An 8-Week, Open-Label Study Evaluating the Effectiveness, Safety and Tolerability of SEP-363856 in Subjects With Schizophrenia Switched From Typical or Atypical Antipsychotic Agents
Phase: PHASE3
Conditions: Schizophrenia
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

Titlpage 
 
 
SEP-363856 
Clinical Study Protocol SEP361-308 
 
An 8-Week, Open-Label Study Evaluating the Effectiveness, 
Safety and Tolerability of SEP-363856 in Subjects with 
Schizophrenia Switched from Typical or Atypical Antipsychotic 
Agents 
 
IND No. 115,629 
 
Version 5.00 
Incorporating Substantial Amendment 4.00 
 
06 November 2023 
 
 
SUMITOMO PHARMA AMERICA, INC. 
84 Waterford Drive 
Marlborough, MA 01752, USA 
(508) 481-6700 

Protocol SEP361-308, Version 5.00  
 
SEP-363856 
 
Confidential and Proprietary 
2 
06 Nov 2023 
RESTRICTED DISTRIBUTION OF PROTOCOLS 
This document contains information confidential and/or of proprietary interest to Sumitomo 
Pharma Co., Ltd. (SMP) and/or Sumitomo Pharma America Inc. (SMPA) (including their 
predecessors, subsidiaries or affiliates). The information cannot be disclosed to any third party or 
used for any purpose other than the purpose for which it is being submitted without the prior 
written consent of the appropriate Sumitomo Pharma company. 
This information is being provided to you for the purpose of conducting a clinical study for 
Sumitomo Pharma America, 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 Sumitomo Pharma America, 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 Sumitomo 
Pharma America, Inc., and should be handled consistently with that stated above. 

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Protocol SEP361-308, Version 5.00  
 
SEP-363856 
 
Confidential and Proprietary 
4 
06 Nov 2023 
1. 
SYNOPSIS 
Name of Sponsor/Company: Sumitomo Pharma America, Inc. 
Name of Investigational Product: SEP-363856 
Name of Active Ingredient: SEP-363856-01 (hydrochloride salt) 
Title of Study: An 8-Week, Open-Label Study Evaluating the Effectiveness, Safety and Tolerability 
of SEP-363856 in Subjects with Schizophrenia Switched from Typical or Atypical Antipsychotic 
Agents 
Proposed Indication: Schizophrenia 
Study Centers: Approximately 24 sites in North America 
Phase of Development: 3 
Study Objectives:  
Primary: 
• 
To evaluate the safety and effectiveness of switching clinically stable outpatients with 
schizophrenia from a typical or atypical antipsychotic to SEP-363856 over a period of 
8 weeks as assessed by the percentage of subjects who discontinue from the study due to an 
adverse event or lack of efficacy 
Secondary: 
• 
To evaluate the safety and effectiveness of switching clinically stable outpatients with 
schizophrenia from a typical or atypical antipsychotic to SEP-363856 over a period of 
8 weeks as assessed by the percentage of subjects who discontinue for any reason (ie, all 
causes of discontinuation) 
Other: 
• 
To evaluate the tolerability and safety of switching clinically stable outpatients with 
schizophrenia from a typical or atypical antipsychotic to SEP-363856 over a period of 
8 weeks using:  
o Adverse event reports 
o Clinical laboratory tests 
o Vital sign measurements 
o 12-lead electrocardiograms (ECG) 
o Columbia – Suicide Severity Rating Scale (C-SSRS) 
o Barnes Akathisia Rating Scale (BARS) 
o Abnormal Involuntary Movement Scale (AIMS) 
o Simpson-Angus Scale (SAS) 
• 
To evaluate the effectiveness of SEP-363856 using:  
o Positive and Negative Syndrome Scale (PANSS) 
o Clinical Global Impression-Severity (CGI-S) scale 
o Clinical Global Impression-Improvement (CGI-I) scale 
o Brief Negative Symptom Scale (BNSS) 
• To evaluate the effects of SEP-363856 on health-related quality of life as measured by the 
Short Form Health Survey (SF-12) 

Protocol SEP361-308, Version 5.00  
 
SEP-363856 
 
Confidential and Proprietary 
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06 Nov 2023 
• To evaluate the effects of SEP-363856 on functional capacity as measured by the Personal and 
Social Performance Scale (PSP) 
• To evaluate medication satisfaction as measured by the Medication Satisfaction Questionnaire 
(MSQ) 
• To evaluate sleep as measured by the Pittsburgh Sleep Quality Index (PSQI) 
• To evaluate the impact of SEP-363856 on healthcare resource utilization (HCRU) 
Study Design:  
This is an 8-week, outpatient, multicenter, open-label, single-group, flexible-dose study designed to 
evaluate the safety and tolerability, as well as effectiveness of switching clinically stable adult 
subjects with schizophrenia from a typical or atypical antipsychotic to SEP-363856. This study is 
projected to enroll approximately 120 subjects into a single treatment group (SEP-363856). Over the 
8-week treatment period, subjects will receive flexibly dosed SEP-363856 (50 to 100 mg/day) and the 
Investigator will have the discretion to discontinue each subject’s pre-switch antipsychotic treatment 
by the end of Week 2, 3, 4, 5, or 6. Appropriate duration of pre-switch antipsychotic taper for 
individual subjects will be provided as in Section 21 Appendix II. 
Once the pre-switch antipsychotic has been fully discontinued, subjects will continue to receive 
SEP-363856 flexible 50 to 100 mg/day until study endpoint, at the end of Week 8. Study drug will 
be taken at the same time each evening at bedtime and can be taken with or without food. 
The study will consist of three periods: Screening/Washout (up to 21 days), Treatment (8 weeks) and 
a Follow-up visit (7 ± 2 days after the last dose of study drug for those subjects who discontinue prior 
to the Week 8 visit or who complete the study but do not enroll in the open-label extension study 
SEP361-309) as shown in Figure 1. Overall study design details provided in Section 7.1 and Table 2 
schedule of assessments. 
Number of Subjects (planned): 120 
Diagnosis and Key Criteria for Subject Inclusion:  
Section 8 of the full protocol includes the complete list of inclusion and exclusion criteria. 
Key Inclusion criteria (not all inclusive): 
• 
Male or female subject between 18 to 65 years of age (inclusive) at the time of consent. 
• 
Subject meets Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition (DSM-5) 
criteria for a diagnosis of schizophrenia as established by clinical interview (using the DSM-5 
as a reference and confirmed using the Structured Clinical Interview for DSM-5, Clinical 
Trials Version [SCID-5-CT]). The time since the subject's diagnosis must be ≥ 1 year prior to 
Screening. Every attempt should be made to obtain medical records or to have 
correspondence with a previous or current treating provider for the purposes of confirming 
that the previous course and treatment is consistent with schizophrenia. 
• 
Subject must have a CGI-S score ≤ 4 at Screening and Baseline. 
• 
Subject must have a PANSS total score ≤ 80 at Screening and Baseline. 
• 
Subject is judged to be clinically stable (ie, no evidence of an acute exacerbation of 
schizophrenia) by the Investigator for at least 8 weeks prior to Baseline. 
• 
Subject must not have been hospitalized for psychiatric illness for at least 8 weeks prior to 
Screening. 
• 
Subject must be judged by the Investigator to be an appropriate candidate for switching 
current antipsychotic medication due to safety or tolerability concerns and/or insufficient 
efficacy. 

Protocol SEP361-308, Version 5.00  
 
SEP-363856 
 
Confidential and Proprietary 
6 
06 Nov 2023 
Investigational Product, Dosage and Mode of Administration:  
SEP-363856 tablets (50 mg, 75 mg, or 100 mg) will be utilized. SEP-363856 will be administered 
orally once daily. SEP-363856 will be taken at the same time each evening at bedtime and may be 
taken without regard for food. 
Duration of Treatment: 8 weeks 
Reference Therapy, Dosage and Mode of Administration: Not applicable 
Prior and Concomitant Medications: 
Subjects will remain on their pre-switch antipsychotic and switch to SEP-363856 as described in 
Section 7.1. Subjects who enter Screening on two antipsychotic medications must washout of their 
secondary antipsychotic prior to Baseline (see Section 8.1 Inclusion criterion 12). Subjects are 
permitted to remain on non-prohibited psychotropic medications other than the primary pre-switch 
antipsychotic or secondary antipsychotic, that have been part of their ongoing treatment regimen. 
Except for medications listed in Section 10.3.4, the psychotropic medication must have been stable for 
at least 6 weeks prior to Screening and will be maintained at a stable dose and regimen throughout 
study participation (see Section 10.3.1 for psychotropic medication adjustments).  
Allowable concomitant psychotropic medications are described in Section 10.3.4. Treatment with 
sedative hypnotics is permitted during the Screening/Washout Period but should be tapered as 
clinically appropriate prior to receiving SEP-363856. This is to conform with and adequately prepare 
the subject for the protocol-specified limitations applicable to these agents. 
Medications used to treat extrapyramidal symptoms (EPS) should not be given prophylactically. They 
are to be tapered and discontinued while the pre-switch antipsychotic is being tapered in a manner that 
is consistent with labeling recommendations and conventional medical practice. These medications 
may be reinstated, after consultation with the Medical Monitor, if EPS or akathisia symptoms emerge 
after treatment discontinuation.  
See Section 10.3 for further information on prior and concomitant medications. 
Study Endpoints: 
Primary Endpoint:  
• 
Percentage of subjects who discontinue for clinical reasons (ie, discontinued due to an adverse 
event [AE] or lack of efficacy) 
Secondary Endpoint: 
• 
Percentage of subjects who discontinue for any reason (ie, all causes for discontinuation) 
Other Endpoints: 
• 
The incidence of overall AEs, serious adverse events [SAEs], and AEs leading to 
discontinuation 
• 
Observed values and changes from Baseline in clinical laboratory tests (hematology, 
chemistry and urinalysis) (Section 23 Appendix IV) 
• 
Observed values and changes from Baseline in vital signs (including body weight, body mass 
index [BMI], waist circumference, temperature, blood pressure [supine and standing], heart 
rate [supine and standing] and respiratory rate) 
• 
Observed values and changes from Baseline in 12-lead ECG parameters 
• 
Frequency of subjects with suicidal ideation and suicidal behavior based on the C-SSRS 
• 
Changes from Baseline in BARS, AIMS and SAS scores 
• 
Changes from Baseline to Week 8 in: 

Protocol SEP361-308, Version 5.00  
 
SEP-363856 
 
Confidential and Proprietary 
7 
06 Nov 2023 
o PANSS total score and subscale scores (positive, negative, and general psychopathology) 
o PANSS Marder Factor (five-factor) scores (positive, disorganized, negative, hostility, and 
depression/anxiety), and Uncorrelated PANSS Score Matrix (UPSM) 
o CGI-S score 
o BNSS total score 
o SF-12 scores 
o PSP total score 
o MSQ score 
o PSQI global score 
• 
CGI-I score at Week 8 
• 
HCRU (including numbers of physician office visits, emergency room (ER) visits and 
hospitalizations, length of hospital stays, employment status and average number of hours 
caregiver(s) spends helping subjects per week.) 
• 
Nicotine use at baseline and Week 8 (end of treatment [EOT]/early termination [ET]) 
Statistical Methods:  
The analysis of safety and tolerability, and functionality will be based on the safety population, which 
includes all subjects who receive at least one dose of study drug during the 8-week Treatment Period. 
The analysis of effectiveness will be based on the effectiveness population, which consists of all 
subjects who are enrolled, have received at least one dose of study drug, and have a Baseline and at 
least one post-Baseline effectiveness measurement in PANSS or CGI‑S. 
Percentage of subjects who discontinue for clinical reasons, ie, due to adverse event or lack of 
efficacy, will be summarized by presenting the number and percentage of subjects who drop out of the 
study for each reason. In addition, the subset of subjects who discontinue due to an AE indicative of 
worsening schizophrenic illness will be tabulated separately. 
Percentage of subjects who discontinue for any reason (ie, “all cause discontinuation”) will be 
summarized by presenting the number and percentage of subjects who drop out of the study for each 
reason. 
AEs, AEs leading to discontinuation, and serious AEs will be summarized by presenting 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 up to 9 days following the last 
dose of study drug. All AEs starting after the last dose of study drug up to 9 days following the last 
dose will be summarized separately. 
Observed values and changes from Baseline in clinical laboratory tests (including hematology, 
chemistry and urinalysis), vital sign parameters (temperature, body weight, BMI, waist circumference, 
blood pressure [supine and standing], heart rate [supine and standing], and respiratory rate) and 
12 lead ECG parameters will be summarized descriptively. The frequency of subjects with suicidal 
ideation and suicidal behavior based on the C-SSRS will be provided. 
Measures of motor function will be assessed using the SAS, BARS, and AIMS scales. Mean changes 
from Baseline in these measures by scheduled visit will be presented. 
Descriptive statistics will be presented on the change from Baseline to Week 8 in PANSS total score 
and subscale scores, CGI-S score, BNSS total score, PSP total score, PSQI global score, SF-12 score, 
and MSQ score. For CGI-I score, descriptive statistics by visit, including Week 8, will be presented. 
Descriptive statistics by visit will be presented for the HCRU. The frequency and percentage of 
subjects with physician office visits, ER visits, hospitalizations at Baseline and at each post-Baseline 

Protocol SEP361-308, Version 5.00  
 
SEP-363856 
 
Confidential and Proprietary 
8 
06 Nov 2023 
scheduled visit will be summarized. The change in the number of physician’s office visits, ER visits, 
and hospitalizations per month, the average length of hospital stays, and the average number of hours 
a caregiver spends per week helping the subject from Baseline at each post-Baseline scheduled visit 
will be summarized. 
Subgroup analyses will be described in the statistical analysis plan (SAP). 
Sample Size:  
Approximately 120 subjects will be required for this study. This sample size was determined by the 
width of the 95% confidence interval for the proportion of subjects who may discontinue due to 
clinical reasons by Week 8 to ensure the precision of the estimate of the true discontinuation treatment 
failure rate due to clinical reasons. Assuming 1) 15% of SEP-363856 treated subjects will experience 
discontinuation due to clinical reasons by Week 8 and 2) 6.4% as the half width (the distance between 
the upper/lower limits to the point estimate) of the 95% confidence interval (ie, [8.6%, 21.4%]), 
approximately 120 subjects will be required. 
 

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Protocol SEP361-308, Version 5.00 
 
SEP-363856 
Confidential and Proprietary 
11 
06 Nov 2023 
Table 2: 
Schedule of Assessments (Continued) 
 
Screening 
Period 
Treatment Period 
Follow-up Period 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
 
Screeninga 
Pre-switch 
Baseline 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week 
7 TC 
Week 8b 
EOT/ETc 
Week 9d 
Follow-up 
Study Day e 
Days 
-21 to -1 
Day  
1 
Day  
8 
Day  
15 
Day  
22 
Day  
29 
Day  
36 
Day  
43 
Day  
50 
Day  
57 
7 ± 2 days 
after last dose 
Abnormal Involuntary 
Movement Scale (AIMS)q 
 
X 
 
 
 
 
 
 
 
X 
 
SF-12 
 
X 
 
 
 
 
 
 
 
X 
 
Medication Satisfaction 
Questionnaire (MSQ) 
 
X 
 
 
 
 
 
 
 
X 
 
Personal and Social 
Performance Scale (PSP) 
 
X 
 
 
 
 
 
 
 
X 
 
Healthcare Resource 
Utilization (HCRU)r 
 
X 
 
 
 
 
 
 
 
X 
 
Pretreatment/Adverse events 
(AE) monitorings 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Duplicate Subject Checkt 
X 
 
 
 
 
 
 
 
 
X 
 
Tokenization consent 
(optional) f  
X 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; BARS = Barnes Akathisia Rating Scale; β hCG = human chorionic gonadotropin; BMI = Body Mass Index; BNSS = Brief” 
Negative Symptom Scale; C-SSRS = Columbia Suicide Severity Rating Scale; eCRF = electronic case report form; EDC = electronic data capture; 
DSM-5 = Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition; EOT = end of treatment; ET = early termination; FSH = Follicle stimulating 
hormone; MSQ = Medication Satisfaction Questionnaire; PANSS = Positive and Negative Syndrome Scale; PSP = Personal and Social Performance Scale; 
PK = pharmacokinetic; PSQI = Pittsburgh Sleep Quality Index; SAS = Simpson-Angus Scale; SCID-5-CT = Structured Clinical Interview for DSM-5; 
SF-12 = Short Form Health survey; Clinical Trials Version; TC = telephone contact visit; UDS = urine drug screen. 
a. Subjects who screen fail can be re-screened up to 2 times after consultation with the Medical Monitor. Screening assessments may occur over multiple days. 
The Screening Period may be extended for up to 7 days after approval from the Medical Monitor. 
b. All procedures and assessments scheduled for Week 8 will be utilized as Baseline procedures and assessments for the open-label extension study 
(SEP361-309). 
c. If a subject discontinues from the study, all Early Termination (ET) procedures should be performed at the ET visit, within 48 hours of last study dose. 
d. Subjects who discontinue early from the study or complete the study and do not enter the extension study (SEP361-309) will have a safety Follow-up Visit 
7 (± 2) days after their last dose of study drug. While every effort should be made to complete the Follow-up Visit in the clinic, administration of C-SSRS, and 
collection of AEs, and concomitant medications may occur by telephone contact if the subject is unable to come to the clinic for the Follow-up Visit. 
e. Visit window for Day 8 is +2 days and visit windows post Day 8 are ± 2 days for every Visit. 
f. Requested, but not required for study participation. 

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I

Protocol SEP361-308, Version 5.00 
 
SEP-363856 
Confidential and Proprietary 
13 
06 Nov 2023 
2. 
TABLE OF CONTENTS 
RESTRICTED DISTRIBUTION OF PROTOCOLS ......................................................................2 
EMERGENCY CONTACTS...........................................................................................................3 
1. 
SYNOPSIS ...................................................................................................................4 
2. 
TABLE OF CONTENTS ...........................................................................................13 
LIST OF TABLES .........................................................................................................................19 
LIST OF FIGURES .......................................................................................................................19 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................20 
4. 
INTRODUCTION ......................................................................................................24 
4.1. 
Background .................................................................................................................24 
4.2. 
Study Conduct Rationale ............................................................................................24 
4.3. 
Risk-Benefit Assessment ............................................................................................25 
5. 
STUDY OBJECTIVES ..............................................................................................27 
5.1. 
Primary Objective .......................................................................................................27 
5.2. 
Secondary Objective ...................................................................................................27 
5.3. 
Other Objectives .........................................................................................................27 
6. 
STUDY ENDPOINTS ................................................................................................28 
6.1. 
Primary Endpoint ........................................................................................................28 
6.2. 
Secondary Endpoint ....................................................................................................28 
6.3. 
Other Endpoints ..........................................................................................................28 
7. 
INVESTIGATIONAL PLAN .....................................................................................30 
7.1. 
Overall Study Design ..................................................................................................30 
7.2. 
Treatment Assignment and Blinding ..........................................................................32 
7.2.1. 
Treatment Assignment ................................................................................................32 
7.2.2. 
Blinding ......................................................................................................................32 
7.2.3. 
Emergency Unblinding Procedures ............................................................................32 
7.3. 
Rationale .....................................................................................................................32 
7.3.1. 
Rationale for the Study Design ...................................................................................32 
7.3.2. 
Rationale for the Dosages ...........................................................................................33 
7.3.3. 
Rationale for the Study Population .............................................................................33 
7.3.4. 
Rationale for the Endpoints ........................................................................................34 
7.4. 
Prevention of Missing Data ........................................................................................34 

Protocol SEP361-308, Version 5.00 
 
SEP-363856 
Confidential and Proprietary 
14 
06 Nov 2023 
8. 
SELECTION OF SUBJECTS ....................................................................................35 
8.1. 
Subject Inclusion Criteria ...........................................................................................35 
8.2. 
Subject Exclusion Criteria ..........................................................................................36 
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 ............................................................................41 
10. 
TREATMENT OF SUBJECTS ..................................................................................43 
10.1. 
Study Medication ........................................................................................................43 
10.1.1. 
Dose Adjustment Criteria for SEP-363856 ................................................................43 
10.1.2. 
Pre-switch Antipsychotic Taper .................................................................................43 
10.2. 
Treatment Compliance ................................................................................................43 
10.3. 
Prior and Concomitant Medications ...........................................................................44 
10.3.1. 
Prior Medications ........................................................................................................44 
10.3.2. 
Prohibited Medications ...............................................................................................44 
10.3.3. 
Prohibited Therapies ...................................................................................................45 
10.3.4. 
Allowed Concomitant Psychotropic Medications ......................................................45 
10.3.5. 
Concomitant Non-psychotropic Medications .............................................................46 
10.4. 
Contraception Requirements ......................................................................................47 
10.5. 
Guidance for Overdose ...............................................................................................48 
10.6. 
Eligibility Review Process ..........................................................................................48 
11. 
STUDY ASSESSMENTS ..........................................................................................49 
11.1. 
Demographics and Baseline Characteristics ...............................................................49 
11.2. 
Prior and Concomitant Medication Review ...............................................................49 
11.3. 
Structured Clinical Interview for DSM-5 Axis I Disorders-Clinical Trials 
version (SCID-5-CT) ..................................................................................................49 
11.4. 
Safety Assessments .....................................................................................................49 
11.4.1. 
Adverse Events ...........................................................................................................50 

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CCI

Protocol SEP361-308, Version 5.00 
 
SEP-363856 
Confidential and Proprietary 
16 
06 Nov 2023 
11.9.10. 
Visit 10, End of Treatment (EOT) or Early Termination (ET) - (Week 8; 
Day 57 ± 2 days) .........................................................................................................62 
11.9.11. 
Visit 11 (7 ± 2 days after last dose) - Follow-up Period .............................................63 
11.9.12. 
Unscheduled Visit for Dose Adjustment ....................................................................63 
12. 
SAFETY REPORTING ..............................................................................................65 
12.1. 
Definitions ..................................................................................................................65 
12.1.1. 
Adverse Events ...........................................................................................................65 
12.1.2. 
Serious Adverse Events ..............................................................................................65 
12.2. 
Objective Findings ......................................................................................................66 
12.3. 
Collection and Recording of Adverse Events .............................................................66 
12.4. 
Immediately Reportable Events ..................................................................................68 
12.4.1. 
Serious Adverse Event ................................................................................................68 
12.4.2. 
Pregnancy ...................................................................................................................69 
13. 
TERMINATION OF SUBJECT FROM STUDY ......................................................70 
13.1. 
Criteria for Subject Termination .................................................................................70 
13.2. 
Clinical Assessments After Study Drug Discontinuation ...........................................70 
14. 
STUDY TERMINATION ..........................................................................................71 
15. 
STATISTICS ..............................................................................................................72 
15.1. 
Sample Size ................................................................................................................72 
15.2. 
Analysis Populations ..................................................................................................72 
15.2.1. 
Safety Population ........................................................................................................72 
15.2.2. 
Effectiveness Population ............................................................................................72 
15.3. 
Data Analysis ..............................................................................................................72 
15.3.1. 
Subject Disposition .....................................................................................................72 
15.3.2. 
Study Drug Exposure and Compliance .......................................................................72 
15.3.3. 
Important Protocol Deviations ....................................................................................73 
15.3.4. 
Demographic and Baseline Characteristics ................................................................73 
15.3.5. 
Safety Analyses ..........................................................................................................73 
15.3.5.1. 
Primary and Secondary Endpoint Analysis ................................................................73 
15.3.5.2. 
Adverse Events ...........................................................................................................74 
15.3.5.3. 
Clinical Laboratory Assessments ...............................................................................74 
15.3.5.4. 
ECGs ...........................................................................................................................75 
15.3.5.5. 
Vital Signs ..................................................................................................................75 

Protocol SEP361-308, Version 5.00 
 
SEP-363856 
Confidential and Proprietary 
17 
06 Nov 2023 
15.3.5.6. 
Physical and Neurological Examination .....................................................................75 
15.3.5.7. 
Concomitant Medications ...........................................................................................75 
15.3.5.8. 
Suicidality Measure ....................................................................................................76 
15.3.5.9. 
Measures of Motor Function ......................................................................................76 
15.3.5.10. Pittsburgh Sleep Quality Index ...................................................................................76 
15.3.5.11. Subgroup Analysis (Safety Parameters) .....................................................................76 
15.3.6. 
Effectiveness Analyses ...............................................................................................76 
15.3.6.1. 
Healthcare Resource Utilization .................................................................................77 
15.3.6.2. 
Nicotine Use Information ...........................................................................................77 
15.3.6.3. 
Adjustment for Multiplicity ........................................................................................77 
15.3.7. 
Pharmacokinetic Analysis ..........................................................................................77 
15.3.8. 
Pharmacodynamic Analysis........................................................................................77 
15.3.9. 
Interim Analysis ..........................................................................................................78 
15.3.10. 
Treatment of Missing Data .........................................................................................78 
16. 
PROCEDURE FOR CLINICAL STUDY QUALITY CONTROL /DATA 
COLLECTION, MANAGEMENT, AND QUALITY ASSURANCE ......................79 
16.1. 
Data Collection/Electronic Data Capture (EDC) ........................................................79 
16.2. 
Computerized Systems Used for Source Data ............................................................79 
16.3. 
Study Monitoring ........................................................................................................80 
16.4. 
Audits ..........................................................................................................................81 
16.5. 
Study Documentation .................................................................................................81 
16.6. 
Clinical Laboratory Certification and Normal Values ................................................81 
17. 
ETHICAL AND REGULATORY OBLIGATIONS..................................................82 
17.1. 
Study Conduct ............................................................................................................82 
17.2. 
Institutional Review Board/Independent Ethics Committee ......................................82 
17.3. 
Informed Consent .......................................................................................................83 
17.3.1. 
Consent and Collection of Specimens for Genetic Analysis ......................................83 
17.4. 
Subject Privacy ...........................................................................................................84 
17.5. 
Protocol Amendments and Emergency Deviations ....................................................84 
17.6. 
Records Retention .......................................................................................................85 
17.7. 
Inspection of Records .................................................................................................85 
17.8. 
Financial Disclosure ...................................................................................................85 
17.9. 
Publication Policy .......................................................................................................85 

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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Schedule of Assessments ..............................................................................................9 
Table 3: 
List of Abbreviations ..................................................................................................20 
Table 4: 
Definition of Key Study Terms ..................................................................................23 
Table 5: 
Investigational Product ...............................................................................................40 
Table 6: 
Computerized Systems Used for Source Data ............................................................79 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................30 
 

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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 
5-HT 
5-Hydroxytryptamine (serotonin) 
AE 
Adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BARS 
Barnes Akathisia Rating Scale 
β-hCG 
Beta-Human Chorionic Gonadotropin 
BMI 
Body Mass Index  
BNSS 
Brief Negative Symptom Scale 
BUN 
Blood Urea Nitrogen 
CAP 
College of American Pathologists 
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 
COVID-19 
Coronavirus Disease 2019 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
C-SSRS 
Columbia – Suicide Severity Rating Scale 
DNA 
Deoxyribonucleic Acid 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition 
ECG 
Electrocardiogram 
ECT 
Electroconvulsive Therapy 

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Table 3: 
List of Abbreviations (Continued) 
Abbreviation 
Full Form 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EEG 
Electroencephalogram 
EOT 
End of Treatment 
EPS 
Extrapyramidal Symptoms 
ET 
Early Termination 
ER 
Emergency Room 
FDA 
U.S. Food and Drug Administration 
fMRI 
Functional Magnetic Resonance Imaging  
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HCRU 
Healthcare Resource Utilization 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus  
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee  
IND 
Investigational New Drug 
IPD 
Important Protocol Deviation 
IRB 
Institutional Review Board 
LC-MS/MS 
Liquid chromatography-tandem mass spectrometry method for determining 
plasma concentrations 
LIMS 
Laboratory Information Management System 
LOCF 
Last Observation Carried Forward 
MAOIs 
Monoamine Oxidase Inhibitors 
MCS-12 
Mental Component Summary of the SF-12 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSQ 
Medication Satisfaction Questionnaire 
MTD 
Maximum Tolerated Dose 
 
 

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Table 3: 
List of Abbreviations (Continued) 
Abbreviation 
Full Form 
OLE 
Open Label Extension 
PANSS 
Positive And Negative Syndrome Scale 
PCS 
Potentially Clinically Significant 
PCS-12 
Physical Component Summary of the SF-12 
PD 
Pharmacodynamic(s) 
PE 
Physical Examination 
PGx 
Pharmacogenomic(s) 
PK 
Pharmacokinetic(s) 
POPPK 
Population Pharmacokinetics 
PPD-PVG 
CRO acting on Sunovion’s behalf for Pharmacovigilance activities 
PR interval 
Time between P wave and QRS in electrocardiography 
PS 
Pre-Switch 
PSP 
Personal and Social Performance Scale 
PSQI 
Pittsburgh Sleep Quality Index 
PT 
Preferred Term 
PVG 
Pharmacovigilance 
QRS interval 
Electrocardiographic wave (complex or interval) 
QT interval 
Electrocardiographic interval from the beginning of the QRS complex to the 
end of the T wave 
QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
REM 
Rapid Eye Movement 
RR interval 
Distance between two consecutive R waves 
RTSM 
Randomization and Trial Supply Management system 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Simpson-Angus Scale 
SCID-5-CT 
Structured Clinical Interview for DSM-5, Clinical Trials Version 
SF-12 
Short Form Health Survey 
 
 

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Table 3: 
List of Abbreviations (Continued) 
Abbreviation 
Full Form 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TAAR1 
Trace Amine Associated 1 Receptors 
UDS 
Urine Drug Screen 
UPSM 
Uncorrelated PANSS Score Matrix 
US, USA 
United States, United States of America 
WHO-DD 
World Health Organization - Drug Dictionary 
 
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 dosed. 
Study Drug (or 
Study medication) 
Term to cover investigational drug. 
Treatment Period 
The period of the study in which the study drug is administered. 
Completed Subject 
Any subject who participated throughout the duration of the Treatment Period, 
up to and including Week 8. 
Early Termination 
Subject 
Any subject who was successfully screened and was dosed into the Treatment 
Period of the study but did not complete the Treatment Period of the study. 
End of Treatment 
The day that the subject receives protocol-defined last dose of the study drug.  

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4. 
INTRODUCTION 
4.1. 
Background 
Schizophrenia is a chronic and disabling neurodegenerative disorder characterized by a mixture 
of positive symptoms (eg, hallucinations, delusions, and disordered thought), 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). Despite scientific 
advances, schizophrenia remains one of the most challenging diseases to treat due to its variable 
nature, the heterogeneity of clinical response, and the side effects associated with current 
treatments. New treatments with greater efficacy and tolerability are needed to reduce the 
associated high rates of morbidity and mortality (Lehman-2004; Tandon-2008). 
The patient population with schizophrenia is estimated to be about 2.2 million in the United 
States (US) and 51 million worldwide, with an incidence of 100,000 patients/year in the US and 
1.5 million patients worldwide (Schizophrenia Statistics 2022). Schizophrenia is believed to be 
caused by a combination of genetic and environmental factors (Minzenberg-2008), and 
dopaminergic, serotonergic, and glutamatergic systems are believed to play a role in the disease 
pathology and symptomatology (Kuroki-2008; Kim-2009). Presently available treatments are 
only partially effective in alleviating acute and chronic symptoms. 
The current standard of care for the treatment of schizophrenia is the use of second generation 
antipsychotics or “atypical antipsychotics” (Lehman-2004; Kreyenbuhl-2009; 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 are 
associated with 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 comorbid 
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 before 18 months because of lack of efficacy or occurrence of side 
effects (Lieberman-2005). Noncompliance often leads to relapse of symptoms and the need for 
rehospitalization (Ascher-Svanum-2010; Munro-2011; Morken-2008). Clearly, an unmet need 
exists for new, effective, and well-tolerated treatments for schizophrenia. 
4.2. 
Study Conduct Rationale 
SEP-363856 is a central nervous system (CNS)-active compound, which shows broad efficacy in 
animal models of schizophrenia (ie. positive and negative symptoms), cognition, and depression. 
The molecular target responsible for the therapeutic profile of SEP-363856 has not been 
completely elucidated, but it does not act on dopamine D2 receptors and it has agonist activity at 
trace amine–associated receptor 1 (TAAR1) and 5-hydroxytryptamine type 1A (5-HT1A) 

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receptors, which suggests SEP-363856 may represent a new class of psychotropic agent for the 
treatment of psychosis in schizophrenia (Koblan-2020; Dedic-2021). 
SEP-363856 has shown broad efficacy in animal models of schizophrenia (Dedic-2019). Rat 
electroencephalogram (EEG) 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. 
As of 24 September 2021, in clinical studies, a total of 914 adult subjects have received oral 
doses of SEP-363856 in 16 completed and 6 ongoing studies. A total of 657 adult subjects 
received oral doses of SEP-363856 in completed and ongoing studies in subjects with 
schizophrenia. SEP-363856 demonstrated statistically significant efficacy and overall safety and 
tolerability compared to placebo in a Phase 2 clinical trial, SEP361-201, in acutely ill adults with 
schizophrenia (Koblan-2020) and in a long-term open-label extension, SEP361-202 
(Correll-2021). Additional acute and long-term Phase 3 studies of acute schizophrenia are 
underway. 
Switching between antipsychotic medications is common in the treatment of schizophrenia 
(Faries-2009). There may be many reasons for switching antipsychotic treatment, including 
unsatisfactory response to current treatment, poor tolerability, comorbid physical and psychiatric 
conditions, and patient request. Clinically warranted switches can provide benefits by enhancing 
treatment effectiveness, tolerability, and overall acceptance by patients (Weiden-2003). Studies 
have shown that up to one-third of outpatients with schizophrenia in the United States switch 
antipsychotic therapy within one year (Weiden-2006, Buckley-2007). According to most 
empirically based criteria (Kinon-2000), successful switching paradigms involve gradual 
discontinuation of the original antipsychotic drug upon initiation of the new treatment. Individual 
patient characteristics, as well as the binding profile and dose level of the original antipsychotic, 
can influence the appropriate duration for successful discontinuation (Buckley-2007; 
Cerovecki-2013; Takeuchi-2018). 
In light of the novel mechanism of action of SEP-363856, it is important to understand the safety 
and effectiveness by which a patient can be switched to SEP-363856 using common methods 
employed in a clinical outpatient setting. 
Therefore, the current study is an 8-week, outpatient, multicenter, flexible-dose, single-group 
study designed to evaluate safety and tolerability as well as effectiveness of switching clinically 
stable outpatients with schizophrenia, who can potentially benefit from a switch for tolerability 
or efficacy reasons, from their pre-switch antipsychotic medication to SEP-363856. 
4.3. 
Risk-Benefit Assessment 
In an adequate and well-controlled 4-week Phase 2 study in adults with schizophrenia 
(Study SEP361-201), SEP-363856 demonstrated a statistically significant improvement in 
Positive and Negative Syndrome Scale (PANSS) total score compared to placebo with an effect 
size of 0.45, supporting antipsychotic efficacy. 
Coadministration of SEP-363856 with other antipsychotic drugs during a 2 to 6-week cross taper 
has not been fully elucidated. 

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Hypotension / orthostatic hypotension and syncope are potential risks associated with 
administration of SEP-363856 to subjects with schizophrenia. In general, events of hypotension / 
orthostatic hypotension experienced by the schizophrenia population have been transient, mild or 
moderate in severity, non-serious, infrequently led to discontinuation of study drug, and did not 
require concomitant treatment or intervention. In general, events of syncope experienced by 
subjects with schizophrenia have been self-limiting, non-serious, transient (duration of the 
associated loss of consciousness [when reported] ranged between 10-20 seconds), moderate in 
intensity, did not lead to discontinuation of study drug, and did not require concomitant treatment 
or intervention. 

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5. 
STUDY OBJECTIVES 
5.1. 
Primary Objective 
• To evaluate the safety and effectiveness of switching clinically stable outpatients with 
schizophrenia from a typical or atypical antipsychotic to SEP-363856 over a period of 
8 weeks as assessed by the percentage of subjects who discontinue from the study due 
to an adverse event or lack of efficacy 
5.2. 
Secondary Objective 
• To evaluate the safety and effectiveness of switching clinically stable outpatients with 
schizophrenia from a typical or atypical antipsychotic to SEP-363856 over a period of 
8 weeks as assessed by the percentage of subjects who discontinue for any reason (ie, 
all causes of discontinuation) 
5.3. 
Other Objectives 
• To evaluate the tolerability and safety of switching clinically stable outpatients with 
schizophrenia from a typical or atypical antipsychotic to SEP-363856 over a period of 
8 weeks using:  
o Adverse event reports 
o Clinical laboratory tests 
o Vital sign measurements 
o 12-lead electrocardiograms (ECG) 
o Columbia – Suicide Severity Rating Scale (C-SSRS) 
o Barnes Akathisia Rating Scale (BARS) 
o Abnormal Involuntary Movement Scale (AIMS) 
o Simpson-Angus Scale (SAS) 
• To evaluate the effectiveness of SEP-363856 using:  
o Positive and Negative Syndrome Scale (PANSS) 
o Clinical Global Impression-Severity (CGI-S) scale 
o Clinical Global Impression-Improvement (CGI-I) scale 
o Brief Negative Symptom Scale (BNSS) 
• To evaluate the effects of SEP-363856 on health-related quality of life as measured 
by the Short Form Health Survey (SF-12) 
• To evaluate the effects of SEP-363856 on functional capacity as measured by the 
Personal and Social Performance Scale (PSP) 
• To evaluate medication satisfaction as measured by the Medication Satisfaction 
Questionnaire (MSQ) 
• To evaluate sleep as measured by the Pittsburgh Sleep Quality Index (PSQI) 
• To evaluate the impact of SEP-363856 on healthcare resource utilization (HCRU) 

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6. 
STUDY ENDPOINTS 
6.1. 
Primary Endpoint 
• Percentage of subjects who discontinue for clinical reasons (ie, discontinued due to an 
adverse event [AE] or lack of efficacy) 
6.2. 
Secondary Endpoint 
• Percentage of subjects who discontinue for any reason (ie, all causes for 
discontinuation) 
6.3. 
Other Endpoints 
• The incidence of overall AEs, serious adverse events [SAE]s, and AEs leading to 
discontinuation 
• Observed values and changes from Baseline in clinical laboratory tests (hematology, 
chemistry and urinalysis) (Section 23 Appendix IV) 
• Observed values and changes from Baseline in vital signs (including body weight, 
body mass index [BMI], waist circumference, temperature, blood pressure [supine 
and standing], heart rate [supine and standing] and respiratory rate) 
• Observed values and changes from Baseline in 12-lead ECG parameters 
• Frequency of subjects with suicidal ideation and suicidal behavior based on the 
C-SSRS 
• Changes from Baseline in BARS, AIMS and SAS scores 
• Changes from Baseline to Week 8 in: 
o PANSS total score and subscale scores (positive, negative, and general 
psychopathology) 
o PANSS Marder Factor (five-factor) scores (positive, disorganized, negative, 
hostility, and depression/anxiety), and Uncorrelated PANSS Score Matrix 
(UPSM) 
o CGI-S score 
o BNSS total score 
o SF-12 scores 
o PSP total score 
o MSQ score 
o PSQI global score 
• CGI-I score at Week 8 

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• HCRU (including numbers of physician office visits, emergency room [ER] visits and 
hospitalizations, length of hospital stays, employment status and average number of 
hours caregiver(s) spends helping subjects per week.) 
• Nicotine use at baseline and Week 8 (end of treatment [EOT]/early termination [ET]) 

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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is an 8-week, outpatient, multicenter, open-label, single-group, flexible-dose study designed 
to evaluate the safety and tolerability, as well as effectiveness of switching clinically stable adult 
subjects with schizophrenia from a typical or atypical antipsychotic to SEP-363856. This study is 
projected to enroll approximately 120 subjects into a single treatment group (SEP-363856). Over 
the 8-week treatment period, subjects will receive flexibly dosed SEP-363856 (50 to 
100 mg/day) and the Investigator will have the discretion to discontinue each subject’s 
pre-switch antipsychotic treatment by the end of Week 2, 3, 4, 5, or 6. Appropriate duration of 
pre-switch antipsychotic taper for individual subjects will be provided as in Section 21 Appendix 
II. 
Once the pre-switch antipsychotic has been fully discontinued, subjects will continue to receive 
SEP-363856 flexible 50 to 100 mg/day until study endpoint, at the end of Week 8. Study drug 
will be taken at the same time each evening at bedtime and can be taken with or without food. 
The study will consist of three periods: Screening/Washout (up to 21 days), Treatment (8 weeks) 
and a Follow-up visit (7 ± 2 days after the last dose of study drug for those subjects who 
discontinue prior to the Week 8 visit or who complete the study but do not enroll in the 
open-label extension study SEP361-309). 
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 11.9, Study Visits and Assessments. If necessary, subjects may return to the clinic at any 
time for an unscheduled visit. 
 
Figure 1: Study Schematic 
 
 
 

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Screening Period (up to 21 days): 
Informed consent will be obtained from each subject before any study procedures are performed. 
Subjects will be evaluated for eligibility during a Screening Period of up to 21 days, during 
which they will continue on their pre-switch antipsychotic medication while being tapered off 
any prohibited medications (Section 10.3.2) in a manner that is consistent with labeling 
recommendations and conventional medical practices. Non-prohibited psychotropic medications 
other than the pre-switch antipsychotic may be continued during the study but must have been 
stable for at least 6 weeks prior to Screening and should be maintained at a stable dose and 
regimen (see Section 10.3.1). 
Subjects who are being treated with two antipsychotic medications will be permitted to enter the 
Screening Period. At the start of Screening, the Investigator will determine which antipsychotic 
medication is considered “primary”, and the other one will be tapered off during the Screening 
Period. 
Subjects who screen fail may be re-screened twice, if judged appropriate by the Investigator after 
discussion with the Medical Monitor. Re-screened subjects will be re-consented, assigned a new 
subject number, and all Visit 1 procedures will be repeated. 
Open-label Treatment Period (8 weeks): 
At Baseline (Day 1) (pre-switch [PS] Baseline), subjects who have successfully completed 
Screening and have met the eligibility criteria will begin open-label treatment with SEP-363856 
while continuing to take the full dose of their pre-switch antipsychotic. SEP-363856 dosing will 
begin the evening of the PS Baseline visit and will continue once-daily, in the evening at 
bedtime, for the remainder of the Treatment Period, during which the procedures outlined in 
Table 2 will be conducted. Subjects will be evaluated at PS Baseline and weekly throughout the 
rest of the study. Section 10.3 describes the circumstances and specifications for which prior and 
concomitant psychotropic medications other than the pre-switch antipsychotic are allowed in this 
study.  
Subjects will receive SEP-363856 50 mg/day from Day 1 through Day 3 and 75 mg/day from 
Day 4 through Day 7. Every effort should be made to maintain subjects at 75 mg/day from Day 4 
through Day 7. Beginning on Day 8, the dose of SEP-363856 can be adjusted in increments of 
25 mg among 3 dose levels (50, 75 and 100 mg), according to the following requirements: 
• The SEP--363856 dose should be increased to 100 mg/day on Day 8 to help ensure 
adequate coverage of symptoms, provided there are no significant tolerability 
problems as judged by the Investigator. Dose increases are to be made no more 
frequently than weekly to the next highest dose level (in 25 mg increments). Increases 
in dose will occur at regularly scheduled study visits, when possible. Dose increases 
between regularly scheduled visits may occur after prospective approval by the 
Medical Monitor. If a dose increase is performed between regularly scheduled visits, 
subjects will be required to return to the clinic at an unscheduled visit for drug 
dispensation. 
• SEP-363856 dose reductions can be made to the next lowest dose level (in 25 mg 
increments) at any time beginning on Day 8 for safety and intolerability issues as 

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judged by the Investigator. If a dose decrease is needed between study visits, subjects 
will be asked to return to the clinic for an unscheduled visit for drug dispensation. 
Beginning on Day 8, the Investigator is permitted to start tapering the subject’s pre-switch 
antipsychotic (further guidelines are provided in Section 21 Appendix II). The Investigator has 
the discretion to complete the discontinuation of the pre-switch antipsychotic by the end of 
Weeks 2, 3, 4, 5, or 6. As outlined in Section 10.3.4, concomitant medications for the treatment 
of extrapyramidal symptoms (EPS) and akathisia will be tapered during the antipsychotic 
tapering period. Once the pre-switch antipsychotic has been fully discontinued, subjects will 
remain on SEP-363856 (50 to 100 mg/day) until the end of Week 8. 
For subjects who have received study drug and who prematurely discontinue from the study 
treatment, every effort should be made to complete procedures within 48 hours of the last study 
drug dose at the end of treatment (EOT)/early termination (ET) visit. 
Subjects who complete the 8-week Open-label Treatment Period will be eligible to participate in 
a separate open-label extension study (Study SEP361-309). Subjects who early terminate (ET) 
from the SEP361-308 study are not eligible to enroll in SEP361-309. 
Follow-up Period (1 week): 
Subjects who take any dose of SEP-363856 then discontinue early from the study or complete 
study and do not enter the extension study (Study SEP361-309) will be required to complete the 
Follow-up Visit 7 days (± 2 days) post last dose of study drug. 
7.2. 
Treatment Assignment and Blinding 
7.2.1. 
Treatment Assignment 
This is an open label, flexibly dosed SEP-363856 (50 to 100 mg/day) study. 
7.2.2. 
Blinding 
This is an open label study. 
7.2.3. 
Emergency Unblinding Procedures 
This is an open label study. 
7.3. 
Rationale 
7.3.1. 
Rationale for the Study Design 
The 8-week, outpatient, single-group, open-label design with flexible dosing and flexible switch 
duration was chosen to approximate a usual care setting for stable outpatients with schizophrenia 
who are in need of a switch from a previous antipsychotic. There will be a screening period to 
confirm diagnosis and ensure enrollment criteria are met. Subjects who satisfy enrollment 
criteria will be maintained on an antipsychotic treatment and enter an 8-week switch period 
where SEP-363856 is introduced during the first week using the same procedure as has been 
used in prior phase 2 and phase 3 studies (ie, start at 50 mg/day for Days 1-3, followed by 
75 mg/day for Days 4-7). The pre-switch antipsychotic will not be adjusted during the first week 
of the study while Investigators are introducing SEP-363856. Beginning on Day 8, Investigators 

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will have the option to taper the pre-switch antipsychotic by the end of Week 2, 3, 4, 5, or 6. The 
variable duration for tapering of the pre-switch antipsychotic is intended to approximate a real-
world clinical environment whereby the Investigator considers the needs of the individual patient 
as well as clinically relevant issues that could influence the switch outcome, such as reason for 
switch, type of pre-switch antipsychotic, dosage etc. Concomitant psychotropic medications that 
serve as adjuncts to antipsychotic treatment are common in clinical management of 
schizophrenia, and the study design permits enrollment of subjects taking non-prohibited 
concomitant psychotropic medications to support generalizability of the study results (see 
Section 10.3.1). All study subjects who complete the 8-week switch period will have experienced 
a minimum of 2 weeks on SEP-363856 monotherapy.  
Study completers will be eligible to roll over into the 24-week open label extension study 
SEP361-309 for purposes of evaluating longer-term safety and tolerability as well as 
effectiveness of SEP-363856 in subjects switched from typical or atypical antipsychotic agents. 
7.3.2. 
Rationale for the Dosages 
Selection of these doses was guided by the results from the development program to-date, 
including the maximum tolerated dose (MTD) determined for single doses of SEP-363856 
administered to subjects with schizophrenia in Study SEP361-105 (100 mg); by the single doses 
administered to healthy adult subjects in Studies SEP361-103 and SEP361-104 (50 mg) which 
were found to have robust CNS activity and by Study SEP361-201, which demonstrated a 
statistically significant difference in change from Baseline to Week 4 in PANSS total score for 
SEP-363856 (50 to 75 mg/day flexible dose) versus placebo in adults with an acute exacerbation 
of schizophrenia and which showed that SEP-363856 at doses of 50 to 75 mg/day for up to 
28 days was well-tolerated. 
The MTD for multiple doses of SEP-363856 in adults with schizophrenia was previously 
determined to be 75 mg/day (Study SEP361-106). In Study SEP361-106, as more than 50% of 
SEP-363856 subjects in 100 mg/day cohort (5 of 9 subjects) experienced multiple moderate AEs 
assessed as related to SEP-363856 the protocol defined MTD for multiple daily oral 
administration of SEP-363856 to adult subjects with schizophrenia was determined as 
75 mg/day. The only moderate AEs assessed as related to SEP-363856 experienced by more than 
1 subject in the 100 mg/day dose group were somnolence and dizziness, none of which resulted 
in treatment discontinuation. 
However, in Study SEP361-201, where the majority of subjects received 75 mg/day for 4 weeks, 
the tolerability and safety profile was shown to be similar to that of placebo. This indicates that a 
dose higher than 75 mg/day may be tested to maximize efficacy, based on an acceptable 
expected benefit/risk ratio. In study SEP361-201, subjects were required to receive 50 mg/day 
for at least 3 days before titrating up to 75 mg/day. The dose of 100 mg/day was chosen because 
it is the highest dose in the proposed therapeutic dose range being examined in the ongoing 
Phase 3 program (25 to 100 mg). 
7.3.3. 
Rationale for the Study Population 
The study population will be similar to the population studied in other clinical switch studies in 
this indication. It will be comprised of adult outpatients aged 18 to 65 years old with a diagnosis 
of schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders – Fifth 

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Edition (DSM-5). Due to the outpatient nature of this study, subjects are also required to be 
judged psychiatrically stable, having had no evidence of an acute exacerbation of schizophrenia 
for at least 8 weeks prior to Baseline, no hospitalizations for psychiatric illness for at least 
8 weeks prior to screening, and are taking a stable antipsychotic regimen for at least 6 weeks 
prior to screening. Subjects must be judged by the Investigator to be an appropriate candidate for 
switching current antipsychotic medication due to safety or tolerability concerns and/or 
insufficient efficacy. Subjects who are taking additional psychotropic medications are being 
permitted in the study in order to enroll subjects who are representative of the target 
schizophrenia clinical population in support of sample generalizability to the schizophrenia 
population at large. 
7.3.4. 
Rationale for the Endpoints 
The objective of this study is to demonstrate that clinically stable outpatients with schizophrenia 
who are in need of a switch from their current antipsychotic treatment can be safely and 
effectively transitioned to SEP-363856. The primary outcome measure, discontinuations due to 
clinical reasons, is a descriptive measure providing a percentage of subjects who drop out of the 
study due to safety or lack of efficacy. The secondary outcome measure, discontinuations due to 
any reason, is a similar descriptive index producing a percentage of subjects who drop out of the 
study for all causes, including but not limited to clinical reasons. Together, these endpoints will 
provide important information on the likelihood of a successful switch from a previous 
antipsychotic treatment to SEP-363856. Other endpoints in this study include standard safety 
measures (eg, AE’s, SAE’s, movement disorder measures, cardiometabolic measures) and 
validated efficacy assessments for schizophrenia (eg, PANSS, CGI-S, CGI-I) that were also 
employed in phase 2 and phase 3 studies of SEP-363856 for the purpose of providing important 
safety and efficacy data. Additionally, validated functional measures assessing social 
performance, medication satisfaction, quality of life, sleep, and healthcare utilization are 
intended to provide information on real-world and overall health aspects associated with 
transitioning between treatments. 
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: 
• Study is conducted as outpatient. 
• Some concomitant psychotropic medications are allowed, as needed, during study 
participation. 
• Dose reductions of SEP-363856 are allowed for drug tolerability purposes. 
• Study centers are chosen based on a strong record of enrolling and retaining eligible 
subjects and producing quality data. 
• Study centers are trained 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. 
• Data collection is monitored at the site level for adherence during the study. 
See Section 15.3.10 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. In the Investigator’s opinion, the subject is appropriate for this study and is willing and 
able to comply with the protocol, including taking study medication, attending required 
visits and adhering to study procedures. 
3. Subject must be able to understand and follow verbal and written instructions. 
4. Male or female subject between 18 to 65 years of age (inclusive) at the time of consent. 
5. Subject meets DSM-5 criteria for a diagnosis of schizophrenia as established by clinical 
interview (using the DSM-5 as a reference and confirmed using the Structured Clinical 
Interview for DSM-5, Clinical Trials Version [SCID-5-CT]). The time since the subject's 
diagnosis must be ≥ 1 year prior to Screening. Every attempt should be made to obtain 
medical records or to have correspondence with a previous or current treating provider 
for the purposes of confirming that the previous course and treatment is consistent with 
schizophrenia. 
6. Subject must have a CGI-S score ≤ 4 at Screening and Baseline. 
7. Subject must have a PANSS total score ≤ 80 at Screening and Baseline. 
8. Subject is judged to be clinically stable (ie, no evidence of an acute exacerbation of 
schizophrenia) by the Investigator for at least 8 weeks prior to Baseline. 
9. Subject must not have been hospitalized for psychiatric illness for at least 8 weeks prior 
to Screening. 
10. Subject must be judged by the Investigator to be an appropriate candidate for switching 
current antipsychotic medication due to safety or tolerability concerns and/or insufficient 
efficacy. 
11. Subject is taking an oral antipsychotic and the antipsychotic regimen has been stable for 
at least 6 weeks prior to Screening. Subjects are permitted to remain on non-prohibited 
psychotropic medications other than the primary pre-switch antipsychotic that have been 
part of their ongoing treatment regimen as described in Section 10.3.1. 
12. Subjects taking two antipsychotic medications (but not more) at screening are eligible for 
study inclusion, provided the total daily dose is equivalent to ≤ 12 mg/day haloperidol. 
However, the antipsychotic medication determined to be “secondary”, based on 
Investigator judgment, must be discontinued prior to receiving SEP-363856. All subjects 
must be on a single antipsychotic medication at study baseline (Day 1). 
13. Subject’s body mass index (BMI) must be 18 kg/m2 to 40 kg/m2 (inclusive) at 
Screening. 

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14. For subjects taking nonpsychotropic medications for treating allowed chronic medical 
conditions, the dose and regimen must have been stable (± 25% total daily dose) for at 
least 30 days prior to screening. 
15. Female subjects of childbearing potential must have a negative serum pregnancy test at 
Screening. 
16. Female subjects of childbearing potential must agree to use acceptable 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. Details on contraception requirement are provided in Section 10.4. 
17. Male subjects must agree to avoid fathering a child and to use acceptable effective 
methods of birth control from screening until at least 30 days after the last study drug 
administration. Details on contraception requirement are provided in Section 10.4. 
18. Subject is, in the opinion of the Investigator, generally healthy based on screening 
medical history, physical examination (PE), neurological examination, vital signs, 
electrocardiogram (ECG) and clinical laboratory values (hematology, chemistry and 
urinalysis). 
19. Subject has a stable living arrangement at the time of Screening and anticipates stable 
living arrangement for the duration of the study. 
20. Subject’s eligibility confirmed through formal review process (See Section 10.6). 
 
8.2. 
Subject Exclusion Criteria 
Subjects who meet any of the following criteria will not be eligible to participate in the study: 
Note: For clinical laboratory criteria, retesting is allowed once, and the retest results will be 
used to determine eligibility. 
1. Subject has a current DSM-5 diagnosis or presence of symptoms consistent with a major 
psychiatric disorder, other than schizophrenia, that is the primary focus of treatment. 
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), or lifetime history of schizoaffective disorder or bipolar I or II disorder.  
2. Subject is judged to be resistant to antipsychotic treatment by the Investigator, based on 
failure to respond to 2 or more marketed antipsychotic agents within a 1-year period prior 
to Screening, given at adequate dose as per labeling, for at least 4 weeks. 
3. Subject is receiving a total daily dose of antipsychotic medication equivalent to 
> 12 mg/day haloperidol at Screening (See Section 22, Appendix III for haloperidol 
equivalent doses for common oral antipsychotic medications). 
4. Subject has demonstrated a clinically significant change in symptom status according to 
Investigator judgment between Screening and Baseline. 
5. 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 

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and intent) on the C-SSRS assessment at Screening (ie, in the past one month) or at 
Baseline (ie, since last visit). 
6. Subject is at significant risk of harming self or others based on Investigator’s judgment. 
7. Subject has attempted suicide within 6 months prior to Screening. 
8. Subject has received treatment with any of the following psychotropic medications, 
which are prohibited during the study, unless the following washout requirements are met 
(See Section 10.3.2 for further details): 
• Monoamine oxidase inhibitors (MAOIs) must be discontinued at least 28 days prior 
to receiving SEP-363856. 
• Subjects with a history of treatment with clozapine for any reason at doses greater 
than 200 mg/day or at doses less than or equal to 200 mg/day for an indication other 
than insomnia, agitation, or anxiety are excluded from study participation. Clozapine 
used at 200 mg/day or less for insomnia, agitation, or anxiety must be discontinued 
prior to Study Day 1 dosing over a 1–2-week period, as judged to be safe by the 
Investigator. 
• Depot neuroleptics must have been discontinued at least 6 weeks or one cycle 
(whichever is longer) prior to receiving SEP-363856. 
9. Subject has received electroconvulsive therapy (ECT) treatment within the 3 months 
prior to Screening or is expected to require ECT during the study. 
10. 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 (Note: Every attempt should 
be made to obtain medical records for any pre-existing medical conditions that impact a 
subject’s eligibility): 
a. Hematological (including deep vein thrombosis) or bleeding disorder, renal, 
metabolic, endocrine, pulmonary, gastrointestinal, urological, cardiovascular 
(including unstable hypertension), hepatic, neurologic, or allergic disease that is 
clinically significant or unstable (except for seasonal allergies). Note: Any subject 
with a known cardiovascular disease or condition, including hypertension (even if 
under control and considered stable) must be discussed with the Medical Monitor 
before receiving SEP-363856 in the study. 
b. Subject has a history of neuroleptic malignant syndrome or serotonin syndrome. 
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. 
d. Subject has a history of pituitary tumors of any duration. 
e. Subject has a history of malabsorption. 
f. Subject has a clinically significant abnormal 12-lead ECG that may jeopardize the 
subject’s ability to complete the study or that may confound study results as 
determined by the Investigator, or a Screening centrally overread 12-lead ECG 
demonstrating any one of the following: heart rate > 100 beats per minute, heart rate 
< 50 beats per minute, QRS > 120 ms, QT interval corrected for heart rate using 

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Fridericia’s formula (QTcF) > 450 ms (males), QTcF > 470 ms (females), or 
PR > 220 ms. Subjects with an ECG that has a centrally overread overall 
interpretation of “abnormal, significant” or “abnormal, potentially clinically 
significant” must be discussed with the Medical Monitor. A repeat ECG for 
determination of eligibility may be administered once during the Screening Period 
and once at Baseline; requests for additional repeat ECGs must be discussed with the 
Medical Monitor. The repeat ECG during Screening can be conducted on a different 
day within the Screening Period, if needed. 
g. Subjects with known history of human immunodeficiency virus (HIV) seropositivity. 
h. Subject has type I diabetes mellitus or insulin-dependent type II diabetes. 
i. In the Investigator’s judgment, the subject has current symptoms suggestive of a 
diagnosis of Coronavirus Disease 2019 (COVID-19), or the presence of long-term 
medical, neurologic, or psychiatric sequelae of prior COVID-19. 
11. Subject has a history of sick sinus syndrome, second or third-degree atrioventricular 
(AV) block, New York Heart Association (NYHA) Class II-IV heart failure, congenital 
long QT syndrome, or ECG findings of myocardial ischemia/infarction or the following 
cardiac arrhythmias: atrial flutter or fibrillation, junctional rhythm, idioventricular 
rhythm, supraventricular tachycardia, ventricular tachycardia. 
12. Female subject who is pregnant or lactating. 
13. Subject with a supine systolic blood pressure ≥ 150 mmHg and/or supine diastolic blood 
pressure ≥ 95 at Screening or Baseline. A repeat blood pressure measurement is allowed 
once during the Screening Period and once at Baseline; requests for additional repeat 
blood pressure measurements for determination of eligibility must be discussed with the 
Medical Monitor. The repeat blood pressure measurement at Screening can be conducted 
on a different day within the screening period, if needed. 
14. Subject has any clinically significant abnormal laboratory value(s) at Screening 
(hematology, chemistry, and urinalysis) as determined by the Investigator. (Note: 
Retesting to determine eligibility is allowed once during the Screening Period. Abnormal 
findings of questionable significance will be discussed with the Medical Monitor prior to 
including any subject.) 
15. Subject demonstrates evidence of acute hepatitis, clinically significant chronic hepatitis, 
or evidence of clinically significant impaired hepatic function through clinical and 
laboratory evaluation. Subjects who test positive for hepatitis C antibody at Screening 
and have a positive or indeterminate confirmatory test for hepatitis C are excluded. 
Subjects who test positive for hepatitis B surface antigen at screening are excluded. 
16. Subjects with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3 
times the upper limit of the reference ranges provided by the central laboratory at 
Screening. 
17. Subject has a serum blood urea nitrogen (BUN) or serum creatinine (Cr) value 
≥ 1.5 times the upper limit of normal of the reference range provided by the central 
laboratory at Screening. 
18. For subjects who do not have type 2 diabetes mellitus or glucose intolerance, screening 
glucose must be ≤ 125 mg/dL / 6.9 mmol/L (fasting) or ≤ 179 mg/dL / 9.9 mmol/L 

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(nonfasting). If nonfasting screening glucose is greater than this value, subjects must be 
retested in a fasted state and the retest value must be ≤ 125 mg/dL / 6.9 mmol/L. 
Hemoglobin A1c (HbA1c) must be ≤ 7%. 
Subjects with type 2 diabetes mellitus or glucose intolerance are excluded unless their 
condition is stable as determined by satisfying ALL of the following: 
a. Glucose must be ≤ 179 mg/dL / 9.9 mmol/L (fasting) or < 200 mg/dL / 11.1 mmol/L 
(nonfasting). If nonfasting screening glucose is ≥ 200 mg/dL / 11.1 mmol/L, subjects 
must be retested in a fasted state and the retest value must be ≤ 179 mg/dL / 
9.9 mmol/L.  
b. Hemoglobin A1c (HbA1c) must be < 8.0%, AND 
c. Subject has been maintained on a stable regimen of oral or non-insulin injectable anti-
diabetic medication(s) for at least 28 days prior to screening or diabetes has been 
well-controlled by diet for at least 28 days prior to screening. 
d. Subject has not had any hospitalizations within the 12 months prior to screening due 
to diabetes or complications related to diabetes, AND 
e. Subject’s diabetes is not newly diagnosed during screening for the trial. 
19. Subject has a prolactin concentration > 200 ng/mL at Screening. Subjects with prolactin 
levels > 100 ng/mL and ≤ 200 ng/mL at Screening are eligible only after discussion with 
the Medical Monitor to ensure exclusion of nonpsychotropic drug-related causes of 
elevated prolactin levels. 
20. Subject tests positive for drugs of abuse at Screening. However, a positive urine drug 
screen may not result in exclusion of subjects if the Investigator determines that the 
positive test is a result of prescription medicine(s); note that this provision does not apply 
to prescribed cannabinoids, which are excluded. 
21. Subject has received an investigational product or device within 90 days prior to signing 
informed consent. Subjects who have participated in COVID vaccine related studies will 
be permitted, provided they meet the 90-day criterion. 
22. Subject has previously received SEP-363856. 
23. Subject is a staff member of the study center or the relative of a staff member of the study 
center. 
24. Subject is, in the opinion of the Investigator, unsuitable in any other way to participate in 
this study. 

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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 
SEP-363856 
Dosage form 
Tablet 
Tablet 
Tablet 
Dosage strength 
50 mg 
75 mg 
100 mg 
Route of 
administration 
Oral 
Oral 
Oral 
Physical description 
Yellow oval tablet 
Yellow oval tablet 
Yellow oval tablet 
Active 
Pharmaceutical 
ingredient (API) 
SEP-363856-01 
(hydrochloride salt) 
SEP-363856-01 
(hydrochloride salt) 
SEP-363856-01 
(hydrochloride salt) 
Excipients  
-Microcrystalline cellulose  
-Mannitol 
-Sodium starch glycolate 
-Magnesium stearate 
Film coating:  
-Hydroxypropyl 
methylcellulose 
-Hydroxypropyl cellulose 
-Titanium dioxide 
-Yellow iron oxide 
Carnauba wax 
-Microcrystalline cellulose  
-Mannitol 
-Sodium starch glycolate 
-Magnesium stearate 
Film coating:  
-Hydroxypropyl 
methylcellulose 
-Hydroxypropyl cellulose 
-Titanium dioxide 
-Yellow iron oxide 
Carnauba wax 
-Microcrystalline cellulose  
-Sodium starch glycolate 
-Magnesium stearate 
 
Film coating:  
-Hydroxypropyl 
methylcellulose 
-Hydroxypropyl cellulose 
-Titanium dioxide 
-Yellow iron oxide 
Carnauba wax 
 
9.2. 
Study Drug Packaging and Labeling 
9.2.1. 
Package Description 
Study drug will be provided in one-week blister cards containing 9 tablets of SEP-363856 
(7 days + 2 extra days). 
9.2.2. 
Labeling Description  
All packaging for the study medications will be labeled with: 
• Protocol number 
• Sponsor’s name and address 
• Name of investigational drug and dosage form 
• Contents (eg, number of tablets) 
• Investigational New Drug/caution statement 

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• Batch number 
• Blank space to record visit number 
• Blank space for subject identifiers 
• Unique medication /kit ID number 
9.3. 
Study Drug Storage 
All study drug should be stored at 15°C to 25°C (59°F to 77°F). Excursions of 9°C to 30°C 
(48°F to 86°F) are permitted during shipment of study drug to investigational sites. 
9.4. 
Dispensing of Study Drug  
A Randomization and Trial Supply Management (RTSM) System (also referred to as Interactive 
web-based response system [IWRS]) will be used to manage subject screening and enrollment. 
The RTSM is an integrated web-based subject and drug management system. 
Blister cards containing SEP-363856 tablets will be assigned by the RTSM based on the 
treatment schedule. The RTSM will generate instructions for which blister card (Medication No.) 
to dispense to each subject at each visit. RTSM drug dispensing guidelines should be followed 
for dispensing study drug to the subject. A specific user manual will be supplied. 
Subjects will take one tablet of study drug per day at approximately the same time each evening 
at bedtime. Study drug may be taken without regard for food. 
9.5. 
Study Drug Accountability 
The Investigator or designee is responsible for maintaining adequate and up to date records of 
study drug disposition that includes the dates and quantity of dispensations, and use/return by 
subjects. 
Upon receipt of study drug, the Investigator or designee will inspect the supplies and confirm 
receipt of the shipment in the RTSM, confirming the date of receipt, inventory and condition of 
study drug received. 
The RTSM will also be used for the accountability of the study drug at the clinical site. The 
Investigator or designee will maintain the records for accountability within RTSM, including 
study drug dispensation, return and availability of study drug received. The Investigator or 
designee will collect and document the status of all used and unused study drug from study 
subjects at appropriate study visits. 
9.6. 
Study Drug Handling and Disposal 
The Investigator or designee is responsible for storing the study drug in a secure location. Study 
drug should be maintained under the strict control of qualified site staff at all times. Proper 
handling and storage guidelines should be followed. 
If the study is stopped for any reason or completed, all unused supplies will be returned to the 
Sponsor, unless other instructions are provided in writing by the Sponsor/contract research 
organization (CRO). 

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The Investigator or designee is required to return all used and unused 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 of the study drug in 
accordance with local regulatory requirements. 
Study drug will not be dispensed to any person who is not a study subject under this protocol. 

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10. 
TREATMENT OF SUBJECTS 
10.1. 
Study Medication 
All doses of study drug will consist of SEP-363856 50 mg, 75 mg, or 100 mg tablets 
administered orally once daily and will be supplied as described in Section 9. 
Subjects will take study drug at approximately the same time each evening at bedtime without 
regard for food. 
10.1.1. 
Dose Adjustment Criteria for SEP-363856 
Subjects will receive SEP-363856 50 mg/day from Day 1 through Day 3 and 75 mg/day from 
Day 4 through Day 7. Every effort should be made to maintain subjects at 75 mg/day from Day 4 
through Day 7. Beginning on Day 8, the dose of SEP-363856 can be adjusted in increments of 
25 mg among 3 dose levels (50, 75 and 100 mg), according to the following requirements: 
The SEP-363856 dose should be increased to 100 mg/day on Day 8 to help ensure 
adequate coverage of symptoms, provided there are no significant tolerability problems 
as judged by the Investigator. Dose increases are to be made no more frequently than 
weekly to the next highest dose level (in 25 mg increments). Increases in dose will occur 
at regularly scheduled study visits, when possible. Dose increases between regularly 
scheduled visits may occur after prospective approval by the Medical Monitor. If a dose 
increase is performed between regularly scheduled visits, subjects will be required to 
return to the clinic at an unscheduled visit for drug dispensation (see Section 11.9.12). 
Beginning on Day 8, the SEP-363856 dose can be decreased at any time in 25 mg increments 
(including less than weekly intervals) as needed for safety or intolerability concerns as judged by 
the Investigator. If a dose decrease is needed between study visits, subjects will be asked to 
return to the clinic for an unscheduled visit for drug dispensation (see Section 11.9.12). 
10.1.2. 
Pre-switch Antipsychotic Taper 
The pre-switch antipsychotic is held stable for the first week. Beginning on Day 8, the 
Investigator can start to taper pre-switch antipsychotic and has discretion to complete the taper 
by end of Week 2, 3, 4, 5, or 6. See Section 21 Appendix II for guidelines for pre-switch 
antipsychotic taper. 
10.2. 
Treatment Compliance 
The Investigator will record the dose of the study drug and the date and time of the initial and 
final administration for each visit. 
Compliance must be monitored closely and determined at each visit. Subjects will be instructed 
to bring all used blister cards and unused study drug with them to each visit. Compliance will be 
assessed by counting tablets and dividing the actual number of doses taken (per tablet 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. 
Subjects who take less than 75% of scheduled doses or take more than 125% of the scheduled 
doses during their entire participation in the study will be considered noncompliant. Evidence of 

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noncompliance must be immediately reported to the Clinical Research Associate (CRA) and/or 
Medical Monitor. 
10.3. 
Prior and Concomitant Medications 
Details on all medications taken in the 60 days prior to Screening (including dosing changes) 
will be recorded in electronic data capture (EDC). 
Every effort should be made to collect medical and/or pharmacy records for medications used in 
the past 60 days on the electronic case report form (eCRF). However, if medical records cannot 
be obtained, prior medications are to be reported based on subject or informant report. 
Thereafter, any changes in concomitant medications or new medications added up to the 
Follow-up Visit from the study will be recorded. At a minimum, the following information on 
prior and concomitant medications will be recorded on the eCRF: Medication name, dose, 
frequency, route, start date and time, stop date and time, and indication. 
Information on the format and version of the coding dictionary is provided in the Data Coding 
Guidelines. All medications will be coded using World Health Organization – Drug Dictionary 
(WHO-DD). 
10.3.1. 
Prior Medications 
Subjects will remain on their pre-switch antipsychotic and switch to SEP-363856 as described in 
Section 7.1. Subjects who enter Screening on two antipsychotic medications must washout of 
their secondary antipsychotic prior to Baseline (see Section 8.1 Inclusion criterion 12). Subjects 
are permitted to remain on non-prohibited psychotropic medications other than the primary pre-
switch antipsychotic or secondary antipsychotic, that have been part of their ongoing treatment 
regimen. Except for medications listed in Section 10.3.4, the psychotropic medication must have 
been stable for at least 6 weeks prior to Screening and will be maintained at a stable dose and 
regimen throughout study participation. Investigator requests to adjust the dose or frequency of 
these psychotropic medications based on specific clinical circumstances will be evaluated on a 
case-by-case basis upon discussion with the Medical Monitor. 
Treatment with sedative hypnotics is permitted during the Screening/Washout Period but should 
be tapered as clinically appropriate prior to receiving SEP-363856. This is to conform with and 
adequately prepare the subject for the protocol-specified limitations applicable to these agents. 
Treatment with medications used to treat movement disorders must be discontinued as outlined 
in Section 10.3.4. 
See Section 10.3.4 for allowed concomitant psychotropic medications. 
10.3.2. 
Prohibited Medications 
Treatment with the following medications are prohibited during the treatment phase of this study 
and must be discontinued as outlined below in a manner that is consistent with labeling 
recommendations and conventional medical practice. 
• MAO inhibitors must be discontinued at least 28 days prior to receiving SEP-363856. 

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• Subjects with a history of treatment with clozapine for any reason at doses greater 
than 200 mg/day or at doses less than or equal to 200 mg/day for an indication other 
than insomnia, agitation, or anxiety are excluded from study participation. Clozapine 
used at 200 mg/day or less for insomnia, agitation, or anxiety must be discontinued 
prior to Study Day 1 dosing over a 1–2-week period, as judged to be safe by the 
Investigator. 
• Depot neuroleptics must have been discontinued at least 6 weeks or one cycle 
(whichever is longer) prior to receiving SEP-363856. 
Initiation or adjustment of additional psychotropic medications is permitted after the last dose of 
study medication, provided they are not administered prior to the final PANSS assessment. 
The use of herbal supplements, dietary supplements or other complementary or alternative 
medications is permitted after the last dose of study medication, provided they are not 
administered prior to the final PANSS assessment. 
Subjects who are administered a psychotropic medication (other than the study drug, pre-switch 
antipsychotic during taper, and the acceptable medications described below under Allowed 
Concomitant Psychotropic Medications in Section 10.3.4) for the purposes of treating an 
exacerbation of symptoms associated schizophrenia or due to lack of efficacy of the study 
treatment will be discontinued from the study. 
10.3.3. 
Prohibited Therapies 
Subjects must not receive electroconvulsive therapy (ECT) treatment within the 3 months prior 
to Screening nor during the Treatment Period up through the Follow-up Visit. Subjects who 
received ECT treatment during the Treatment Period will be discontinued from the study. 
10.3.4. 
Allowed Concomitant Psychotropic Medications 
See Section 10.3.1 for when subjects are permitted to remain on psychotropic medications other 
than the pre-switch antipsychotic during the study.  
Treatment with benztropine up to 6 mg/day is permitted, as needed, for extrapyramidal 
symptoms (EPS). 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 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) is 
permitted as needed for akathisia. These allowed medications for the treatment of EPS and 
akathisia may be given in any formulation (oral, intramuscular [IM] or intravenous [IV]) as 
deemed appropriate by the Investigator.  
Medications used to treat EPS should not be given prophylactically. They are to be tapered and 
discontinued while the pre-switch antipsychotic is being tapered in a manner that is consistent 
with labeling recommendations and conventional medical practice. These medications may be 
reinstated, after consultation with the Medical Monitor, if EPS or akathisia symptoms emerge 
after treatment discontinuation. 

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Concomitant use of lorazepam, temazepam, eszopiclone, zaleplon, zolpidem, and zolpidem-
controlled release (CR) is permitted at the discretion of the Investigator with the following 
restrictions:  
• Oral lorazepam is permitted for clinically significant anxiety/agitation or as a 
sedative/hypnotic up to a maximum daily dose of 6 mg/day. Intramuscular (IM) 
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), and zolpidem CR (≤ 12.5 mg/day) 
may be administered at bedtime for insomnia, as needed. 
• Diphenhydramine ≤ 100 mg/day and melatonin ≤ 5 mg/day may be administered at 
bedtime for insomnia, as needed. Over-the-counter melatonin should be used. 
Combination melatonin products are not allowed. 
• Medications that are used for insomnia should be administered no more than once 
nightly and should not be used in combination. 
• 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). 
Similar drugs at equivalent dosages may be permitted after consultation with the Medical 
Monitor. 
The following requirements are not applicable to nonprohibited psychotropic medications that 
have been part of their ongoing treatment regimen. The date and time of the last dose of any 
concomitant psychotropic medication(s) taken prior to scheduled effectiveness assessments must 
be recorded at each visit. Subjects should be encouraged to avoid taking any psychotropic 
medication (or any agents that may cause sedation) within 8 hours of effectiveness assessments. 
Opioids for the treatment of pain may be allowed in rare cases for a limited period of time with 
prior authorization from the Medical Monitor. 
10.3.5. 
Concomitant Non-psychotropic Medications 
Non-psychotropic medications used to treat mild, chronic medical conditions may be used during 
screening and after receiving SEP-363856 if the dose and regimen have been stable (± 25% total 
daily dose) for at least 30 days prior to screening. The dose for the concomitant medication may 
change, as needed, after receiving SEP-363856 (or be discontinued). This includes β-adrenergic 
antagonists and other medications used to treat stable hypertension. Routine vaccines (ie, 
seasonal influenza, pneumonia, COVID-19, etc.) are allowed based on the Investigator’s 
judgment. 
In addition, use of non-prescription pain medications (eg, aspirin, acetaminophen/paracetamol, 
ibuprofen) are allowed during the study provided these medications do not have a propensity for 
psychotropic effects. 

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The Medical Monitor should be consulted, if possible, before administering medications for 
short-term treatment of an acute medical condition. If medications are administered for short-
term treatment of an acute medical condition without prior consultation with the Medical 
Monitor, the Medical Monitor is to be informed of such medication use as soon as possible and 
the appropriateness for the subject to continue in the study should be discussed with the Medical 
Monitor. 
Female subjects may use contraception as detailed in Section 10.4. 
 
10.4. 
Contraception Requirements 
Female subjects who participate in this study must be of: 
• Non-childbearing potential (ie, physiologically incapable of becoming pregnant), 
which includes: 
− Women who have had a hysterectomy, bilateral oophorectomy, bilateral 
salpingectomy, bilateral tubal ligation or bilateral tubal occlusion (as determined 
by subject’s medical history) 
OR 
− Postmenopausal females, defined as at least 12 months of spontaneous 
amenorrhea and confirmed by follicle stimulating hormone (FSH) concentrations 
within postmenopausal range as determined by the central laboratory 
-OR- 
• Childbearing potential with a negative serum pregnancy test at screening and 
satisfying one of the following requirements: 
− Completely abstinent from intercourse as part of the preferred and usual lifestyle 
of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, 
post-ovulation methods) and the withdrawal method are not acceptable methods 
of contraception. Subject must have been abstinent for at least 60 days prior to 
administration of the first dose of study drug, throughout the Treatment Period 
and for a minimum of 30 days after completion or premature discontinuation from 
the study drug. 
− Exclusively in a same sex relationship (if this is the subject’s usual lifestyle 
choice). Subject must have been exclusively engaging in same sex relations for at 
least 60 days prior to administration of the first dose of study drug, throughout the 
Study and for a minimum of 30 days after completion or premature 
discontinuation from the study drug. 
− Use of acceptable effective methods of contraception during the Treatment Period 
and for 30 days after last dose of study drug. Acceptable effective forms of 
contraception include: 
 Subcutaneous hormonal implant (such as Norplant®) implanted at least 
90 days prior to Screening; 

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 Injectable hormonal contraception (such as medroxyprogesterone acetate 
injection) given at least 14 days prior to Screening; 
 Oral or transdermal hormonal contraception used as directed for at least 
30 days prior to Screening. 
 Vaginal ring (eg, NuvaRing®) used as directed for at least 30 days prior to 
Screening. 
 Intrauterine device implanted at least 30 days prior to Screening. 
 Intrauterine hormone-releasing system implanted at least 30 days prior to 
Screening. 
 Two barrier methods used in combination (eg, condom and spermicide or 
diaphragm with spermicide). Note: a female condom and a male condom 
should not be used together due to friction between the 2 barrier methods 
reducing effectiveness of contraception. 
Post-coital methods of contraception are not permitted. 
Male subjects with a female partner(s) of childbearing potential must agree to avoid fathering a 
child and must be surgically sterile (with the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate) or use acceptable effective methods of contraception from 
Screening until at least 30 days after the last dose of study drug. Male subjects must also refrain 
from donation of semen/sperm 30 days prior to administration of the first dose of study drug, 
during the Treatment Period and for 30 days after last dose of the study drug. 
10.5. 
Guidance for Overdose 
Potential overdose to SEP-363856 has not been evaluated. The effects of an overdose of 
SEP-363856 are unknown and there is no known treatment in case of overdose. Appropriate 
supportive measures should be instituted, and close medical supervision and monitoring should 
be used in the case of pharmacological effects or overdose until the subject recovers. Consider 
the possibility of multiple-drug overdose. 
10.6. 
Eligibility Review Process 
All subjects will be evaluated by the Sponsor and/or designee to determine their eligibility for 
the study prior to enrollment. 
Sites will complete a form for each subject in screening, which provides information that 
supports the subject’s appropriateness for participation in the study. In addition, data from 
12-lead ECGs, vital sign measurements, and clinical laboratory tests may also be reviewed. Each 
form must be approved by the Sponsor or designee prior to the subject being enrolled. 
In addition, audio recordings of the Screening PANSS scale may be reviewed by the Sponsor’s 
designee with clinical expertise in PANSS scale administration. The outcome of the PANSS 
audio recording review may be utilized by the Sponsor or designee to evaluate the subject’s 
eligibility. 

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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, age, sex, ethnicity, race), prior and current medications, and 
medical and psychiatric history will be collected. 
A medical and psychiatric history will be obtained by the Investigator or qualified designee as 
listed on the Form Food and Drug Administration (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). 
Subjects will be checked for multiple study enrollment at screening by clinical site staff using 
available registries of subjects participating in clinical trials. 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. Prior and 
concomitant medications taken in the past 60 days will be recorded at Visit 1 (Screening). 
Thereafter, any changes in concomitant medications or new medications added up to Week 9 or 
discontinuation from the study will be recorded. 
At a minimum, the following information on prior and concomitant medications will be recorded 
on the CRF: Medication name, dose, frequency, route, start date, stop date, and indication. 
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-5-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 with at least 2 years 
of clinical experience with schizophrenia patients. The administration time is approximately 
30 - 40 minutes. 
11.4. 
Safety Assessments 
The Investigator or appropriate designee will review results of safety assessments on a regular 
basis and the Sponsor or designee must be kept fully informed of any clinically significant 
findings either at Screening or subsequently during study conduct. 

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11.4.1. 
Adverse Events 
Adverse events will be collected for each subject. Subjects should be queried in a non-leading 
manner, without specific prompting (eg, “Has there been any change in your health status since 
your last visit?”). See Section 12, Safety Reporting. 
AEs and SAEs will be monitored throughout the study at all visits. 
11.4.2. 
Clinical Laboratory Tests 
The clinical laboratory tests required by protocol are listed in Section 23, Appendix IV. 
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) (or equivalent) certified. 
Point of care rapid testing will be used for the rapid urine pregnancy test and rapid urine drug 
test. 
Clinically significant laboratory assessment 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. Positive drug screen findings observed during 
study participation must be discussed with the Medical Monitor to assess and determine subject 
disposition. 
11.4.3. 
Vital Signs 
Blood pressure and pulse rate measurements will be taken in a supine and standing position. 
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 
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. 
Respiratory rate and temperature will also be measured, and all measurements will be recorded 
in the source and in the eCRF. 
Height will be measured without shoes only at Visit 1 (Screening). 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). BMI for all other visits will be 
derived within the Electronic Data Capture (EDC) system and calculated during statistical 
analysis. Waist circumference will be measured. 
Vital signs will be obtained prior to clinical laboratory collection. 
Clinically significant vital sign abnormalities 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. 

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11.4.4. 
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. ECGs will be centrally read at a core lab according to 
established quality assurance procedures for inter/intra reader variability. 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 centrally-read overall ECG interpretation (Normal; Abnormal, insignificant; 
Abnormal, potentially significant; Abnormal significant) including type of abnormality, if 
present. QTcF and QTcB will also be reported. 
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 continuation in the study. All ECG tracings and over-read reports will be reviewed, 
signed and dated by the Investigator. The Investigator must determine and note the clinical 
significance of all abnormal ECGs. The same physician should review all ECG reports for a 
given subject whenever possible. 
Any clinically significant ECG changes from Screening, as determined by the Investigator, will 
be noted as AEs in the CRF. 
ECGs with possibly drug-related or clinically significant abormal findings of uncertain causality 
will be repeated. 
The original ECG tracing will be kept with subject’s source documentation. A copy may be 
collected by the Sponsor. 
11.4.5. 
Physical and Neurological Examination 
Complete PEs as well as neurological exams 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). The neurological exam 
includes an assessment of general appearance, mental status, cranial nerves, motor system, 
sensory system, reflexes, coordination, and gait. 
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. 
11.4.6. 
Safety Scales 
Raters will receive specific training regarding each assessment prior to performing scales. 
11.4.6.1. 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 

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(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. 
11.4.6.2. 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. 
11.4.6.3. 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 will be administered by a qualified rater at the site. 
11.4.6.4. 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 (Posner-2007). 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. 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. 
If a 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 
any post-Baseline C-SSRS assessment, an associated AE must be reported. 
11.4.6.5. Pittsburgh 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). The PSQI will be completed by the subject with 
supervision from a qualified rater at the site. 

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11.5. 
Effectiveness Assessments 
Raters will receive specific training regarding each assessment prior to performing assessments. 
11.5.1. 
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 subscales: the Positive subscale 
assesses hallucinations, delusions, and related symptoms; the Negative subscale assesses 
emotional withdrawal, lack of motivation, and similar symptoms; and the General 
Psychopathology subscale 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 subscales, 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 to 40 minutes (Kay-1994, Opler-1992; Perkins-2000). The 
PANSS requires input from an informant (eg, caregiver, relative, friend, case worker, or hospital 
staff). PANSS interviews will be audio recorded and the recording may be reviewed by 
Sponsor’s designee to monitor the quality of the rater interviews, where allowed by 
local/regional regulations. No identifying information will be associated with the audio 
recording. PANSS raters will be required to meet specific training and education criteria before 
they are certified to rate for this study. 
11.5.2. 
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. 
11.5.3. 
Clinical Global Impressions – Improvement Scale (CGI-I) 
The CGI-I scale is a standard 7-point scale (Guy-1976) that requires the clinician to assess how 
much the subject's overall symptoms have improved or worsened relative to a baseline state. The 
CGI-I will be administered by a qualified rater at the site. 
11.5.4. 
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 (Kirkpatrick-2011). The measure is comprised of 
13 individual items and 6 subscale scores (blunted affect, alogia, avolition, anhedonia, asociality, 
and distress). The 6 subscale 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 subscale. BNSS raters will be 
required to meet specific training and education criteria before they are certified to rate for this 
study. 

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11.5.5. 
12-Item Short Form Survey (SF-12) 
The SF-12 is a 12-item self-reported questionnaire that is a subset of the SF-36 Health Survey. 
The survey captures physical and mental health. There are 8 subscales including: Physical 
functioning, Role-physical, Bodily pain, General health, Vitality, Social Functioning, Role 
emotional, and Mental health. The responses are reported on a 3- or 5-point Likert scale, 
depending on the question. The SF-12 uses 2-items each to estimate scores for 4 of the 8 health 
concepts (physical functioning, role-physical, role-emotional, and mental health). Score for the 
remaining 4 healthy concepts (bodily pain, general health, vitality, and social functioning) are 
estimated using 1 item each. Physical Component Summary (PCS-12) and Mental Component 
Summary (MCS-12) are computed using the scores of 12 questions and range from 0 to 100, 
where a zero score indicates the lowest level of health measured by the scales and 100 indicates 
the highest level of health. The SF-12 will be administered by a qualified rater at the site. 
11.5.6. 
Personal and Social Performance Scale (PSP) 
The PSP is a 100-point single-item rating scale of personal and social functioning 
(Morosini-2000). The rating is based on the assessment of a patient's functioning in four areas: 
1) socially useful activities; 2) personal and social relationships; 3) self-care; and 4) disturbing 
and aggressive behaviors. Higher scores indicate better functioning. Scores of 0-30 indicate poor 
functioning; scores of 31-70 indicate varying degrees of difficulty; and scores of 71-100 reflect 
only mild difficulties at most. The PSP will be administered by a qualified rater at the site. 
11.5.7. 
Medication Satisfaction Questionnaire (MSQ) 
The MSQ is a single-item, patient-rated questionnaire that requires the subject to use a 7-point, 
Likert-type scale to rate how satisfied they are with their current antipsychotic medication 
(antipsychotic medication taken at the time of screening or within 30 days of screening) 
(Vernon-2010). The subject will be asked the following question: 
• “Overall, how satisfied are you with your current antipsychotic medication” 
Subjects will select 1 of 7 potential responses based on their level of satisfaction from 
(1) extremely dissatisfied to (7) extremely satisfied as follows: 
(1) Extremely dissatisfied 
(2) Very dissatisfied 
(3) Somewhat dissatisfied 
(4) Neither dissatisfied nor satisfied 
(5) Somewhat satisfied 
(6) Very satisfied 
(7) Extremely satisfied 
11.5.8. 
Healthcare Resource Utilization 
Healthcare resource utilization will be assessed by recording the following at Baseline: 

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Protocol SEP361-308, Version 5.00 
 
SEP-363856 
Confidential and Proprietary 
57 
06 Nov 2023 
 
Screening Visit (V1) 
Baseline (V2) to Visit 10 (V10) 
Assessments will be collected at each visit as 
specified in Table 2 
Visit 11 (V11) 
(Week 9 / Follow-up) 
1. SCID-5-CT  
1. PANSS 
1.C-SSRS  
2. PANSS  
2. BNSS 
3. C-SSRS  
3. C-SSRS  
4. CGI-S 
4. SAS/BARS/AIMS  
 
5. PSP 
 
6. Healthcare resource utilization (HRU) 
 
7. CGI-S 
 
8. CGI-I 
 
9. PSQI 
 
10. SF-12 
 
11. MSQ 
Note: Rating assessments will be performed by the rater or subject using an electronic tablet. In the event that the 
electronic tablet is not available or assessment not available on the tablet, the rating assessments will be performed 
by the rater or subject using a paper version of the assessment. SCID-5-CT will be performed using a paper 
version. 
11.9.1. 
Screening: Visit 1 (Day -21 to -1) 
After a subject provides consent, a unique subject number will be assigned at screening by the 
RTSM system, consisting of a 3-digit protocol number, 3-digit site number, and a unique 3-digit 
subject identifier (eg, the second screened subject from site #006 will be 308006002). Subjects 
will be numbered consecutively. No subject numbers are to be reused once assigned. This 
number will track a subject throughout their participation in the study and the open-label 
extension (OLE) study. 
Subjects will be evaluated at the Screening Visit to determine their eligibility for the study. 
Screening assessments may occur over multiple days. The subject’s eligibility assessment will be 
reviewed by the sponsor and/or designee based on protocol specified inclusion and exclusion 
criteria. In the event the sponsor/designee and site do not agree on a subject’s eligibility then the 
subject will not be enrolled. 
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, after discussion with the Medical Monitor. Re-screened subjects will be 
re-consented, assigned a new subject number, and all Visit 1 procedures will be repeated. 
The Screening Period may be extended for up to 7 days after approval from the Medical 
Monitor. 

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Protocol SEP361-308, Version 5.00 
 
SEP-363856 
Confidential and Proprietary 
60 
06 Nov 2023 
• Collect concomitant medications 
• Vital sign measurements 
• Blood sample POPPK 
• PANSS 
• CGI-S 
• CGI-I 
• C-SSRS 
• Collect adverse events 
• Study drug accountability 
• Dispense study drug 
11.9.4. 
Visit 4 (Week 2; Day 15 ± 2 days) – Treatment Period 
The following procedures will be conducted during this visit: 
• Collect concomitant medications 
• Vital sign measurements 
• PANSS 
• CGI-S 
• CGI-I 
• C-SSRS 
• Collect adverse events 
• Study drug accountability 
• Dispense study drug 
11.9.5. 
Visit 5 (Week 3; Day 22 ± 2 days) – Treatment Period 
The following procedures will be conducted during this visit: 
• Collect concomitant medications 
• Vital sign measurements 
• C-SSRS 
• Collect adverse events 
• Study drug accountability 
• Dispense study drug 
11.9.6. 
Visit 6 (Week 4; Day 29 ± 2 days) – Treatment Period 
The following procedures will be conducted during this visit: 

Protocol SEP361-308, Version 5.00 
 
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• Collect concomitant medications 
• Vital sign measurements 
• Weight and waist circumference (BMI derived in the electronic data system) 
• Blood sample for POPPK 
• Urine sample for βhCG (for female subjects) and UDS 
• PANSS 
• CGI-S 
• CGI-I 
• BNSS 
• PSQI 
• C-SSRS 
• Collect adverse events 
• Study drug accountability 
• Dispense study drug 
11.9.7. 
Visit 7 (Week 5; Day 36 ± 2 days) – Treatment Period 
The following procedures will be conducted during this visit: 
• Collect concomitant medications 
• Vital sign measurements 
• C-SSRS 
• Collect adverse events 
• Study drug accountability 
• Dispense study drug 
11.9.8. 
Visit 8 (Week 6; Day 43 ± 2 days) – Treatment Period 
The following procedures will be conducted during this visit: 
• Collect concomitant medications 
• Vital sign measurements 
• PANSS 
• CGI-S 
• CGI-I 
• C-SSRS 
• Collect adverse events 

Protocol SEP361-308, Version 5.00 
 
SEP-363856 
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06 Nov 2023 
• Study drug accountability 
• Dispense study drug 
11.9.9. 
Visit 9 Telephone Contact (Week 7; Day 50 ± 2 days) – Treatment Period 
The following procedures will be conducted during this visit: 
• Collect concomitant medications 
• C-SSRS 
• Collect adverse events 
11.9.10. 
Visit 10, End of Treatment (EOT) or Early Termination (ET) - (Week 8; 
Day 57 ± 2 days) 
The following procedures will be conducted during this visit: 
• Collect concomitant medications 
• Collect nicotine use information 
• Physical and neurological examination 
• Vital sign measurements 
• Weight and waist circumference (BMI derived in the electronic data system) 
• Perform standard 12-lead ECG 
• Fasted blood samples for clinical laboratory evaluation (hematology and serum 
chemistry) and β-hCG (for female subjects) 
• Blood sample for POPPK 
• Urine sample for urinalysis, rapid urine β-hCG (females), rapid urine drug screen, and 
UDS 
• PANSS 
• CGI-S 
• CGI-I 
• BNSS 
• PSQI 
• C-SSRS 
• SAS 
• BARS 
• AIMS 
• SF-12 
• MSQ 

Protocol SEP361-308, Version 5.00 
 
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Confidential and Proprietary 
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06 Nov 2023 
• PSP 
• HCRU (since last visit) 
• Collect adverse events 
• Study drug accountability 
• Duplicate subject check 
At this visit, subjects who have participated throughout the duration of the Treatment Period, up 
to and including Week 8 will have the option to enroll and continue treatment in an open -label 
extension study (Study SEP361-309). 
For subjects entering the extension study, the Week 8 Visit in this study (SEP361-308) will serve 
as the OLE Baseline visit for the extension study (SEP361-309) and subjects will not need to 
return for further visits in this study. 
Subjects who do not enter the extension study will complete the Follow-up Period. 
11.9.11. 
Visit 11 (7 ± 2 days after last dose) - Follow-up Period 
All subjects who discontinue early or do not elect to enroll in the open-label extension study 
(Study SEP361-309) will have a safety Follow-up Visit 7 ± 2 days after their last dose of study 
drug. While every effort should be made to complete the Follow-up Visit in the clinic, 
administration of C-SSRS, and collection of AEs and concomitant medications may occur by 
telephone contact if the subject is unable to come to the clinic for the Follow-up Visit. 
The following procedures will be conducted during this visit: 
• Concomitant medications 
• Physical and neurological examinations 
• Vital sign measurements 
• Urine sample for βhCG (for female subjects) 
• C-SSRS 
• Adverse events 
11.9.12. 
Unscheduled Visit for Dose Adjustment 
If a dose increase or decrease is needed between regularly scheduled visits, the subject must 
return to the clinic for an unscheduled visit. The following procedures will be conducted during 
this visit for dose adjustment: 
• Study drug accountability 
• Dispense study drug 
• Adverse event monitoring 
• Concomitant medication review 

Protocol SEP361-308, Version 5.00 
 
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Confidential and Proprietary 
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06 Nov 2023 
Other assessments are not required at such dose adjustment visits, but are permitted, based on the 
Investigator’s judgment. 
No dose decreases are allowed prior to Day 8. 

Protocol SEP361-308, Version 5.00 
 
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06 Nov 2023 
12. 
SAFETY REPORTING 
12.1. 
Definitions 
12.1.1. 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
Untoward medical occurrences that occur between the time of signing the informed consent form 
(ICF) and first drug administration are pre-treatment events. Those that occur after first 
administration of study drug are considered AEs. 
An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease occurring after the administration of a medicinal (investigational) 
product, whether or not considered related to the medicinal (investigational) product. AEs may 
include the onset of new illness and the exacerbation of pre-existing conditions. AEs will be 
collected from the signing of the ICF to the last study visit (including Follow-up Visit for those 
not enrolling in open-label extension). 
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. 
If a 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 
any post-Baseline C-SSRS assessment, an associated AE must be reported. 
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. 

Protocol SEP361-308, Version 5.00 
 
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06 Nov 2023 
During the study, if a subject has a hospitalization or procedure (eg, elective surgery) that was 
scheduled before the study entry, ie, before informed consent for an event/condition that 
occurred before the study, the hospitalization is considered a therapeutic intervention and not the 
result of a SAE. However, if the event/condition worsens during the study, it should be reported 
as an AE (or SAE, if the event/condition results in a serious outcome such as prolongation of 
hospitalization). 
Life-threatening means that the subject was, in the view of the Investigator, at immediate risk of 
death from the event as it occurred. This definition does not include an event that had it occurred 
in a more severe form might have caused death. 
SAE criteria information will be captured on the CRF. 
12.2. 
Objective Findings 
Any clinically significant changes from Screening in objective findings (eg, clinical laboratory 
value, ECG value, vital sign values and physical / neurological examination observation), as 
determined by the Investigator, will 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 and ECG tracings and over-read reports will be reviewed, signed 
and dated by the Investigator. The Investigator must determine the clinical significance of all out 
of range values for clinical laboratory tests and all abnormal ECG findings. 
Any clinical laboratory value outside the normal range and any centrally over-read abnormal 
ECG finding will be flagged for the attention of the Investigator or appropriate designee at the 
study center. The Investigator or appropriate designee will indicate whether the value/finding is 
of clinical significance. Subjects with any clinically significant abnormal laboratory value(s) or 
ECG finding at Screening will not be allowed into the study (see Section 8.2). Retesting is 
allowed during the Screening Period and the retest used to determine eligibility after approval 
from the Medical Monitor. If a clinically significant laboratory or ECG abnormality is found 
after Screening, 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. Possibly 
drug-related or clinically relevant abnormal values of uncertain causality or clinical significance 
must be repeated. Additional laboratory and ECG testing during the study may be performed if 
medically indicated. 
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. Pre-treatment events 
and AEs and SAEs that occur from the signing of informed consent to the subject’s last study 
visit must be recorded on the CRF. Determination of whether an event is a pre-treatment event, 
or an adverse event will be made programmatically by the Sponsor or designee, not by the site. 

Protocol SEP361-308, Version 5.00 
 
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06 Nov 2023 
All AEs will be followed until resolution, stabilization of the condition, the event is otherwise 
explained, or the subject is lost to follow-up. 
Each AE is to be evaluated for duration, severity, frequency, seriousness, action taken with the 
study treatment, outcome, and causal relationship to the study treatment. Additional information 
will be collected for the non-serious psychiatric AEs that led to discontinuation from the study as 
well as all serious psychiatric AEs within the study. 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 

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• Unknown 
The causal relationship of the AE to the study treatment:  
• Not related 
o  Not related - Improbable temporal relationship and is plausibly related to 
other drugs or underlying disease. 
• 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 that occur from the signing of the ICF up to the last visit must be recorded on 
the CRF and the data recorded should agree with those on the SAE form. In addition, 
pretreatment events that meet the definition of serious (Section 12.1.2) should be reported 
following the same guidelines. 
Should the Investigator become aware of an SAE greater than 30 days post last dose, 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. 

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An initial or follow-up SAE form as applicable must be completed and signed and sent via fax or 
email (see Table 1) to PPD-PVG immediately but not more than 24 hours after the Investigator 
or study center staff become aware of the event. Response to specific questions included on the 
SAE form for psychiatric SAEs is required. The SAE form must be signed by the Investigator or 
appropriate designee. The Sponsor provides the SAE form used to report SAEs. 
The Sponsor or designee will promptly notify all study centers and Investigators of an SAE that 
is determined to be expedited to the Regulatory Authorities in accordance with applicable law(s) 
and regulation(s). These SAEs must be promptly reported to the Institutional Review Board 
(IRB) or Independent Ethics Committee (IEC) by the Investigator or the appropriate person at 
the study center if required per IRB/IEC guidelines. 
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 medication will be collected and reported on the Pregnancy Event 
Form. 
If a subject becomes pregnant during the course of the study, she will be instructed to commence 
discontinuation of the study medication. Further, the subject will be instructed to return to the 
study center within 48 hours of the first notification of pregnancy and undergo a serum 
pregnancy test, as confirmation of pregnancy. If positive, the female pregnant subject will no 
longer receive any additional study medication. All pregnancies, whether or not the subject 
received any additional study medication, will be followed until resolution (ie, termination 
[voluntary or spontaneous] or birth). Infants may be followed for up to one year following birth. 
If a pregnancy is reported for a study subject’s partner from time of subject’s first dose to 
30 days post last dose, the subject’s partner may be asked to sign a consent form to allow the 
Sponsor to follow her pregnancy. The Sponsor’s representative will provide instructions on how 
to collect pregnancy information in accordance with local requirements. Proper consent to collect 
the partner’s information will be obtained before the collection of any information. 
To report a pregnancy, the Pregnancy Event Form must be completed and sent via fax to 
PPD-PVG immediately but no more than 24 hours after the Investigator or study center staff 
becomes aware of the pregnancy. The Sponsor provides the Pregnancy Event Form. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study 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 
13.1. 
Criteria for Subject Termination 
Subjects may be discontinued from study participation / the study drug at any time for any of the 
following reasons. The possible reasons for termination of study participation / study drug are as 
follows: 
• Adverse event 
• Lack of efficacy (specify)  
• Lost to follow-up (specify) 
• Withdrawal by subject (specify) 
• Non-compliance with study drug (specify) 
• Protocol deviation (specify) 
• Death 
• 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. Subjects discontinued from 
study drug will be discontinued from the study. 
The reason for discontinuation of “Lack of efficacy” should be selected when a subject early 
terminates from the study because there has been insufficient therapeutic benefit of the study 
drug (perceived or actual) and the subject’s baseline condition has neither worsened nor 
improved significantly. 
The reason 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.Subjects who prematurely terminate the 
study participation will not be replaced. 
13.2. 
Clinical Assessments After Study Drug Discontinuation 
Subjects who have not received any 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 Week 8), every effort should be made to complete the 
final evaluation procedures, in accordance with the ET visit described in Section 11.9.10. 
Subjects who complete the study but do not elect to enroll in the open-label extension study 
(Study SEP361-309) and those subjects who discontinue the study early will complete a follow 
up visit 7 (±2) days after the last dose of study drug as described in Section 11.9.11. 

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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 medication 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 undergo final evaluation procedures in 
accordance with the early termination (ET) visit described in Section 11.9.10 and safety 
Follow-up Visit as described in Section 11.9.11. 

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15. 
STATISTICS 
The Statistical Analysis Plan (SAP) will provide the details on the statistical methods planned for 
this study and will be finalized before the database lock of the study.  
15.1. 
Sample Size 
Approximately 120 subjects will be required for this study. This sample size was determined by 
the width of the 95% confidence interval for the proportion of subjects who may discontinue due 
to clinical reasons by Week 8 to ensure the precision of the estimate of the true discontinuation 
rate due to clinical reasons. Assuming, 1) 15% of SEP-363856 treated subjects will experience 
discontinuation due to clinical reasons by Week 8, and 2) 6.4% as the half width (the distance 
between the upper/lower limits to the point estimate) of the 95% confidence interval (ie, [8.6%, 
21.4%]), approximately 120 subjects will be required. 
15.2. 
Analysis Populations 
15.2.1. 
Safety Population 
The safety population will consist of all subjects who are enrolled and receive study medication. 
All safety and tolerability assessments will be performed using the safety population. 
15.2.2. 
Effectiveness Population 
The effectiveness population will consist of all subjects who are enrolled, have received at least 
one dose of study drug, and have a Baseline and at least one post-Baseline effectiveness 
measurement in PANSS or CGI-S. Subjects will be included in the population regardless of any 
protocol deviation. The effectiveness population will be the primary population for the 
effectiveness analyses. 
15.3. 
Data Analysis 
Descriptive statistics will be compiled for all endpoints. 
15.3.1. 
Subject Disposition 
Subject disposition will be summarized for all subjects. The number and percentage of subjects, 
who are screened, screen-failed, enrolled, received study drug, and completed or discontinued 
early from the open-label treatment period will be presented. 
15.3.2. 
Study Drug Exposure and Compliance 
Descriptive statistics on treatment exposure and treatment compliance will be summarized for 
the safety population. 
Exposure, defined as number and percentage of subjects with ≥ 1, ≥ 7, ≥ 14, ≥ 21, ≥ 28, ≥ 35, 
≥ 42, ≥ 49, and ≥ 56 days exposure, will be compiled. Descriptive statistics (n, mean, standard 
deviation, median, 25th and 75th percentile, minimum, and maximum) will also be calculated on 
exposure in days. Duration of exposure (in days) will be calculated as: last dose date - first study 
dose date + 1. An additional listing will also be generated to display the length of time that each 
subject received pre-switch anti-psychotic medication (with corresponding name and dosage). 

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Percent compliance will be calculated overall for the treatment 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 treatment period. Subjects with 
missing compliance will not be classified as non-compliant. Percent compliance will be 
summarized both as a continuous variable and categorically (ie. number and percentage of 
subjects in each compliance category: < 75%, 75% ‑ 125%, > 125%, and missing). 
Mean daily dose will be calculated for the treatment period as the cumulative dose (mg) of 
SEP-363856 divided by the duration of exposure (in days), where cumulative dose is the sum of 
all doses a subject received during the treatment period. Modal daily dose will be determined as 
the daily dose that is taken for the most time (in terms of number of days) among all doses taken. 
Both mean daily dose and modal daily dose will be summarized. 
15.3.3. 
Important Protocol Deviations 
Important protocol deviations (IPDs) will be identified and documented based on reviews of data 
listings and the protocol deviations log. The IPD categories may include, but may not be limited 
to: 
• Did not satisfy important inclusion and/or exclusion criteria 
• Received prohibited medication 
• Overall compliance rate < 75% or > 125%. 
IPDs will be identified for all enrolled subjects and presented in a data listing. The number and 
percentage of subjects within each IPD category will be summarized for the safety population. 
15.3.4. 
Demographic and Baseline Characteristics 
Basic demographics (eg, age, gender, race, ethnicity, etc.) will be summarized for all screened 
subjects. In addition, demographic and baseline characteristics will be summarized for each 
defined analysis population. Medical history will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) and will be summarized 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). Psychiatric history data will also be summarized for the safety 
population. 
15.3.5. 
Safety Analyses 
The primary analyses for this study will be performed for the safety endpoints, which are stated 
in Section 6. 
15.3.5.1. Primary and Secondary Endpoint Analysis 
The primary endpoint is the percentage of subjects who discontinued for clinical reasons, such as 
due to AE or lack of efficacy. This percentage will be calculated by a proportion consisting of 
the number of subjects who experience a discontinuation event due to clinical reasons as the 
numerator divided by the number of subjects in the safety population as the denominator 
multiplied by 100 along with a corresponding 95% confidence interval (CI). 

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The secondary endpoint is the percentage of subjects who discontinued for any reason (ie, all 
cause discontinuation). The percentage will be calculated similarly as that of the primary 
endpoint along with a corresponding 95% CI. 
The number and percentage of subjects, who discontinued early from the open-label treatment 
period (including both clinical reasons, ie, discontinued due to an AE (primary endpoint) and any 
reason for discontinuation (secondary endpoint)) will be presented.  
As an exploratory analysis, the time-to-discontinuation for both clinical reason and for any 
reason will be summarized descriptively, (eg, n, median, 25th percentile, 75th percentile, 
minimum and maximum, and 95% CI on median, where possible) and presented with 
corresponding Kaplan-Meier plots. 
15.3.5.2. Adverse Events 
Both AEs and pre-treatment events will be coded using MedDRA. 
The following summaries will be provided by MedDRA SOC and PT: 
• All AEs (including incidence rate and event count) 
• AEs by severity (mild, moderate, severe; including incidence rate) 
• AEs by relationship to study drug (related, not related; including incidence rate) 
The following conventions will be followed in summarizing AEs: 
• For incidence rate summaries, each subject will be counted only once within each 
SOC and within each PT. 
• If a subject reports more than one AE within a PT and/or a SOC, the AE with the 
highest known severity will be used in the by severity summary. AEs with a missing 
severity will be assigned to the highest severity. 
• For summaries by relationship to study drug, AEs will be grouped as “related” or “not 
related.” AEs assessed as “possible,” “probable,” or “definite,” will be grouped as 
“related.” AEs with a missing relationship to study drug will be regarded as related. If 
a subject reports more than one AE within the same SOC and PT, and any are related, 
the AE will be summarized as related. 
Summaries of serious AEs (SAEs) and AEs leading to discontinuation will also be provided. In 
addition, summaries of all AEs, SAEs, and AEs leading to discontinuation by modal daily dose 
will be provided. The summary of AEs will include any AE occurring on or after the first dose of 
study drug up to 9 days following the last dose of study drug. All AEs starting after the last dose 
of the study drug up to 9 days following the last dose will be summarized separately. Data 
listings of AEs, SAEs, AEs leading to discontinuation, and deaths will be presented. 
15.3.5.3. Clinical Laboratory Assessments 
Clinical laboratory parameters will be summarized by presenting shift tables and by-visit 
summaries of the observed values including the Week 8 last observation carried formula (LOCF) 
Endpoint along with change from Baseline values. For parameters with categorical outcomes, the 
number and percentage of subjects with each outcome will be summarized by visit. The number 

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and percentage of subjects with at least one potentially clinically significant (PCS) value post 
Baseline for selected parameters will also be presented. PCS criteria for clinical laboratory 
parameters will be provided in the SAP. 
15.3.5.4. ECGs 
ECG analysis will be based on the centrally read data. Observed values and changes from 
Baseline in ECG parameters will be summarized along with shift in ECG overall assessment. In 
addition, the number and percentage of subjects with prolonged QTc intervals (> 450 msec, 
> 480 msec, and > 500 msec) and changes in QTc intervals ≥ 30 but < 60 msec and ≥ 60 msec 
will be summarized. Fridericia’s correction (QTcF) and Bazett’s correction (QTcB) will be used 
for QT interval correction. 
15.3.5.5. Vital Signs 
Vital sign parameters will be summarized by presenting by visit and Week 8 LOCF endpoint 
summaries of the observed values and the change from Baseline values. In addition, the number 
and percentage of subjects with at least one PCS value post Baseline for selected parameters will 
be presented. PCS criteria for the vital sign parameters will be provided in the SAP. 
Orthostatic hypotension is defined as a decrease of ≥ 20 mmHg in systolic blood pressure or 
≥ 10 mmHg in diastolic blood pressure after a subject has 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 pulse rate increase of ≥ 20 bpm and 
a pulse rate of > 100 bpm after a subject has been standing for at least 2 to 4 minutes, compared 
to the pulse 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. 
15.3.5.6. Physical and Neurological Examination  
Any clinically significant physical and neurological examination findings at screening will be 
captured as medical history and summarized together with the other medical history data. 
Clinically significant new findings or changes from the screening visit will be captured as AEs as 
appropriate and summarized together with the other AEs. 
15.3.5.7. Concomitant Medications 
All medications will be coded to indication-specific Anatomical Therapeutic Chemical (ATC) 
classification (ie, 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/time on or after the first 
dose of study drug and on or before the last dose of study drug; or with a start date/time prior to, 
and an end date/time on or after, the first dose of study drug, or marked as ongoing, will be 
considered concomitant medications. Medications that ended prior to the first dose of study drug 
will be considered prior medications. Medications that started after the last dose of study drug 
will not be considered concomitant but will be considered post-treatment. Prior and Concomitant 

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medications will be summarized for the number and percentage of subjects using each 
medication and by the drug class and preferred name for the safety population. 
15.3.5.8. Suicidality Measure 
Frequency and severity of suicidal ideation and suicidal behavior as measured by the C-SSRS 
scale will be summarized for the overall post-Baseline period and by visit. 
15.3.5.9. Measures of Motor Function 
Measures of motor function include SAS, BARS and AIMS. Descriptive statistics for these 
measures of motor function will be compiled for observed values and change-from-baseline by 
visit and for Week 8 LOCF endpoint. Additional analyses on the measures of motor function, as 
necessary, will be described in the SAP. 
15.3.5.10. Pittsburgh Sleep Quality Index 
Descriptive statistics for Pittsburgh Sleep Quality Index will be compiled for observed values 
and change from baseline by visit and for Week 8 LOCF endpoint. 
15.3.5.11. Subgroup Analysis (Safety Parameters) 
Selected safety data will be summarized by subgroups of geographic region, sex, age, number of 
prior hospitalizations for treatment of schizophrenia, and duration of schizophrenia. Further 
details of subgroup analysis of the safety data will be provided in SAP, as needed. 
15.3.6. 
Effectiveness Analyses 
SEP-363856 effectiveness will be evaluated by descriptive statistics on the following:  
• Change from baseline in the PANSS total score and subscale scores (positive, negative, 
and general psychopathology) at Week 8 
• Change from baseline in the PANSS Marder Factor (five-factor) score at Week 8 
• Change from baseline in the CGI-S at Week 8 
• Change from baseline in the BNSS at Week 8 
• Change from baseline in the SF-12 at Week 8 
• Change from baseline in the PSP at Week 8 
• Change from baseline in the MSQ at Week 8 
• CGI-I at Week 8 
This is an uncontrolled, open-label study. Hence, no inferential statistics on efficacy / 
effectiveness will be presented. Descriptive statistics (ie, sample size, mean, standard deviation, 
minimum, median, maximum, and a 95% confidence interval) will be displayed for each visit, 
including the last visit and the Week 8 last-observation-carried-forward (LOCF) endpoint. The 
response variables will include the change from the baseline assessment (except CGI-I) and the 
endpoint assessments throughout the study. Confidence intervals will be based on means and 
standard deviations estimated without adjustment for any center or baseline effects. 

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15.3.6.1. Healthcare Resource Utilization 
The number of physician’s office visits, ER visits, and hospitalizations (for any reason and those 
related to schizophrenia) per month at Baseline and at Week 8, as well as the average length of 
hospital stays (for any reason and those related to schizophrenia), will be summarized. The 
frequency and percentage of subjects receiving unpaid care at each time point, along with the 
average number of hours a caregiver spends per week helping the subject, will also be 
summarized. 
The change in the number of physician’s office visits, ER visits, and hospitalizations, the average 
length of hospital stays, and the average number of hours a caregiver spends per week helping 
the subject from Baseline at Week 8 will be summarized. Shifts from Baseline to Week 8 in 
whether the subjects receive unpaid care will also be summarized. 
15.3.6.2. Nicotine Use Information 
Nicotine use data will be summarized descriptively at Baseline and Week 8 (end of treatment 
[EOT]/early termination [ET]). For each nicotine type, the amount being used at each visit in 
comparison with the amount being used at Baseline will be classified as “increased”, 
“decreased”, or “unchanged” for every subject, based on the reported amount used in a given 
period. 
• Then for subjects whose changes in amount for all nicotine types between Baseline 
and Week 8 (end of treatment [EOT]/early termination [ET]) are not in opposite 
directions, a subject’s overall nicotine consumption at each scheduled post-Baseline 
visit in comparison with Baseline will be classified as “increased”, “decreased”, or 
“unchanged”. 
The number and percentage of subjects in each overall consumption amount change category 
will be summarized. 
In addition, for subjects who reported using “Cigarettes” at either Baseline or each scheduled 
post-Baseline visit or at both time points, the amount of cigarette used per day and the change 
from Baseline values will be summarized by visit. 
Further details regarding the specifics of this analysis will be described in the SAP. 
15.3.6.3. Adjustment for Multiplicity 
Not applicable as only descriptive statistics for effectiveness parameters will be compiled. 
15.3.7. 
Pharmacokinetic Analysis 
Plasma concentrations of SEP-363856 will be presented in a data listing. Population 
pharmacokinetic (POPPK) analysis will be performed using plasma concentrations of 
SEP-363856, the results of which will be reported separately. 
15.3.8. 
Pharmacodynamic Analysis 
The relationship between PANSS total score and plasma concentrations of SEP-363856 will be 
explored using POPPK/pharmacodynamics (PD) methods, the results of which will be reported 
separately. 

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15.3.9. 
Interim Analysis 
None planned. 
15.3.10. 
Treatment of Missing Data 
For scales with more than one item, such as PANSS, if any item score contributing to the 
total/subscale score is missing, the total/subscale score will be set to missing. 
Missing data at Week 8 will be imputed using the LOCF approach. The LOCF endpoint is 
defined as the last non-missing value at a scheduled or unscheduled visit post-baseline during the 
treatment period excluding the follow-up visit. 

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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, ECG results, POPPK, PGX and some scales) will be recorded in the subject’s electronic 
CRF. Data will be entered into source documents prior to being transcribed into the CRF. The 
study centers will use an EDC system that is compliant with relevant FDA regulatory 
requirements per 21 Code of Federal Regulation (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. 
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 6: 
Computerized Systems Used for Source Data 
Protocol Step 
Computerized System Type 
or Description 
Informed consent 
A 
Review inclusion/exclusion criteria  
A 
Prior/concomitant medication review 
A 
Dispensation of study drug 
F 
Study drug accountability 
A, F 
Demography 
A 
Medical history 
A 
Psychiatric history 
A 
Nicotine use information 
A 
SCID-5-CT 
none 
Physical and neurological examination 
A 
Height 
A 
Vital signs 
A 
Weight (including BMI) 
A 
Waist circumference 
A 
12-lead Electrocardiogram (ECG) 
B 
Hematology, chemistry, and urinalysis 
G 
Blood sample for hepatitis 
G 
Serum follicle stimulating hormone (FSH) 
G 
Serum human chorionic gonadotropin (β-hCG), (females)  
G 

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Protocol SEP361-308, Version 5.00 
 
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Confidential and Proprietary 
81 
06 Nov 2023 
16.4. 
Audits 
The study may be subject to audit by the Sponsor/designee. If such an audit occurs, the 
Investigator must agree to allow access to required subject records. This is dependent on the 
subject granting consent by signing the ICF. By signing this protocol, the Investigator grants 
permission to personnel from the Sponsor or its representatives for on-site monitoring and 
auditing of all appropriate study documentation, as well as on-site review of the procedures 
employed in CRF generation, where clinically appropriate. 
In accordance with ICH GCP the Sponsor may select this study for audit. During the audit the 
Sponsor representative will carry out an inspection of center facilities (eg, pharmacy, drug 
storage areas, laboratory) and review study related records in order to evaluate the study 
compliance with the Sponsor/center standard operating procedures (SOPs), protocol, ICH GCP 
and local regulations. The PI or appropriate designee must also agree to inspection of all study 
documents by the regulatory authorities and the Independent Ethics Committee (IEC). Should 
the PI or appropriate designee be notified of a regulatory inspection involving this study they 
should notify the Sponsor immediately. 
16.5. 
Study Documentation 
Study records are comprised of source documents, CRFs, and all other administrative 
documents, eg, Institutional Review Board (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 handwritten 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 of the clinical laboratory tests for this study. The 
central laboratory will provide the Investigator, Sponsor/CRO with laboratory certification(s) 
and 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. 

Protocol SEP361-308, Version 5.00 
 
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06 Nov 2023 
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. 
The Investigator must provide a copy of current curriculum vitae (including a copy of a current 
medical license, where applicable) and financial disclosure information. In countries where 
medical licensure is not issued, the following documentation is acceptable, as applicable: 
• Registration number/stamp with a registration number stated on curriculum vitae. 
• Appropriate diploma number stated on curriculum vitae. 
• Copy of the diploma. 
The Investigator must sign and return a completed Form FDA 1572 "Statement of Investigator" 
to Sponsor/CRO. 
17.2. 
Institutional Review Board/Independent Ethics Committee 
Documented approval for conducting the study from appropriate Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) will be obtained for all participating study centers 
prior to initiation of the study, according to ICH GCP, applicable local law(s) and regulation(s). 
When necessary, an extension, amendment or renewal of the IRB/IEC approval must be obtained 
and also forwarded to the Sponsor. The IRB/IEC must supply the Sponsor a list of the IRB/IEC 
membership, and a statement to confirm that the IRB/IEC is organized and operates according to 
ICH GCP, applicable law(s) and regulation(s). 
A copy of written IRB/IEC approval or favorable opinion of the protocol, informed consent form 
and subject recruitment material (if applicable) must be provided to Sponsor/CRO prior to start 
of the study. The approval or favorable opinion letter must be signed by the IRB/IEC chairman 
or designee identify the IRB/IEC name and address, identify the clinical protocol by title and/or 
protocol number, and include the date that approval or favorable opinion was granted. The letter 
must also contain a statement that the IRB/IEC complies with the requirements in 21 CFR 
Part 56 for a study conducted under a US 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. 

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Protocol SEP361-308, Version 5.00 
 
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Confidential and Proprietary 
85 
06 Nov 2023 
17.6. 
Records Retention 
The Investigator/the study center must arrange for retention of study records at the study center 
for at least 15 years (or at least 25 years in the European Union [EU]) from time of participation 
in the study or longer in accordance with applicable regulations and Sponsor SOPs. The 
Investigator/site should take measures to prevent accidental or premature destruction of these 
documents. Documents cannot be destroyed without written Sponsor authorization. The Sponsor 
will inform the Investigator/the study center when the destruction of documents is permitted. 
17.7. 
Inspection of Records 
In the event of an inspection, the Investigator agrees to allow representatives of the Sponsor, and 
its representative, and the regulatory authorities’ access to all study records. The Investigator will 
promptly notify the Sponsor/CRO of all requests to inspect a Sunovion-sponsored study by 
government agencies and will promptly forward a copy of all such inspection reports. 
17.8. 
Financial Disclosure 
By signing this protocol, the Investigator agrees to provide to the Sponsor prior to start of study 
accurate financial information to allow the Sponsor to submit complete and accurate certification 
and disclosure statements as required by the US FDA regulations (21 CFR Part 54). The 
Investigator further agrees to provide this information on a Financial Disclosure/Certification 
Form that is provided by the Sponsor. The Investigator will update this information if there are 
any relevant changes during the conduct of the study and for one year after completion of the 
study. 
The Investigator also consents to the transmission of this information to the Sponsor for these 
purposes. This may involve the transmission of information to countries that do not have laws 
protecting personal data. 
17.9. 
Publication Policy 
Any formal presentation or publication of data collected as a direct or indirect result of the study 
will be considered a joint publication by the Investigators and the appropriate personnel of the 
Sponsor. For multicenter studies, it is mandatory that the first publication is based on all data 
obtained from all analyses as stipulated in the protocol. Investigators participating in multicenter 
studies must agree not to present data gathered individually or by a subgroup of centers before 
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 SEP361-308, Version 5.00 
 
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Confidential and Proprietary 
86 
06 Nov 2023 
18. 
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discontinuing atypical antipsychotics: theoretical background and practical recommendations. 
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Guy W. EDCEU Assessment Manual for Psychopharmacology – Revised (DHEW Publ No 
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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. 
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. 
Rand Health Care. 12-Item Short Form Survey (SF-12). Available from: 
https://www.rand.org/health-care/surveys_tools/mos/12-item-short-form.html. (Accessed 
24 May 2022). 

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Schizophrenia Statistics 2022. https://www.singlecare.com/blog/news/schizophrenia-
statistics/#us-schizophrenia-statistics. [assessed 2022 May 03] 
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. 
Sugitani T, Posch M, Bretz F, Koenig F. Flexible alpha allocation strategies for confirmatory 
adaptive enrichment clinical trials with a prespecified subgroup. Statistics in Medicine. 2018; 
1-16. https://doi.org/10.1002/sim.7851 [accessed: 22 Jan 2021] 
Takeuchi H, Thiyanavadivel S, Agid O, Remington G. Rapid vs. slow antipsychotic initiation in 
schizophrenia: A systematic review and meta-analysis. Schizophr Res. 2018 Mar;193:29-36. 
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. 
Vernon MK, Revicki DA, Awad AG, Dirani R, et al. Psychometric evaluation of the Medication 
Satisfaction Questionnaire (MSQ) to assess satisfaction with antipsychotic medication among 
schizophrenia patients. Schizophr Res. 2010;118:271-278. 
Wassmer G, Brannath W. Group sequential and confirmatory adaptive designs in clinical trials. 
New York: Springer, 2016. 
Webber MA, Marder SR. Better pharmacotherapy for schizophrenia: what does the future hold? 
Current Psychiatry Reports. 2008;10:352-358. 
Weiden PJ. Switching antipsychotics: an updated review with a focus on quetiapine. J 
Psychopharmacology. 2006; 20: 104-118. 
Weiden PJ, Simpson GM., et al. Effectiveness of switching to ziprasidone for stable but 
symptomatic outpatients with schizophrenia. J Clin Psychiatry. 2003; 64:580-588. 
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. 
 

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19. 
INVESTIGATOR APPROVAL 
I have read the protocol SEP361-308, Version 5.00 “An 8-Week, Open-Label Study Evaluating 
the Effectiveness, Safety and Tolerability of SEP-363856 in Subjects with Schizophrenia 
Switched from Typical or Atypical Antipsychotic Agents”, and agree that it contains all 
necessary details for conducting the study and to conduct the study in strict accordance with the 
specifications outlined herein. 
I agree that no additional procedure(s) will be added during the conduct of the study except 
through protocol amendment by Sunovion Pharmaceuticals Inc. and after documentation of IRB 
approval. 
 
 
Investigator Signature: ____________________________________________________ 
 
Print Investigator Name: __________________________________________________ 
 
Date: ___________________________________________ 

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20. 
APPENDIX I. CARDIAC SAFETY MONITORING (ECG) 
1. Requirements for Testing 
ECG equipment and supplies will be provided by the 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 at least 5 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 overread 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. 
 

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APPENDIX II: GUIDELINE FOR PRE-SWITCH 
ANTIPSYCHOTIC TAPER 
• Prior to the first dose of investigational product (IP), plan a taper strategy of the pre-
switch antipsychotic for each subject (changes to the plan may be needed during the 
study based on subject response / tolerability) 
o Consider treatment history, clinical presentation and reason for switch 
o Attempt to reduce the pre-switch antipsychotic by at least 50% half-way through 
the taper 
• If the pre-switch antipsychotic is considered to have a strong binding affinity for 
muscarinic-cholinergic (M1) and/or histaminergic (H1) receptors, consider a longer, 
more gradual taper (ie, 4 - 6 weeks to complete) 
o Examples: asenapine, olanzapine, quetiapine 
• If the pre-switch antipsychotic is considered to have a strong binding affinity for 
dopaminergic (D2, D3) receptors, consider a moderately gradual taper (ie, 3 - 5 weeks to 
complete) 
o Examples: lurasidone, paliperidone, risperidone, ziprasidone, haloperidol (and 
other first-generation antipsychotics)  
• If the pre-switch antipsychotic is considered to have a long half-life, a faster, less gradual 
taper may be appropriate (ie, 2 - 3 weeks to complete) 
o Examples: aripiprazole, brexpiprazole, cariprazine 
• For any type of pre-switch antipsychotic, if the dose is at the upper end of the 
recommended daily dose range for that particular medication, consider a longer, more 
gradual taper 
• If the subject has been taking a D2 antagonist for lengthy period of time, consider longer 
more gradual taper 
 

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APPENDIX III. HALOPERIDOL EQUIVALENT DOSES 
 
Medications 
Haloperidol Equivalent (12 mg) 
Typical Antipsychotics 
Chlorpromazine 
600 mg 
Chlorprothixene 
500 mg 
Fluphenazine 
15 mg 
Haloperidol 
12 mg 
Perphenazine 
40 mg 
Thioridazine 
500 mg 
Thiothixene 
30 mg 
Trifluoperazine 
25 mg 
 
Medications 
Haloperidol Equivalent (12 mg) in mg 
Atypical Antipsychotics 
Amisulpride 
800 
Aripiprazole 
30 
Asenapine 
30 
Brexpiprazole 
4.5 
Cariprazine 
4.5 
Clozapine 
900 
Haloperidol 
12 
Iloperidone 
24 
Lurasidone 
120 
Olanzapine 
20 
Paliperidone 
9 
Quetiapine 
700 
Risperidone 
6 
Sertindole 
36 
Sulpiride 
800 
Ziprasidone 
160 
For antipsychotics not listed in the tables above, please consult the Medical Monitor. 
References: 
https://www.whocc.no/atc_ddd_index/?code=N05AX15 [assessed 02 Sept 2020] 
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. 
Leucht S, Samara M, Heres S, Patel MX, Furukawa T, Cipriani A, Geddes J, Davis JM. Dose equivalents for 
second-generation antipsychotic drugs: the classical mean dose method. Schizophrenia bulletin. 2015 Nov 
1;41(6):1397-402. 
Rothe PH, Heres S, Leucht S. Dose equivalents for second generation long-acting injectable antipsychotics: The 
minimum effective dose method. Schizophrenia Research 2018;193: 23–28. 
Stahl SM. A pocket guide to atypical antipsychotics: dosing, switching, and other practical information. Arbor 
Scientia; 2013.  

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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, Red blood cell (RBC) Count, White blood cell (WBC) 
- Total Count, WBC Differential, (Basophils, Eosinophils, Lymphocytes, Monocytes, 
Neutrophils) 
 
BLOOD CHEMISTRIES: Alanine aminotransferase (ALT), Albumin, Alkaline Phosphatase 
(ALP), Aspartate aminotransferase (AST), Bicarbonate, Bilirubin (Total, Direct, Indirect), Blood 
Urea Nitrogen (BUN), Calcium (Ca), Chloride (Cl), Cholesterol, Creatinine, Creatinine 
clearance (calculated GFR), Creatinine phosphokinase (CPK), Free T3, Free T4, 
HDL-Cholesterol, hs C-reactive Protein (CRP), Glucose, Hemoglobin A1c (HbA1c), 
LDL-Cholesterol, Magnesium (Mg), Phosphorus (P), Potassium (K), Prolactin, Protein (Total), 
Serum Insulin, Sodium (Na), Thyroid stimulating hormone (TSH), Triglycerides, Uric Acid 
 
URINALYSIS: Blood, Glucose, Ketones, Leukocyte esterase, Microscopic examination, 
Nitrites, pH, Protein 
 
URINE DRUG SCREENING / RAPID URINE DRUG SCREENING: Amphetamines, 
Barbiturates, Benzodiazepines, Cannabinoids (Urine Drug Screen), Cocaine, Marijuana (THC) 
(Rapid Urine Drug Screen), Methamphetamines, Methadone, Methylenedioxymethamphetamine 
(MDMA), Phencyclidine (PCP), Opiates, Oxycodone 
 
SEROLOGY PANEL: Hepatitis B Ag, Hepatitis C Ab 
 
OTHER TESTS: Serum Pregnancy (β-hCG) (in female subjects only), Urine Pregnancy Test 
(in female subjects only), Rapid Urine Pregnancy Test (in female subjects only), Follicle 
stimulating hormone (in female subjects with suspected menopause) 
 
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 until 
the test(s) has (have) normalised or stabilised. 
 

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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 as long as possible. 
For each defined PK sampling time point, collect 6 mL blood sample into a K2EDTA 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 into 2 polypropylene tubes with 
approximately equal volume, and label as Primary and Backup. 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 
6 mL  
Day 8 
Anytime (Actual date and clock time will be recorded) 
6 mL 
Day 29 
Anytime (Actual date and clock time will be recorded) 
6 mL 
Day 57 / EOT / ET 
Anytime (Actual date and clock time will be recorded) 
6 mL 
 
 

CCI