Investigator will 
promptly notify the Sponsor/CRO of all requests to inspect a Sunovion-sponsored study by 
government agencies and will promptly forward a copy of all such inspection reports. 
17.8. 
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. 
The Sponsor will disclose the study results, in the form of a clinical study report synopsis, to the 
IEC and the applicable regulatory authorities within one year of the end of the study. The format 
of this synopsis and that of the clinical study report should comply with ICH E3 guidelines for 
structure and content of a clinical study report. 
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. 


Protocol SEP361-201, Version 3.01 
 
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Confidential and Proprietary 
81 
17 August 2017 
18. 
REFERENCES 
American Psychiatric Association (APA). Diagnostic and Statistical Manual of Mental 
Disorders. 4th ed; 2000. 
Andreasen NC, Pressler M, Nopoulos P, Miller D, Ho BC. Antipsychotic dose equivalents and 
dose-years: a standardized method for comparing exposure to different drugs. Biol Psychiatry. 
2010 Feb 1;67(3):255-62. 
Ascher-Svanum H, Zhu B, Faries DE, Salkever D, Slade EP, Peng X, Conley RR. The cost of 
relapse and the predictors of relapse in the treatment of schizophrenia. BMC 
Psychiatry. 2010;10:2-7. 
Barnes TRE. A rating scale for drug-induced akathisia. Br J Psychiatry 1989;154:672-676. 
Barnes TRE. The Barnes Akathisia Rating Scale – Revisited. J Psychopharmacology 2003; 
17(4): 365-370. 
Buysse, Daniel J.; Reynolds, Charles F.; Monk, Timothy H.; Berman, Susan R.; Kupfer, David J. 
(May 1989). "The Pittsburgh sleep quality index: A new instrument for psychiatric practice and 
research". Psychiatry Research 28 (2): 193–213. .doi:10.1016/0165-1781(89)90047-4. 
Davis JM, Chen N. Dose response and dose equivalence of antipsychotics. J Clin 
Psychopharmacology. 2004;24:192-208. 
First 2015 MB, Williams JBW, Karg RS, Spitzer RL: Structured Clinical Interview for DSM-5 
Disorders, Clinical Trials Version (SCID-5-CT). Arlington, VA, American Psychiatric 
Association, 2015. 
Guy W. EDCEU Assessment Manual for Psychopharmacology – Revised (DHEW Publ No 
ADM 76-338). Rockville, MD, U.S. Department of Health, Education, and Welfare, Public 
Health Service, Alcohol, Drug Abuse, and Mental Health Administration, NIMH 
Psychopharmacology Research Branch, Division of Extramural Research Programs, 
1976:534-537. 
Inada T, Inagaki A. Psychotropic dose equivalence in Japan. Psychiatry Clin Neurosci. 2015 
Aug;69(8):440-7. 
Kay SR, Opler LA, Fisbein A. Positive and Negative Syndrome Scale Manual. North 
Tonawanda, NY: Multi-Health Systems, 1994. 
Kapur S, Remington G. Atypical antipsychotics: new directions and new challenges in the 
treatment of schizophrenia. Annu Rev Med 2001;52:503-517. 
Keefe RSE, Bilder RM, Harvey PD, Davis SM, Palmer BW, Gold JM, et al. Baseline 
neurocognitive deficits in the CATIE schizophrenia trial. Neuropsychopharmacology. 
2006;31:2033-2046. 
Kim DH, Maneen MJ, Stahl SM. Building a better antipsychotic: receptor targets for the 
treatment of multiple symptom dimensions of schizophrenia. Neurotherapeutics. 2009;6:78-85. 


Protocol SEP361-201, Version 3.01 
 
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17 August 2017 
Kreyenbuhl J, Buchanan RW, Dickerson FB, Dixon LB. The Schizophrenia Patient Outcomes 
Research Team (PORT): updated treatment recommendations 2009. Schizophr Bull. 
2010;36:94-103. 
Kuroki T, Nagao N, Nakahara T. Neuropharmacology of second-generation antipsychotic drugs: 
a validity of the serotonin-dopamine hypothesis. Prog Brain Res. 2008;172:199-212. 
Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with 
schizophrenia, second edition. Am J Psychiatry. 2004;161(suppl 2):1-56. 
Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-
generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009;373:31-41. 
Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, et al. 
Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J 
Med. 2005;353:1209-1223. 
Meltzer HY, Cucchiaro J, Silva R, Ogasa M, Philips D, Xu, J, Kalali, AH, Schweizer E, Pikalov 
A, Loebel A. Lurasidone in the treatment of schizophrenia: a randomized, double-blind, 
placebo-and olanzapine-controlled study. Am J Psychiatry. 2011;168:957-967. 
Minzenberg, et al. Chapter 10: Schizophrenia. In: Hales RE, Yudofsky SC, Gabbard GO, eds. 
The American Psychiatric Publishing Textbook of Psychiatry. 5th edition. Arlington, VA: 
American Psychiatric Publishing, Inc; 2008. 
Morken G, Widen JH, Grawe RW. Non-adherence to antipsychotic medication, relapse and 
rehospitalization in recent-onset schizophrenia. BMC Psychiatry. 2008;8:32-37. 
Munetz MR, Benjamin S. How to examine subjects using the Abnormal Involuntary Movement 
Scale. Hospital and Community Psychiatry 1988; 39: 1172-1177. 
Munro J, Osborne S, Dearden L, Pascoe K, Gauthier A, Price M. Hospital treatment and 
management in relapse of schizophrenia in the UK: associated costs. The Psychiatrist. 
2011;35:95-100. 
Naber D, Lambert M. The CATIE and CUtLASS studies in schizophrenia: results and 
implications for clinicians. CNS Drugs. 2009;23:649-659. 
Nakamura M, Ogasa M, Guarino J, Phillips D, Severs J, Cucchiaro J, Loebel A. Lurasidone in 
the treatment of acute schizophrenia: a double-blind, placebo-controlled trial. J Clin Psychiatry. 
2009;70:829-836. 
Narrow WE, Rae DS, Robins LN, Regier DA. Revised prevalence estimates of mental disorders 
in the United States: using a clinical significance criterion to reconcile 2 surveys' estimates. Arch 
Gen Psychiatry. 2002;59:115-123. 
National Institute of Mental Health (NIMH). Schizophrenia. 
http://www.nimh.nih.gov/health/publications/schizophrenia/schizophrenia-booket-2009.pdf. 
Accessed October 20, 2010. 
Newcomer JW. Antipsychotic medications: metabolic and cardiovascular risk. J Clin Psychiatry. 
2007;68 (suppl 4):8-13. 


Protocol SEP361-201, Version 3.01 
 
SEP-363856 
 
Confidential and Proprietary 
83 
17 August 2017 
Opler LA, Kay SSR, Lindenmayer JP, Fiszbein A. Structured Clinical Interview for the Positive 
and Negative Syndrome Scale (SCI-PANSS). Toronto: Multi-Health Systems, 1992. 
Patel KH, Hlavinka PF. Schizophrenia: Optimal therapy with second-generation antipsychotic 
agents. Pharmacy Today. 2007;13:71-84. 
Pearlson GD. Neurobiology of schizophrenia. Ann Neurol. 2000;48:556-566. 
Perkins DO, Stroup TS, Lieberman JA. Psychotic disorders measures. In Handbook of 
Psychiatric Measures. Washington, D.C.: American Psychiatric Association, 2000 p. 485-513.  
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 Jul; 164 (7):1035-1043. 
Schultz SK, Andreasen NC. Schizophrenia. Lancet. 1999;353:1425-1430. 
Siddiqui O, Hung HM, O'Neil R. MMRM versus LOCF: A comprehensive comparison based on 
simulation study and 25 NDA datasets. Journal of Biopharmaceutical Statistics, 2009; 19: 
227-246. 
Simpson GM, Angus JWS. A rating scale for extrapyramidal side effects. Acta Psychiatrica 
Scandinavia, Suppl 1970; 212S: 11-19. 
Tandon R, Belmaker RH, Gattaz WF, et al. World Psychiatric Association Pharmacopsychiatry 
Section statement on comparative effectiveness of antipsychotics in the treatment of 
schizophrenia. Schizophrenia Res. 2008;100:20-38. 
Webber MA, Marder SR. Better pharmacotherapy for schizophrenia: what does the future hold? 
Current Psychiatry Reports. 2008;10:352-358. 
Williams JBW, Kobak KA. Development and reliability of a structured interview guide for the 
Montgomery-Asberg Depression Rating Scale (SIGMA). Br J Psych. 2008; 192: 5-58. 
Wu EQ, Shi L, Birnbaum H, Hudson T, Kessler R. Annual prevalence of diagnosed 
schizophrenia in the USA: a claims data analysis approach. Psychol Med. 2006;36:1535-1540. 


Protocol SEP361-201, Version 3.01 
 
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Confidential and Proprietary 
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19. 
INVESTIGATOR APPROVAL 
I have read the protocol, SEP361-201, Version 3.01 “A 4-Week, Randomized, Double-blind, 
Parallel-group, Placebo-controlled, Flexibly-dosed, Multicenter Study to Evaluate the Efficacy 
and Safety of SEP-363856 in Acutely Psychotic Adult Subjects With Schizophrenia”, 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: ___________________________________________ 


Protocol SEP361-201, Version 3.01 
 
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20. 
APPENDIX I. CARDIAC SAFETY MONITORING (ECG) 
1. Requirements for Testing 
Electrocardiogram (ECG) equipment and supplies will be provided by the centralized cardiac 
safety vendor and should be used for all in-clinic protocol ECG assessments. 
• All 12-lead ECGs will be recorded in the same manner. 
• The study center 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. 
• ECGs will be recorded with at least one 10-second single-lead tracing recorded from 
Lead II. 
2. Subject Restrictions and Instructions 
• Prior to ECG acquisition, the subject will have rested 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 subjects’ 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 study 
center for review and signature. 
• The ECG tracing will be kept with subject’s source documentation and / or CRF 
unless it is specified otherwise. The original ECG and the cardiologist’s over-read 
will be retained at the study center. 
4. Data Standardization 
ECG data will be transmitted to a centralized cardiac safety vendor and centrally over-read 
and interpreted using standardized procedures. 


Protocol SEP361-201, Version 3.01 
 
SEP-363856 
 
Confidential and Proprietary 
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21. 
APPENDIX II. HIGHLY EFFECTIVE CONTRACEPTIVE 
PROCEDURES FOR AND DURING THE STUDY 
For female subjects 
Female subject of reproductive potential agrees to remain abstinent or use highly effective 
and reliable contraception throughout the study and for at least 30 days after the last dose of 
study drug has been taken. In the Investigator's judgment, the subject will adhere to this 
requirement. 
a. Highly effective contraception is defined as continuous use of either two barrier 
methods (eg, condom and spermicide or diaphragm with spermicide) or a hormonal 
contraceptive. Highly effective hormonal contraceptives include the following:  
i) 
contraceptive implant (such as Norplant®) implanted at least 90 days prior to 
screening;  
ii) 
injectable contraception (such as medroxyprogesterone acetate injection) given 
at least 14 days prior to screening; or 
iii) 
 oral contraception taken as directed for at least 30 days prior to screening. 
b. Subjects who are of non-reproductive potential, ie, subject who is surgically sterile, 
has undergone tubal ligation, or is postmenopausal (defined as at least 12 months of 
spontaneous amenorrhea or between 6 and 12 months of spontaneous amenorrhea 
with follicle stimulating hormone (FSH) concentrations within postmenopausal range 
as determined by laboratory analysis) are not required to remain abstinent or use 
highly effective contraception. 
For Male Subjects 
Male subjects with female partner(s) of childbearing potential must agree to avoid fathering a 
child and use highly effective methods of birth control from screening until at least 30 days 
after the last study drug administration. Male subjects must be surgically sterile or willing to 
use an effective method of double-barrier birth control as outlined for female subjects above. 


Protocol SEP361-201, Version 3.01 
 
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Confidential and Proprietary 
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22. 
APPENDIX III. HALOPERIDOL EQUIVALENT DOSES 
 
Medications 
Haloperidol Equivalent (12 mg) 
Typical Antipsychoticsa 
Chlorpromazine 
600 mg 
Fluphenazine 
15 mg 
Haloperidol 
12 mg 
Perphenazine 
40 mg 
Thioridazine 
500 mg 
Thiothixene 
30 mg 
Trifluoperazine 
25 mg 
Fluphenazine decanoate (mg/2–3 wk) 
34 mg/2-3 wk 
Haloperidol decanoate (mg/4 wk) 
159 mg/4 wk 
 
Medications 
Haloperidol Equivalent (12 mg) 
Atypical Antipsychoticsa 
Aripiprazole 
30 
Asenapine 
30 
Clozapine 
900 
Haloperidol 
12 
Iloperidone 
24 
Lurasidone 
120 
Olanzapine 
20 
Paliperidone 
9 
Quetiapine 
450 
Risperidone 
6 
Sertindole 
36 
Ziprasidone 
160 
a. 
Antipsychotics: The tables are provided for guidance purposes only. Dose range allowed must be 
determined for the region after consultation with the medical monitor. 
References: 
Gardner DM, Murphy AL, O’Donnell HO, Centorrino F, Baldessarini RJ. International consensus study of 
antipsychotic dosing. Am J Psychiatry 2010;167:686-693. 
Leucht S, Samara M, Patel M, Woods S, and Davis J. Dose Equivalents for Second-Generation antipsychotics: 
The Minimum Effective Dose Method. Schizophr Bull. 2014 Feb;40 (2):314-326. 
Stahl SM. A pocket guide to atypical antipsychotics: dosing, switching, and other practical information. Arbor 
Scientia; 2013.  


Protocol SEP361-201, Version 3.01 
 
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Confidential and Proprietary 
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23. 
APPENDIX IV. CLINICAL LABORATORY TESTS 
Detailed instructions will be provided in a study center manual. 
The following clinical laboratory tests are to be performed:  
 
Clinical Safety Panel 
 
HEMATOLOGY: (Differential reported as % and absolute value) 
Hemoglobin, Hematocrit, Platelet Count, RBC Count, WBC - Total Count, WBC Differential, 
(Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils) 
 
BLOOD CHEMISTRIES: Alanine aminotransferase (ALT), Albumin, Alkaline Phosphatase 
(ALP), Aspartate aminotransferase (AST), Bicarbonate (HCO3), Bilirubin (Total, Direct, 
Indirect), Blood Urea Nitrogen (BUN), Calcium (Ca), Chloride (Cl), Creatinine, Creatine 
phosphokinase (CPK), Glucose, Magnesium (Mg), Phosphorus (P), Potassium (K), Prolactin, 
Protein (Total), Sodium (Na), Uric Acid 
 
URINALYSIS: Blood, Glucose, Ketones, Leukocyte esterase, Microscopic examination, 
Nitrites, pH, Protein 
 
LIPID PANEL: LDL-Cholesterol, HDL-Cholesterol, Triglycerides 
 
THYROID PANEL: Free T3, Free T4, Thyroid stimulating hormone (TSH) 
 
URINE DRUG SCREENING: Amphetamines, Barbiturates, Benzodiazepines, Cannabinoids, 
Cocaine, Methamphetamines, Methadone, Methylenedioxymethamphetamine (MDMA), 
Phencyclidine (PCP), Opiates, Oxycodone 
 
OTHER TESTS: Serum Pregnancy (β-HcG) (in female subjects only), Urine Pregnancy Test 
(in female subjects only), Glycosylated hemoglobin (HbA1c) 
 
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. 


Protocol SEP361-201, Version 3.01 
 
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24. 
APPENDIX V. PHARMACOKINETIC SAMPLING AND SAMPLE 
HANDLING GUIDELINE  
Please refer to the Laboratory Investigator Manual for all collection and shipping instructions. 
BLOOD SAMPLES FOR PLASMA PHARMACOKINETICS 
When blood sample for PK assessment and clinical lab sample collections share the same 
designated time points (including predose sample), the blood samples should be collected during 
the same venipuncture. 
For each defined PK sampling time point, collect 6 mL blood sample into a K2-EDTA treated 
tube. Invert gently 8 to 10 times. Keep the blood collection tube on wet ice upon blood draw, and 
centrifuge for 20 minutes at ca. x 1300 g to isolate plasma within 30 minutes of blood draw. To 
ensure a more homogenous sample, all plasma samples should first be transferred to 1 tube, 
capped and mixed well. Split the harvest plasma sample with approximately equal volume into 
2 polypropylene tubes, and label as Primary and Back-up. Freeze plasma tubes in a freezer set at 
approximately -20°C or lower. The date and clock time of blood collection must be recorded. 
Blood must be collected from all subjects at the time points indicated below. 
All samples will be shipped with sufficient dry ice protection. 
 
Study Day 
Collection Time 
Volume Collected 
Day 1 
Pre-dose (approximately 10 minutes prior to dosing) 
6 mL  
Day 29 
Post-dose (Actual date and clock time will be recorded) 
6 mL  
 


Protocol SEP361-201, Version 3.01 
 
SEP-363856 
 
Confidential and Proprietary 
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17 August 2017 
25. 
APPENDIX VI. SAMPLE COLLECTION AND HANDLING 
GUIDELINES FOR PHARMACOGENOMICS ASSESSMENT 
Please refer to the Laboratory Investigator Manual for all collection and shipping instructions. 
BLOOD SAMPLES FOR PHARMACOGENOMICS 
• A blood sample (approximately 4.0 mL) will be collected predose on Day 1 using a 
4-mL Vacutainer® (or equivalent) collection tube containing K2-EDTA as an 
anticoagulant. 
• The tubes containing blood samples will be labeled with the following information: 
unique barcode (if possible), protocol number, subject number, and sample date of 
collection. 
• Blood samples will be kept upright on wet ice upon blood draw and will be stored 
frozen at approximately -70°C within 10 min of collection until shipment to the 
appropriate laboratory.  
• The blood samples for pharmacogenomics will be shipped in leak-proof double-
plastic sealed bags with approximately 20 pounds of dry ice placed in insulated 
shipping containers labeled on the outside with “Human Specimens/Non-infectious”. 
Packing material such as bubble-wrap or other cushioning material will be placed 
around the samples to prevent breakage during shipping. Samples will be shipped in 
conformance with International Air Transport Association (IATA) regulations 
relating to the handling and shipping of hazardous goods. 
• Samples will be shipped via Sponsor-specified overnight courier service on Monday 
through Wednesday (should be shipped at least 2 days prior to National Holiday) 


Protocol SEP361-201, Version 3.01 
 
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26. 
APPENDIX VII. MINIMUM PANSS TOTAL SCORE CRITERIA 
AT BASELINE 
The following formula is to be utilized to determine the PANSS total score change at Baseline 
(Visit 2): 
PANSS total score at Screening - PANSS total score at Baseline
PANSS total score at Screening - 30
× 100% 
 
PANSS total score at 
Screening (V1) 
MINIMUM Permissible 
PANSS total score at 
Baseline (V2) 
80 
80 
81 
80 
82 
80 
83 
80 
84 
80 
85 
80 
86 
80 
87 
80 
88 
80 
89 
80 
90 
80 
91 
80 
92 
80 
93 
81 
94 
82 
95 
83 
96 
83 
97 
84 
98 
85 
99 
86 
100 
87 
101 
87 
102 
88 


Protocol SEP361-201, Version 3.01 
 
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Confidential and Proprietary 
92 
17 August 2017 
PANSS total score at 
Screening (V1) 
MINIMUM Permissible 
PANSS total score at 
Baseline (V2) 
103 
89 
104 
90 
105 
91 
106 
91 
107 
92 
108 
93 
109 
94 
110 
95 
111 
95 
112 
96 
113 
97 
114 
98 
115 
99 
116 
99 
117 
100 
118 
101 
119 
102 
120 
103 
121 
103 
122 
104 
123 
105 
124 
106 
125 
107 
126 
107 
127 
108 
128 
109 
129 
110 
130 
111 
 

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Statistical Analysis Plan 
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Document: 
  
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Version Number:
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reproduction is strictly prohibited. 
STATISTICAL ANALYSIS PLAN 
SEP361-201 
A 4-WEEK, RANDOMIZED, DOUBLE-BLIND, PARALLEL-GROUP, PLACEBO-CONTROLLED, FLEXIBLY-
DOSED, MULTICENTER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF SEP-363856 IN
ACUTELY PSYCHOTIC ADULT SUBJECTS WITH SCHIZOPHRENIA 
AUTHOR: 
VERSION NUMBER AND DATE: FINAL V1.0, 28AUG2018 


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Statistical Analysis Plan 
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Author: 
 
Version Number:
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Effective Date: 01Apr2016 
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reproduction is strictly prohibited. 
MODIFICATION HISTORY 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
1.0 
28Jul2017 
 
Not Applicable – First Version
2.0 
15Sep2017 
 
Incorporate comments 
3.0 
30Nov2017 
 
Incorporate comments 
3.1 
08Mar2018 
 
Incorporate comments 
Final draft 
15Aug2018 
 
Incorporate comments 
Final V1.0 
28Aug2018 
 
Incorporate comments 


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TABLE OF CONTENTS 
1.
INTRODUCTION ............................................................................................................................. 12
2.
STUDY OBJECTIVES ...................................................................................................................... 12
2.1. 
Primary Objective................................................................................................................................... 12 
2.2. 
Secondary Objectives ............................................................................................................................. 12 
2.3. 
Other Objectives .................................................................................................................................... 13 
3.
STUDY DESIGN ............................................................................................................................... 13
3.1. 
General Description ................................................................................................................................ 13 
3.2. 
Schedule of Events ................................................................................................................................. 14 
3.3. 
Determination of Sample Size................................................................................................................. 19 
3.4. 
Method of Assigning Subjects to Treatment Groups ................................................................................ 19 
3.5. 
Blinding .................................................................................................................................................. 19 
3.6. 
Changes in conduct of the study ............................................................................................................. 20 
3.7. 
Changes to Analysis from Protocol .......................................................................................................... 20 
4.
PLANNED ANALYSES .................................................................................................................... 20
4.1. 
Data Monitoring Committee (DMC) ........................................................................................................ 21 
4.2. 
Interim Analysis ..................................................................................................................................... 21 
4.3. 
Final Analysis ......................................................................................................................................... 21 
5.
ANALYSIS POPULATIONS ........................................................................................................... 21
5.1. 
Modified Intent-to-Treat [mITT] Population ............................................................................................ 21 


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5.2. 
Per Protocol [PP] Population .................................................................................................................. 21 
5.3. 
Safety Population ................................................................................................................................... 22 
6.
GENERAL CONSIDERATIONS ..................................................................................................... 22
6.1. 
Reference Start Date and Study Day ....................................................................................................... 22 
6.2. 
Baseline ................................................................................................................................................. 23 
6.3. 
Derived Time Points ............................................................................................................................... 23 
6.4. 
Retests, Unscheduled Visits and Early Termination Data ......................................................................... 23 
6.5. 
Windowing Conventions ........................................................................................................................ 24 
6.6. 
Statistical Tests ...................................................................................................................................... 24 
6.7. 
Common Calculations ............................................................................................................................. 24 
6.8. 
Software Version .................................................................................................................................... 24 
7.
STATISTICAL CONSIDERATIONS ............................................................................................. 24
7.1. 
Adjustments for Covariates to be Included in Analyses ........................................................................... 24 
7.2. 
Multicenter Studies ................................................................................................................................ 24 
7.3. 
Missing data ........................................................................................................................................... 25 
7.4. 
Multiple Comparisons/ Multiplicity ........................................................................................................ 25 
7.5. 
Examination of Subgroups ...................................................................................................................... 25 
8.
OUTPUT PRESENTATIONS ......................................................................................................... 26
9.
DISPOSITION AND WITHDRAWALS ....................................................................................... 26
10.
IMPORTANT PROTOCOL DEVIATIONS ............................................................................... 26
11.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ...................................... 27


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11.1. 
Derivations ......................................................................................................................................... 29 
12.
MEDICAL AND SURGICAL HISTORY ..................................................................................... 29
13.
MEDICATIONS ............................................................................................................................ 29
14.
STUDY MEDICATION EXPOSURE .......................................................................................... 29
14.1. 
Derivations ......................................................................................................................................... 30 
15.
STUDY MEDICATION COMPLIANCE ..................................................................................... 30
15.1. 
Derivations ......................................................................................................................................... 30 
16.
EFFICACY OUTCOMES .............................................................................................................. 31
16.1. 
Primary Efficacy .................................................................................................................................. 31 
16.1.1. 
Primary Efficacy Variable & Derivation .....................................................................................................31 
16.1.2. 
Missing Data Methods for Primary Efficacy Variable ...............................................................................35 
16.1.3. 
Primary Analysis of Primary Efficacy Variable ..........................................................................................35 
16.1.4. 
Sensitivity Analysis of Primary Efficacy Variable .......................................................................................36 
16.1.4.1. 
Graphical examination ......................................................................................................................36 
16.1.4.2. 
Pattern-mixture model with placebo-based multiple imputation ....................................................36 
16.1.4.3. 
Tipping point analysis .......................................................................................................................37 
16.1.4.4. 
Analysis of covariance .......................................................................................................................38 
16.1.4.5. 
Complete case analysis .....................................................................................................................38 
16.1.4.6. 
Analysis on the per protocol population ..........................................................................................38 
16.1.5. 
Subgroup Analysis of Primary Efficacy Variable .......................................................................................38 
16.2. 
Secondary Efficacy .............................................................................................................................. 39 
16.2.1. 
Secondary Efficacy Variables & Derivations .............................................................................................39 
16.2.1.1. 
Change from baseline in CGI-S score at Week 4 ...............................................................................39 
16.2.1.2. 
Change from baseline in PANSS subscale scores at Week 4 .............................................................39 
16.2.1.3. 
Change from baseline in PANSS five-factor model scores at Week 4 ...............................................39 
16.2.1.4. 
Change from baseline in PANSS seven-factor model scores at Week 4 ...........................................39 
16.2.1.5. 
Change from baseline in MADRS total score at Week 4 ...................................................................39 
16.2.1.6. 
Change from baseline in BNSS total scores at Week 4 .....................................................................40 
16.2.1.7. 
Proportion of subjects who achieve a PANSS response ...................................................................40 
16.2.2. 
Missing Data Methods for Secondary Efficacy Variable(s) .......................................................................40 
16.2.3. 
Analysis of Secondary Efficacy Variables ..................................................................................................40 
16.2.3.1. 
Analysis of change from baseline in CGI-S score at Week 4 .............................................................40 
16.2.3.2. 
Analysis of other continuous secondary efficacy variables ..............................................................41 


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16.2.3.3. 
Analysis of PANSS responders ..........................................................................................................41 
16.2.3.4. 
Subjects with given PANSS percent changes from baseline .............................................................41 
16.3. 
Exploratory Efficacy ............................................................................................................................ 42 
16.3.1. 
Exploratory Efficacy Variables & Derivation .............................................................................................42 
16.3.1.1. 
Change from baseline in the CBB composite score at Week 4 .........................................................42 
16.3.2. 
Missing Data Method for Exploratory Efficacy Variables .........................................................................43 
16.3.3. 
Analysis of Exploratory Efficacy Variables ................................................................................................43 
16.3.3.1. 
Change from baseline in the CBB composite score at Week 4 .........................................................43 
17.
SAFETY OUTCOMES .................................................................................................................. 43
17.1. 
Adverse Events ................................................................................................................................... 43 
17.1.1. 
All AEs .......................................................................................................................................................44 
17.1.1.1. 
Severity .............................................................................................................................................44 
17.1.1.2. 
Relationship to Study Medication ....................................................................................................45 
17.1.2. 
AEs Leading to Discontinuation of Study Medication ...............................................................................45 
17.1.3. 
AEs Leading to Discontinuation from the Study .......................................................................................45 
17.1.4. 
Serious Adverse Events .............................................................................................................................45 
17.1.5. 
Adverse Events Leading to Death .............................................................................................................45 
17.1.6. 
Adverse Events by Subgroup ....................................................................................................................45 
17.2. 
Laboratory Evaluations ....................................................................................................................... 46 
17.3. 
ECG Evaluations .................................................................................................................................. 48 
17.4. 
Vital Signs ........................................................................................................................................... 49 
17.4.1. 
Orthostatic Effects ....................................................................................................................................51 
17.5. 
Other Safety Assessments .................................................................................................................. 51 
17.5.1. 
Movement Disorder Measures .................................................................................................................51 
17.5.2. 
Pittsburgh Sleep Quality Index .................................................................................................................53 
17.5.3. 
Drug Effects Questionnaire .......................................................................................................................53 
17.5.4. 
Columbia Suicide Severity Rating Scale (C-SSRS) ......................................................................................53 
18.
PHARMACOKINETIC ANALYSIS ............................................................................................ 55
18.1. 
Population Pharmacokinetic Analysis .................................................................................................. 55 
18.2. 
Pharmacodynamic Analysis ................................................................................................................ 55 
19.
DATA NOT SUMMARIZED OR PRESENTED ....................................................................... 56


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20.
CHANGES IN THE ANALYSIS SPECIFIED IN THE STATISTICAL ANALYSIS PLAN .. 56
21.
REFERENCES ............................................................................................................................... 57
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS ............................................... 58 
Output Conventions .......................................................................................................................................... 58 
Dates & Times ................................................................................................................................................... 59 
Spelling Format ................................................................................................................................................. 59 
Presentation of Treatment Groups .................................................................................................................... 60 
Listings .............................................................................................................................................................. 60 
APPENDIX 2. PARTIAL DATE CONVENTIONS .............................................................................. 61 
Algorithm for Adverse Events: ........................................................................................................................... 61 
Algorithm for Prior / Concomitant / Post-treatment Medications: ..................................................................... 63 
Partial Date Imputation Rules for Initial Onset of Schizophrenia: ....................................................................... 68 
Partial Date Imputation Rules for Onset of Acute Exacerbation: ......................................................................... 68 
APPENDIX 3. STATISTICAL MODEL SPECIFICATIONS (SAMPLE SAS CODE) ..................... 69 
Mixed Model for Repeated Measures (MMRM) ................................................................................................. 69 
Pattern-Mixture Model (PMM) with Placebo-Based MI ...................................................................................... 70 
Tipping Point Analysis ....................................................................................................................................... 73 
APPENDIX 4. PSQI SOCRING SHEET ................................................................................................ 76 


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LIST OF ABBREVIATIONS 
Abbreviation
Explanation
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
BLQ 
Below the Lower Limit of Quantification 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CBB 
Cogstate Brief Battery 
CGI-S 
Clinical Global Impression – Severity of Illness 
CI 
Confidence Interval 
CRF 
Case Report Form 
CSP 
Clinical Study Protocol 
DMC 
Data Monitoring Committee 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorder, 5th Edition 
ECG 
Electrocardiogram 
HLT 
High Level Term 
HR 
Heart Rate 
IPD 
Important Protocol Deviations 
mITT 
Modified Intent-to-Treat 
LOCF 
Last Observation Carried Forward 
LS 
Least Squares 
MAR 
Missing At Random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measures 
PANSS 
Positive and Negative Syndrome Scale 
PMM 
Pattern Mixture Model 
PP 
Per Protocol 
PT 
Preferred Term 


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Abbreviation
Explanation
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SE 
Standard Error 
SI 
International System of Units 
SOC 
System Organ Class 
ULQ 
Above the Upper Limit of Quantification 
UPSM 
Uncorrelated PANSS Score Matrix 
VAS 
Visual Analogue Scale 


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1. INTRODUCTION
This document describes the rules and conventions to be used in the presentation and analysis of efficacy 
and safety data for protocol SEP361-201. It describes the data to be summarized and analyzed, including 
specifics of the statistical analyses to be performed.  
This statistical analysis plan (SAP) is based on protocol version 3.01 (17-Aug-2017). Hereafter, this 
protocol version is referred to as the Clinical Study Protocol (CSP). 
2. STUDY OBJECTIVES
2.1. PRIMARY OBJECTIVE 
To evaluate the efficacy of flexibly dosed SEP-363856 (50 or 75 mg/day) compared with placebo in 
acutely psychotic adult subjects with schizophrenia as measured by the Positive and Negative Syndrome 
Scale (PANSS).  
2.2. SECONDARY OBJECTIVES 
To evaluate the efficacy of flexibly-dosed SEP-363856 (50 or 75 mg/day) compared with placebo in 
acutely psychotic adult subjects with schizophrenia as measured by: 
•
Clinical Global Impression-Severity (CGI-S)
•
PANSS subscale scores (positive, negative, and general psychopathology)
•
Brief Negative Symptom Scale (BNSS)
•
Montgomery-Asberg Depression Rating Scale (MADRS)
To evaluate the safety and tolerability of flexibly-dosed SEP-363856 (50 or 75 mg/day) using:  
•
physical examinations (PE)
•
12-lead electrocardiograms (ECG)
•
vital signs
•
adverse event (AE) reports
•
clinical laboratory results
•
body weight and body mass index (BMI)


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•
Columbia – Suicide Severity Rating Scale (C-SSRS)
2.3. OTHER OBJECTIVES 
•
To assess whether SEP-363856 is associated with extrapyramidal symptoms as measured
by the Barnes Akathisia Rating Scale (BARS), the Abnormal Involuntary Movement Scale
(AIMS), and the Simpson-Angus Scale (SAS).
•
To characterize the effects of SEP-363856 as measured by the Drug Effects Questionnaire
(DEQ).
•
To explore the subjective effects of SEP-363856 on sleep as measured by the Pittsburgh
Sleep Quality Index (PSQI).
•
To assess the effects of SEP-363856 on cognition based on the CogState Brief Battery
(CBB).
•
To perform population pharmacokinetic (POPPK) analysis using plasma SEP-363856
concentrations.
•
To characterize the relationship between PANSS total score and plasma SEP-363856
exposure using population PK/pharmacodynamics (PD) methods.
•
To explore the impact of cytochrome (CYP) P450 CYP2D6 metabolizer status on SEP-
363856 plasma exposure.
3. STUDY DESIGN
3.1. GENERAL DESCRIPTION 
This is a multicenter, randomized, double-blind, parallel-group, flexibly-dosed, study evaluating the 
efficacy and safety of SEP-363856 in acutely psychotic adult subjects with schizophrenia using SEP-
363856 (50 or 75 mg/day [i.e., once daily]) versus placebo over a 4-week treatment period.  
This study is projected to randomize at least 240 subjects to 2 treatment groups (SEP-363856 or placebo) 
in a 1:1 ratio. Treatment assignment will be balanced within each clinical site. 
The study will consist of 3 periods: Screening/Washout (up to 14 days), Treatment (4 weeks in-patient), 
and a Follow-up visit (7 days after last study drug dose for subjects who discontinue prior to Visit 7 or who 
complete the study but do not elect to enrol in the open-label extension study [SEP361-202]) as shown in 
Figure 1.  


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Figure 1: Study Schematic  
* Screening/washout period will be up to 14 days.
** Follow-up visit 7 ± 2 days after last dose only for subjects not continuing in to open-label extension 
study SEP361-202. Hospitalization will be allowed for up to an additional 7 days to stabilize the subject, if 
necessary. 
3.2. SCHEDULE OF EVENTS 
Schedule of events can be found in section 11 of the CSP. 


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Table 1. Schedule of Assessments 
Study Visit Number 
Study Visit Week 
Visit 1 
Screeninga 
Visit 2 
Baseline 
Visit 3 
Day 4 
Visit 4 
Week 1 
Visit 5 
Week 2 
Visit 6 
Week 3 
Visit 7 
Week 4 
or ETb 
Visit 8 
Week 5 
Study Visit Day 
-14 to -1 
1 
4 
8 
15 
22 
29 
7 ± 2days 
after Last Dose 
Study Visit Type 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
follow-upc
Obtain informed consent
X
Review inclusion/exclusion criteria  
X 
X 
Review randomization criteria
X
Prior/concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
Randomize (IXRS) to treatment  
X 
Administration of study drugd
X
X
X
X
X
Study drug accountability 
X 
X 
X 
X 
X 
Clinical and Laboratory Evaluations 
Demography
X
Medical history
X
Psychiatric history/mental status 
X 
SCID-CTe
X
Physical and neurological examination 
X 
X 
Height
X
Vital signsf
X
X
X
X
X
X
X
Weight (including BMI)g
X
X
X
X
Waist circumference
X
X


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Study Visit Number 
Study Visit Week 
Visit 1 
Screeninga 
Visit 2 
Baseline 
Visit 3 
Day 4 
Visit 4 
Week 1 
Visit 5 
Week 2 
Visit 6 
Week 3 
Visit 7 
Week 4 
or ETb 
Visit 8 
Week 5 
Study Visit Day 
-14 to -1 
1 
4 
8 
15 
22 
29 
7 ± 2days 
after Last Dose
Study Visit Type 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
follow-upc 
Electrocardiogram (ECG)
X
X
X
Hematology, chemistry, and urinalysis  
X 
X 
X 
Serum prolactin
X
X
X
Glycosylated hemoglobin (HbA1c)
X
X
Glucose and Lipid panelh 
X 
X 
X 
Serum follicle stimulating hormone (FSH)i 
X 
Serum human chorionic gonadotropin (β-hCG)  
X
Blood sample for pharmacogenomics (CYPP450 
2D6) 
X
Blood sample for Population PKj 
X 
X 
Urine drug screenk 
X 
X 
X 
Urine β-hCGl
X
X
Positive and Negative Syndrome Scale (PANSS) 
X 
X 
X 
X 
X 
X 
X 
Clinical Global Impression – Severity (CGI-S) 
X 
X 
X 
X 
X 
X 
X 
Brief Negative Symptom Scale (BNSS) 
X 
X 
X 
X 
X 
X 
X 
Montgomery-Asberg Depression Rating Scale 
(MADRS) 
X
X
X
X
X
X
Columbia Suicide Severity Rating Scale 
(C-SSRS)  
X
X
X
X
X
X
X
X


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Study Visit Number 
Study Visit Week 
Visit 1 
Screeninga 
Visit 2 
Baseline 
Visit 3 
Day 4 
Visit 4 
Week 1 
Visit 5 
Week 2 
Visit 6 
Week 3 
Visit 7 
Week 4 
or ETb 
Visit 8 
Week 5 
Study Visit Day 
-14 to -1 
1 
4 
8 
15 
22 
29 
7 ± 2days 
after Last Dose
Study Visit Type 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
Inpatient 
follow-upc 
Barnes Akathisia Rating Scale (BARS)m 
X 
X 
X 
X 
X 
X 
X 
Abnormal Involuntary Movement Scale 
(AIMS)m 
X
X
X
X
X
X
X
Simpson-Angus Scale (SAS)m 
X 
X 
X 
X 
X 
X 
X 
Drug Effects Questionnaire (DEQ) 
X 
X 
Pittsburg Sleep Quality Index (PSQI) 
X 
X 
CogState Brief Battery (CBB) 
X 
X 
Pretreatment event monitoring
X
Adverse events (AE) monitoring 
X 
X 
X 
X 
X 
X 
X 
Duplicate Subject Checkn 
X 
X 
X 
Abbreviations: AE = adverse event; BARS = Barnes Akathisia Rating Scale; β-hCG = human chorionic gonadotropin; BMI = Body Mass Index; BNNS = Brief Negative 
Symptom Scale; C-SSRS = Columbia Suicide Severity Rating Scale; ET = early termination; FSH = Follicle stimulating hormone; IXRS = interactive response 
technology; MADRS = Montgomery-Asberg Depression Rating Scale; SAS = Simpson-Angus Scale; PANSS = Positive and Negative Syndrome Scale; PSQI = Pittsburg 
Sleep Quality Index; PK = pharmacokinetic; SCID-CT = Structured Clinical Interview for DSM-5, Clinical Trials Version. 
a Subjects who screen fail may be re-screened up to two times, if judged appropriate by the Investigator. 
b If a subject discontinues from the study, all Visit 7 procedures should be performed at the ET visit, within 48 hours of last study dose. All procedures and assessments 
scheduled for Visit 7 (Week 4) will be utilized as the Baseline procedures and assessments for the open-label extension study (SEP361-202). 
c All subjects will have an inpatient/outpatient safety follow-up prior to discharge (7 [± 2]) days after their last dose of study drug. 
d All study drug will be taken once daily in the evening by mouth.  
e The SCID-CT will be used to support the DSM-5 diagnosis and must be administered by a qualified rater listed on Form 1572 with at least 2 years' experience with the 
population under study. 
f Vital signs will include supine and standing measurements of blood pressure; and heart rate, respiratory rate, and oral body temperature. 
g BMI will be calculated and recorded in the eCRF at the clinical site at Screening for other visits, BMI will be calculated during statistical analysis. 


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h Subjects must be fasted (no food or drink except water at least 8 hours prior to specified blood tests). Blood samples should be drawn in the morning followed by a snack 
or meal. 
i Blood samples for follicle stimulating hormone (FSH) will be collected if menopause is suspected. 
j Blood samples for determination of plasma SEP-363856 and SEP-363854 concentrations will be collected predose (prior to administration of the first dose) on Day 1; 
one postdose sample will be collected on Day 29. The time and date of the 3 previous doses of study drug, time, and date of sampling must be recorded. Time and date of 
food intake must be recorded on Day 29 when blood samples are collected for determination of SEP-363856 and SEP-363854 concentrations. 
k If a subject is issued a day pass, an unscheduled urine drug screen will be performed upon returning to the site. Urine drug screen may be ordered at other visits as 
deemed clinically appropriate. These results should be discussed with the Medical Monitor. 
l Any positive urine β-hCG test should be confirmed by a serum β-hCG test. 
m Unscheduled BARS, AIMS, and SAS scales should be administered if a subject develops extrapyramidal symptoms (EPS) requiring treatment. See Section 10.3. 
n Following the last contact with a subject, the duplicate enrollment system should be updated, as appropriate (US sites only). 
Note: With the exception of SCID-CT and DEQ, all rating assessments will be performed by the rater using a tablet. In the event that a tablet is not available, the rating 
assessments will be performed by the rater using a paper version of the assessment. 


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3.3. Determination of Sample Size 
A sample size of 100 subjects per treatment group (SEP-363856 and placebo) will provide 80% power to 
detect a treatment effect size of 0.4 in change from baseline in PANSS total score at Week 4 for SEP-
363856 versus placebo, using a two independent sample t-test method with 2-sided significance level of 
0.05. A clinically meaningful effect size of 0.4 was estimated based on review of published studies of other 
antipsychotics for the short-term treatment of schizophrenia. It is anticipated that 17% of all randomized 
subjects will discontinue early from the study. An upward adjustment of the sample size is thus used to 
compensate for missing data from subjects who are randomized and discontinue from the study. The total 
sample size will be 240 randomized subjects (or 120 subjects per treatment group). 
3.4. Method of Assigning Subjects to Treatment Groups 
The randomization schedule is based on permuted blocks and is generated by a non-study biostatistician.  
Site dynamic block randomization is used to assign subjects to treatments. Subjects are randomized to 
treatment arms based on a block of randomization codes that have been assigned to the subject’s site. 
When the first subject for a site is randomized, one entire block is bound to that site. The next subject 
randomized in that site will use the next randomization code in that bound block.  A subject from another 
site will be randomized to a treatment group from the block of codes assigned to their site. A subject being 
randomized after a block is used up will cause another block to be bound to the site depending on how 
many blocks should be maintained at all times. Further details on treatment assignment are provided in 
the Randomization Specifications Document. 
Once a subject is deemed eligible to be randomized at Day 1 (Visit 2), an IXRS (the Oracle Interactive 
Response Technology system) will perform treatment assignment. Subjects will be randomized to one of 
the following treatment groups in a 1:1 ratio and balanced within each clinical site: 
•
SEP-363856 (50 or 75 mg/day flexible dosing for 4 weeks)
•
Placebo (once daily for 4 weeks)
Once a randomization number has been assigned, it cannot be reused. 
3.5. Blinding 
Subjects, Investigator staff, persons performing the assessments, clinical operations personnel, data 
analysts, and personnel at central laboratories (including imaging) will remain blind to the identity of the 
treatment from the time of randomization until database lock and unblinding, using the following methods; 
(1) randomization data are kept strictly confidential until the time of unblinding, and will not be accessible 
by anyone else involved in the study with the exception of bioanalytical personnel involved in the analysis 
of PK samples; (2) the identity of the treatments will be concealed by the use of study drugs that are all 
identical in packaging, labeling, schedule of administration and appearance. 


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Actual subject identity for plasma concentrations of SEP-363856 and SEP-363854 will not be disclosed 
before the database lock and the unblinding of the double-blind treatment phase. 
In the case of medical emergency, where knowledge of study drug by the Investigator or an authorized 
delegate is essential for immediate medical management, a 24-hour code-break service will be available 
via the IXRS. The date and reason for unblinding are to be documented in the source documents. Any 
subject for whom the treatment assignment was unblinded is to be discontinued from further study 
participation, other than the follow-up visit. 
3.6. Changes in conduct of the study 
The first subject entered the study under protocol version 2.00 (23 June 2016), following the 
implementation of Amendment 1.00 (23 June 2016) and non-substantial Amendments 1 (8 September 
2016) and 2 (7 October 2016). The protocol versions and amendments listed below were implemented 
after the screening and randomization of the first subject.  
•
Protocol version 3.00 (22-Mar-2017); Amendment 2.00 (22-Mar-2017)
•
Protocol version 3.01 (17-Aug-2017); Non-substantial Amendment 1.00 (17-Aug-2017)
3.7. CHANGES TO ANALYSIS FROM PROTOCOL 
•
The protocol specified ANCOVA analysis on the Week 4 LOCF endpoint of Cogstate Brief
Battery (CBB) composite score. This analysis will not be performed because a Week 4
LOCF endpoint will not be calculated for the CBB composite score. CBB is only scheduled
to be measured at baseline and at Week 4.
•
The protocol specified that the total score will be used as a summary measure of the
subject’s ratings on the Simpson-Angus Rating Scale (SAS). Rather than the total score, the
mean score will be used, which is calculated as the average of the 10 item scores.
•
The per protocol population definition is updated to exclude subjects who received
benzodiazepines or hypnotics within 8 hours of the Visit 2 or Visit 7/ET PANSS assessment.
4. PLANNED ANALYSES
The following analyses will be performed for this study: 
•
Final analysis


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4.1. DATA MONITORING COMMITTEE (DMC) 
There will be no planned DMC for this study. 
4.2. INTERIM ANALYSIS  
No interim analysis is planned for this study. 
4.3. FINAL ANALYSIS 
The final, planned analysis identified in this SAP will be performed by QuintilesIMS Biostatistics following 
Sunovion authorization of this SAP, Sunovion authorization of analysis populations, database lock, and 
unblinding of treatment. 
5. ANALYSIS POPULATIONS
Agreement and authorization of subjects included/excluded from each analysis population will be 
conducted prior to database lock and the unblinding of the study.  
5.1. MODIFIED INTENT-TO-TREAT [MITT] POPULATION 
The Modified Intent-to-Treat (mITT) population is defined as all subjects who were randomized, received 
at least one dose of study medication, and had a baseline and at least one post-baseline efficacy 
measurement in PANSS or CGI-S. Subjects will be included in the mITT population regardless of any 
protocol deviation.  
The mITT population will be the primary population for the efficacy analyses. Subjects will be analyzed 
based on the treatment to which they are randomized. 
5.2. PER PROTOCOL [PP] POPULATION 
The per protocol (PP) population comprises all mITT subjects who:  
•
Received assigned study medication as randomized;
•
Have 14 days or more overall exposure to study medication;
•
Have 75%-125% compliance, both limit values inclusive;


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•
Did not receive benzodiazepines or hypnotics within 8 hours of the Visit 2 or Visit 7/ET
PANSS assessment
•
Have no important protocol deviations (IPDs), determined by blinded data reviews prior to
database lock.
Subjects who received benzodiazepines or hypnotics within 8 hours of the Visit 2 or Visit 7/ET PANSS 
assessment will be identified by clinical review of the concomitant medications data, date and time of 
PANSS assessments, and the psychotropic medications within 8 hours of an efficacy assessment data. 
Selected efficacy endpoints will be analyzed using the PP population. Subjects will be analyzed based on 
the treatment to which they are randomized. 
5.3. SAFETY POPULATION 
The safety population includes subjects who were randomized and received at least one dose of study 
medication.  
Safety population will be the primary population for the safety analyses. Subjects will be analyzed based 
on the actual treatment received. This will generally be the same as the randomized treatment group, 
unless the subject takes incorrect therapy during the entire study. 
6. GENERAL CONSIDERATIONS
6.1. REFERENCE START DATE AND STUDY DAY 
Study day will be calculated from the reference start date, and will be used to show start/stop day of 
assessments and events.  
Reference start date is defined as the date of the first dose of study medication (Day 1).  
•
If the date of the event is on or after the reference start date then:
o
Study day = (date of event – reference start date) + 1.
•
If the date of the event is prior to the reference start date then:
o
Study day = (date of event – reference start date).
In the situation where the event date is partial or missing, study day, and any corresponding durations will 
appear missing in the listings. Partial dates will be however presented as is in the listings. 


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6.2. BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior to the 
first dose of study medication (including unscheduled assessments).  
Whenever available, the time information should be accounted for in the derivation of baseline values. In 
the case where time isn’t available and the date of last non-missing measurement and the date of first 
dose of study medication coincide, that measurement will be considered baseline.  
6.3. DERIVED TIME POINTS 
The last post-baseline measurement collected during the study will be carried forward and will be defined 
as the last observation carried forward (LOCF) endpoint, using the post-baseline value up to and including 
the Week 4 visit data.  
The LOCF endpoint will be derived for the following outcome measures: PANSS total score, CGI-S score, 
PANSS subscale scores, PANSS five-factor model factor scores, PANSS seven-factor model factor 
scores, BNSS total score, BNSS subtotal score, MADRS total score, AIMS total score, AIMS global 
severity score (item 8), BARS total score, BARS individual item scores, SAS mean score, and the C-
SSRS suicidal ideation score. In addition, the LOCF endpoint will be derived for vital signs, body weight, 
and BMI data.  
Both scheduled and unscheduled assessments as well as the early termination assessments that are 
collected post baseline will contribute to the derivation of the LOCF endpoint. 
6.4. RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA 
In general, for by-visit summaries, data recorded at the scheduled visits will be presented. 
Unscheduled measurements will not be included in by-visit summaries. Unscheduled measurements 
collected prior to the first dose of study medication will contribute to the derivation of the baseline value. 
Unscheduled measurements collected post baseline will contribute to the derivation of the LOCF endpoint 
value, potentially clinically significant (PCS) value, and best/ worst case value where required (e.g. shift 
tables).  
Early termination data collected post baseline will be assigned to the next planned visit for that 
assessment. This mapping will be done for all data points used in the efficacy and safety analyses. 
In the case of a retest (same visit number assigned), the latest available measurement for that visit will be 
used for by-visit summaries. 
Listings will include scheduled, unscheduled, retest and early termination data. 


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6.5. WINDOWING CONVENTIONS  
All data will be analyzed according to the schedule outlined in the CSP and according to the visit denoted 
on the case report form (CRF). No visit windowing will be performed during the analysis for this study. 
6.6. STATISTICAL TESTS 
All statistical inference, unless otherwise stated, will be performed with two-sided tests at the significance 
level of 0.05, and two-sided 95% confidence intervals (CIs) will be calculated whenever appropriate. 
6.7. COMMON CALCULATIONS 
For quantitative measurements, change from baseline will be calculated as: 
•
Value at visit X – baseline value
Percentage change from baseline in PANSS total score will be calculated as: 
•
(Value at visit X – baseline value)*100 / (baseline value – 30)
6.8. SOFTWARE VERSION 
All data analyses will be conducted using SAS version 9.4 or later. 
7. STATISTICAL CONSIDERATIONS
7.1. ADJUSTMENTS FOR COVARIATES TO BE INCLUDED IN ANALYSES 
The following covariates are used in the analyses. For details of their inclusion in the models, see specific 
analysis sections. 
•
Pooled study center
•
Baseline value of the variable to be analyzed
7.2. MULTICENTER STUDIES 
This study will be conducted by multiple investigators at multiple sites in 5 countries.  


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When specified, statistical analyses will be adjusted for pooled study centers. Centers will be pooled by 
country. 
7.3. MISSING DATA 
Missing efficacy data will be handled as described in section 16.1.2 of this statistical analysis plan.  
7.4. MULTIPLE COMPARISONS/ MULTIPLICITY 
There is only one primary efficacy comparison of change from baseline in PANSS total score at Week 4. 
Therefore no adjustment for multiplicity is planned in this study. For all other analyses, nominal p-values 
will be presented; no multiplicity adjustment will be performed. 
7.5. EXAMINATION OF SUBGROUPS 
Subgroup analyses will be conducted as stated in the respective efficacy and safety analysis sections. It 
should be noted that the study was not powered to detect treatment differences within subgroups. 
The following subgroups will be assessed: 
•
Geographic region
o
US
o
Non-US
•
Country
o
US
o
Hungary
o
Romania
o
Russia
o
Ukraine
•
Sex
o
Female
o
Male
•
Age group (years)
o
<25
o
>=25
•
Race


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o
White
o
Black
o
Other
•
Number of prior hospitalizations for treatment of schizophrenia
o
0
o
1
o
2
•
Duration of schizophrenia (years)
o
< 5
o
>= 5
8. OUTPUT PRESENTATIONS
APPENDIX 1 shows conventions for presentation of data in outputs. 
The templates provided with this SAP describe the presentations for this study and therefore the format 
and content of the summary tables, figures and listings to be provided by QuintilesIMS Biostatistics. 
9. DISPOSITION AND WITHDRAWALS
All subjects who provide informed consent will be accounted for in this study.  
Subject disposition will be summarized by the randomized treatment group (where applicable) and overall 
for all subjects. The number and percentage of subjects who were screened, screen-failed, randomized, 
received study medication, and completed or discontinued early from the double-blind treatment phase 
(including reasons for discontinuation) will be presented. In addition, the number and percentage of 
subjects who will rollover to the open-label extension study (SEP361-202) in each treatment group and 
overall will be presented. 
With respect to the above, the following definitions apply: 
•
Screened Subjects: All subjects who provided informed consent for this study.
•
Enrolled Subjects: Screened subjects who passed screening.
•
Randomized Subjects: Enrolled subjects who were randomized to study treatments.
10.
IMPORTANT PROTOCOL DEVIATIONS
Important protocol deviations (IPDs) will be identified and documented based on blinded reviews of data 
listings. The IPD categories may include, but may not be limited to: 


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•
Did not satisfy important inclusion, exclusion, and/or randomization criteria
•
Received any disallowed concomitant medication
•
Overall double-blind compliance rate < 75% or > 125%
Further details on the identification of IPDs are provided in the Important Protocol Deviation Review 
Specifications document. 
IPDs will be identified for all randomized subjects and presented in data listings. The number and 
percentage of subjects within each IPD category will be summarized for the mITT population. 
11.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Demographic data and other baseline characteristics will be presented for the mITT population, safety 
population, and PP population. For mITT population and PP population, the data will be presented by 
randomized treatment groups. For safety population, the data will be presented by the actual treatments 
received. Demographic data will also be summarized for all screened subjects by randomization status 
(i.e. randomized vs. not randomized). No statistical testing will be carried out for demographic or other 
baseline characteristics. The following demographic and other baseline characteristics will be reported for 
this study: 
•
Age (years), calculated relative to date of informed consent; as a continuous variable and
categorically
o
<18
o
18 to <25
o
25 to <=40
o
>40
•
Sex
•
Race
o
American Indian or Alaska Native
o
Asian
o
Black or African American
o
Native Hawaiian or Other Pacific Islander
o
White
o
Multiracial
o
Other
•
Ethnicity
o
Hispanic or Latino
o
Not Hispanic or Latino
•
Country


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•
Geographic region
•
Weight (kg)
•
Height (cm)
•
Waist circumference (cm)
•
BMI (kg/m2), as a continuous variable and categorically:
o
Underweight: <18.5
o
Normal: 18.5 to <25.0
o
Overweight: 25.0 to <30.0
o
Obese: >=30.0
•
Baseline PANSS total score and subscale scores, as continuous variables and categorically:
o
< Overall median value at baseline
o
>= Overall median value at baseline
o
Positive subscale score < Negative Subscale score
o
Positive subscale score >= Negative Subscale score
•
Baseline CGI-S score, as a continuous variable and categorically:
o
< 4
o
>= 4 to <= 5
o
> 5
The following psychiatric history data will be summarized for the mITT population, safety population, and 
PP population in a separate table: 
•
Time since initial onset of schizophrenia, in years, calculated relative to date of informed
consent; both as a continuous variable and categorically
o
< 5
o
>= 5 to < 10
o
>= 10 to < 20
o
>= 20
•
Time since onset of current acute exacerbation of psychotic symptoms, in days, calculated
relative to date of informed consent
•
DSM-5 schizophrenia subtype diagnosis
•
Other current psychiatric diagnoses
•
Number (0, 1, 2, 3 or more) of prior hospitalizations for treatment of an acute exacerbation
of schizophrenia


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11.1. DERIVATIONS 
•
BMI (kg/m2) = weight (kg)/ height (m)2
12.
MEDICAL AND SURGICAL HISTORY
Medical and surgical history information, including both past and concomitant medical conditions and 
major surgical history, as collected on the Medical History CRF form, will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA), Version 18.1 or higher, and presented for the safety 
population by System Organ Class (SOC) and Preferred Term (PT).  
13.
MEDICATIONS
Medications will be presented for the safety population and coded using the WHO drug dictionary, Version 
01MAR2016E or higher. 
Whenever available, the time information should be accounted for in the derivation of prior, concomitant, 
and post-treatment medications. See APPENDIX 2 for the handling of partial dates for medications. In the 
case where it is not possible to define a medication as prior, concomitant, or post-treatment, the 
medication will be classified by the worst case; i.e. concomitant.  
•
Prior medications are medications which stopped prior to the first dose of study medication.
•
Concomitant medications are medications which started at the same time of or after the first
dose of study medication and at the same time of or before the last dose of study
medication; or started prior to and ended at the same time of or after the first dose of study
medication; or started at the same time of or prior to the last dose of study medication and
marked as ongoing.
•
Post-treatment medications are medications which started after the last dose of study
medication.
Prior and concomitant medication use will be summarized by Anatomical Therapeutic Chemical (ATC) 
Level 3 classification and preferred name using frequencies and percentages. Prior, concomitant, and 
post-treatment medications will be provided in data listings. 
14.
STUDY MEDICATION EXPOSURE
Duration of exposure to study medication will be summarized for the safety population.  
Duration of exposure (in days) will be summarized both as a continuous variable for the double-blind 
treatment period and categorically: 


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•
Number and percentage of subjects with drug exposure ≥ 1, ≥ 3, ≥ 7, ≥ 14, ≥ 21, and ≥ 28
days;
•
Number and percentage of subjects with drug exposure for 1 - 2, 3 - 6, 7 - 13, 14 - 20, 21 -
27, and ≥ 28 days
The modal daily dose (i.e. the dose level that a subject was on for the most number of days during the 
study) will be summarized categorically by treatment group: 
o
50 mg/day
o
75 mg/day
o
Tie
The number of days that a subject was on the 50 mg/day dose level and on the 75 mg/day dose level will 
also be summarized, both as a continuous variable and categorically: 
o
1 – 2 days
o
3 – 6 days
o
7 – 13 days
o
14 – 20 days
o
21 – 27 days
o
≥ 28 days
The dose adjustment decision at each visit will be summarized in a shift table. 
14.1. DERIVATIONS 
Duration of exposure (days) = last dose date - first dose date + 1. 
15.
STUDY MEDICATION COMPLIANCE
Compliance to study medication will be summarized for the safety population.  
Percent compliance will be calculated by visit and overall for the double-blind treatment period. Non-
compliance is defined as less than 75% or more than 125% non-missing compliance for the double-blind 
period. Subjects with missing compliance will not be classified as non-compliant. Compliance will be 
summarized both as a continuous variable and categorically: 
•
Number and percentage of subjects with compliance < 75%, 75% - 125%, > 125%, and
missing
15.1. DERIVATIONS 
Compliance with study medication will both be calculated for each period defined by study visits (i.e. per-
visit compliance) and overall. 
Per-visit compliance for the period defined by visit (V-1) and visit V will be calculated as: 


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# Capsules dispensed at Visit ሺV-1ሻ - # Capsules returned at Visit V - # Capsules reported lost during this period
# Capsules should be taken per day × ൫Date of Visit V - Date of Visit ሺV-1ሻ൯
 × 100% 
If any of the following numbers are missing, per-visit compliance will not be calculated for the period 
impacted: number capsules dispensed at Visit (V-1), number capsules returned at Visit V, and number 
capsules reported lost during this period. 
If a subject discontinued from the study in between Visit (V-1) and Visit V, then the above formula will be 
modified to: 
# Capsules dispensed at Visit ሺV-1ሻ - # Capsules returned at Visit ET - # Capsules reported lost during this period
# Capsules should be taken per day × ൫Date of Visit ET - Date of Visit ሺV-1ሻ൯
 × 100% 
The per-visit compliance calculated above will contribute to the summary of per-visit compliance for the 
period defined by visit (V-1) and visit V. 
Overall compliance will be calculated as: 
Total # capsules dispensed - Total # capsules returned - Total # capsules reported lost
# Capsules should be taken per day × Duration of Exposure
 × 100% 
Duration of exposure is calculated as specified in section 14.1. 
If any of the following numbers are missing at one or more visits, overall compliance will not be calculated: 
number capsules dispensed, number capsules returned, number capsules reported lost. 
For subjects whose Visit 2 and Visit 3 drug accountability records are folded into one record, the by-visit 
compliance will be set to missing for these 2 visits. 
16.
EFFICACY OUTCOMES
In addition to the analyses described in sections 16.1, 16.2 and 16.3, all efficacy variables will be 
summarized descriptively by treatment group and visit for the mITT population. For PANSS total score and 
CGI-S score, the data will also be summarized descriptively for each subgroup.  
16.1. PRIMARY EFFICACY 
The analyses of the primary efficacy variable will be performed on the mITT population, unless otherwise 
specified. 
16.1.1. 
PRIMARY EFFICACY VARIABLE & DERIVATION 
The primary efficacy variable is the change from baseline in PANSS total score at Week 4. 
PANSS is used to measure the psychopathology in adults with psychotic disorders, comprising 30 items 
and 3 subscales. The positive subscale assesses hallucinations, delusions and related symptoms (7 
items), the negative subscale assesses emotional withdrawal, lack of motivation and related symptoms (7 
items), and the general psychopathology subscale assesses other symptoms such as anxiety, somatic 


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concern and disorientation (16 items). An anchored Likert scale from 1 to 7 (1 = absent, 7 = extreme, with 
values of 2 and above indicating the presence of progressively more severe symptoms) is used to score 
each item. Individual items are summed to derive the following scores: 
•
Total score = sum of all 30 items. Total score ranges from 30 to 210.
•
Subscale scores = sum of items within each of the following subscales:
o
Positive subscale: delusions, conceptual disorganization, hallucinatory behavior,
excitement, grandiosity, suspiciousness/persecution, hostility. This subscale score ranges
from 7 to 49.
o
Negative subscale: blunted affect, emotional withdrawal, poor rapport, passive/apathetic
social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of
conversation, stereotyped thinking. This subscale score ranges from 7 to 49.
o
General psychopathology subscale: somatic concern, anxiety, guilt feelings, tensions,
mannerisms and posturing, depression, motor retardation, uncooperativeness, unusual
thought content, disorientation, poor attention, lack of judgment and insight, disturbance of
volition, poor impulse control, preoccupation, active social avoidance. This subscale score
ranges from 16 to 112.
•
Five-factor model scores – sum of items within each of the following factors (Marder, Davis,
Chouinard. 1997):
o
Negative symptoms: blunted affect, emotional withdrawal, poor rapport, passive/apathetic
social withdrawal, lack of spontaneity and flow of conversation, motor retardation, active
social avoidance
o
Positive symptoms: delusions, hallucinatory behavior, grandiosity,
suspiciousness/persecution, stereotyped thinking, somatic concern, unusual thought
content, lack of judgment and insight
o
Disorganized thought: conceptual disorganization, difficulty in abstract thinking,
mannerisms and posturing, poor attention, disturbance of volition, preoccupation,
disorientation
o
Uncontrolled hostility/excitement: excitement, hostility, uncooperativeness, poor impulse
control
o
Anxiety/depression: anxiety, guilt feelings, tension, depression
•
Seven-factor model scores
The PANSS item scores of each subject at each visit will be transformed using the uncorrelated PANSS 
score matrix (UPSM), to obtain the scores of 7 transformed PANSS factors (Hopkins et al. 2018): 
o
POS: Positive
o
DIS: Disorganized
o
NAA: Negative apathy/avolition
o
NDE: Negative deficit of expression
o
HOS: Hostility
o
ANX: Anxiety
o
DEP: Depression


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The transformation will be done as follows: 
ሾPANSS DataሿሺN×30ሻ∗ሾUPSMሿሺ30×7ሻൌሾTransformed PANSS Factor DataሿሺN×7ሻ 
where  
ሾPANSS DataሿሺN×30ሻ is a matrix with N PANSS assessments and 30 columns containing the scores of 30 
PANSS items ordered in the same way as shown in UPSM. 
ሾUPSMሿሺ30×7ሻ is a matrix with 30 rows (one for each PANSS item) and 7 columns (one for each of the 7 
transformed PANSS factors) 
ሾTransformed PANSS Factor DataሿሺN×7ሻ is the transformed matrix with N sets of scores for the 7 
transformed PANSS factors 


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Table 2. Uncorrelated PANSS Score Matrix (UPSM) for Generating Transformed PANSS Factor Scores 
PANSS 
POS 
DIS 
NEG 
HOS 
DEP/ 
ANX 
POS 
DIS 
NAA 
NDE 
HOS 
ANX 
DEP 
ITEM 
PANSS01 
1 
0 
0 
0 
0 
0.579
-0.155
-0.083
0.007
-0.059
-0.074
0.002 
P01 DELUSIONS
PANSS06 
1 
0 
0 
0 
0 
0.354
-0.063
0.048
0.001
0.019
-0.016
0.006 
P06 SUSPICIOUSNESS/PERSECUTION
PANSS03 
1 
0 
0 
0 
0 
0.207
-0.018
-0.025
-0.013
-0.030
0.000
0.029 
P03 HALLUCINATORY BEHAVIOR
PANSS23 
1 
0 
0 
0 
0 
0.143
0.094
-0.033
-0.037
-0.068
-0.021
-0.018 
G09 UNUSUAL THOUGHT CONTENT
PANSS26 
1 
0 
0 
0 
0 
0.014
0.155
-0.031
-0.033
0.026
-0.058
-0.063 
G12 LACK OF JUDGEMENT AND INSIGHT
PANSS14 
1 
0 
0 
0 
0 
-0.011
0.146
-0.028
0.002
-0.006
-0.012
0.004 
N07 STEREOTYPED THINKING
PANSS05 
1 
0 
0 
0 
0 
-0.034
-0.030
-0.004
-0.023
-0.007
-0.031
0.031 
P05 GRANDIOSITY
PANSS15 
1 
0 
0 
0 
0 
-0.036
0.055
-0.038
0.011
-0.031
0.044
0.106 
G01 SOMATIC CONCERN
PANSS29 
0 
1 
0 
0 
0 
-0.052
0.291
0.003
-0.032
-0.044
-0.005
0.057 
G15 PREOCCUPATION
PANSS25 
0 
1 
0 
0 
0 
-0.104
0.281
-0.048
0.003
0.004
-0.023
0.040 
G11 POOR ATTENTION
PANSS02 
0 
1 
0 
0 
0 
0.029
0.198
-0.026
-0.023
-0.037
-0.001
-0.036 
P02 CONCEPTUAL DISORGANIZATION
PANSS27 
0 
1 
0 
0 
0 
-0.057
0.187
-0.014
0.058
-0.015
-0.037
0.046 
G13 DISTURBANCE OF VOLITION
PANSS12 
0 
1 
0 
0 
0 
0.004
0.106
0.026
-0.030
-0.013
0.010
-0.069 
N05 DIFFICULTY IN ABSTRACT THINKING
PANSS19 
0 
1 
0 
0 
0 
-0.046
0.049
-0.032
0.103
-0.014
0.029
-0.044 
G05 MANNERISMS AND POSTURING
PANSS24 
0 
1 
0 
0 
0 
-0.038
-0.032
-0.026
-0.018
-0.027
-0.021
-0.018 
G10 DISORIENTATION
PANSS11 
0 
0 
1 
0 
0 
-0.094
-0.086
0.461
-0.029
-0.019
-0.019
-0.013 
N04 PASSIVE/APATHETIC SOCIAL WITHDRAWAL
PANSS09 
0 
0 
1 
0 
0 
-0.032
-0.024
0.332
-0.023
-0.051
-0.015
0.011 
N02 EMOTIONAL WITHDRAWAL
PANSS30 
0 
0 
1 
0 
0 
-0.011
-0.001
0.286
-0.061
0.018
-0.030
0.037 
G16 ACTIVE SOCIAL AVOIDANCE
PANSS21 
0 
0 
1 
0 
0 
-0.035
-0.037
-0.078
0.441
-0.007
-0.019
0.046 
G07 MOTOR RETARDATION
PANSS13 
0 
0 
1 
0 
0 
0.004
0.005
0.001
0.258
-0.009
0.019
-0.104 
N06 LACK OF SPONTANEITY AND FLOW OF CONVERSATION
PANSS08 
0 
0 
1 
0 
0 
-0.005
-0.029
0.057
0.247
-0.039
0.019
-0.009 
N01 BLUNTED AFFECT
PANSS10 
0 
0 
1 
0 
0 
-0.074
-0.040
-0.010
0.016
0.025
-0.018
-0.017 
N03 POOR RAPPORT
PANSS07 
0 
0 
0 
1 
0 
-0.038
-0.177
-0.030
0.031
0.503
-0.100
0.057 
P07 HOSTILITY
PANSS22 
0 
0 
0 
1 
0 
-0.080
0.033
-0.009
-0.020
0.286
-0.057
-0.053 
G08 UNCOOPERATIVENESS
PANSS28 
0 
0 
0 
1 
0 
-0.075
0.017
-0.027
-0.003
0.255
-0.020
-0.008 
G14 POOR IMPULSE CONTROL
PANSS04 
0 
0 
0 
1 
0 
-0.034
0.012
0.001
-0.072
0.138
0.111
-0.105 
P04 EXCITEMENT
PANSS18 
0 
0 
0 
0 
1 
-0.093
-0.033
-0.013
0.023
-0.029
0.512
-0.031 
G04 TENSION
PANSS16 
0 
0 
0 
0 
1 
-0.033
-0.082
-0.033
-0.053
-0.039
0.458
0.120 
G02 ANXIETY
PANSS20 
0 
0 
0 
0 
1 
-0.034
-0.069
-0.041
0.038
0.004
-0.064
0.451 
G06 DEPRESSION
PANSS17 
0 
0 
0 
0 
1 
-0.037
0.000
-0.002
-0.041
-0.027
-0.025
0.246 
G03 GUILT FEELINGS
The coefficients of UPSM (a matrix of 30 rows of PANSS items × 7 columns of transformed PANSS factors) will be used to transform 
individual PANSS assessments (items scores at each visit) to reduce the 30 items into 7 factors for each PANSS assessment. Each column 
of the score matrix (POS, DIS, NAA, NDE, HOS, ANX, DEP) represents a transformed PANSS factor.  


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For the above total, subscale, or factor scores, if any item contributing to its calculation is missing then the 
score will be set to missing. 
16.1.2. 
MISSING DATA METHODS FOR PRIMARY EFFICACY VARIABLE 
The PANSS total score will be set to missing if any one item is missing. The primary efficacy variable, change 
from baseline in PANSS total score at Week 4, will be set to missing if PANSS total score at Week 4 is 
missing. The same applies to all other visits.  
The primary analysis of the primary efficacy variable will use a mixed model for repeated measures (MMRM) 
based on observed data (with early termination data mapped as described in section 6.4). Missing data will not 
be imputed. 
The ANCOVA analysis of the primary efficacy variable will utilize the Week 4 LOCF endpoint, which is imputed 
as described in section 6.3. 
16.1.3. 
PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
The primary objective of this study is to test whether the mean changes from baseline in PANSS total score at 
Week 4 in the SEP-363856 (50 or 75 mg/day) group and the placebo group are equal.  
Let μSEP and μPBO represent the mean changes from baseline at Week 4 in PANSS total score for the SEP-
363856 (50 or 75 mg/day) and placebo groups, respectively. The following hypothesis will be tested: 
H0: μSEP = μPBO versus H1: μSEP ≠ μPBO 
The primary efficacy analysis will be performed on the mITT population. 
Change from baseline in PANSS total score at Week 4 will be analyzed using an MMRM model, with fixed 
factors for pooled study center, visit (Day 4, Weeks 1, 2, 3, and 4; as a categorical variable), treatment, and 
treatment-by-visit interaction, and with baseline PANSS total score as a covariate. An unstructured covariance 
matrix will be used to model the within-subject correlation. The Kenward-Roger approximation will be used to 
calculate the denominator degrees of freedom. Pooled centers will be generated by country. 
In case the model above fails to converge, a spatial exponential covariance structure and a spatial power 
covariance structure will be assumed sequentially. The first covariance structure to yield convergence will be 
used in the analysis. 
Within group effect size at each time point will be calculated as the least squares (LS) mean of each treatment 
group divided by the model estimate of standard deviation, obtained as the square root of the corresponding 
diagonal element of the residual covariance matrix (R matrix from PROC MIXED). Between group effect size 
at each time point will be calculated as the LS mean difference divided by the model estimate of standard 
deviation, obtained as described above. 


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16.1.4. 
SENSITIVITY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
16.1.4.1. 
Graphical examination 
Patterns of missing data in the primary endpoint will be assessed through graphical tools based on the reason 
and timing of study withdrawal by subjects.  
Graphs of change from baseline in PANSS total score by visit will be plotted by reasons of early 
discontinuation (adverse event, lack of efficacy, progressive disease, withdrawal by subject, protocol deviation, 
noncompliance with study medication, death, pregnancy, other reasons) and for completers, separately for 
each treatment group. Similar reasons may be combined, depending on the number of subjects under each 
reason. 
Graphs of change from baseline in PANSS total score by visit will also be plotted by time of termination (Day 4 
terminators, Week 1 terminators, Week 2 terminators, Week 3 terminators, Week 4 terminators) and for 
completers, separately for each treatment group. 
o
Day 4 terminators: subjects who discontinued before or on Visit 3.
o
Week 1 terminators: subjects who discontinued after Visit 3 but before or on Visit 4
o
Week 2 terminators: subjects who discontinued after Visit 4 but before or on Visit 5.
o
Week 3 terminators: subjects who discontinued after Visit 5 but before or on Visit 6.
o
Week 4 terminators: subjects who discontinued after Visit 6 but before Visit 7.
16.1.4.2. 
Pattern-mixture model with placebo-based multiple imputation 
The MMRM model used in the primary analysis makes the assumption that data are missing at random 
(MAR). However the missing data mechanism may or may not be at random. Sensitivity to the missing data 
assumptions will be tested by using the pattern-mixture model with placebo-based multiple imputation method 
(Ratitch, O’Kelly, Tosiello. 2013), exploring the robustness of the MMRM results of the primary efficacy 
analysis. In this analysis, missing values in the SEP-363856 (50 or 75 mg/day) treatment group will be 
imputed based on data of the placebo group, assuming that, after withdrawal, subjects from the SEP-363856 
(50 or 75 mg/day) group will exhibit the same future evolution of schizophrenia as subjects from the placebo 
group, and that subjects who discontinue from the placebo group will exhibit the same future evolution of 
schizophrenia as subjects in the placebo group remaining in the study. This approach does not assume a 
sustained benefit of experimental treatment after discontinuation. 
Two separate imputation procedures are used to impute missing values. Firstly, the Markov chain Monte Carlo 
(MCMC) method is used to perform partial imputation to obtain datasets with monotone missing patterns. 
Then a sequential regression multiple imputation method is used to impute the monotone missing values.  
Under the assumption that the PANSS total scores have a multivariate normal distribution, the MCMC method 
is used to impute only intermittent missing values (using the SAS MI procedure with MCMC statement), by 
using a data augmentation algorithm, with each iteration n consisting of an imputation step and a posterior 
step. The imputation step uses a random draw of θ(n), parameter of the joint imputation model, to sample 
missing values from a conditional distribution P(Ymis|x, yobs, θ(n)), obtaining ymis(n), the subset of missing values 
that need to be filled in to achieve monotone missingness. The posterior step simulates a new draw of the 
parameter θ(n+1) from the posterior distribution given the current monotone missing data P(θ|x, yobs, ymis(n)) with 
a non-informative Jeffreys prior. These steps are repeated to obtain 500 datasets with monotone missingness. 
The random seed number is specified in the sample code.  


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The remaining monotone missing data will be imputed using sequential regression multiple imputation, where 
a separate regression model is estimated for imputation of each variable (i.e., PANSS total score at each time 
point). Imputation of values in the placebo group will assume MAR. Imputation of values in the SEP-363856 
(50 or 75 mg/day) group will be done as if the subject had been a member of the placebo group. Missing 
values in the SEP-363856 (50 or 75 mg/day) group will be imputed using the imputation model of the placebo 
group, i.e., conditional on subject values observed at time points prior to discontinuation relative to the mean 
of the model for the placebo group. Each sequential regression model (i.e., for imputation of values at a given 
time point) will include explanatory variables for pooled study center and all previous (Baseline, Day 4, Week 
1, 2, and 3) values of PANSS total score. Missing values at a given time point in placebo and SEP-363856 (50 
or 75 mg/day) arms will be imputed from the same imputation model, conditional on subject values observed 
or imputed at previous time points. The SAS MI procedure with the MONOTONE REG statement is used to 
specify that the regression method will be used for the imputation. The random seed numbers are specified in 
the sample code. 
No rounding restriction will be applied to imputed PANSS total scores. The imputed PANSS total scores must 
be within the range of 30 to 210. 
Each of the 500 imputed datasets will be analyzed using the same MMRM model as the primary efficacy 
analysis. Results from the analysis of each imputed dataset, i.e. the LS means of each treatment group, the 
LS mean treatment difference, and their standard errors, will be combined using Rubin’s imputation rules 
(using the SAS MIANALYZE procedure) to produce pooled LS mean estimates, their standard errors and 95% 
CI, and a pooled p-value for the test of null hypothesis of no treatment effect.  
16.1.4.3. 
Tipping point analysis 
Sensitivity to departures from the MAR assumption will also be investigated using a tipping point analysis. In 
this analysis, departures from MAR in the SEP-363856 (50 or 75 mg/day) group will be assessed assuming 
that subjects who discontinue the study have, on average, efficacy outcomes after discontinuation that are 
worse by some amount δ compared to other similar subjects with observed data at the same time point (i.e., 
compared to a value which would have been assumed under a MAR model).  
A series of analyses will be performed with increasing values of δ until the analysis conclusion of a statistically 
significant treatment effect no longer holds. The value of δ that overturns the primary results will represent a 
tipping point. An interpretation of clinical plausibility of the assumption underlying the tipping point will be 
provided.  
Change from baseline in PANSS total score will be analyzed based on data observed while the subject 
remains on study as well as data imputed using multiple imputation methodology for the time points at which 
no value is observed. Intermittent (non-monotone) missing data will be imputed first based on the MAR 
assumption and a multivariate joint Gaussian imputation model using the MCMC method within each 
treatment arm, as described above for the pattern-mixture model with placebo-based multiple imputation. 
The remaining monotone missing data will be imputed using sequential regression multiple imputation, where 
a separate regression model is estimated for imputation of each variable (i.e., PANSS total score at each time 
point). Each regression model will include explanatory variables for treatment, pooled study center and all 
previous (Baseline, Day 4, Week 1, 2, and 3) values of PANSS total score. After the MAR-based imputations 
have been generated for PANSS total score at each time point, the change from baseline values based on the 
imputed PANSS total scores in the SEP-363856 (50 or 75 mg/day) group will be penalized by a value of δ. 
This approach assumes that the marginal mean of unobserved subject measurements is worse by δ at each 
time point after discontinuation compared to the marginal mean of subjects with observed data at the same 


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time point. 
No rounding restriction will be applied to imputed continuous values. The imputed PANSS total scores must be 
within the range of 30 to 210. 
Five hundred (500) imputed datasets will be generated. The random seed numbers for the partial imputation 
step and the sequential regression imputation step are specified in the sample code. 
Each of the 500 imputed and δ-adjusted datasets will be analyzed using the same MMRM model as the 
primary efficacy analysis. Results from the analysis of each imputed dataset, i.e. the LS mean treatment 
difference and its standard error, will be combined using Rubin’s imputation rules (using the SAS MIANALYZE 
procedure) to produce a pooled LS mean estimate of treatment difference, its standard error and 95% CI, and 
a pooled p-value for the test of null hypothesis of no treatment effect. 
Analyses will be conducted with different values of δ at each visit, which represents a percentage of the LS 
mean treatment difference at that visit, starting at 10% with 10% increments, until either the tipping point is 
identified or the 100% penalty is applied. 
16.1.4.4. 
Analysis of covariance 
As another supportive analysis of the primary efficacy analysis, an analysis of covariance (ANCOVA) will be 
performed on the change from baseline in PANSS total score at each scheduled post-baseline visit and the 
Week 4 LOCF endpoint, with treatment and pooled study center as categorical factors, and baseline PANSS 
total score as a covariate. Between-group difference for baseline PANSS total score will be based on an 
ANCOVA model adjusting for pooled center. 
Within group effect size will be calculated as the least squares (LS) mean of each treatment group divided by 
the standard deviation, obtained as the standard error of the LS mean multiplied by the square root of the 
treatment group sample size. Between group effect size will be calculated as the LS mean difference divided 
by the pooled standard deviation, obtained as the standard error of the LS mean difference divided by the 
square root of the sum of inverse treatment group sample sizes. 
16.1.4.5. 
Complete case analysis 
The complete case analysis will be performed on the subset of subjects in the mITT population who completed 
the double-blind treatment period and have Week 4 PANSS total score data available. 
The MMRM analysis used in the primary efficacy analysis will be repeated on the above subjects. 
16.1.4.6. 
Analysis on the per protocol population 
Sensitivity to the analysis population will be tested by repeating the MMRM analysis used in the primary 
efficacy analysis on the PP population. 
16.1.5. 
SUBGROUP ANALYSIS OF PRIMARY EFFICACY VARIABLE 
For each of the subgroup factors listed in section 7.5, change from baseline in PANSS total score will be 
analyzed using the MMRM method. For the subgroup factors other than country, the MMRM model will include 
fixed effects for treatment, subgroup, visit, pooled center, baseline PANSS total score, and treatment-by-
subgroup, treatment-by-visit, subgroup-by-visit, and treatment-by-subgroup-by-visit interactions. For the 


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subgroup factor of geographic region, the pooled centers will be nested within region. 
For the subgroup factor of country, the MMRM model will include fixed effects for treatment, country, visit, 
baseline PANSS total score, and treatment-by-country, treatment-by-visit, country-by-visit, and treatment-by-
country-by-visit interactions. 
The estimates obtained from the MMRM models will be presented separately for each subgroup. The p-value 
for the treatment-by-subgroup interaction at Week 4 will be presented. Its statistical significance will be 
assessed at the 0.10 level for homogeneity of the treatment effect across the different categories of a 
subgroup factor. In case a significant interaction effect is detected, estimates by subgroup will be examined to 
determine the nature of the interaction (qualitative or quantitative). 
16.2. SECONDARY EFFICACY 
The analyses of the secondary efficacy variables will be performed on the mITT population. 
16.2.1. 
SECONDARY EFFICACY VARIABLES & DERIVATIONS 
16.2.1.1. 
Change from baseline in CGI-S score at Week 4 
The CGI-S is a clinician-rated assessment of the subject’s current illness state on a 7-point scale, where a 
higher score is associated with a greater illness severity. The CGI-S score takes one of the following values: 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 patients). 
16.2.1.2. 
Change from baseline in PANSS subscale scores at Week 4 
See section 16.1.1 for the derivation of PANSS subscale scores. 
16.2.1.3. 
Change from baseline in PANSS five-factor model scores at Week 4 
See section 16.1.1 for the derivation of PANSS five-factor model scores. 
16.2.1.4. 
Change from baseline in PANSS seven-factor model scores at Week 4 
See section 16.1.1 for the derivation of PANSS seven-factor model scores. 
16.2.1.5. 
Change from baseline in MADRS total score at Week 4 
The MADRS is a 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. MADRS total score will be 
calculated by the sum of all 10 item scores. 


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16.2.1.6. 
Change from baseline in BNSS total scores at Week 4 
The BNSS is a rating scale to measure the current level of severity of negative symptoms in schizophrenia 
and schizoaffective disorder. The measure is comprised of 13 individual items organized in 6 subscales 
(blunted affect (items 9, 10, 11), alogia (items 12, 13), avolition (items 7, 8), anhedonia (items 1, 2, 3), 
asociality (items 5, 6), and distress (item 4)). The 13 individual items provide a composite total score (ranging 
from 0 to 78). Each of the items are scored on a Likert-type 7-point scale from 0 - 6, where values of 0 
indicates symptom is absent and a value of 6 means the symptom is a severe form. In addition BNSS 
subscale scores will be calculated by summing the item scores under each subscale. 
16.2.1.7. 
Proportion of subjects who achieve a PANSS response 
PANSS response is defined as having at least 20% improvement in PANSS total score from baseline to the 
Week 4 LOCF endpoint. See section 16.1.1 for the derivation of PANSS total score. The percent change in 
PANSS total score from baseline will be calculated by:  
PANSS total score at the Week 4 LOCF endpoint - PANSS total score at baseline
PANSS total score at baseline - 30
 × 100% 
For each subject, the responder indicator will be set to 1 if the percent change as calculated above is  
<= -20%. The indicator will be set to 0 if the percentage is > -20%. The indicator will be set to missing if the 
percentage is missing.  
PANSS response rate will also be calculated for each scheduled visit (i.e. Day 4, Week 1, Week 2, Week 3, 
and Week 4) using a similar method as above. 
16.2.2. 
MISSING DATA METHODS FOR SECONDARY EFFICACY VARIABLE(S) 
For rating scales with more than one item, such as PANSS subscales, PANSS five-factor model, PANSS 
seven-factor model, BNSS, and MADRS, if any item score contributing to the total/ subscale/ factor score is 
missing, then the total/ subscale/ factor score will be set to missing. The change from baseline scores will also 
be set to missing accordingly. In addition, for BNSS, if any individual item is given a score of “9” (i.e. not 
rated), the BNSS total score and subscale score will be set to missing.  
The MMRM analysis of the continuous secondary efficacy variables will be based on observed data (with early 
termination data mapped as described in section 6.4). Missing data will not be imputed. PANSS responder 
calculation will be based on the PANSS total score at the Week 4 LOCF endpoint. The ANCOVA analyses of 
the continuous secondary efficacy variables will utilize the change from baseline at the Week 4 LOCF 
endpoints. 
16.2.3. 
ANALYSIS OF SECONDARY EFFICACY VARIABLES 
16.2.3.1. 
Analysis of change from baseline in CGI-S score at Week 4 
Change from baseline in CGI-S score at Week 4 will be analyzed using an MMRM model similar to the model 
used in the primary analysis of the primary efficacy variable (see section 16.1.3), with baseline CGI-S score as 
a covariate.  
Sensitivity analyses of this variable will be performed similarly to those outlined in section 16.1.4. For CGI-S, 


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the complete case analysis will be performed on the subset of subjects in the mITT population who completed 
the double-blind treatment period and have Week 4 CGI-S score data available. 
Subgroup analysis of this variable will be performed similarly to those described in section 16.1.5. 
16.2.3.2. 
Analysis of other continuous secondary efficacy variables 
The secondary efficacy variables of change from baseline at Week 4 in PANSS subscale scores, factor scores 
of the PANSS five-factor model, factor scores of the PANSS seven-factor model, BNSS total score, and 
MADRS total score will be analyzed using MMRM similarly to the primary analysis of the primary efficacy 
variable (see section 16.1.3), with the respective baseline scores as a covariate. 
In addition, ANCOVA analysis on the change from baseline scores will be performed, similarly to the ANCOVA 
analysis described in section 16.1.4.4. 
A sensitivity analysis for BNSS will be performed where a BNSS subtotal score will be calculated by summing 
the scores of items 1-6 and 8-13. Item 7 (Avolition: Behavior) is excluded due to a large number of subjects 
being given a score of ‘9’ for this item when ‘9’ is not a valid rating. Among the 12 items contributing to BNSS 
subtotal score, if any item is rated as ‘9’, the subtotal score will be set to missing. The same analyses 
performed on BNSS total score will be repeated on BNSS subtotal score.  
16.2.3.3. 
Analysis of PANSS responders 
The secondary efficacy variable of PANSS response will be analyzed using logistic regression with geographic 
region and treatment as categorical factors, and baseline PANSS total score as a covariate. The analysis will 
be performed for the Week 4 LOCF endpoint as well as for each of the scheduled visits. 
Odds ratio and its 95% CI as estimated by the model will be presented. In addition, the number-needed-to-
treat (NNT) will be calculated for the SEP-363856 (50 or 75 mg/day) group as:  
NNT=
1
Absolute Risk Reduction =
1
PANSS Response RateSEP-363856 - PANSS Response RatePlacebo
The 95% CI of NNT will be obtained by taking the reciprocal of the 95% CI bounds of the Absolute Risk 
Reduction when both lower and upper confidence limits are positive. The NNT and its 95% CI will be provided 
as integers; any fractional values will be rounded up to the nearest integer (the lower confidence limit will be 
rounded down and the upper confidence limit will be rounded up). 
16.2.3.4. 
Subjects with given PANSS percent changes from baseline 
The proportion of subjects achieving a given PANSS percent change from baseline or lower at the Week 4 
LOCF endpoint will be calculated for each treatment group. This calculation will be performed at multiple levels 
of percent change from baseline, from -100% to >=100%, with 5% increments. The results will be reported in a 
graph with the percent change from baseline threshold on the x-axis and proportion of subjects in each 
treatment group on the y-axis. 


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16.3. EXPLORATORY EFFICACY  
Analyses of the exploratory efficacy variable will be performed on the mITT population. 
16.3.1. 
EXPLORATORY EFFICACY VARIABLES & DERIVATION 
16.3.1.1. 
Change from baseline in the CBB composite score at Week 4 
The Cogstate Brief Battery (CBB) assesses four domains. The Detection test (Psychomotor Function Domain) 
measures speed of performance. The mean of the log10 transformed reaction times for correct responses is 
utilized to determine the score. Lower scores correspond to better performance. The Identification test 
(Attention Domain) also measures speed of performance. The mean of the log10 transformed reaction times 
for correct responses is utilized to determine the score. Lower scores correspond to better performance. The 
One Card Learning test (Visual Learning Domain) measures accuracy of performance. The arcsine 
transformation of the square root of the proportion of correct responses is utilized to determine the domain 
score. Higher scores correspond to better performance. The One Back test (Working Memory Domain) 
measures speed of performance. The mean of log10 transformed reaction times for correct responses is used 
to determine the domain score. Lower scores correspond to better performance. 
A standardized z-score is derived for each test by using the following formula: 
z = (Subject score - Age-adjusted normalization table mean)×Multiplicand
Age-adjusted normalization table standard deviation
where 
o
multiplicand = -1 when a lower score indicates improved performance (i.e. Detection Test,
Identification Test, One Back Test);
o
multiplicand = 1 when a higher score indicates improved performance (i.e. One Card Learning Test)
The age-adjusted normalization table mean and standard deviation for each test is shown in the table below: 
Cogstate Tests 
Normative Mean and Standard Deviation 
Detection Test (DET) 
2.46 
0.09 
Identification Test (IDN)
2.66
0.08
One Card Learning Test (OCL)
1.05 
0.13 
One Back Test (ONB) 
2.79 
0.10 
A completion flag and an integrity flag are populated for each test. Test completion refers to criteria that 
determine whether a sufficient number of responses were recorded during the administration of a test to allow 
computation of reliable performance measures. Any tests that failed the completion criteria will be excluded 
from statistical analysis.  
Test integrity is a measure of whether a subject performed in accord with the test requirements. When a 
particular test administration fails to meet criteria for data integrity, this suggests with high probability that the 
observed score may not reflect the study population or the effect of the compound under investigation. 
Statistical analysis will be performed both with the tests that failed the integrity criteria included and excluded 


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(as a sensitivity analysis). 
Based on the z-scores of individual tests, a CBB composite score will be derived as the average of the z-
scores of four tests. If two or more tests are missing or are excluded from the analysis, the composite score 
will be set to missing. 
The change from baseline in CBB composite score and each individual standardized score at Week 4 will then 
be calculated for each subject. 
16.3.2. 
MISSING DATA METHOD FOR EXPLORATORY EFFICACY VARIABLES 
The ANCOVA analysis of change from baseline in CBB composite score and the individual standardized 
scores at Week 4 will be based on observed data (with early termination data mapped as described in section 
6.4). Missing data will not be imputed. 
16.3.3. 
ANALYSIS OF EXPLORATORY EFFICACY VARIABLES 
16.3.3.1. 
Change from baseline in the CBB composite score at Week 4 
Change from baseline in the CBB composite score and the individual standardized scores at Week 4 will be 
analyzed using an ANCOVA model with treatment and pooled center as categorical factors and baseline CBB 
composite score or individual standardized scores as a covariate. Between-group difference for baseline CBB 
composite score and the individual standardized scores will be based on an ANCOVA model adjusting for 
pooled center. 
17.
SAFETY OUTCOMES
All outputs for safety outcomes will be based on the safety population.  
There will be no statistical comparisons between the treatment groups for safety data, unless otherwise 
specified in the relevant sections.  
17.1. ADVERSE EVENTS 
Both adverse events (AEs) and pre-treatment events will be coded using MedDRA central coding dictionary, 
Version 18.1 or higher. 
Adverse events are untoward medical occurrences that started at the same time of or after the first dose of 
study medication. Untoward medical occurrences that started between ICF and prior to the first dose of study 
medication are pre-treatment events. 
Adverse events (including serious adverse events) are collected into the clinical database until the last study 
visit. For subjects who do not roll over to study 361-202, the last study visit will be the follow-up visit which per 
protocol should occur 7 (± 2) days after the last dose of study medication. For subjects continuing into study 
361-202 (the open-label extension), the last study visit in study 361-201 will be Visit 7 which per protocol 


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should occur 1 day after the last dose of study medication. For these subjects, adverse events that started 
before the first dose of open-label study medication in study 361-202 are considered to belong to study 361-
201 and will be recorded in the 361-201 database. Adverse events that started at the same time of or after the 
first dose of open-label study medication in study 361-202 are considered to belong to study 361-202 and will 
be recorded in the 361-202 database. If an adverse event (or pre-treatment event) started in study 361-201 
and was ongoing as of the first dose of open-label study medication, this adverse event (pre-treatment event) 
will be carried over to the 361-202 database and its outcome will be monitored and updated in the 361-202 
database.  
For the purpose of statistical analysis, all adverse events in the 361-201 database which started within 9 days 
after the last dose of study medication, or had a partial or missing start date such that it cannot be determined 
whether the adverse event is within the 9-day window, will be included in table summaries. All adverse events 
in the 361-201 database, including those that started beyond 9 days after the last dose of study medication, 
will be listed in data listings. 
Whenever available, the time information should be taken into consideration in the determination of adverse 
events vs. pre-treatment events. In the case where time isn’t available, untoward medical occurrences that 
started on or after the day of the first dose of study medication will be considered adverse events; those that 
started before the day of the first dose of study medication will be considered pre-treatment.  
See APPENDIX 2 for handling of partial dates for adverse events. In the case where it is not possible to define 
an untoward medical occurrence as adverse event or pre-treatment event, it will be classified by the worst 
case, i.e. adverse event.  
An overall summary of the incidence of adverse events within each of the categories described in the following 
sections will be provided as specified in the templates. This summary will also be repeated by the region, sex, 
age, number of prior hospitalizations for acute exacerbation of schizophrenia, and duration of schizophrenia 
subgroups. The overall incidence summary will also be provided for AEs related to study medication. 
Listings will be provided for all AEs, AEs leading to discontinuation of study medication, AEs leading to 
discontinuation from the study, serious adverse events (SAE), and AEs leading to death. A listing for pre-
treatment events will also be presented. 
For incidence summaries, each subject will be counted only once within each SOC and PT. If not otherwise 
specified, all summaries will present incidence (number of subjects and percentages) and number of events. 
17.1.1. 
ALL AES
AEs will be presented by SOC, High Level Term (HLT), and PT for AE incidence and number of events. AEs 
will also be presented by maximum severity and by strongest relationship to the study medication as specified 
in the sections below. 
AEs that occurred in >= 5% of subjects in either treatment group will be summarized by SOC and PT. 
17.1.1.1. 
Severity 
Severity is classed as mild/ moderate/ severe (increasing severity). AEs with a missing severity will be 
summarized as missing severity. If a subject reports an AE more than once within the same SOC/ PT, the AE 
with the worst severity will be used in the corresponding severity summaries. For this summary, AEs will be 
presented by SOC and PT. 


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17.1.1.2. 
Relationship to Study Medication 
Relationship, as indicated by the investigator, is classed as “not related”/ “possible”/ “probable”/ “definite” 
(increasing strength of relationship). A “related” AE is defined as an AE with a relationship to the study 
medication of “possible”, “probable” or “definite”. A “not related” AE is defined as an AE with a relationship to 
the study medication of “not related”. AEs with a missing relationship to the study medication will be regarded 
as “related” to the study medication. If a subject reports the same AE more than once within the same SOC/ 
PT, the AE with the strongest relationship to study medication will be used in the corresponding relationship 
summaries. For this summary, AEs will be presented by SOC and PT. 
17.1.2. 
AES LEADING TO DISCONTINUATION OF STUDY MEDICATION 
AEs leading to permanent discontinuation of study medication are AEs for which “Drug Withdrawn” is selected 
for “Action Taken with Study Treatment” on the AE CRF page. A summary of AEs leading to discontinuation of 
study medication by SOC and PT will be presented.  
17.1.3. 
AES LEADING TO DISCONTINUATION FROM THE STUDY 
AEs leading to discontinuation from the study are AEs with “Caused Study Discontinuation” = “Yes” on the AE 
CRF page. A summary of AEs leading to discontinuation from the study by SOC and PT will be presented. 
17.1.4. 
SERIOUS ADVERSE EVENTS 
SAEs are those AEs recorded as “Serious” on the AE CRF page. Summaries of serious AEs and non-serious 
AEs by SOC and PT will be prepared. 
17.1.5. 
ADVERSE EVENTS LEADING TO DEATH 
AEs leading to death are those AEs which are recorded as having an outcome of “Fatal” on the AE CRF page. 
A summary of AEs leading to death by SOC and PT will be prepared. 
17.1.6. 
ADVERSE EVENTS BY SUBGROUP 
As stated above, overall incidence summaries will be presented by the subgroups of region, sex, age, prior 
number of hospitalizations for acute exacerbation of schizophrenia, and duration of schizophrenia. The same 
subgroup factors will also apply to the by-subgroup summaries for the following events: 
•
All AEs, by SOC and PT
•
SAEs, by SOC and PT
•
AEs leading to discontinuation of study medication, by SOC and PT


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•
AEs leading to discontinuation from the study, by SOC and PT
In addition, all AEs (by SOC and PT) will be summarized by the BMI (kg/m2) category: 
o
Underweight: <18.5
o
Normal: 18.5 to <25.0
o
Overweight: 25.0 to <30.0
o
Obese: >=30.0
17.2. LABORATORY EVALUATIONS 
Laboratory data to be reported for this study include hematology, serum chemistry (including lipid panel and 
thyroid panel), urinalysis, coagulation, urine drug screening, and urine and serum pregnancy test (only listed). 
Presentations will use international system of units (SI).  
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of quantification (BLQ), or 
“> X”, i.e. above the upper limit of quantification (ULQ), will be converted to X for the purpose of quantitative 
summaries, but will be presented as recorded, i.e. as “< X” or “> X” in listings. 
The following summaries will be provided for laboratory data: 
•
By visit summary of observed values and changes from baseline for continuous data in
hematology, chemistry, urinalysis, and coagulation. Prolactin results will be summarized
separately by gender. Glucose and lipid panel results will be summarized separately by fasting
status.
•
By visit summary of the number and percentage of subjects in each outcome category for
categorical data in urinalysis and urine drug screening. For urine drug screening, the results will
be reported as “Positive”/ “Negative”.
•
Shift in lab results (chemistry, hematology, urinalysis, coagulation) from baseline to Week 4
according to the reference range criteria provided by the central laboratory.
•
Summary of the number and percentage of subjects with at least one post-baseline PCS value
for selected laboratory parameters (Table 3). The period of evaluation includes both double-blind
treatment period and the double-blind follow-up period.
The change from baseline values at Week 4 for selected laboratory parameters will be evaluated using a 
nonparametric rank ANCOVA analysis. Baseline values and change from baseline values will be ranked. A 
linear regression analysis will be performed on the change from baseline value ranks with the baseline value 
ranks as the independent variable, to produce regression residuals. Using the values of the residuals as 
scores, the Cochran-Mantel-Haenszel row mean scores test will be used to compare between the treatment 
groups. This analysis will be conducted for prolactin, lipid panel, HbA1c, and glucose. Prolactin will be analyzed 
separately by gender. 
All laboratory data will be provided in data listings, with the values outside the reference ranges and PCS 
values flagged. 


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Table 3. PCS Criteria for Laboratory Parameters – SI Units 
Category 
PCS Low 
PCS High 
Parameter Name  
Age/Gender Restriction, if any 
HEMATOLOGY 
WBC 
≤ 2.8 x 109/L
≥ 16 x 109/L 
Neutrophils (abs) 
< 0.5 x 109/L
> 13.5 x 109/L 
Lymphocytes (abs) 
N/A
> 12 x 109/L 
Monocytes (abs) 
N/A
> 2.5 x 109/L 
Eosinophils (abs) 
N/A
> 1.6 x 109/L 
Basophils (abs) 
N/A
> 1.6 x 109/L 
Neutrophils (relative) 
≤ 0.15
> 0.85 
Lymphocytes (relative) 
N/A
≥0.75 
Monocytes (relative) 
N/A
≥0.15 
Eosinophils (relative) 
N/A
≥0.10 
Basophils (relative) 
N/A
≥0.10 
Hemoglobin 
Male 
≤ 115 g/L
≥ 190 g/L 
Female 
≤ 95 g/L
≥ 175 g/L 
Hematocrit 
   Male 
≤ 0.37
≥ 0.60 
   Female 
≤ 0.32
≥ 0.54 
RBC 
≤ 3.5 x 1012/L
≥ 6.4 x 1012/L 
Platelet Count 
≤ 75 x 109/L
≥ 700 x 109/L 
SERUM CHEMISTRY 
Sodium 
< 130 mmol/L
> 150 mmol/L 
Potassium 
< 3 mmol/L
> 5.5 mmol/L 
Chloride 
≤ 90 mmol/L
≥ 118 mmol/L 
Calcium 
< 1.75 mmol/L
≥ 3.1 mmol/L 
Phosphate 
< 0.65 mmol/L
> 1.65 mmol/L 
Bicarbonate 
< 15.1 mmol/L
> 34.9 mmol/L 
Magnesium 
< 0.4 mmol/L
> 1.23 mmol/L 
AST (IU/L) 
N/A
≥ 3 x ULN 
ALT (IU/L) 
N/A
≥ 3 x ULN 
Alkaline Phosphatase (IU/L) 
N/A
≥ 1.5 x ULN 
CK (IU/L) 
N/A
> 2.5 x ULN 
Creatinine 
N/A
≥ 177 umol/L 
BUN 
N/A
≥ 10.7 mmol/L 
Total bilirubin (mg/dL) 
N/A
≥ 34.2 umol/L OR > 2 x ULN
Total protein 
≤ 45 g/L
≥ 100 g/L 
Albumin 
≤ 25 g/L
N/A
Total Cholesterol 
N/A 
> 7.76 mmol/L 
HDL-Cholesterol 
< 0.78 mmol/L
N/A
LDL-Cholesterol 
N/A
> 4.14 mmol/L 
Triglycerides 
N/A 
> 3.42 mmol/L 


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Uric acid 
Male 
N/A
> 595 umol/L 
Female
N/A
> 476 umol/L 
Glucose 
< 2.78 mmol/L
> 13.9 mmol/L 
HbA1c 
N/A
≥ 0.075 
Prolactin 
N/A
≥ 5 x ULN 
COAGULATION 
aPTT (sec) 
N/A
> 1.5 x ULN 
INR (ratio) 
N/A
> 1.5 x ULN 
THYROID FUNCTION 
Free T3 
< 3.07 pmol/L 
> 6.38 pmol/L 
Free T4 
< 9.65 pmol/L
> 22.5 pmol/L 
TSH 
< 0.34 mIU/L
> 5.6 mIU/L 
URINALYSIS 
RBC 
N/A
> 25 hpf 
WBC 
N/A
> 25 hpf 
17.3. ECG EVALUATIONS 
Results from the central ECG (Electrocardiogram) will be included in the reporting of this study. 
The following ECG parameters will be reported for this study: 
•
PR Interval (msec)
•
RR Interval (msec)
•
QRS Duration (msec)
•
QRS Axis (deg)
•
QT Interval (msec)
•
QTcF Interval (msec) [derived]
•
QTcB Interval (msec) [derived]
•
Heart rate (HR) (beats/min)
•
ECG findings
•
Overall assessment of ECG (investigator’s judgment):
o
Normal
o
Abnormal, Significant


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o
Abnormal, Insignificant
The following summaries will be provided for ECG data: 
•
By visit summary of observed values and changes from baseline (for quantitative
measurements)
•
Number and percentage of subjects with QTc levels in each of the QTc categories
•
By visit summary of ECG overall assessment results
•
Shift in ECG overall assessments from baseline to Week 4.
The number and percentage of subjects with QTc values in the following categories will be identified. The 
same criteria apply to both QTcF and QTcB.  
•
> 450 msec at any post-baseline time point (including unscheduled visits) not present at
baseline
•
> 480 msec at any post-baseline time point (including unscheduled visits) not present at
baseline
•
> 500 msec at any post-baseline time point (including unscheduled visits) not present at
baseline
•
≥ 30 msec increase from baseline for at least one post-baseline measurement (including
unscheduled visits) and < 60 msec increase from baseline for all post-baseline measurements
(including unscheduled visits)
•
≥ 60 msec increase from baseline for at least one post-baseline measurement (including
unscheduled visits)
All ECG parameters, overall interpretation, and findings will be provided in data listings.  
17.4. VITAL SIGNS 
The following vital signs measurements will be reported for this study: 
•
Supine Systolic Blood Pressure (mmHg)
•
Standing Systolic Blood Pressure (mmHg)
•
Supine Diastolic Blood Pressure (mmHg)
•
Standing Diastolic Blood Pressure (mmHg)
•
Supine Pulse Rate (beats/min)


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•
Standing Pulse Rate (beats/min)
•
Respiratory Rate (breaths/min)
•
Temperature (oC)
•
Weight (kg)
•
BMI (kg/m2)
•
Waist Circumference (cm)
The following summaries will be provided for vital signs data: 
•
Observed value and change from baseline by visit
•
Observed value and change from baseline by visit for baseline BMI category:
o
Underweight: <18.5
o
Normal: 18.5 to <25.0
o
Overweight: 25.0 to <30.0
o
Obese: >=30.0
•
Number and percentage of subjects with at least one post-baseline PCS value for selected vital
signs parameters (Table 4). The period of evaluation includes both double-blind treatment period
and the double-blind follow-up period.
Change from baseline at the Week 4 LOCF endpoint in weight and BMI will be analyzed using nonparametric 
rank ANCOVA similarly to those described in section 17.2. 
All vital signs data will be provided in data listings, with the PCS values flagged.  
Table 4. PCS Criteria for Vital Signs Parameters 
Parameter Name 
PCS Low 
PCS High 
Systolic Blood Pressure (mmHg) 
Value ≤ 90 and ≥ 20 decrease from 
baseline 
Value ≥ 180 and ≥ 20 increase 
from baseline 
Diastolic Blood Pressure (mmHg) 
Value ≤ 50 and ≥ 15 decrease from 
baseline 
Value ≥ 105 and ≥ 15 increase 
from baseline 
Pulse Rate (beats/min) 
Value ≤ 50 and ≥ 15 decrease from 
baseline 
Value ≥ 120 and ≥ 15 increase 
from baseline 
Weight (kg) 
≥ 7% decrease from baseline 
≥ 7% increase from baseline 
Temperature (°C) 
NA 
Value ≥ 38.3°C and ≥ 0.8°C 
increase from baseline 


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17.4.1. 
ORTHOSTATIC EFFECTS 
Orthostatic hypotension is defined as a decrease of >= 20 mmHg in systolic blood pressure or >= 10 mmHg in 
diastolic blood pressure after the subject had been standing for at least 2 to 4 minutes, compared to the 
systolic blood pressure and diastolic pressure measured in the supine position, respectively. 
Orthostatic tachycardia is defined as a heart rate increase of >= 20 beats per minute (bpm) and a heart rate of 
>100 bpm after the subject was standing for at least 2 to 4 minutes, compared to the heart rate measured in 
the supine position. 
The number and percentage of subjects with orthostatic hypotension and orthostatic tachycardia will be 
summarized for baseline and the overall post-baseline period, as well as by visit. As specified in section 6.4 of 
the statistical analysis plan, any orthostatic hypotension or tachycardia events that occurred at the early 
termination visit will be assigned to the next planned visit. 
17.5. OTHER SAFETY ASSESSMENTS 
17.5.1. 
MOVEMENT DISORDER MEASURES 
Abnormal Involuntary Movement Scale (AIMS) 
The AIMS is a clinician-rated assessment of abnormal movements. It contains 12 items that assess facial and 
oral movements (items 1 - 4), extremity movements (items 5 - 6), trunk movements (item 7), global judgments 
(items 8 - 10) and dental status (items 11 - 12). AIMS total score will be calculated as the sum of items 1 
through 7 (ranging from 0 to 28). Higher values of AIMS total score indicate increased severity in abnormal 
movement. If any item score contributing to the calculation of AIMS total score is missing, the total score will 
be set to missing. Items 8 through 12 will not be used in total score calculation. The global severity score (item 
8) will be summarized separately.
Change from baseline in AIMS total score will be analyzed using MMRM similarly to the primary analysis of 
the primary efficacy variable (see section 16.1.3), with baseline AIMS total score as a covariate. The MMRM 
analysis will be repeated for subgroups based on whether or not the subjects took concomitant medications for 
treatment of movement disorders. The list of medications will be determined by a review of the coded 
medication terms before database lock. 
In addition, ANCOVA analysis on change from baseline in AIMS total score will be performed, similarly to the 
analysis described in section 16.1.4.4. 
AIMS total score (observed value and change from baseline) will be summarized numerically by visit. In 
addition, the AIMS total score at each visit will be classified as “abnormal” if: either at least two items (out of 
items 1 - 7) have a response of “mild” or higher, or at least one item (out of items 1 - 7) has a response of 
“moderate” or higher. Otherwise, the non-missing total score will be classified as “normal”. This is a 
modification of the Schooler-Kane criteria for tardive dyskinesia. Shifts from baseline in AIMS total score 
classification will be summarized by visit and overall for all post-baseline assessments during the double-blind 
treatment period. 
The AIMS global severity score will be summarized both numerically and categorically by visit. 


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The post-baseline AIMS global severity assessment will be classified as “worsened” (score is higher than 
baseline), “unchanged” (score is equal to baseline), or “improved” (score is lower than baseline), relative to a 
subject’s baseline response. These post-baseline changes will be summarized by visit. 
Barnes Akathisia Rating Scale (BARS) 
The BARS is a clinician-rated assessment to measure the observable, restless movements that characterize 
drug-induced akathisia. It contains 4 items: an objective rating (objective restlessness), 2 subjective ratings 
(awareness of restlessness, distress related to restlessness), and a global clinical assessment of akathisia. 
The subjective and objective items (items 1 through 3) will be summed to yield the BARS total score (ranging 
from 0 to 9). Higher values of BARS total score indicate higher severity of akathisia. If any item score 
contributing to the calculation of BARS total score is missing, the total score will be set to missing. The global 
clinical assessment rating will be analyzed separately.  
Change from baseline in BARS total score will be analyzed using MMRM similarly to the primary analysis of 
the primary efficacy variable (see section 16.1.3), with baseline BARS total score as a covariate. The MMRM 
analysis will be repeated for subgroups based on whether or not the subjects took concomitant medications for 
treatment of movement disorders. The list of medications will be determined by a review of the coded 
medication terms before database lock. Similar analyses will be performed on the BARS global clinical 
assessment rating score.  
In addition, ANCOVA analysis on change from baseline in BARS total score will be performed, similarly to the 
analysis described in section 16.1.4.4. A similar analysis will be performed on the BARS global clinical 
assessment rating score. 
BARS total score (observed value and change from baseline) will be summarized numerically by visit. In 
addition, the BARS item scores for the four items will be summarized both numerically and categorically by 
visit.  
The post-baseline BARS global clinical assessment of akathisia will be classified as “worsened” (score is 
higher than baseline), “unchanged” (score is equal to baseline), or “improved” (score is lower than baseline), 
relative to a subject’s baseline response. These post-baseline changes will be summarized by visit. 
Simpson-Angus Scale (SAS) 
The SAS is a clinician-rated assessment of neuroleptic-induced Parkinsonism consisting of 10 items (each 
ranging from 0 to 4). SAS mean score is calculated as the average of all 10 item scores. Lower values of SAS 
mean score indicate milder symptoms. If any item score is missing, the mean score will be set to missing. 
Change from baseline in SAS mean score will be analyzed using MMRM similarly to the primary analysis of 
the primary efficacy variable (see section 16.1.3), with the baseline SAS mean values as a covariate. The 
MMRM analysis will be repeated for subgroups based on whether or not the subjects took concomitant 
medications for treatment of movement disorders. The list of medications will be determined by a review of the 
coded medication terms before database lock. 
In addition, ANCOVA analysis on change from baseline in SAS mean score will be performed, similarly to the 
analysis described in section 16.1.4.4.  
SAS mean score (observed value and change from baseline) will be summarized numerically by visit. In 
addition, SAS mean score at each visit will be classified as “abnormal” if it exceeds 0.3. Otherwise, non-
missing mean scores will be classified as “normal”. Shifts from baseline in SAS mean score classification will 
be summarized by visit and overall for all post-baseline assessments during the double-blind treatment period. 
All data from the three scales will be presented in the data listings. 


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17.5.2. 
PITTSBURGH SLEEP QUALITY INDEX 
The Pittsburgh Sleep Quality Index (PSQI) contains 19 self-rated questions and 5 questions rated by the bed 
partner or roommate (if one is available). Only self-rated questions are included in the scoring. The 19 self-
rated items are combined to form seven “component” scores, each of which has a range of 0-3 points. The 
seven component scores are then added to yield one global score, with a range of 0-21 points, “0” indicating 
no difficulty and “21” indicating severe difficulties in all areas (Buysse et al. 1989). 
If any of the component scores are missing, the PSQI global score will be set to missing. The PSQI scoring 
algorithm as downloaded from the University of Pittsburgh Sleep and Chronobiology Center is inserted in 
Appendix 4. 
Change from baseline in the PSQI global score at Week 4 will be analyzed using an ANCOVA model similar to 
that described in section 16.3.3.1. 
17.5.3. 
DRUG EFFECTS QUESTIONNAIRE 
The Drug Effects Questionnaire (DEQ) consists of 3 questions scored on a visual analog scale (VAS). 
Data from the DEQ questionnaire will be summarized descriptively by visit. For Describe Drug Effect and Like 
Drug Effect, if the Result is “Negative”, the numeric measurement will first be converted to a negative number 
before being summarized.  
17.5.4. 
COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS) 
The C-SSRS is a tool designed to systematically assess and track suicidal behavior and suicidal ideation for 
life time, one month (30 days) prior to the screening visit, and 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 C-SSRS Baseline/Screening Version is used at the screening visit and 
the C-SSRS Since Last Visit Version is used from Visit 2 onward. 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.  
C-SSRS includes four sections: Suicidal Ideation, Intensity of Ideation, Suicidal Behavior, and Answer for 
Actual Suicide Attempts.  
The following outcomes are C-SSRS categories and have binary responses (yes/no). The categories are re-
ordered from the scale to facilitate the definitions of the C-SSRS endpoints, and to provide clarity in the 
presentation of the results. 
Suicidal ideation is measured by 5 categories, representing 5 subtypes of suicidal ideation with increasing 
severity: 
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 


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Category 4: Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Category 5: Active Suicidal Ideation with Specific Plan and Intent 
Suicidal behavior is measured by 5 categories, representing 5 subtypes of suicidal behavior: 
Category 6: Preparatory Acts or Behavior 
Category 7: Aborted Attempt 
Category 8: Interrupted Attempt 
Category 9: Actual Attempt (non-fatal) 
Category 10: Completed Suicide 
The 10 categories above are not mutually exclusive. Subjects will be counted in each category for which they 
have an event. 
Self-injurious behavior without suicidal intent is a non-suicide-related C-SSRS outcome, and also has a binary 
response (yes/no). 
For the purpose of C-SSRS analysis, “baseline” and “post-baseline” are defined as follows. 
Time point 
Study Visit 
C-SSRS Version 
Derivation Rule 
Baseline 
Screening/Visit 1 
Baseline/Screening – Past 1 
Month 
Most severe outcome
Randomization/Visit 2 
Since Last Visit 
Post-baseline 
All post-baseline visits up to 
and including Week 4/Visit 7, 
including unscheduled visits 
Since Last Visit 
Most severe outcome
C-SSRS composite endpoints will be derived for each time point of interest (i.e. baseline, post baseline, and 
each study visit) as follows: 
•
Any suicidal ideation: A “yes” answer to any one of the 5 suicidal ideation questions on C-SSRS
(Categories 1-5).
•
Any suicidal behavior: A “yes” answer to any one of the 5 suicidal behavior questions on the C-SSRS
(Categories 6-10).
•
Any suicidality: A “yes” answer to any one of the 10 suicidal ideation and behavior questions on the C-
SSRS (Categories 1-10).
For each subject, the suicidal ideation score at each time point of interest (i.e. baseline, post baseline, each 
study visit, and the Week 4 LOCF endpoint) is defined as the maximum suicidal ideation category (1-5) 
present for the time of interest. If no ideation is present a score of 0 is assigned. A suicidal ideation score of 4 
or 5 is considered serious. 
The number and percentage of subjects with any suicidality, any suicidal ideation and subtypes of ideation, 
any suicidal behavior and subtypes of behavior, and any non-suicidal self-injurious behavior will be presented 
for: 
•
Baseline (as defined above)


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•
Post-baseline (as defined above)
•
Each scheduled study visit: Screening (lifetime; past 1 month), Randomization/Visit 2, Day 4/Visit 3,
Week 1/Visit 4, Week 2/Visit 5, Week 3/Visit 6, Week 4/Visit 7, Follow-up/Visit 8.
Difference between treatment groups for any post-baseline suicidality, suicidal behavior, and suicidal ideation 
will be evaluated using Fisher’s Exact test. 
Shift in suicidal ideation score from baseline to the post-baseline time point and to each the following study 
visits will be presented by treatment: Day 4/Visit 3, Week 1/Visit 4, Week 2/Visit 5, Week 3/Visit 6, Week 
4/Visit 7, Week 4 LOCF, and Follow-up/Visit 8.  
Intensity of ideation for the most severe ideation subtype is measured in terms of frequency, duration, 
controllability, deterrents, and reasons for ideation. Each is measured with responses ranging from 0 to 5 for 
frequency and duration, and from 1 to 5 for controllability, deterrents, and reasons for ideation. The ideation 
intensity total score is the sum of responses to the five items and can range from 2 to 25 for subjects with 
endorsed suicidal ideation. If one or more of these five items are missing at an assessment, the total score will 
be set to missing. If a subject did not endorse any suicidal ideation, a score of 0 for the ideation intensity total 
score will be given. 
Actual 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 actual attempts (if actual lethality = 0) is rated 
on a 3-point scale from 0 = ‘Behavior not likely to result in injury’ to 2 = ‘Behavior likely to result in death 
despite available medical care. 
The ideation intensity total score and the actual lethality and potential lethality of actual attempts will be 
presented in data listings. 
18.
PHARMACOKINETIC ANALYSIS
18.1. POPULATION PHARMACOKINETIC ANALYSIS 
All plasma concentrations of SEP-363856 and SEP-363854 will be presented in data listings.  
Population pharmacokinetic (PK) analysis will be performed using plasma SEP-363856 concentrations. The 
results will be reported separately. 
18.2. PHARMACODYNAMIC ANALYSIS 
The relationship between PANSS total score and plasma SEP-363856 exposure using population 
PK/pharmacodynamics (PD) methods will be explored. The results will be reported separately. 
The impact of cytochrome (CYP) P450 CYP2D6 metabolizer status on plasma SEP-363856 exposure will be 
explored. The results will be reported separately. 


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19.
DATA NOT SUMMARIZED OR PRESENTED
The data not summarized or presented are: 
•
Any data other than disposition, demographics and adverse events that are collected on screen
failures and on enrolled subjects at the previously failed screenings.
These data will not be summarized or presented, but will be avialble in the clinical study database, SDTM 
and/or ADaM datasets. 
20.
CHANGES IN THE ANALYSIS SPECIFIED IN THE STATISTICAL ANALYSIS PLAN
Any changes or deviations during the analysis and reporting process from the statistical analysis plan 
designed will be described and justified in the final report. 


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reproduction is strictly prohibited. 
21.
REFERENCES
Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new 
instrument for psychiatric practice and research. Psychiatry Res 1989;28:193-213. 
Hopkins SC, Ogirala A, Loebel A, Koblan KS. Transformed PANSS factors intended to reduce 
pseudospecificity among symptom domains and enhance understanding of symptom change in antipsychotic-
treated patients with schizophrenia. Schizophr Bull 2018;44(3):593-602. 
Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of schizophrenia 
derived by factor analysis: combined results of the North American trials. J Clin Psychiatry 1997;58:538–46. 
Ratitch B, O'Kelly M, Tosiello R. Missing data in clinical trials: from clinical assumptions to statistical analysis 
using pattern mixture models. Pharm Stat 2013;12(6):337-47. 


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APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
OUTPUT CONVENTIONS 
Where applicable, the Appendix Compilation Working Guidelines Final 07May2014 .pdf document – provided 
by Sunovion – will be followed. 
In addition, the following output conventions are to be followed: 
o
The first row in the body of the table or listing should be blank
o
The left hand column should start in column 1. No indenting or centering of the output should occur.
o
Rounding should be done with the SAS function ROUND.
o
Numbers in tables should be rounded, not truncated.
o
Alphanumeric output should be left aligned.
o
Numbers should be decimal point aligned.
o
Whole numbers should be right aligned.
o
Text values should be left aligned.
o
The first letter of a text entry should be capitalized.
o
The width of the entire output should match the line size (134)
•
Univariate Statistics:
o
If the raw data has N decimal places, then the summary statistics should have the following decimal
places:
o
Minimum and maximum: N
o
Mean, median, Q1, and Q3: N + 1
o
SD: N + 2
•
Frequencies and percentages (n and %):
o
Percent values should be reported inside parentheses, with one space between the count (n) and the
left parenthesis of the percentage. Parentheses should be justified to accept a maximum of 100.0 as a
value and padded with blank space if the percent is less than 100.0.
o
Percentages will be reported to one decimal place, except cases where percent <100.0% but >99.9%
will be presented as ‘>99.9%’ (e.g., 99.99% is presented as >99.9%); and cases where percent <
0.1% will be presented as ‘<0.1%’ (e.g., 0.08% is presented as <0.1%). Rounding will be applied after
the <0.1% and >99.9% rule.
o
Where counts are zero, no percentage should appear in the output.
•
Confidence Intervals:
o
Confidence intervals and estimates are presented to one place more than the raw data, and standard
errors to two places more than the raw data.
o
Confidence intervals should be justified so that parentheses displayed on consecutive lines of a table
“line up”.
o
Boundary values of confidence intervals should be separated by a comma.
o
Boundary values should be padded as necessary to accept negative values and to allow alignment of
the decimal place.


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•
P-values:
o
P-values should be reported to three decimal places, except values <1.000 but >0.999 will be
presented as ‘>0.999’ (e.g., 0.9998 is presented as >0.999); and values <0.001 will be presented as
‘<0.001’ (e.g., 0.0009 is presented as <0.001). Rounding will be applied after the <0.001 and >0.999
rule.
•
Ratios:
o
Ratios should be reported to one more decimal place than the raw data.
•
Spacing:
o
There must be a minimum of 1 blank space between columns (preferably 2).
•
Missing values:
o
A “0” should be used to indicate a zero frequency.
o
A blank will be used to indicate missing data in an end-of-text table or subject listing.
•
Figures:
o
Figures should be provided in RTF files using the SAS Output Delivery System (ODS), as Computer
Graphics Metafile (CGM) formatted graphical output generated by SAS.
o
The CGM file itself should contain the title or footer.
o
The image should be clear and of high quality when viewed in the Word document, and when printed.
o
In general, boxes around the figures should be used.
•
Footers should be defined as follows:
o
A continuous line of underscores (‘_’) will follow the body of the table or listing prior to any footnotes at
the bottom of the page.
o
Table footnotes should be defined using compute statements in the proc report, and should appear
directly after the body of the table.
o
If text wraps across more than one line (for a note), the first letter for all lines of text after the first one
will be indented to align beneath the first letter of the text in the first line.
DATES & TIMES 
Depending on data available, dates and times will take the form yyyy-mm-ddThh:mm:ss. 
SPELLING FORMAT 
English US. 


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PRESENTATION OF TREATMENT GROUPS 
For outputs, treatment groups will be represented as follows and in that order: 
Treatment Group 
For Tables, Graphs and Listings
Placebo
Placebo
SEP-363856 (50 or 75 mg/day) SEP-363856 
LISTINGS 
All listings will be ordered by the following (unless otherwise indicated in the template): 
•
Actual treatment received, displaying SEP-363856 first and then placebo,
•
Subject ID,
•
Date/Time (where applicable) - listings of adverse events, concomitant medications, medical
histories etc. should be sorted in chronological order, with earliest adverse event, medication or
history coming first,
•
For listings where non-randomized subjects are included, these will appear in a category after
the randomized treatment groups labelled ‘Not Randomized’.


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APPENDIX 2. PARTIAL DATE CONVENTIONS 
Imputed dates will not be presented in the listings.  
ALGORITHM FOR ADVERSE EVENTS: 
The algorithm below applies to all AE and pre-treatment event records contained in the 361-201 database. 
The concept of “date” below should also include time information whenever available. 
START DATE 
STOP 
DATE 
ACTION 
Known
Known 
If start date < 361-201 study med start date, then pre-
treatment events 
If start date >= 361-201 study med start date, then 
361-201 AE 
Known
Partial 
If start date < 361-201 study med start date, then pre-
treatment events 
If start date >= 361-201 study med start date, then 
361-201 AE 
Known
Missing 
If start date < 361-201 study med start date, then pre-
treatment events 
If start date >= 361-201 study med start date, then 
361-201 AE 
Partial, but known components 
show that it cannot be on or after 
361-201 study med start date 
Known 
Pre-treatment events 
Partial, but known components 
show that it cannot be on or after 
361-201 study med start date 
Partial 
Pre-treatment events 
Partial, but known components 
show that it cannot be on or after 
361-201 study med start date 
Missing 
Pre-treatment events 
Partial, could be on or after 361-
201 study med start date 
Known 
If stop date < 361-201 study med start date, then pre-
treatment events 
If stop date >= 361-201 study med start date, then 
361-201 AE 


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START DATE 
STOP 
DATE 
ACTION 
Partial, could be on or after 361-
201 study med start date 
Partial 
Impute stop date as latest possible date (i.e. last day 
of month if day unknown or 31st December if day and 
month are unknown). 
Then: 
If stop date < 361-201 study med start date, then pre-
treatment events 
If stop date >= 361-201 study med start date, then 
361-201 AE 
Partial, could be on or after 361-
201 study med start date 
Missing 
Assumed 361-201 AE 
Partial, and known components 
show that it is on or after 361-201 
study med start date 
Known 
361-201 AE 
Partial, and known components 
show that it is on or after 361-201 
study med start date 
Partial 
361-201 AE 
Partial, and known components 
show that it is on or after 361-201 
study med start date 
Missing 
361-201 AE 
Missing 
Known 
If stop date < 361-201 study med start date, then pre-
treatment events 
If stop date >= 361-201 study med start date, then 
361-201 AE 
Missing 
Partial 
Impute stop date as latest possible date (i.e. last day 
of month if day unknown or 31st December if day and 
month are unknown). 
Then: 
If stop date < 361-201 study med start date, then pre-
treatment events 
If stop date >= 361-201 study med start date, then 
361-201 AE 
Missing 
Missing 
Assumed 361-201 AE 


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ALGORITHM FOR PRIOR / CONCOMITANT / POST-TREATMENT MEDICATIONS:
The concept of “date” below should also include time information whenever available. 
For the case where the medication start date is known and is equal to the end of treatment date, and the 
medication start time is unknown, or the case where the imputed medication start date is equal to the end of 
treatment date: 
•
If CRF question ‘Started after last dose of study medication?’ = No, then assign as concomitant.
•
If CRF question ‘Started after last dose of study medication?’ = Yes, then assign as post treatment.
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If stop date < study med start date, assign as prior. 
If stop date >= study med start date and start date <= end of 
treatment, assign as concomitant. 
If stop date >= study med start date and start date > end of 
treatment, assign as post treatment. 
Known 
Partial 
Impute stop date as latest possible date: 
•
If only day unknown, impute as the earlier of (last day of the
month; end date of the last study visit). 
•
If month and day unknown, impute as the earlier of (31st
December; end date of the last study visit). 
Then: 
If stop date < study med start date, assign as prior. 
If stop date >= study med start date and start date <= end of 
treatment, assign as concomitant. 
If stop date >= study med start date and start date > end of 
treatment, assign as post treatment. 
Known 
Missing 
If stop date is missing could never be assumed a prior medication. 
If start date <= end of treatment, assign as concomitant. 
If start date > end of treatment, assign as post treatment. 


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START DATE 
STOP DATE 
ACTION 
Partial 
Known 
Impute start date as earliest possible date: 
CRF questions: ‘Started prior to study?’ = Yes; ‘Started after last 
dose of study medication?’ = No. 
•
If only day unknown, impute as the later of (first day of the
month; date of birth).
•
If month and day unknown, impute as the later of (1st
January; date of birth).
CRF questions: ‘Started prior to study?’ = No; ‘Started after last dose 
of study medication?’ = Yes. 
•
If only day unknown, impute as the later of (first day of the
month; end of treatment + 1).
•
If month and day unknown, impute as the later of (1st
January; end of treatment + 1).
CRF questions: ‘Started prior to study?’ = No; ‘Started after last dose 
of study medication?’ = No. 
•
If only day unknown, impute as the later of (first day of the
month; date of ICF).
•
If month and day unknown, impute as the later of (1st
January; date of ICF).
Then: 
If stop date < study med start date, assign as prior. 
If stop date >= study med start date and start date <= end of 
treatment, assign as concomitant. 
If stop date >= study med start date and start date > end of 
treatment, assign as post treatment. 


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START DATE 
STOP DATE 
ACTION 
Partial 
Partial 
Impute start date as earliest possible date: 
CRF questions: ‘Started prior to study?’ = Yes; ‘Started after last 
dose of study medication?’ = No. 
•
If only day unknown, impute as the later of (first day of the
month; date of birth). 
•
If month and day unknown, impute as the later of (1st
January; date of birth). 
CRF questions: ‘Started prior to study?’ = No; ‘Started after last dose 
of study medication?’ = Yes. 
•
If only day unknown, impute as the later of (first day of the
month; end of treatment + 1). 
•
If month and day unknown, impute as the later of (1st
January; end of treatment + 1). 
CRF questions: ‘Started prior to study?’ = No; ‘Started after last dose 
of study medication?’ = No. 
•
If only day unknown, impute as the later of (first day of the
month; date of ICF). 
•
If month and day unknown, impute as the later of (1st
January; date of ICF). 
Impute stop date as latest possible date: 
•
If only day unknown, impute as the earlier of (last day of the
month; end date of the last study visit). 
•
If month and day unknown, impute as the earlier of (31st
December; end date of the last study visit). 
Then: 
If stop date < study med start date, assign as prior. 
If stop date >= study med start date and start date <= end of 
treatment, assign as concomitant. 
If stop date >= study med start date and start date > end of 
treatment, assign as post treatment. 


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START DATE 
STOP DATE 
ACTION 
Partial 
Missing 
Impute start date as earliest possible date: 
CRF questions: ‘Started prior to study?’ = Yes; ‘Started after last 
dose of study medication?’ = No. 
•
If only day unknown, impute as the later of (first day of the
month; date of birth). 
•
If month and day unknown, impute as the later of (1st
January; date of birth). 
CRF questions: ‘Started prior to study?’ = No; ‘Started after last dose 
of study medication?’ = Yes. 
•
If only day unknown, impute as the later of (first day of the
month; end of treatment + 1). 
•
If month and day unknown, impute as the later of (1st
January; end of treatment + 1). 
CRF questions: ‘Started prior to study?’ = No; ‘Started after last dose 
of study medication?’ = No. 
•
If only day unknown, impute as the later of (first day of the
month; date of ICF). 
•
If month and day unknown, impute as the later of (1st
January; date of ICF). 
Then: 
If stop date is missing could never be assumed a prior medication. 
If start date <= end of treatment, assign as concomitant. 
If start date > end of treatment, assign as post treatment. 
Missing 
Known 
If stop date < study med start date, assign as prior. 
If stop date >= study med start date and CRF question ‘Started after 
last dose of study medication?’ = No, assign as concomitant. 
If CRF question ‘Started after last dose of study medication?’ = Yes, 
assign as post treatment. 
Missing 
Partial 
Impute stop date as latest possible date: 
•
If only day unknown, impute as the earlier of (last day of the
month; end date of the last study visit). 
•
If month and day unknown, impute as the earlier of (31st
December; end date of the last study visit). 
Then: 
If stop date < study med start date, assign as prior. 
If stop date >= study med start date and CRF question ‘Started after 
last dose of study medication?’ = No, assign as concomitant. 
If CRF question ‘Started after last dose of study medication?’ = Yes, 
assign as post treatment. 


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START DATE 
STOP DATE 
ACTION 
Missing 
Missing 
If CRF question ‘Started after last dose of study medication?’ = No, 
assign as concomitant. 
If CRF question ‘Started after last dose of study medication?’ = Yes, 
assign as post treatment. 


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reproduction is strictly prohibited. 
PARTIAL DATE IMPUTATION RULES FOR INITIAL ONSET OF SCHIZOPHRENIA:  
For subjects with partial onset dates of schizophrenia, impute the onset date using the following rules: 
•
If only day unknown, impute as the earlier of: last day of the month, or date of ICF.
•
If both month and day unknown, impute as the earlier of: 31st December of the year, or date of
ICF.
PARTIAL DATE IMPUTATION RULES FOR ONSET OF ACUTE EXACERBATION: 
For subjects with partial onset dates of acute exacerbation, impute the onset date using the following rules: 
•
If only day unknown, impute as the later of: first day of the month, or date of initial onset of
schizophrenia (actual or imputed).
•
If both month and day unknown, impute as the later of: 1st January of the year, or date of initial
onset of schizophrenia (actual or imputed).


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APPENDIX 3. 
STATISTICAL MODEL SPECIFICATIONS (SAMPLE SAS CODE) 
Definition 
Variable 
Subject number (character) 
SUBJID 
Planned double-blind treatment group (numeric) 
TRT01PN (1=” SEP-36385 50 or 75 mg/day”; 
2=”Placebo”) 
Visit (numeric) 
AVISITN (3=”Day 4”; 4=”Week 1”; 5=”Week 2”; 
6=”Week 3”; 7=”Week 4”) 
Change from baseline values (numeric) 
CHG 
PANSS total score at each post-baseline visit 
PANSS3 to PANSS7 
Last visit with PANSS total score available 
(numeric) 
LASTVISN (3=”Day 4”; 4=”Week 1”; 5=”Week 2”; 
6=”Week 3”; 7=”Week 4”) 
MIXED MODEL FOR REPEATED MEASURES (MMRM) 
ODS OUTPUT LSMEstimates=xxxx CovParms=xxxx Tests3=xxxx Coef=xxxx; 
PROC MIXED DATA=xxxx; 
   CLASS SUBJID <Pooled study center> TRT01PN AVISITN; 
   MODEL CHG = <Baseline PANSS total score> <Pooled study center> TRT01PN AVISITN  
TRT01PN*AVISITN / DDFM=KR SOLUTION; 
   REPEATED AVISITN / SUB=SUBJID TYPE=UN; 
   LSMESTIMATE TRT01PN*AVISITN "SEP-363856 at Day 4"  [1, 1 1], 
"SEP-363856 at Week 1" [1, 1 2], 
"SEP-363856 at Week 2" [1, 1 3], 
"SEP-363856 at Week 3" [1, 1 4], 
"SEP-363856 at Week 4" [1, 1 5] / E CL; 
   LSMESTIMATE TRT01PN*AVISITN "Placebo at Day 4"  [1, 2 1], 
"Placebo at Week 1" [1, 2 2], 
"Placebo at Week 2" [1, 2 3], 
"Placebo at Week 3" [1, 2 4], 
"Placebo at Week 4" [1, 2 5] / E CL; 
   LSMESTIMATE TRT01PN*AVISITN  
"SEP-363856 vs Placebo at Day 4"  [1, 1 1] [-1, 2 1], 
"SEP-363856 vs Placebo at Week 1" [1, 1 2] [-1, 2 2], 
"SEP-363856 vs Placebo at Week 2" [1, 1 3] [-1, 2 3], 
"SEP-363856 vs Placebo at Week 3" [1, 1 4] [-1, 2 4], 
"SEP-363856 vs Placebo at Week 4" [1, 1 5] [-1, 2 5] / E CL; 


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RUN; 
In case the MMRM model assuming unstructured covariance model fails to converge, the spatial exponential 
model and then the spatial power model will be assumed sequentially. 
DATA xxxx; 
   SET xxxx; 
   IF AVISITN=3 THEN AVDY=4; 
   ELSE IF AVISITN=4 THEN AVDY=8; 
   ELSE IF AVISITN=5 THEN AVDY=15; 
   ELSE IF AVISITN=6 THEN AVDY=22; 
   ELSE IF AVISITN=7 THEN AVDY=29; 
RUN; 
ODS OUTPUT LSMEstimates=xxxx CovParms=xxxx Tests3=xxxx Coef=xxxx; 
PROC MIXED DATA=xxxx EMPIRICAL; 
   CLASS SUBJID <Pooled study center> TRT01PN AVISITN; 
   MODEL CHG = <Baseline PANSS total score> <Pooled study center> TRT01PN AVISITN  
TRT01PN*AVISITN / SOLUTION; 
   /* only retain one of the following two REPEATED statements */ 
   REPEATED AVISITN / SUB=SUBJID TYPE=SP(EXP)(AVDY); /* spatial exponential */ 
   REPEATED AVISITN / SUB=SUBJID TYPE=SP(POW)(AVDY); /* spatial power */ 
   LSMESTIMATE TRT01PN*AVISITN "SEP-363856 at Day 4"  [1, 1 1], 
"SEP-363856 at Week 1" [1, 1 2], 
"SEP-363856 at Week 2" [1, 1 3], 
"SEP-363856 at Week 3" [1, 1 4], 
"SEP-363856 at Week 4" [1, 1 5] / E CL; 
   LSMESTIMATE TRT01PN*AVISITN "Placebo at Day 4"  [1, 2 1], 
"Placebo at Week 1" [1, 2 2], 
"Placebo at Week 2" [1, 2 3], 
"Placebo at Week 3" [1, 2 4], 
"Placebo at Week 4" [1, 2 5] / E CL; 
   LSMESTIMATE TRT01PN*AVISITN  
"SEP-363856 vs Placebo at Day 4"  [1, 1 1] [-1, 2 1], 
"SEP-363856 vs Placebo at Week 1" [1, 1 2] [-1, 2 2], 
"SEP-363856 vs Placebo at Week 2" [1, 1 3] [-1, 2 3], 
"SEP-363856 vs Placebo at Week 3" [1, 1 4] [-1, 2 4], 
"SEP-363856 vs Placebo at Week 4" [1, 1 5] [-1, 2 5] / E CL; 
RUN; 
PATTERN-MIXTURE MODEL (PMM) WITH PLACEBO-BASED MI 
Step 1: Partial imputation to get monotone missing pattern. 
PROC MI DATA=xxxx OUT=xxxx_mono NIMPUTE=500 SEED=123 MINIMUM=30 MAXIMUM=210  
MINMAXITER=100; 


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   BY TRT01PN; 
   VAR <Baseline PANSS total score> PANSS3 PANSS4 PANSS5 PANSS6 PANSS7; 
   MCMC CHAIN=MULTIPLE INITIAL=EM IMPUTE=MONOTONE NBITER=5000 NITER=200; 
RUN; 
Step 2: Impute with sequential regression method.
Step 2.1: Separate dataset xxxx_mono into two parts: Part 1 includes all subjects in the placebo group and 
those subjects in the SEP-363856 group with PANSS total score missing for the Day 4 visit; Part 2 includes 
those subjects in the SEP-363856 group with PANSS total score available for the Day 4 visit. Impute missing 
PANSS total scores in Part 1. Then put the two parts back together. 
DATA mono_imp3 mono_rest3; 
   SET xxxx_mono; 
   IF TRT01PN=1 AND LASTVISN>=3 THEN OUTPUT mono_rest3; 
   ELSE OUTPUT mono_imp3; 
RUN; 
PROC SORT DATA=mono_imp3; BY _IMPUTATION_; RUN; 
PROC MI DATA=mono_imp3 OUT=mono_reg3 NIMPUTE=1 SEED=234 MINIMUM=. 30 30  
MAXIMUM=. 210 210 MINMAXITER=100; 
   BY _IMPUTATION_; 
   VAR <Pooled study center> <Baseline PANSS total score> PANSS3; 
   CLASS <Pooled study center>; 
   MONOTONE REG(PANSS3); 
RUN; 
DATA mono_panss3; 
   SET mono_reg3 mono_rest3; 
RUN; 
Note: If an imputation failed because the imputed value is not within the specified min-max range, that 
particular imputation won’t exist in mono_reg3. In that case need to remove the corresponding imputation in 
mono_rest3 before re-assembling the 2 datasets together. 
Step 2.2: Separate dataset mono_panss3 into two parts: Part 1 includes all subjects in the placebo group and 
those subjects in the SEP-363856 group with PANSS total score missing for the Week 1 visit; Part 2 includes 
those subjects in the SEP-363856 group with PANSS total score available for the Week 1 visit. Impute missing 
PANSS total scores in Part 1. Then put the two parts back together. 
DATA mono_imp4 mono_rest4; 
   SET mono_panss3; 
   IF TRT01PN=1 AND LASTVISN>=4 THEN OUTPUT mono_rest4; 
   ELSE OUTPUT mono_imp4; 
RUN; 
PROC SORT DATA=mono_imp4; BY _IMPUTATION_; RUN; 


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PROC MI DATA=mono_imp4 OUT=mono_reg4 NIMPUTE=1 SEED=345 MINIMUM=. 30 30 30  
MAXIMUM=. 210 210 210 MINMAXITER=100; 
   BY _IMPUTATION_; 
   VAR <Pooled study center> <Baseline PANSS total score> PANSS3 PANSS4; 
   CLASS <Pooled study center>; 
   MONOTONE REG(PANSS4); 
RUN; 
DATA mono_panss4; 
   SET mono_reg4 mono_rest4; 
RUN; 
Note: If an imputation failed because the imputed value is not within the specified min-max range, that 
particular imputation won’t exist in mono_reg4. In that case need to remove the corresponding imputation in 
mono_rest4 before re-assembling the 2 datasets together. 
Steps 2.3 – 2.5: Continue with the above step to impute missing PANSS total scores for the Week 2, Week 3, 
and Week 4 visits. The seed number for the respective imputation steps are 456, 567, and 678. 
Step 3: Fit the primary MMRM model and calculate the effect size on each imputed dataset. 
Step 3.1: Re-format dataset mono_panss7 from Step 2, which has all missing PANSS total scores imputed, 
into long format. Suppose the new dataset is analysis. Derive change from baseline values CHG for each 
post-baseline visit. Other variables in analysis should include: SUBJID, TRT01PN, <Pooled study
center>, AVISITN, <Baseline PANSS total score>, AVAL (PANSS total score at each post-baseline 
visit), and _IMPUTATION_. 
Suppose the primary MMRM model adopted the unstructured covariance model: 
ODS OUTPUT LSMEstimates=lsmest_pbomi CovParms=xxxx Tests3=xxxx; 
PROC MIXED DATA=analysis; 
   BY _IMPUTATION_; 
   CLASS SUBJID <Pooled study center> TRT01PN AVISITN; 
   MODEL CHG = <Baseline PANSS total score> <Pooled study center> TRT01PN AVISITN  
TRT01PN*AVISITN / DDFM=KR SOLUTION; 
   REPEATED AVISITN / SUB=SUBJID TYPE=UN; 
   LSMESTIMATE TRT01PN*AVISITN "SEP-363856 at Day 4"  [1, 1 1], 
"SEP-363856 at Week 1" [1, 1 2], 
"SEP-363856 at Week 2" [1, 1 3], 
"SEP-363856 at Week 3" [1, 1 4], 
"SEP-363856 at Week 4" [1, 1 5] / E CL; 
   LSMESTIMATE TRT01PN*AVISITN "Placebo at Day 4"  [1, 2 1], 
"Placebo at Week 1" [1, 2 2], 
"Placebo at Week 2" [1, 2 3], 
"Placebo at Week 3" [1, 2 4], 
"Placebo at Week 4" [1, 2 5] / E CL; 
   LSMESTIMATE TRT01PN*AVISITN  
"SEP-363856 vs Placebo at Day 4"  [1, 1 1] [-1, 2 1], 


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"SEP-363856 vs Placebo at Week 1" [1, 1 2] [-1, 2 2], 
"SEP-363856 vs Placebo at Week 2" [1, 1 3] [-1, 2 3], 
"SEP-363856 vs Placebo at Week 3" [1, 1 4] [-1, 2 4], 
"SEP-363856 vs Placebo at Week 4" [1, 1 5] [-1, 2 5] / E CL; 
RUN; 
Step 3.2: Extract the diagonal elements of the R matrix (from CovParms). Suppose the diagonal elements are 
stored in variable COVAREST in dataset covar. Dataset covar should also include variables _IMPUTATION_
and AVISITN. Add variable AVISITN also to dataset lsmest_pbomi. Merge covar with lsmest_pbomi by 
_IMPUTATION_ and AVISITN. Then calculate the within group and between group effect sizes at each time 
point. 
DATA lsmest_pbomi; 
   SET lsmest_pbomi; 
   EFFSIZE=ESTIMATE/SQRT(COVAREST); 
RUN;
Step 4: Combine results using Rubin’s imputation rules. 
PROC SORT DATA=lsmest_pbomi; BY LABEL _IMPUTATION_; RUN; 
ODS OUTPUT ParameterEstimates=lsmest_pbomi_mian; 
PROC MIANALYZE PARMS=lsmest_pbomi; 
   BY LABEL; 
   MODELEFFECTS TRT01PN*AVISITN; 
RUN; 
ODS OUTPUT summary=mean_effsize_pbomi; 
PROC MEANS DATA=lsmest_pbomi N MEAN STD MIN MAX Q1 Q3; 
   VAR EFFSIZE; 
   CLASS LABEL; 
RUN; 
TIPPING POINT ANALYSIS 
Step 1: Run the primary MMRM analysis. Obtain LS mean difference between SEP-363856 group and the 
placebo group at each visit. Suppose these values are stored in variable LSMDIFF in dataset diff. This 
dataset should also contain variable AVISITN. These differences will be used when applying penalty on the 
imputed values. 
Step 2: Partial imputation to get monotone missing pattern. 
PROC MI DATA=xxxx OUT=xxxx_mono NIMPUTE=500 SEED=123 MINIMUM=30 MAXIMUM=210  
MINMAXITER=100; 
   BY TRT01PN; 
   VAR <Baseline PANSS total score> PANSS3 PANSS4 PANSS5 PANSS6 PANSS7; 
   MCMC CHAIN=MULTIPLE INITIAL=EM IMPUTE=MONOTONE NBITER=5000 NITER=200; 


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RUN; 
Step 3: Impute the remaining missing data using an MAR-based regression model. 
PROC MI DATA=xxxx_mono OUT=xxxx_impute NIMPUTE=1 SEED=234  
MINIMUM=. . 30 30 30 30 30 30 MAXIMUM=. . 210 210 210 210 210 210  
MINMAXITER=100; 
   BY _IMPUTATION_; 
   VAR TRT01PN <Pooled study center> <Baseline PANSS total score> PANSS3 PANSS4  
PANSS5 PANSS6 PANSS7; 
   CLASS TRT01PN <Pooled study center>; 
   MONOTONE REGRESSION; 
RUN; 
Step 4: For a range of penalty values (i.e. 10%, 20%, 30%, etc. of the LS mean difference obtained in Step 1), 
apply penalty to the change from baseline values calculated from imputed PANSS total scores in the SEP-
363856 group at each post-baseline visit.  
Suppose analysis is the dataset reformatted from xxxx_impute that contains each subject’s data in long 
format. It should contain the missing value flag MISSVAL (i.e. whether the PANSS total score for a given visit 
is missing in the monotone missing data): 1 = missing; 0 = available. Other variables in analysis should 
include: SUBJID, TRT01PN, <Pooled study center>, AVISITN, <Baseline PANSS total score>, 
AVAL (PANSS total score at each post-baseline visit), CHG, LSMDIFF, and _IMPUTATION_. 
DATA analysis_penalty; 
   SET analysis; 
   /* store the original CHG values in ORIGCHG */ 
   ORIGCHG = CHG; 
   /* if a PANSS total score is missing in the original dataset, apply a penalty 
to the CHG value in the SEP-363856 group only */ 
   DELTA = xxx; 
   IF MISSVAL=1 AND TRT01PN=1 THEN CHG = ORIGCHG – ((DELTA/100)*LSMDIFF); 
RUN; 
Repeat the above step for all delta values, i.e. 10, 20, 30, …, 100. 
Step 5: Fit the MMRM model on each imputed and penalized dataset. 
Suppose the MMRM model adopted the unstructured covariance model: 
ODS OUTPUT LSMEstimates=lsmest_tipping CovParms=xxxx; 
PROC MIXED DATA=analysis_penalty; 
   BY DELTA _IMPUTATION_; 
   CLASS SUBJID <Pooled study center> TRT01PN AVISITN; 
   MODEL CHG = <Baseline PANSS total score> <Pooled study center> TRT01PN AVISITN  
TRT01PN*AVISITN / DDFM=KR; 
   REPEATED AVISITN / SUB=SUBJID TYPE=UN; 
   LSMESTIMATE TRT01PN*AVISITN  


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"SEP-363856 vs Placebo at Week 4" [1, 1 5] [-1, 2 5] / E CL; 
RUN; 
Step 6: Combine results using Rubin’s imputation rules. 
PROC SORT DATA=lsmest_tipping; BY DELTA LABEL _IMPUTATION_; RUN; 
ODS OUTPUT ParameterEstimates=lsmest_tipping_mian; 
PROC MIANALYZE PARMS=lsmest_tipping; 
   BY DELTA LABEL; 
   MODELEFFECTS TRT01PN*AVISITN; 
RUN; 


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APPENDIX 4. 
PSQI SOCRING SHEET 
Source: http://www.sleep.pitt.edu/research/instruments.html 


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Pittsburgh Sleep Quality Index (PSQI) 
Form Administration Instructions, References, and Scoring 
Form Administration Instructions 
The range of values for questions 5 through 10 are all 0 to 3. 
Questions 1 through 9 are not allowed to be missing except as noted below.  If these questions are missing 
then any scores calculated using missing questions are also missing.  Thus it is important to make sure that all 
questions 1 through 9 have been answered.   
In the event that a range is given for an answer (for example, ‘30 to 60’ is written as the answer to Q2, minutes 
to fall asleep), split the difference and enter 45. 
Reference 
Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ:  The Pittsburgh Sleep Quality Index:  A new 
instrument for psychiatric practice and research.  Psychiatry Research 28:193-213, 1989. 
Scores – reportable in publications 
On May 20, 2005, on the instruction of Dr. Daniel J. Buysse, the scoring of the PSQI was changed to set the 
score for Q5J to 0 if either the comment or the value was missing.  This may reduce the DISTB score by 1 
point and the PSQI Total Score by 1 point. 
PSQIDURAT  
DURATION OF SLEEP 
IF Q4 > 7, THEN set value to 0 
IF Q4 < 7 and > 6, THEN set value to 1 
IF Q4 < 6 and > 5, THEN set value to 2 
IF Q4 < 5, THEN set value to 3 
Minimum Score = 0 (better); Maximum Score = 3 (worse) 
PSQIDISTB
SLEEP DISTURBANCE
IF Q5b + Q5c + Q5d + Q5e + Q5f + Q5g + Q5h + Q5i + Q5j (IF Q5JCOM is null or 
Q5j is null, set the value of Q5j to 0) = 0, THEN set value to 0 
IF Q5b + Q5c + Q5d + Q5e + Q5f + Q5g + Q5h + Q5i + Q5j (IF Q5JCOM is null or 
Q5j is null, set the value of Q5j to 0) > 1 and < 9, THEN set value to 1 
IF Q5b + Q5c + Q5d + Q5e + Q5f + Q5g + Q5h + Q5i + Q5j (IF Q5JCOM is null or 
Q5j is null, set the value of Q5j to 0) > 9 and < 18, THEN set value to 2 
IF Q5b + Q5c + Q5d + Q5e + Q5f + Q5g + Q5h + Q5i + Q5j (IF Q5JCOM is null or 
Q5j is null, set the value of Q5j to 0) > 18, THEN set value to 3 
Minimum Score = 0 (better); Maximum Score = 3 (worse) 


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PSQILATEN  
SLEEP LATENCY 
First, recode Q2 into Q2new thusly: 
IF Q2 > 0 and < 15, THEN set value of Q2new to 0 
IF Q2 > 15 and < 30, THEN set value of Q2new to 1 
IF Q2 > 30 and < 60, THEN set value of Q2new to 2 
IF Q2 > 60, THEN set value of Q2new to 3 
Next 
IF Q5a + Q2new = 0, THEN set value to 0 
IF Q5a + Q2new > 1 and < 2, THEN set value to 1 
IF Q5a + Q2new > 3 and < 4, THEN set value to 2 
IF Q5a + Q2new > 5 and < 6, THEN set value to 3 
Minimum Score = 0 (better); Maximum Score = 3 (worse) 
PSQIDAYDYS  
DAY DYSFUNCTION DUE TO SLEEPINESS 
IF Q8 + Q9 = 0, THEN set value to 0 
IF Q8 + Q9 > 1 and < 2, THEN set value to 1 
IF Q8 + Q9 > 3 and < 4, THEN set value to 2 
IF Q8 + Q9 > 5 and < 6, THEN set value to 3 
Minimum Score = 0 (better); Maximum Score = 3 (worse) 
PSQIHSE  
SLEEP EFFICIENCY 
Diffsec = Difference in seconds between day and time of day Q1 and day Q3 
Diffhour = Absolute value of diffsec / 3600 
  newtib =IF diffhour > 24, then newtib = diffhour – 24 
       IF diffhour < 24, THEN newtib = diffhour 
(NOTE, THE ABOVE JUST CALCULATES THE HOURS BETWEEN GNT (Q1) AND 
GMT (Q3)) 
tmphse = (Q4 / newtib) * 100 
IF tmphse > 85, THEN set value to 0 
IF tmphse < 85 and > 75, THEN set value to 1 
IF tmphse < 75 and > 65, THEN set value to 2 
IF tmphse < 65, THEN set value to 3 
Minimum Score = 0 (better); Maximum Score = 3 (worse) 
PSQISLPQUAL  
OVERALL SLEEP QUALITY 
Q6 
Minimum Score = 0 (better); Maximum Score = 3 (worse) 
PSQIMEDS  
NEED MEDS TO SLEEP 
Q7 
Minimum Score = 0 (better); Maximum Score = 3 (worse) 
PSQI 
TOTAL 
DURAT + DISTB + LATEN + DAYDYS + HSE + SLPQUAL + MEDS 
Minimum Score = 0 (better); Maximum Score = 21 (worse) 


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Interpretation:   TOTAL < 5 associated with good sleep quality 
TOTAL > 5 associated with poor sleep quality