A Randomized, Double-blind, Active Comparator-Controlled Study to Evaluate the Long-term Safety and Tolerability of SEP-363856 in Subjects With Schizophrenia
Phase: PHASE3
Conditions: Schizophrenia
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

Titlpage
SEP-363856 
Clinical Study Protocol SEP361-304 
A Randomized, Double-blind, Active Comparator-Controlled 
Study to Evaluate the Long-term Safety and Tolerability of  
SEP-363856 in Subjects with Schizophrenia
IND No. 115,629 
EudraCT No. 2019-002259-40 
Version 3.00 
Incorporates Substantial Amendment 2.00 
14 January 2021 
SUNOVION PHARMACEUTICALS INC. 
84 Waterford Drive 
Marlborough, MA 01752, USA 
(508) 481-6700

Protocol SEP361-304, Version 3.00 
SEP-363856 
Confidential and Proprietary 
2 
14 January 2021 
RESTRICTED DISTRIBUTION OF PROTOCOLS 
This document contains information confidential and/or of proprietary interest to Sumitomo 
Dainippon Pharma Co. Ltd. and/or Sunovion Pharmaceuticals Inc. (including their 
predecessors, subsidiaries or affiliates). The information cannot be disclosed to any third party or 
used for any purpose other than the purpose for which it is being submitted without the prior 
written consent of the appropriate Sumitomo Dainippon Pharma company. 
This information is being provided to you for the purpose of conducting a clinical study for 
Sunovion Pharmaceuticals, Inc. You may disclose the contents of this protocol to the study 
personnel under your supervision and to your Institutional Review Board or Independent Ethics 
Committee for the above purpose. You may not disclose the contents of this protocol to any 
other parties, unless such disclosure is required by government regulations or laws, without the 
prior written permission of Sunovion Pharmaceuticals, Inc. 
Any data gathered during the conduct of this protocol and supplemental information (eg, a 
protocol amendment) that may be added to this document is also proprietary to Sunovion 
Pharmaceuticals, Inc, and should be handled consistently with that stated above. 

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Protocol SEP361-304, Version 3.00 
SEP-363856 
Confidential and Proprietary 
4 
14 January 2021 
1.
SYNOPSIS
Name of Sponsor/Company: Sunovion Pharmaceuticals Inc. 
Name of Investigational Product: SEP-363856 
Title of Study: A Randomized, Double-blind, Active Comparator-Controlled Study to Evaluate the 
Long-term Safety and Tolerability of SEP-363856 in Subjects with Schizophrenia 
Proposed Indication: Schizophrenia 
Study Centers: Approximately 50 global study centers 
Phase of Development: 3 
Study Objectives:  
Primary Objective: 
To evaluate the long-term safety and tolerability of flexibly-dosed SEP-363856 (50, 75, and 
100 mg/day) in clinically stable adult subjects with chronic schizophrenia based on safety parameters, 
including the incidence of overall adverse events (AEs), serious AEs (SAEs) and AEs leading to 
discontinuation. 
Other Safety Objectives: 
•
To evaluate the long-term safety and tolerability of SEP-363856 by assessing:
−
physical examinations (PE)
−
12-lead electrocardiograms (ECG)
−
vital sign measurements
−
clinical laboratory tests
−
suicidality using the Columbia – Suicide Severity Rating Scale (C-SSRS)
−
movement disorder abnormalities using the Simpson-Angus Scale (SAS), the Barnes
Akathisia Rating Scale (BARS) and the Abnormal Involuntary Movement Scale
(AIMS)
•
To evaluate the effects of SEP-363856 (50 to 100 mg/day) on prolactin, HbA1c, lipids,
and glucose concentrations, body weight, and body mass index (BMI) compared to
quetiapine XR (400 to 800 mg/day)
•
To evaluate the impact of SEP-363856 on healthcare resource utilization
Other Efficacy Objectives: 
•
To evaluate the long-term effectiveness of SEP-363856 and quetiapine XR using the
−
Positive and Negative Syndrome Scale (PANSS)
−
Clinical Global Impression-Severity (CGI-S) scale
−
Brief Negative Symptom Scale (BNSS)
−
Montgomery-Asberg Depression Rating Scale (MADRS)
•
To evaluate the maintenance efficacy of SEP-363856 and quetiapine XR (including time
to relapse, rate of relapse and frequency of hospitalization due to relapse)
•
To evaluate adherence to study treatment based on time to all cause discontinuation

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Protocol SEP361-304, Version 3.00 
SEP-363856 
Confidential and Proprietary 
6 
14 January 2021 
Screening/Washout Period beyond one week may be allowed after approval from the Medical 
Monitor. 
Subjects who screen fail may be re-screened once, 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. 
Double-Blind Treatment Period (52 weeks): 
At Baseline (Day 1), subjects who have successfully completed the washout of psychotropic 
medications and have met the eligibility criteria will be randomly assigned via interactive web 
response system (IWRS) to SEP-363856 or quetiapine XR treatment groups in a 2:1 ratio. Study drug 
dosing will begin the evening of the Baseline visit. Treatment 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 seen at Baseline, Weeks 1, 2 and 4, and then every 
4 weeks thereafter up to Week 52. Telephone calls will be made by a member of the clinical research 
staff to the subject weekly between visits that are more than one week apart to collect AEs and 
concomitant medications, as well as to remind the subject about adherence to study drug 
administration and upcoming visits. 
Subjects may be hospitalized for the first 7 days of the Treatment Period, if deemed clinically 
necessary by the Investigator. Further hospitalization during the Treatment Period will require 
approval from the Medical Monitor. 
Subjects randomized to the SEP-363856 group will receive SEP-363856 50 mg/day from Day 1 
through Day 3 and 75 mg/day from Day 4 through Day 7. Beginning on Day 8, the dose can be 
adjusted among 3 dose levels (50, 75, and 100 mg/day), as deemed clinically appropriate by the 
Investigator. 
Subjects randomized to the quetiapine XR group will receive quetiapine XR 300 mg/day on 
Days 1 and 2, 400 mg/day on Days 3 and 4 and 600 mg/day from Day 5 through Day 7. Beginning on 
Day 8, the dose can be adjusted among 3 dose levels (400, 600, and 800 mg/day), as deemed clinically 
appropriate by the Investigator. 
Dose adjustments made to either SEP-363856 or quetiapine XR will be done in a blinded fashion. 
Dose increases can be made no more frequently than weekly to the next higher dose level beginning 
on Day 8, if the response to the previous dose level is not adequate and there are no significant 
tolerability problems, based on Investigator judgement. Increases in dose will occur at regularly 
scheduled study visits when possible. However, dose increases between regularly scheduled visits 
may occur (as long as the subject has been taking the previous dose level for at least 7 days). 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. 
Dose reductions can be made to the next lower dose level at any time (at least 1 day apart) beginning 
on Day 8 for tolerability issues as judged by the Investigator. If a dose reduction is needed between 
study visits, subjects will be asked to return to the clinic for an unscheduled visit for drug 
dispensation. 
For subjects who have received study drug and who prematurely discontinue from the study 
treatment, every effort should be made to complete the final evaluation procedures within 48 hours of 
the last study drug dose at the early termination (ET) visit. 
Follow-up Period (1 week): 
Subjects who discontinue early from the study or complete the study will be required to complete the 
Follow-up Visit 7 days (± 2 days) post last dose of study drug. 
Number of Subjects (planned): 300 subjects 

Protocol SEP361-304, Version 3.00 
SEP-363856 
Confidential and Proprietary 
7 
14 January 2021 
Diagnosis and Criteria for Subject Inclusion: 
Inclusion criteria: 
The main inclusion criteria include, but are not limited to the following: 
•
Male or female subject between 18 to 65 years of age (inclusive) at the time of consent.
•
Subject meets DSM-5 criteria for a diagnosis of schizophrenia as established by clinical
interview at Screening (using the DSM-5 as a reference and confirmed using the
SCID-CT). The time since the subject's diagnosis must be ≥ 1 year prior to Screening.
•
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 (i.e., no evidence of an acute exacerbation) by the
Investigator for at least 8 weeks prior to Screening.
•
Subject has had no change in antipsychotic medication(s) (minor dose adjustments for
tolerability purposes are permitted) for at least 6 weeks prior to Screening.
•
Subjects taking an antipsychotic agent at Screening may participate in this study only if
there are signs of intolerability or lack of efficacy of the current antipsychotic (as
determined by the Investigator).
•
Subject is, in the opinion of the Investigator, generally healthy based on Screening
medical history, PE, neurological examination, vital signs, electrocardiogram (ECG) and
clinical laboratory values (hematology, chemistry and urinalysis).
Exclusion criteria: 
Main exclusion criteria include, but are not limited to: 
•
Subject was hospitalized for a psychiatric illness within the 8 weeks prior to Screening.
•
Subject has a current DSM-5 diagnosis or presence of symptoms consistent with a DSM-5
diagnosis other than schizophrenia. Exclusionary disorders include but are not limited to
alcohol use disorder (within past 12 months or for a total of ≥ 10 years during the
subject’s lifetime), substance (other than nicotine or caffeine) use disorder within past
12 months or for a total of ≥ 10 years during the subject’s lifetime, major depressive
disorder, schizoaffective disorder, bipolar I or II disorder, obsessive compulsive disorder,
and posttraumatic stress disorder. Symptoms of mild to moderate mood dysphoria or
anxiety are allowed so long as these symptoms are not the primary focus of treatment.
•
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.
•
Subject answers “yes” to “Suicidal Ideation” Item 4 (active suicidal ideation with some
intent to act, without specific plan) or Item 5 (active suicidal ideation with specific plan
and intent) on the C-SSRS assessment at Screening (i.e., in the past one month) or at
Baseline (i.e., since last visit).
•
Subject is at significant risk of harming self or others based on Investigator’s judgment.
•
Subject has attempted suicide within 6 months prior to Screening.
•
Subject has received treatment with a psychotropic medication or herbal supplement
within 3 days or 5 half-lives (whichever is longer) prior to randomization or anticipates

Protocol SEP361-304, Version 3.00 
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Confidential and Proprietary 
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14 January 2021 
the need for psychotropic medications or herbal supplements during their participation in 
this study, with the exception of the medications specified in the Concomitant 
Medications section of this document. The following medications have additional 
washout requirements as specified below: 
−
Monoamine oxidase inhibitors (MAOIs) must be discontinued at least 28 days prior
to randomization.
−
Fluoxetine must be discontinued at least 28 days prior to randomization.
−
Clozapine used at 200 mg/day or less for insomnia, agitation or anxiety must be
discontinued at least 28 days prior to randomization. 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 a usage other than insomnia, agitation, or anxiety
are excluded from study participation.
−
Depot neuroleptics must have been discontinued at least one treatment cycle or at
least 30 days (whichever is longer) prior to randomization.
•
Subject has received electroconvulsive therapy (ECT) treatment within the 3 months prior
to Screening or is expected to require ECT during the study.
•
Subject has been treated with quetiapine or quetiapine XR within the 6 weeks prior to
Screening or has a history of inadequate response or intolerability to quetiapine or
quetiapine XR.
•
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.
•
Subject has any clinically significant abnormal laboratory value(s) at Screening.
Investigational Product, Dosage and Mode of Administration: 
SEP-363856 over-encapsulated tablets (50 mg, 75 mg or 100 mg) will be utilized. Study drug will be 
administered orally once daily. Study drug will be taken at the same time each evening at bedtime and 
may be taken without food or with a light meal. 
Subjects randomized to SEP-363856 will receive SEP-363856 50 mg/day from Day 1 through Day 3 
and 75 mg/day from Day 4 through Day 7. Beginning on Day 8, the SEP-363856 dose can be adjusted 
within the range of 50 mg/day to 100 mg/day in 25 mg increments (i.e. 50, 75, or 100 mg/day). Dose 
increases are to be made no more frequently than weekly. Dose reductions for tolerability issues as 
judged by the Investigator can be made at intervals as short as 1 day. 
Duration of Treatment: 52 weeks 
Reference Therapy, Dosage and Mode of Administration:  
Quetiapine XR matching over-encapsulated tablets (300 mg and 400 mg) will be utilized. Study drug 
will be administered orally once daily. Study drug will be taken at the same time each evening at 
bedtime and may be taken without food or with a light meal. 
Subjects randomized to quetiapine XR will receive quetiapine XR 300 mg/day on Days 1 and 2, 
400 mg/day on Days 3 and 4, and 600 mg/day from Day 5 through Day 7. Beginning on Day 8, the 
quetiapine XR dose can be adjusted within the range of 400 mg/day to 800 mg/day in 200 mg 
increments (400, 600, or 800 mg/day). Dose increases are to be made no more frequently than weekly. 
Dose reductions for tolerability issues as judged by the Investigator can be made at intervals as short 
as 1 day. 

Protocol SEP361-304, Version 3.00 
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Confidential and Proprietary 
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14 January 2021 
Concomitant Medications: 
Prior Medications: 
Treatment with oral psychotropic medications and any other medications with a propensity for 
psychotropic effects (with the exception of the medications described below under Allowed 
Concomitant Psychotropic Medications) must be discontinued at least 3 days or 5 half-lives 
(whichever is longer) prior to randomization in a manner that is consistent with labeling 
recommendations and conventional medical practice.  
The following psychotropic medications have additional washout requirements: 
•
MAO inhibitors must be discontinued at least 28 days prior to randomization.
•
Fluoxetine must be discontinued at least 28 days prior to randomization.
•
Clozapine used at 200 mg/day or less for insomnia, agitation, or anxiety must be discontinued
at least 28 days prior to randomization. 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.
•
Depot neuroleptics must have been discontinued at least one treatment cycle or at least
30 days (whichever is longer) prior to the randomization visit.
Treatment with the sedative hypnotics described below under Allowed Concomitant Psychotropic 
Medications is permitted during the Screening/Washout Period but should be tapered as clinically 
appropriate to conform with and adequately prepare the subject for the protocol-specified limitations 
applicable to these agents following randomization. Subjects should not be taken off their current 
effective medications for treatment of schizophrenia for purposes of participating in this study. 
Treatment with medications used to treat movement disorders must be discontinued at least 1 day 
prior to randomization. 
Prohibited Medications: 
Psychotropic medications and medications with a propensity for psychotropic effects are not 
permitted during the Treatment Period, except for the medications discussed below under Allowed 
Concomitant Psychotropic Medications. The use of 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 for treating psychiatric indications are not permitted during the Treatment Period; 
however, they are 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 and the 
acceptable medications described below under Allowed Concomitant Psychotropic Medications) 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. 
Allowed Concomitant Psychotropic Medications: 
Treatment with benztropine (benzotropine outside the United States [US]) up to 6 mg/day is 
permitted, as needed, for motor symptoms. In cases where benztropine is not available or a subject has 
had an inadequate response or intolerability to benztropine treatment, the following medications may 
be used to treat acute extrapyramidal symptoms (EPS): biperiden (up to 16 mg/day) or 
trihexyphenidyl (up to 15 mg/day) or diphenhydramine (up to 100 mg/day). Treatment with 
propranolol (up to 120 mg/day) 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 motor 

Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
10 
14 January 2021 
symptoms should not be given prophylactically. They are to be tapered and discontinued 1 day prior 
to randomization but may be reinstated if symptoms emerge post-randomization during the study. 
Concomitant use of lorazepam, temazepam, eszopiclone, zaleplon, zolpidem, zolpidem controlled 
release (CR), diphenhydramine, and melatonin is permitted at the discretion of the Investigator with 
the following restrictions:  
• 
Oral lorazepam (or equivalent benzodiazepine) is permitted for clinically significant 
anxiety/agitation or as a sedative/hypnotic up to a maximum daily dose of 6 mg/day. 
Intramuscular lorazepam is permitted up to 4 mg/day for acute anxiety/agitation, as clinically 
indicated. Lorazepam should be used sparingly, when clinically required, per investigator 
judgment. 
• 
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. 
• 
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. 
• 
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 (e.g., lorazepam and 
zolpidem) should not be used in close temporal proximity (defined as administration within 
2 hours of each other). 
In regions that do not have the above specified drugs available, similar drugs at equivalent dosages 
will be permitted in consultation with the Medical Monitor. 
The date and time of the last dose of any concomitant psychotropic medication(s) taken prior to 
scheduled efficacy assessments must be recorded at each visit. Subjects should be encouraged to 
avoid taking any psychotropic medication (or any agents that may cause sedation) within 8 hours of 
efficacy 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. 
Concomitant Non-psychotropic Medications: 
Non-psychotropic medications used to treat mild, chronic medical conditions may be used during 
screening and after randomization if the dose and regimen have been stable (± 25% total daily dose) 
for at least 30 days prior to screening. The dose for the concomitant medication may change, as 
needed, after randomization (or be discontinued). This includes β-adrenergic antagonists used to treat 
stable hypertension. Routine vaccines (i.e., seasonal influenza, pneumonia, etc.) are allowed based on 
the investigator’s judgment. Female subjects may use contraception as detailed in Section 10.5. 
In addition, use of non-prescription pain medications (e.g., aspirin, acetaminophen/paracetamol, 
ibuprofen) are allowed during the study provided these medications do not have a propensity for 
psychotropic effects. 
The Medical Monitor should be consulted, if possible, before administering medications for short-
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Monitor is to be informed of such medication use as soon as possible and the appropriateness for the 
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Protocol SEP361-304, Version 3.00 
SEP-363856 
Confidential and Proprietary 
15 
14 January 2021 
Table 2: 
Schedule of Assessments (Continued) 
Study Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
(EOT/ 
ET)a 
18 
Study Week 
Screening/ 
Washoutb
Baselinec 
1 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
Follow-upd
Study Daye 
-21 to -1 
1 
8 
15 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
7±2 d after 
last dose 
Urine drug screenp 
X 
X 
X 
X 
X 
X 
X 
X 
Urine β-hCG, females 
onlyq
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PANSSv 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BNSS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MADRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SASr 
X 
X 
X 
X 
X 
BARSr
X 
X 
X 
X 
X 
AIMSr
X 
X 
X 
X 
X 
EQ-5D-5L 
X 
X 
ESS 
X 
X 
X 
BACS 
X 
X 
X 
X 
UPSA-B 
X 
X 
X 
X 
SLOF
X 
X 
X 
X 
MSQ 
Xs 
X 
Healthcare resource 
Utilization  
X 
X 
X 
X 
X 

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Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
19 
14 January 2021 
7.3. 
Rationale .....................................................................................................................39 
7.3.1. 
Rationale for the Study Design ...................................................................................39 
7.3.2. 
Rationale for the Dosages ...........................................................................................39 
7.4. 
Prevention of Missing Data ........................................................................................39 
8. 
SELECTION OF SUBJECTS ....................................................................................41 
8.1. 
Subject Inclusion Criteria ...........................................................................................41 
8.2. 
Subject Exclusion Criteria ..........................................................................................42 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................46 
9.1. 
Description of Study Drug ..........................................................................................46 
9.2. 
Study Drug Packaging and Labeling ..........................................................................48 
9.2.1. 
Package Description ...................................................................................................48 
9.2.2. 
Labeling Description ..................................................................................................49 
9.3. 
Study Drug Storage .....................................................................................................49 
9.4. 
Dispensing of Study Drug ..........................................................................................49 
9.5. 
Study Drug Accountability .........................................................................................50 
9.6. 
Study Drug Handling and Disposal ............................................................................50 
10. 
TREATMENT OF SUBJECTS ..................................................................................51 
10.1. 
Study Medication ........................................................................................................51 
10.1.1. 
Dose Adjustment Criteria ...........................................................................................51 
10.2. 
Treatment Compliance ................................................................................................51 
10.3. 
Concomitant Medications ...........................................................................................52 
10.3.1. 
Prior Medications: ......................................................................................................52 
10.3.2. 
Prohibited Medications ...............................................................................................53 
10.3.3. 
Prohibited Therapies ...................................................................................................53 
10.3.4. 
Concomitant Nonpsychotropic Medications ..............................................................53 
10.3.5. 
Allowed Concomitant Psychotropic Medications ......................................................54 
10.4. 
Other Restrictions .......................................................................................................55 
10.5. 
Contraception Requirements ......................................................................................55 
10.6. 
Guidance for Overdose ...............................................................................................56 
10.7. 
Eligibility Adjudication Process .................................................................................56 
11. 
STUDY ASSESSMENTS ..........................................................................................57 
11.1. 
Demographics and Baseline Characteristics ...............................................................57 
11.2. 
Prior and Concomitant Medication Review ...............................................................57 

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CCI

Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
21 
14 January 2021 
11.7.5. 
Visit 5 (Week 4; Day 29 ± 2) ......................................................................................69 
11.7.6. 
Visit 6 (Week 8; Day 57 ± 3) ......................................................................................69 
11.7.7. 
Visit 7 (Week 12; Day 85 ± 3) ....................................................................................70 
11.7.8. 
Visit 8 (Week 16; Day 113 ± 3) ..................................................................................70 
11.7.9. 
Visit 9 (Week 20; Day 141 ± 3) ..................................................................................71 
11.7.10. 
Visit 10 (Week 24; Day 169 ± 3) ................................................................................71 
11.7.11. 
Visit 11 (Week 28; Day 197 ± 3) ................................................................................72 
11.7.12. 
Visit 12 (Week 32; Day 225 ± 3) ................................................................................72 
11.7.13. 
Visit 13 (Week 36; Day 253 ± 3) ................................................................................73 
11.7.14. 
Visit 14 (Week 40; Day 281 ± 3) ................................................................................73 
11.7.15. 
Visit 15 (Week 44; Day 309 ± 3) ................................................................................74 
11.7.16. 
Visit 16 (Week 48; Day 337 ± 3) ................................................................................74 
11.7.17. 
Visit 17 (Week 52; Day 365 ± 3) / End of Treatment (EOT) / Early 
Termination (ET) ........................................................................................................74 
11.7.18. 
Visit 18 (Follow-up 7 ± 2 days after last dose) ..........................................................75 
11.7.19. 
Telephone contacts .....................................................................................................76 
11.7.20. 
Unscheduled Visit for Dose Adjustment ....................................................................76 
12. 
SAFETY REPORTING ..............................................................................................77 
12.1. 
Definitions ..................................................................................................................77 
12.1.1. 
Adverse Events ...........................................................................................................77 
12.1.2. 
Serious Adverse Events ..............................................................................................77 
12.2. 
Objective Findings ......................................................................................................78 
12.3. 
Collection and Recording of Adverse Events .............................................................78 
12.4. 
Immediately Reportable Events ..................................................................................80 
12.4.1. 
Serious Adverse Event ................................................................................................80 
12.4.2. 
Pregnancy ...................................................................................................................81 
12.5. 
Data Monitoring Committee/Data and Safety Monitoring Board ..............................81 
13. 
TERMINATION OF SUBJECT FROM STUDY/DISCONTINUATION OF 
STUDY DRUG ...........................................................................................................82 
13.1. 
Criteria for Subject Termination .................................................................................82 
13.2. 
Clinical Assessments after Study Drug Discontinuation ............................................82 
14. 
STUDY TERMINATION ..........................................................................................83 
15. 
STATISTICS ..............................................................................................................84 

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CCI
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Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
24 
14 January 2021 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Schedule of Assessments ............................................................................................13 
Table 3: 
List of Abbreviations ..................................................................................................25 
Table 4: 
Definition of Key Study Terms ..................................................................................28 
Table 5: 
Over-Encapsulated Drug Product ...............................................................................47 
Table 6: 
Computerized Systems Used for Source Data ............................................................91 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................36 
 

Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
25 
14 January 2021 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The abbreviations and the definitions of key study terms used in the clinical study protocol are 
shown in Table 3 and Table 4. 
Table 3: List of Abbreviations 
Abbreviation 
Full Form 
AE 
Adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
BACS 
Brief Assessment of Cognition in Schizophrenia 
BARS 
Barnes Akathisia Rating Scale 
BMI 
Body mass index  
BNSS 
Brief Negative Symptom Scale 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global Impression - Severity 
CLIA 
Clinical Laboratory Improvement Amendments 
CNS 
Central nervous system 
CR 
Controlled release 
CRF 
Case report form 
CRO 
Contract research organization 
CS 
Clinically significant 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ECT 
Electroconvulsive therapy 
EDC 
Electronic data capture 
EOT 
End of treatment 
EPS 
Extrapyramidal symptoms 
EQ-5D-5L 
EuroQol– 5 Dimensions – 5 Levels 
ESS 
Epworth Sleepiness Scale 
ET 
Early termination 
FDA 
U.S. Food and Drug Administration 

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Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
27 
14 January 2021 
Table 3: 
List of Abbreviations (Continued) 
Abbreviation 
Full Form 
QD 
Once daily 
QRS 
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 
RR interval 
Distance between two consecutive R waves 
SAE 
Serious adverse event 
SAS 
Simpson Angus Scale 
SLOF 
Specific Level of Functioning Scale 
SOC 
System organ class 
TAAR1 
trace amine associated 1 receptors 
UCSD 
University of California San Diego 
UDS 
Urine drug screen 
US 
United States 
UPSA-B 
UCSD Performance-Based Skills Assessment – Brief Version 
VAS 
Visual analogue scale 
WBC 
White blood cells 
WHO-DD 
World Health Organization - Drug Dictionary 

Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
28 
14 January 2021 
 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 randomized. 
Study Drug (or 
Study medication) 
Term to cover investigational drug, placebo, and active 
comparator. 
Treatment Period 
The period of the study in which the study drug is administered. 
Randomized Subject 
Any subject who was randomized into the Treatment Period of 
the study and was assigned a randomization number. 
Completed Subject 
Any subject who participated throughout the duration of the 
Treatment Period, up to and including Visit 17. 
Early Termination  
Any subject who was successfully screened and randomized 
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. 
 
 

Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
29 
14 January 2021 
4. 
INTRODUCTION 
4.1. 
Background 
Schizophrenia is a chronic and disabling neuropsychiatric disorder characterized by a mixture of 
positive symptoms (eg, hallucinations, delusions, and thought and movement disorders), negative 
symptoms (eg, flat affect, anhedonia, alogia, and avolition), and cognitive deficits (eg, impaired 
memory, attention, and planning/organizing). Mood symptoms such as depression, anxiety, 
hostility, and excitement can also be present in patients with schizophrenia (Patel-2007; 
NIMH-2010). Despite scientific advances, schizophrenia remains one of the most challenging 
diseases to treat due to its variable nature, the heterogeneity of clinical response, the side effects 
of treatment, and its association with high morbidity and mortality (Lehman-2004; Tandon-2008; 
NIMH-2010). 
Schizophrenia has an estimated population prevalence of approximately 1% (estimated 2.4 
million adults) (Narrow-2002; Wu-2006). It affects both genders equally (NIMH-2010) typically 
first manifesting in young adults, with the peak ages of onset in the early to mid-20s in men and 
late 20s in women (APA-2000). It is believed to be caused by a combination of genetic and 
environmental factors (Minzenberg-2008). Dopaminergic, serotonergic and glutamatergic 
systems are believed to play a role in schizophrenia (Kuroki-2008; Kim-2009). 
The current standard of care for the treatment of schizophrenia is the use of second-generation 
antipsychotics or “atypical antipsychotics” (Lehman-2004; Kreyenbuhl-2009; NIMH-2010; 
Meltzer-2011; Nakamura-2009). These “atypicals” are thought to have fewer extrapyramidal 
side effects compared to first generation antipsychotics or “typical antipsychotics” (eg, 
haloperidol) (Leucht-2009; Naber-2009). However, some patients respond poorly to both 
atypical and typical antipsychotics and some continue to have symptoms and substantial 
functional/cognitive impairment (Keefe-2006; Webber-2008). Very few patients return to 
baseline (pre-psychosis) function (Schultz-1999; Pearlson-2000; Kapur-2001). In addition, 
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 medical problems (cardiovascular disease, diabetes) 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 need for rehospitalization (Ascher-Svanum-2010; Munro-2011; 
Morken-2008). Clearly, an unmet need exists for new, effective, safe 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 (positive and negative symptoms), cognition and depression. 
The molecular target responsible for the therapeutic profile of SEP-363856 has not been 
completely elucidated but may include actions at 5-HT1A and trace amine associated 1 
(TAAR1) receptors. 

Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
30 
14 January 2021 
As of 24 September 2018, a total of 246 subjects have received oral doses of SEP-363856 in 
8 completed Phase 1 studies (SEP361-101, SEP361-103, SEP361-104, SEP361-105, 
SEP361-106, SEP361-108, SEP361-111 and DA801002). An additional 199 subjects received 
oral doses of SEP-363856 in studies in adults with schizophrenia (Study SEP361-201 and Study 
SEP361-202) and 24 subjects in an ongoing Phase 1 study (Study DA801004) in Japanese adults 
with schizophrenia. 
Study SEP361-106 was a 2-part, randomized, single-blind, placebo-controlled, ascending 
multiple oral dose and open label study assessing the safety, tolerability, and pharmacokinetic 
(PK) profile of SEP-363856 in male and female adults with schizophrenia. Part 1 established the 
maximum tolerated dose (MTD) for 7 days of multiple dosing of SEP-363856 without titration 
as 75 mg/day. In Part 2, treatment with SEP-363856 75 mg/day for 28 days demonstrated 
improvement in efficacy measures (PANSS total score, Clinical Global Impression – Severity 
[CGI-S]) compared with baseline. Results from this study demonstrated an acceptable safety and 
tolerability profile of SEP-363856 75 mg/day for up to 28 days in adults with schizophrenia. 
Study SEP361-201 was a 4-week, randomized, double-blind, placebo-controlled, multicenter 
study evaluating the efficacy and safety of SEP-363856 (flexibly-dosed at 50 to 75 mg/day) in 
acutely psychotic adults with schizophrenia. SEP-363856 demonstrated statistically significant 
improvement in the PANSS total score compared to placebo at Week 4 (primary endpoint) with 
an effect size of 0.45. Significant differences favoring the SEP-363856 group were also 
demonstrated on all secondary efficacy endpoints, including the Clinical Global Impression – 
Severity scale (CGI-S), PANSS subscales encompassing positive, negative and general 
psychopathology symptoms, the Montgomery-Asberg Depression Rating Scale (MADRS) and 
Brief Negative Symptom Scale (BNSS). Overall, the safety and tolerability profile were 
comparable to placebo. There were no clinically relevant findings related to electrocardiogram 
(ECG) parameters, laboratory parameters, vital signs, motor symptoms or suicidality. 
Study SEP361-202 is a, long-term, open-label extension study to Study SEP361-201, which is 
evaluating the safety and tolerability of flexibly dosed SEP-363856 (25, 50, or 75 mg/day) in 
adults with schizophrenia for up to 26 weeks. A total of 156 subjects received SEP-363856 in 
Study SEP361-202 (79 subjects randomized previously to placebo in Study SEP361-201). In 
Study SEP361-202, the most common AEs were schizophrenia, headache, insomnia, and 
anxiety. 
Together, these data support continued development of SEP-363856 as a potential treatment for 
patients with schizophrenia. 
The present study is a 52-week, outpatient, multicenter, parallel-group, flexible-dose study, 
designed to evaluate the long-term safety and tolerability of SEP-363856 (50 to 100 mg/day) 
compared with quetiapine XR (400 to 800 mg/day) in clinically stable adult subjects with 
schizophrenia. 
4.3. 
Risk-Benefit Assessment 
Schizophrenia is a lifelong disorder and despite advances in drug treatment many patients 
continue to experience significant symptoms, disabling side effects and impaired functioning and 
quality of life. Some patients respond poorly to currently available antipsychotics and continue to 
have symptoms and substantial functional/cognitive impairment (Keefe-2006; Webber-2008). 

Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
31 
14 January 2021 
Antipsychotic treatment is associated with medically-important adverse effects, including weight 
gain, metabolic syndrome, sedation, extrapyramidal symptoms (including akathisia), 
hyperprolactinemia and QT interval prolongation (Davis-2004; Lieberman-2005; 
Newcomer-2007; Leucht-2009). These side effects are attributable to both on-target (D2) and 
off-target receptor binding. A significant unmet need still exists for treatments with better 
efficacy, safety and tolerability. 
SEP-363856 has a novel mechanism of action and does not functionally modulate the D2 
receptor nor any of the receptors shown to impart significant side effects of currently approved 
antipsychotics. 
In an adequate and well-controlled four-week double-blind 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. The effectiveness of treatment with SEP-363856 
was also shown to be sustained over a 6-month extension period (Study SEP361-202). Overall, 
the safety and tolerability profile of SEP-363856, including rates of extrapyramidal symptoms 
and hyperprolactinemia, was comparable to placebo. Notably, no clinically significant mean 
changes from baseline in lipid or glucose parameters were found, nor was weight gain observed 
in association with SEP-363856 treatment. 
SEP-363856 has the potential to provide a significantly improved safety profile compared to 
available therapy, while providing efficacy in the treatment of patients with schizophrenia. Data 
generated in the clinical program to date provide an acceptable expected benefit/risk ratio for 
evaluating SEP-363856 in adults with schizophrenia in this study. 
4.4. 
Hypothesis 
This study is intended to evaluate the long-term safety and tolerability of SEP-363856. 

Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
32 
14 January 2021 
5. 
STUDY OBJECTIVES 
5.1. 
Primary Objective 
To evaluate the long-term safety and tolerability of flexibly-dosed SEP-363856 (50, 75, and 
100 mg/day) in clinically stable adult subjects with chronic schizophrenia based on safety 
parameters, including the incidence of overall adverse events (AEs), serious AEs (SAEs) and 
AEs leading to discontinuation. 
5.2. 
Other Safety Objectives 
To evaluate the long-term safety and tolerability of SEP-363856 by assessing:  
• physical examinations (PE) 
• 12-lead electrocardiograms (ECG) 
• vital sign measurements 
• clinical laboratory tests 
• suicidality using the Columbia – Suicide Severity Rating Scale (C-SSRS) 
• movement disorder abnormalities using the Simpson-Angus Scale (SAS), the Barnes 
Akathisia Rating Scale (BARS) and the Abnormal Involuntary Movement Scale 
(AIMS) 
• To evaluate the effects of SEP-363856 (50 to 100 mg/day) on prolactin, HbA1c, 
lipids, and glucose concentration, body weight, and body mass index (BMI) 
compared to quetiapine XR (400 to 800 mg/day). 
• To evaluate the impact of SEP-363856 on healthcare resource utilization. 
5.3. 
Other Efficacy Objectives 
• To evaluate the long-term effectiveness of SEP-363856 and quetiapine XR using the  
− Positive and Negative Syndrome Scale (PANSS) 
− Clinical Global Impression-Severity (CGI-S) scale  
− Brief Negative Symptom Scale (BNSS) 
− Montgomery-Asberg Depression Rating Scale (MADRS) 
• To evaluate the maintenance efficacy of SEP-363856 and quetiapine XR (including 
time to relapse, rate of relapse and frequency of hospitalization due to relapse) 
• To evaluate adherence to study treatment based on time to all cause discontinuation 
• To evaluate the effects of SEP-363856 and quetiapine XR on daytime sleepiness as 
measured by the Epworth Sleepiness Scale (ESS) 
• To assess the effects of SEP-363856 and quetiapine XR on cognition as measured by 
the Brief Assessment of Cognition in Schizophrenia (BACS) 

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Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
34 
14 January 2021 
6. 
STUDY ENDPOINTS 
6.1. 
Primary Endpoints 
• The incidence of overall AEs, SAEs, and AEs leading to discontinuation 
6.2. 
Other Safety Endpoints 
• Observed values and changes from Baseline in clinical laboratory tests (hematology, 
chemistry and urinalysis) 
• 12-lead ECG (including heart rate, RR, PR, QRS, QT, QTc-F and QTc-B) 
• Observed values and changes from Baseline in vital signs (including body weight, 
BMI, waist circumference, temperature, blood pressure [supine and standing], heart 
rate [supine and standing] and respiratory rate) 
• Frequency and severity of suicidal ideation and suicidal behavior based on the 
C-SSRS 
• Changes from Baseline in BARS, AIMS and SAS scores 
• Healthcare resource utilization (HRU) (including numbers of physician office visits, 
ER visits and hospitalizations, length of hospital stays, employment status and 
average number of hours caregiver spends helping subjects per week). 
6.3. 
Other Efficacy Endpoints 
• Changes from Baseline in: 
− PANSS total score and subscale scores (positive, negative, and general 
psychopathology) 
− CGI-S score 
− BNSS total score 
− MADRS total score 
− ESS total score 
− BACS composite score 
− UPSA-B total score 
− SLOF total and subscale scores 
− EQ-5D-5L visual analog scale (VAS), index score and dimension score 
− MSQ score 
• Time to relapse, rate of relapse, and frequency of hospitalization due to relapse. 
Relapse will be defined as the earliest occurrence of any of the following: 
− Worsening of > 30% PANSS total score from Baseline and CGI-S > 3 
− Hospitalization for worsening of psychosis 

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Protocol SEP361-304, Version 3.00 
SEP-363856 
Confidential and Proprietary 
36 
14 January 2021 
7.
INVESTIGATIONAL PLAN
7.1. 
Overall Study Design
This is a 52-week, multicenter, randomized, double-blind, parallel-group, flexible-dose study 
designed to evaluate the long-term safety and tolerability of SEP-363856 (50 to 100 mg/day) in 
clinically stable adults with schizophrenia. This study is projected to randomize approximately 
300 subjects to two treatment groups (SEP-363856 50 to 100 mg/day or quetiapine XR 400 to 
800 mg/day) in a 2:1 ratio. Study drug will be taken at the same time each evening at bedtime 
and should be taken without food or with a light meal. 
The study will consist of three periods: Screening/Washout (up to 21 days), Treatment 
(52 weeks) and a Follow-up visit (7 days after the last study drug dose) as shown in Figure 1. 
Figure 1: 
Study Schematic 
Screening/Washout 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/Washout Period of up to 21 days, 
during which they will be tapered off all psychotropic medications (except as noted in the 
Concomitant Medications section below) in a manner that is consistent with labeling 
recommendations and conventional medical practices. The Screening Period may be extended 
for up to 7 days after approval from the Medical Monitor. 
Subjects may be hospitalized for up to one week prior to randomization during the 
Screening/Washout Period, if deemed clinically necessary by the Investigator. Additional 
hospitalization during the Screening/Washout Period beyond one week may be allowed after 
approval from the Medical Monitor. 
Subjects who screen fail may be re-screened once, 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. 

Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
37 
14 January 2021 
Double-Blind Treatment Period (52 weeks): 
At Baseline (Day 1), subjects who have successfully completed the washout of psychotropic 
medications and have met the eligibility criteria will be randomly assigned via interactive web 
response system (IWRS) to SEP-363856 or quetiapine XR treatment groups in a 2:1 ratio. Study 
drug dosing will begin the evening of the Baseline visit. Treatment 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 seen at Baseline, Weeks 1, 2 and 4, and 
then every 4 weeks thereafter up to Week 52. Telephone calls will be made by a member of the 
clinical research staff to the subjects weekly between visits that are more than one week apart to 
collect AEs and concomitant medications, as well as to remind subject about adherence to study 
drug administration and upcoming visits. 
Subjects may be hospitalized for the first 7 days of the Treatment Period, if deemed clinically 
necessary by the Investigator. Further hospitalization during the Treatment Period will require 
approval from the Medical Monitor. 
Subjects randomized to the SEP-363856 group will receive SEP 363856 50 mg/day from Day 1 
through Day 3 and 75 mg/day from Day 4 through Day 7. Beginning on Day 8, the dose can be 
adjusted among 3 dose levels (50, 75 and 100 mg), as deemed clinically appropriate by the 
Investigator. 
Subjects randomized to the quetiapine XR group will receive quetiapine XR 300 mg/day on 
Days 1 and 2, 400 mg/day on Days 3 and 4, and 600 mg/day from Day 5 through Day 7. 
Beginning on Day 8, the dose can be adjusted among 3 dose levels (400, 600, and 800 mg), as 
deemed clinically appropriate by the Investigator. 
Dose adjustments made to either SEP-363856 or quetiapine XR will be done in a blinded 
fashion. 
Dose increases can be made no more frequently than weekly to the next higher dose level 
beginning on Day 8, if the response to the previous dose level is not adequate and there are no 
significant tolerability problems, based on Investigator judgement. Increases in dose will occur at 
regularly scheduled study visits, when possible. However, dose increases between regularly 
scheduled visits may occur (as long as subject have been taking the previous dose level for at 
least 7 days). 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. 
Dose reductions can be made to the next lower dose level at any time (at least 1 day apart) 
beginning on Day 8 for tolerability issues as judged by the Investigator. If a dose reduction is 
needed between study visits, subjects will be asked to return to the clinic for an unscheduled visit 
for drug dispensation. 
For subjects who have received study drug and who prematurely discontinue from the study 
treatment, every effort should be made to complete the final evaluation procedures within 
48 hours of the last study drug dose at the early termination (ET) visit. 
Follow-up Period (1 week): 
Subjects who discontinue early from the study or complete study will be required to complete the 
Follow-up Visit 7 days (± 2 days) post last dose of study drug. 

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CCI

Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
39 
14 January 2021 
treatment assignment, maintain the confidentiality of the information and do not divulge the 
treatment assignment. 
7.3. 
Rationale 
7.3.1. 
Rationale for the Study Design 
Schizophrenia is a chronic disorder requiring long-term treatment and follow-up care. This study 
will evaluate the long-term safety and tolerability of flexibly dosed SEP-363856 (50, 75 or 
100 mg/day) and the active comparator quetiapine XR (400, 600, or 800 mg/day) in adults with 
schizophrenia. 
7.3.2. 
Rationale for the Dosages 
In the present study, flexible dosing of SEP-363856 50, 75 or 100 mg/day for 52 weeks will be 
investigated. 
Selection of these doses was guided by 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 the results from Study SEP361-201, which demonstrated that 
SEP-363856 flexibly dosed at 50 to 75 mg/day was well-tolerated and showed a statistically 
significant improvement from Baseline to Week 4 in PANSS total score for SEP-363856 versus 
placebo in adults with an acute exacerbation of schizophrenia. SEP-363856 (flexibly dosed at 25, 
50, or 75 mg/day) was also well tolerated in the 6-month, open-label extension study 
SEP361-202. 
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 adults with schizophrenia was determined as 75 mg/day. The 
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. In this study 
(SEP361-304), titration to the 75 and 100 mg/day dosages is included to improve tolerability. 
The quetiapine XR dose range is consistent with labeling recommendations. 
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:  

Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
40 
14 January 2021 
• Some concomitant psychotropic medications are allowed, as needed, during study 
participation. 
• Dose reductions (or SEP-363856 from 100 to 75 mg/day; or from 75 to 50 mg/day; 
For quetiapine XR from 800 to 600 mg/day; or from 600 to 400 mg/day) are allowed 
for drug tolerability purposes. 
• 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. 
• Telephone calls will be made by a member of the clinical research staff to the 
subjects weekly between visits that are more than one week apart to collect AEs and 
concomitant medications, as well as to remind subject about adherence to study drug 
administration and upcoming visits. 
• Data collection is monitored for adherence during the study. 
See Section 15.3 for statistical considerations related to missing data. 

Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
41 
14 January 2021 
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 at Screening (using the DSM-5 as a reference and confirmed using the 
SCID-CT). The time since the subject's diagnosis must be ≥ 1 year prior to Screening. 
6.  Every attempt should be made to obtain medical records or to have correspondence with 
a previous or current treating psychiatrist for the purposes of confirming that the previous 
course and treatment is consistent with schizophrenia. Every attempt should also be made 
to obtain medical records for any preexisting medical conditions that may impact a 
subject’s eligibility. 
7. Subject must have a CGI-S score ≤ 4 at Screening and Baseline. 
8. Subject must have a PANSS total score ≤ 80 at Screening and Baseline. 
9. Subject is judged to be clinically stable (i.e., no evidence of an acute exacerbation) by the 
Investigator for at least 8 weeks prior to Baseline. 
10. Subject has had no change in antipsychotic medication(s) (minor dose adjustments for 
tolerability purposes are permitted) for at least 6 weeks prior to Screening. 
11. Subjects taking an antipsychotic agent at Screening may participate in this study only if 
there are signs of intolerability or lack of efficacy of the current antipsychotic (as 
determined by the Investigator). 
12. Subject’s BMI must be 18 kg/m2 to 35 kg/m2 (inclusive) at Screening. 
13. Female subjects of childbearing potential must have a negative serum pregnancy test at 
Screening. 
14. Female subjects of childbearing potential must agree to use highly effective and reliable 
contraception throughout the study and for at least 30 days after the last dose of study 
drug has been taken. In the Investigator’s judgment, the subject will adhere to this 
requirement. Details on contraception requirements are provided in Section 10.5. 
15. Male subjects must agree to avoid fathering a child and to use highly effective methods 
of birth control from screening until at least 30 days after the last study drug 
administration. Details on contraception requirements are provided in Section 10.5. 

Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
42 
14 January 2021 
16. Subject is, in the opinion of the Investigator, generally healthy based on Screening 
medical history, PE, neurological examination, vital signs, electrocardiogram (ECG) and 
clinical laboratory values (hematology, chemistry and urinalysis). 
17. Subject has a stable living arrangement at the time of Screening and intends to remain in 
a stable living arrangement for the course of the study. 
18. Subject’s eligibility confirmed through formal adjudication process (See Section 10.7). 
8.2. 
Subject Exclusion Criteria 
To qualify for participation, subjects must not meet any of the following exclusion criteria: 
1. Subject was hospitalized for a psychiatric illness within the 8 weeks prior to Screening. 
2. Subject has a current DSM-5 diagnosis or presence of symptoms consistent with a 
DSM-5 diagnosis other than schizophrenia. Exclusionary disorders include but are not 
limited to alcohol use disorder (within past 12 months or for a total of ≥ 10 years during 
the subject’s lifetime), substance (other than nicotine or caffeine) use disorder within past 
12 months or for a total of ≥ 10 years during the subject’s lifetime, major depressive 
disorder, schizoaffective disorder, bipolar I or II disorder, obsessive compulsive disorder, 
and posttraumatic stress disorder. Symptoms of mild to moderate mood dysphoria or 
anxiety are allowed so long as these symptoms are not the primary focus of treatment. 
3. 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. 
4. Subject answers “yes” to “Suicidal Ideation” Item 4 (active suicidal ideation with some 
intent to act, without specific plan) or Item 5 (active suicidal ideation with specific plan 
and intent) on the C-SSRS assessment at Screening (i.e., in the past one month) or at 
Baseline (i.e., since last visit). 
5. Subject is at significant risk of harming self or others based on Investigator’s judgment. 
6.  Subject has attempted suicide within 6 months prior to Screening. 
7. Subject has received treatment with a psychotropic medication or herbal supplement 
within 3 days or 5 half-lives (whichever is longer) prior to randomization or anticipates 
the need for psychotropic medications or herbal supplements during their participation in 
this study, with the exception of the medications specified in Section 10.3.5. The 
following medications have additional washout requirements as specified below: 
• Monoamine oxidase inhibitors (MAOIs) must be discontinued at least 28 days 
prior to randomization. 
• Fluoxetine must be discontinued at least 28 days prior to randomization.  
• Clozapine used at 200 mg/day or less for insomnia, agitation or anxiety must be 
discontinued at least 28 days prior to randomization. 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 a usage other than insomnia, agitation, 
or anxiety are excluded from study participation. 

Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
43 
14 January 2021 
• Depot neuroleptics must have been discontinued at least one treatment cycle or at 
least 30 days (whichever is longer) prior to randomization. 
8. Subject has received electroconvulsive therapy (ECT) treatment within the 3 months 
prior to Screening or is expected to require ECT during the study. 
9. Subject has been treated with quetiapine or quetiapine XR within the 6 weeks prior to 
Screening or has a history of inadequate response or intolerability to quetiapine or 
quetiapine XR. 
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: 
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 being randomized in the study. 
b. Subject has a history of neuroleptic malignant 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. Disorder or history of a gastrointestinal condition or previous gastrointestinal surgery 
(eg, cholecystectomy, vagotomy, or bowel resection) that may interfere with drug 
absorption, distribution, metabolism, excretion, gastrointestinal motility, or gastric 
pH. 
f. Subject has a history of malabsorption. 
g. 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 
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. 
h. Subjects with known history of human immunodeficiency virus (HIV) seropositivity. 
i. Subject has type I diabetes mellitus or insulin-dependent type II diabetes. 
11. Subject exhibits evidence of moderate or severe extrapyramidal symptoms, dystonia, 
tardive dyskinesia, or any other moderate or severe movement disorder. Severity to be 
determined by the Investigator. 

Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
44 
14 January 2021 
12. Female subject who is pregnant or lactating. 
13. Subject has a history of allergic reaction or suspected sensitivity to quetiapine or 
quetiapine XR or any substance that is contained in the quetiapine XR or SEP-363856 
formulations. 
14. Subject with a supine systolic blood pressure ≥ 140 mmHg and/or supine diastolic blood 
pressure ≥ 90 at Screening or Baseline. A repeat blood pressure measurement is allowed 
once during the Screening Period and once at Baseline. The repeat measurements can be 
used to determine eligibility. The repeat blood pressure measurement at Screening can be 
conducted on a different day within the screening period, if needed. 
15. Subject has any clinically significant abnormal laboratory value(s) at Screening 
(hematology, chemistry and urinalysis) as determined by the Investigator. (Note: 
Retesting is allowed once during the Screening Period and the retest will be used to 
determine eligibility after approval from the Medical Monitor; however, the Screening 
Period will not be extended to accommodate repeat laboratory tests, unless repeat tests 
are needed due to a technical issue with laboratory sample processing, shipment or testing 
delay at the central laboratory. Abnormal findings of questionable significance will be 
discussed with the Medical Monitor prior to including any subject.) 
16. 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. 
17. Subjects with ALT or AST ≥ 3 times the upper limit of the reference ranges provided by 
the central laboratory at Screening. 
18. 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. 
19. Subjects with a fasting blood glucose at Screening ≥ 126 mg/dL (7.0 mmol/L) or 
HbA1c > 7.0%. 
20. 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 non-psychotropic drug-related causes of 
elevated prolactin levels. 
21. 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). Subjects who test positive for 
cannabinoids (tetrahydrocannabinol or cannabidiol) at Screening are excluded. 
22. Subject has received an investigational product or device within 1 year prior to signing 
informed consent or has participated in more than 2 studies in psychiatric indications of 
investigational products or devices within their lifetime. 
23. Subject has previously received SEP-363856. 

Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
45 
14 January 2021 
24. Subject is a staff member of the study center or the relative of a staff member of the study 
center. 
25. Subject is, in the opinion of the Investigator, unsuitable in any other way to participate in 
this study. 
 

Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
46 
14 January 2021 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
9.1. 
Description of Study Drug 
SEP-363856 active and placebo tablets will be over-encapsulated in size DB AAel hard gelatin 
capsules and back filled with microcrystalline cellulose. SEP-363856 active tablets including 
50 mg, 75 mg and 100 mg and the matching placebo will be utilized. To maintain the blind, 
over-encapsulated placebo will also be used as part of the blister cards (refer to Section 9.2.1). 
Quetiapine XR tablets (300 mg and 400 mg) will be over-encapsulated in Size DB AAel 
Swedish orange capsules and back filled with microcrystalline cellulose.

Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
47 
14 January 2021 
Table 5: 
Over-Encapsulated Drug Product 
Attribute 
 
Product name 
SEP-363856  
SEP-363856  
SEP-363856  
Placebo 
Seroquel XR 
Seroquel XR 
Dosage form 
Tablet 
Tablet 
Tablet 
Tablet 
Tablet 
Tablet 
Unit dose 
50 mg 
75 mg 
100 mg 
N/A 
300 mg 
400 mg 
Route of 
administration 
Oral 
Oral 
Oral 
Oral 
Oral 
Oral 
Physical description 
Swedish orange 
capsule containing 
one yellow oval 
tablet and white 
powder 
Swedish orange 
capsule containing 
one yellow oval 
tablet and white 
powder  
Swedish orange 
capsule containing 
one yellow oval 
tablet and white 
powder 
Swedish orange 
capsule containing 
one yellow oval 
tablet and white 
powder 
Swedish orange 
capsule containing 
one pale yellow 
capsule-shaped 
tablet engraved 
with “XR 300” and 
white powder 
Swedish orange 
capsule containing 
one white capsule-
shaped tablet 
engraved with “XR 
400” and white 
powder 
Active 
Pharmaceutical 
ingredient (API) 
SEP-363856-01 
(hydrochloride salt) 
SEP-363856-01 
(hydrochloride salt) 
SEP-363856-01 
(hydrochloride salt) 
N/A 
Quetiapine 
fumarate 
Quetiapine 
fumarate 
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 
-Microcrystalline 
cellulose  
-Mannitol 
-Sodium starch 
glycolate 
-Magnesium 
stearate 
Film coating:  
-Hydroxypropyl 
methylcellulose 
-Hydroxypropyl 
cellulose 
-Titanium dioxide 
-Yellow iron oxide 
Carnauba wax 
-Lactose 
monohydrate 
- Microcrystalline 
cellulose 
-Sodium citrate 
- Hydroxypropyl 
methylcellulose 
-Magnesium 
stearate 
Film coating: 
- Hydroxypropyl 
methylcellulose 
-Polyethylene 
glycol 400 
-Titanium dioxide 
-Yellow iron oxide 
-Lactose 
monohydrate 
- Microcrystalline 
cellulose 
-Sodium citrate 
- Hydroxypropyl 
methylcellulose 
-Magnesium 
stearate 
Film coating: 
- Hydroxypropyl 
methylcellulose 
-Polyethylene 
glycol 400 
-Titanium dioxide 

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9.2. 
Study Drug Packaging and Labeling 
9.2.1. 
Package Description 
Study drug will be provided in one-week blister cards containing 18 capsules arranged in 
9 columns and 2 rows. Each card will have a unique number identifier. Cards will contain 
capsules for 9 days (7 days + 2 extra days). Some cards will utilize placebo capsules to maintain 
the blind. Subjects will be instructed to take a column of 2 capsules each day, according to 
dosing instructions. Some doses require 2 active capsules, while others only require 1. 
 
Week 1: Blinded Titration Dose 
Day 
1 
2 
3 
4 
5 
6 
7 
Extra day 
Extra day 
Row 1 
SEP-
363856 
50 mg or  
QXR 
300 mg 
SEP-
363856 
50 mg or  
QXR 
300 mg 
SEP-
363856 
50 mg or  
QXR 
400 mg 
SEP-
363856 
75 mg or  
QXR 
400 mg 
SEP-
363856 
75 mg or  
QXR 
300 mg 
SEP-
363856 
75 mg or  
QXR 
300 mg 
SEP-
363856 
75 mg or  
QXR 
300 mg 
SEP-
363856 
75 mg or  
QXR 
300 mg 
SEP-
363856 
75 mg or  
QXR 
300 mg 
Row 2 
Placebo 
Placebo 
Placebo 
Placebo 
Placebo 
or  
QXR 
300 mg 
Placebo 
or  
QXR 
300 mg 
Placebo 
or  
QXR 
300 mg 
Placebo 
or  
QXR 
300 mg 
Placebo 
or  
QXR 
300 mg 
 
Weeks 2 to 52: Blinded Low Dose 
Day 
1 
2 
3 
4 
5 
6 
7 
Extra day 
Extra day 
Row 1 
SEP-
363856 
50 mg or 
QXR 
400 mg 
SEP-
363856 
50 mg or 
QXR 
400 mg 
SEP-
363856 
50 mg or 
QXR 
400 mg 
SEP-
363856 
50 mg or 
QXR 
400 mg 
SEP-
363856 
50 mg or 
QXR 
400 mg 
SEP-
363856 
50 mg or 
QXR 
400 mg 
SEP-
363856 
50 mg or 
QXR 
400 mg 
SEP-
363856 
50 mg or 
QXR 
400 mg 
SEP-
363856 
50 mg or 
QXR 
400 mg 
Row 2 
Placebo 
Placebo 
Placebo 
Placebo 
Placebo 
Placebo 
Placebo 
Placebo 
Placebo 
 
Weeks 2 to 52: Blinded Middle Dose 
Day 
1 
2 
3 
4 
5 
6 
7 
Extra day 
Extra day 
Row 1 
SEP-
363856 
75 mg or 
QXR 
300 mg 
SEP-
363856 
75 mg or 
QXR 
300 mg 
SEP-
363856 
75 mg or 
QXR 
300 mg 
SEP-
363856 
75 mg or 
QXR 
300 mg 
SEP-
363856 
75 mg or 
QXR 
300 mg 
SEP-
363856 
75 mg or 
QXR 
300 mg 
SEP-
363856 
75 mg or 
QXR 
300 mg 
SEP-
363856 
75 mg or 
QXR 
300 mg 
SEP-
363856 
75 mg or 
QXR 
300 mg 
Row 2 
Placebo 
Or 
QXR 
300 mg 
Placebo 
Or 
QXR 
300 mg 
Placebo 
Or 
QXR 
300 mg 
Placebo 
Or 
QXR 
300 mg 
Placebo 
Or 
QXR 
300 mg 
Placebo 
Or 
QXR 
300 mg 
Placebo 
Or 
QXR 
300 mg 
Placebo 
Or 
QXR 
300 mg 
Placebo 
Or 
QXR 
300 mg 
 

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Weeks 2 to 52: Blinded High Dose 
Day 
1 
2 
3 
4 
5 
6 
7 
Extra day 
Extra day 
Row 1 
SEP-
363856 
100 mg 
or QXR 
400 mg 
SEP-
363856 
100 mg 
or QXR 
400 mg 
SEP-
363856 
100 mg 
or QXR 
400 mg 
SEP-
363856 
100 mg 
or QXR 
400 mg 
SEP-
363856 
100 mg 
or QXR 
400 mg 
SEP-
363856 
100 mg 
or QXR 
400 mg 
SEP-
363856 
100 mg 
or QXR 
400 mg 
SEP-
363856 
100 mg 
or QXR 
400 mg 
SEP-
363856 
100 mg 
or QXR 
400 mg 
Row 2 
Placebo  
or QXR 
400 mg  
Placebo  
or QXR 
400 mg  
Placebo  
or QXR 
400 mg  
Placebo  
or QXR 
400 mg  
Placebo  
or QXR 
400 mg  
Placebo  
or QXR 
400 mg  
Placebo  
or QXR 
400 mg  
Placebo  
or QXR 
400 mg  
Placebo  
or QXR 
400 mg  
9.2.2. 
Labeling Description 
All packaging for the study drugs will be labeled with:  
• Protocol number 
• Sponsor’s name and address 
• Compound/Code or name of investigational drug and dosage form 
• Contents (eg, number of tablets) 
• Investigational Drug/caution statement 
• Instructions for use and storage 
• Batch number 
• Blank space to record visit number 
• Blank space for subject identifiers 
• Period of use (as required) 
• Unique medication/kit ID number 
• Investigator information (if needed) 
9.3. 
Study Drug Storage 
All study drug should be stored between 20°C and 25°C (68° to 77°F). Excursions of 15°C to 
30°C (59°F to 86°F) are permitted during shipment of study drug to investigational sites 
(see United States Pharmacopeia [USP]). 
9.4. 
Dispensing of Study Drug  
An Interactive Web Response System (IWRS) will be used to manage subject enrollment. The 
IWRS is an integrated web-based subject and drug management system. 
Study drug blister cards will be assigned by the IWRS based on the treatment schedule and dose 
adjustment criteria. The IWRS will generate instructions for which blister card ID(s) to dispense 
to the subject. Each subject will be dispensed one to four 9-day (7 days + 2 days extra days) 
blister cards per scheduled visit depending on the timing of the next scheduled visit (see 
Table 2). IWRS drug dispensing guidelines should be followed for dispensing study drug to 
subjects. A specific user manual will be provided. 

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Subjects will take two blinded capsules (one from each row) of study drug per day at 
approximately the same time each evening at bedtime. Study drug may be taken without food or 
with a light meal. 
9.5. 
Study Drug Accountability 
The investigator or designee is responsible for maintaining adequate and up to date records of 
drug disposition that includes dates, quantities, and use by subjects. 
Upon receipt of study drug, the Investigator or designee will inspect the supplies and verify 
receipt of the shipment in the IWRS, confirming the date of receipt, inventory and condition of 
study drug received. 
The IWRS will also be used for the accountability of the study drug at the clinical site. The 
Investigator or designee will maintain records for accountability within the IWRS, 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 Sponsor/contract research 
organization (CRO). 
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 or final disposal 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 consist of SEP-363856 50 mg, 75 mg or 100 mg tablets and quetiapine 
XR tablets 300 mg and 400 mg, administered in capsule form orally once daily and will be 
supplied as described in Section 9. 
Subjects may take study drug without food or with a light meal at approximately the same time 
each evening at bedtime. 
10.1.1. 
Dose Adjustment Criteria 
Subjects randomized to the SEP-363856 group will receive SEP-363856 50 mg/day from Day 1 
through Day 3 and 75 mg/day from Day 4 through Day 7. Beginning on Day 8, the dose can be 
adjusted among 3 dose levels (50, 75 and 100 mg), as deemed clinically appropriate by the 
Investigator. 
Subjects randomized to the quetiapine XR group will receive quetiapine XR 300 mg/day on 
Days 1 and 2, 400 mg/day on Days 3 and 4, and 600 mg/day from Day 5 through Day 7. 
Beginning on Day 8, the dose can be adjusted among 3 dose levels (400, 600, and 800 mg), as 
deemed clinically appropriate by the Investigator. 
Dose adjustments made to either SEP-363856 or quetiapine XR will be done in a blinded 
fashion. 
Dose increases can be made no more frequently than weekly to the next higher dose level 
beginning on Day 8, if the response to the previous dose level is not adequate and there are no 
significant tolerability problems, based on Investigator judgement. Increases in dose will occur at 
regularly scheduled study visits, when possible. However, dose increases between regularly 
scheduled visits may occur (as long as the subject has been taking the previous dose level for at 
least 7 days). 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. 
Dose reductions can be made to the next lower dose level at any time (at least 1 day apart) 
beginning on Day 8 for tolerability issues as judged by the Investigator. If a dose reduction is 
needed between study visits, subjects will be asked to return to the clinic for an unscheduled visit 
for drug dispensation. 
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 capsules and dividing the actual number of doses taken (per capsule count) 
by the number of doses the subject should have taken within a visit period and multiplying by 
100. All subjects will be reminded of the importance of strict compliance with taking study drug 
for the effectiveness of treatment and for the successful outcome of the study. Subjects who miss 
more than 25% of scheduled doses or take more than 125% of the scheduled doses will be 

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considered noncompliant. Evidence of noncompliance must be immediately reported to the 
Clinical Research Associate (CRA) and/or Medical Monitor. 
10.3. 
Concomitant Medications 
Prior use of psychotropic medication during the previous 3 years, and any other medication taken 
during the previous 60 days will be recorded at Visit 1 (Screening). 
Details on all medications taken in the 60 days prior to Screening (including dosing changes) 
will be recorded. For psychotropic medications taken prior to that 60-day period, approximate 
start and stop dates of each unique psychotropic medication will be recorded, along with the 
maximum daily dose of the psychotropic medication ever taken during the specified time period 
(i.e., it is not required to capture every psychotropic dose change during this period). 
Every effort should be made to collect medical and/or pharmacy records for psychotropic 
medications used in the past 3 years and non-psychotropic medications used in the past 60 days 
on the eCRF. However, if medical records cannot be obtained, prior medications are to be 
reported based on subject and caregiver/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 case report form (CRF): Medication name, 
dose, frequency, route, start date and time, stop date and time, and indication. 
Information on the format and version of coding dictionary is provided in the Data Management 
Plan (DMP). All medications will be coded using World Health Organization – Drug Dictionary 
(WHO-DD). 
10.3.1. 
Prior Medications: 
Treatment with oral psychotropic medications and any other medications with a propensity for 
psychotropic effects (with the exception of the medications described below under Allowed 
Concomitant Psychotropic Medications) must be discontinued at least 3 days or 5 half-lives 
(whichever is longer) prior to randomization in a manner that is consistent with labeling 
recommendations and conventional medical practice. 
The following psychotropic medications have additional washout requirements: 
• MAO inhibitors must be discontinued at least 28 days prior to randomization. 
• Fluoxetine must be discontinued at least 28 days prior to randomization. 
• Clozapine used at 200 mg/day or less for insomnia, agitation, or anxiety must be 
discontinued at least 28 days prior to randomization. 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. 
• Depot neuroleptics must have been discontinued at least one treatment cycle or at 
least 30 days (whichever is longer) prior to the randomization visit. 
Treatment with the sedative hypnotics described in Section 10.3.5 is permitted during the 
Screening/Washout Period but should be tapered as clinically appropriate to conform with and 

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adequately prepare the subject for the protocol-specified limitations applicable to these agents 
following randomization. Subjects should not be taken off their current effective medications for 
treatment of schizophrenia for purposes of participating in this study. 
Treatment with medications used to treat movement disorders must be discontinued at least 1 day 
prior to randomization. 
10.3.2. 
Prohibited Medications 
Psychotropic medications and medications with a propensity for psychotropic effects are not 
permitted during the Treatment Period, except for the medications discussed in Section 10.3.5. 
Use of 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 for treating psychiatric indications are not permitted during the Treatment Period; 
however, they are 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 and the 
acceptable medications discussed in Section 10.3.5) 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) during the study up through the 
Follow-up Visit. Subjects who received ECT treatment during the Treatment Period will be 
discontinued from the study. 
10.3.4. 
Concomitant Nonpsychotropic Medications 
Non-psychotropic medications used to treat mild, chronic medical conditions may be used during 
screening and after randomization if the dose and regimen have been stable (± 25% total daily 
dose) for at least 30 days prior to screening. The dose for the concomitant medication may 
change, as needed, after randomization (or be discontinued). This includes β-adrenergic 
antagonists used to treat stable hypertension. Routine vaccines (i.e., seasonal influenza, 
pneumonia, etc.) are allowed based on the investigator’s judgment. Female subjects may use 
contraception as detailed in Section 10.5. 
In addition, use of non-prescription pain medications (e.g., aspirin, acetaminophen/paracetamol, 
ibuprofen) are allowed during the study provided these medications do not have a propensity for 
psychotropic effects. 
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. 

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10.3.5. 
Allowed Concomitant Psychotropic Medications 
Treatment with benztropine (benzotropine outside the United States [US]) up to 6 mg/day is 
permitted, as needed, for motor symptoms. In cases where benztropine is not available or a 
subject has had an inadequate response or intolerability to benztropine treatment, the following 
medications may be used to treat acute extrapyramidal symptoms (EPS): biperiden (up to 
16 mg/day) or trihexyphenidyl (up to 15 mg/day) or diphenhydramine (up to 100 mg/day). 
Treatment with propranolol (up to 120 mg/day) 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 motor symptoms should not be given prophylactically. They are to be 
tapered and discontinued 1 day prior to randomization but may be reinstated if symptoms emerge 
post-randomization during the study. 
Concomitant use of lorazepam, temazepam, eszopiclone, zaleplon, zolpidem, zolpidem 
controlled release (CR), diphenhydramine, and melatonin is permitted at the discretion of the 
Investigator with the following restrictions:  
• Oral lorazepam (or equivalent benzodiazepine) is permitted for clinically significant 
anxiety/agitation or as a sedative/hypnotic up to a maximum daily dose of 6 mg/day. 
Intramuscular lorazepam is permitted up to 4 mg/day for acute anxiety/agitation, as 
clinically indicated. Lorazepam should be used sparingly, when clinically required, 
per investigator judgment. 
• 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. 
• 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. 
• 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 (e.g., lorazepam 
and zolpidem) should not be used in close temporal proximity (defined as 
administration within 2 hours of each other). 
In regions that do not have the above specified drugs available, similar drugs at equivalent 
dosages will be permitted in consultation with the Medical Monitor. 
The date and time of the last dose of any concomitant psychotropic medication(s) taken prior to 
scheduled efficacy assessments must be recorded at each visit. Subjects should be encouraged to 
avoid taking any psychotropic medication (or any agents that may cause sedation) within 8 hours 
of efficacy 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. 

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10.4. 
Other Restrictions 
Subjects must abstain from alcohol from enrollment through the end of the study. 
10.5. 
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. 
− Use of highly effective methods of contraception during the Treatment Period and 
for 30 days after last dose of study drug. Highly effective forms of contraception 
include: 
 Subcutaneous hormonal implant (such as Norplant®) implanted at least 
90 days prior to Screening; 
 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. 

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 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 highly 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. 
10.6. 
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. 
According to SEROQUEL XR® package insert, in clinical trials, survival has been reported in 
acute overdoses of up to 30 grams of quetiapine. Most patients who overdosed experienced no 
adverse events or recovered fully from the reported events. Death has been reported in a clinical 
trial following an overdose of 13.6 grams of quetiapine alone. In general, reported signs and 
symptoms were those resulting from an exaggeration of the drug’s known pharmacological 
effects, ie, drowsiness and sedation, tachycardia, and hypotension. 
There is no specific antidote to quetiapine XR. 
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. 
10.7. 
Eligibility Adjudication Process 
All subjects will be evaluated by the Sponsor and/or designee to determine their eligibility for 
the study prior to randomization. 
Sites will complete a form for each subject in screening, which provides information that 
supports the subject’s appropriateness for participation in the study. Each form must be approved 
by the Sponsor or designee prior to the subject being randomized. 
 

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11. 
STUDY ASSESSMENTS 
A study schematic is presented in Figure 1. A summary of assessments to be conducted at each 
visit is presented in Table 2. 
11.1. 
Demographics and Baseline Characteristics 
Demographics (date of birth, sex, ethnicity, race), prior and current medications, and medical and 
psychiatric history will be collected. 
A medical history will be obtained by the Investigator or qualified designee as listed on the Form 
FDA 1572. If the subject’s historical medical care was provided at another institution or location, 
documented efforts must be made to obtain these outside records to verify that the subject meets 
all inclusion and none of the exclusion criteria. This must be accomplished during the Screening 
Period. Alcohol and substance abuse history should also be obtained and documented in the 
subject’s study chart. The Medical History will subsequently be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). 
For US sites only: At screening subjects will be checked for multiple study enrollment by 
clinical site staff using available registries of subjects participating in clinical trials. US sites will 
be provided training. 
11.2. 
Prior and Concomitant Medication Review 
See Section 10.3.5 for a complete description of medications permitted during the study. Prior 
and concomitant medications will be recorded at Visit 1 (Screening). Thereafter, any changes in 
concomitant medications or new medications added up to Visit 18 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-CT) 
The SCID-5-CT is a modified version of the SCID developed for use in clinical trials. It is a 
semi-structured interview for the purpose of making a DSM-5 diagnosis (First-2015). Clinicians 
administering the SCID should be familiar with the DSM-5 classification and diagnostic criteria. 
The SCID-5-CT will be administered by a qualified rater at the research site listed on Form 
FDA 1572 with at least 2 years of clinical experience with schizophrenia patients. The 
administration time is approximately 30 – 40 minutes. 
11.4. 
Efficacy Assessments 
Raters will receive specific training regarding each assessment prior to rating for the study. The 
same rater should be used for a given subject and a given scale whenever possible. 

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11.4.1. 
Positive and Negative Syndrome Scale (PANSS) 
The PANSS is an interview-based measure of the severity of psychopathology in adults with 
psychotic disorders. The measure is comprised of 30 items and 3 scales: the Positive scale 
assesses hallucinations, delusions, and related symptoms; the Negative scale assesses emotional 
withdrawal, lack of motivation, and similar symptoms; and the General Psychopathology scale 
addresses other symptoms such as anxiety, somatic concern, and disorientation. An anchored 
Likert scale from 1 - 7, where values of 2 and above indicate the presence of progressively more 
severe symptoms, is used to score each item. Individual items are then summed to determine 
scores for the 3 scales, as well as a total score. A Composite scale score (Positive scale score 
minus Negative scale score) can also be calculated to show the relative valence of positive and 
negative symptoms. Total time required for the PANSS interview and scoring is approximately 
30 – 40 minutes (Guy-1976, Kay-1994; Opler-1992; Perkins-2000). The PANSS requires input 
from an informant (e.g., caregiver, relative, friend, case worker, hospital staff). The PANSS-
Informant Checklist (PANSS-IC) will be utilized to capture the information from the informant 
that is required to rate the PANSS. PANSS raters will be required to meet specific training and 
education criteria before they are certified to rate for this study. 
11.4.2. 
Brief Negative Symptom Scale (BNSS) 
The BNSS is a rating scale to measure the current level of severity of negative symptoms in 
schizophrenia and schizoaffective disorder (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. 
11.4.3. 
Montgomery-Asberg Depression Rating Scale (MADRS) 
The MADRS is a clinician-rated assessment of the subject’s level of depression. The measure 
contains 10 items that measure apparent and reported sadness, inner tension, reduced sleep and 
appetite, difficulty concentrating, lassitude, inability to feel, and pessimistic and suicidal 
thoughts. Each item is scored in a range of 0 to 6 points, with higher scores indicating increased 
depressive symptoms. The Structured Interview Guide for the MADRS (SIGMA) 
(Williams-2008) will be used for the administration of the MADRS assessment. The MADRS 
will be administered by a qualified rater at the site. 
11.4.4. 
Clinical Global Impressions – Severity Scale (CGI-S) 
The CGI-S is a clinician-rated assessment of the subject’s current illness state on a 7-point scale, 
where a higher score is associated with greater illness severity. Following a clinical interview, 
the CGI-S can be completed in 1 to 2 minutes. The CGI-S will be administered by a qualified 
rater at the site. 

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11.4.5. 
Epworth Sleepiness Scale (ESS) 
The ESS is a self-administered questionnaire with 8 questions. Respondents are asked to rate, on 
a 4-point scale (0-3), their usual chances of dozing off or falling asleep while engaged in eight 
different activities. The ESS scale (the sum of 8 item scores) can range from 0 to 24. The higher 
the ESS score, the higher that person’s average sleep propensity in daily life or their ‘daytime 
sleepiness’. The questionnaire takes no more than 2 or 3 minutes to answer (Epworth Sleepiness 
Scale-2019). 
11.4.6. 
Brief Assessment of Cognition in Schizophrenia (BACS) 
The BACS assesses six domains of cognition; verbal memory/learning, working memory, motor 
function, verbal fluency, speed of processing, and executive function. Administration time is 
approximately 30 minutes. 
An electronic tablet-based version of the traditional BACS, called the BAC App, will be used in 
this study. The BAC App was developed to allow standardized presentation of task instructions 
and stimuli, audio-recording of responses, and automatized scoring and data management. The 
BAC App provides a composite measure of cognition, as well as individual scores for each of the 
cognitive domains noted below. It has been clinically validated in schizophrenia and has 
demonstrated equivalence with the original pen-and-paper measure (Atkins-2017). 
• Verbal Memory/Learning is assessed with the Verbal Memory task. Subjects are 
presented with a list of 15 words and asked to recall as many words as possible. This 
procedure is repeated 5 times. The outcome measure is the number of words recalled. 
• Working Memory is assessed with the Digit Sequencing task. Subjects are presented 
with auditory clusters of numbers (e.g., 936) of increasing length and asked to tell the 
rater the numbers in order from lowest to highest. The outcome measure is the 
number of correct responses. 
• Motor Function is assessed with the Token Motor task. Subjects are presented with 
tokens and asked to drag them to a center container on the monitor as quickly as 
possible for 60 seconds. The outcome measure is the number of tokens correctly 
dragged into the container. 
• Verbal Fluency is assessed with Semantic Fluency and Letter Fluency tasks. Subjects 
are given 60 seconds to generate as many words as possible in a given category 
(semantic) or for a given letter of the alphabet (letter). The outcome measure for each 
fluency test is the number of words generated. 
• Speed of Processing is assessed with the Symbol Coding task. Subjects are provided a 
key and asked to fill the corresponding number beneath a series of symbols as quickly 
as possible for 90 seconds. The outcome measure is the number of correct items. 
• Executive Function is assessed with the Tower of London task. Subjects are asked to 
give the minimum number of times the balls in one picture would need to be moved 
in order to make the arrangement of balls identical to that in the opposing picture. The 
outcome measure is the number of correct responses. 

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The BAC composite score for each participant at a given timepoint is computed by taking the 
sum of the six scaled test scores and dividing by the standard deviation of the sum of the scaled 
scores from the index population. 
11.4.7. 
University of California, San Diego, Performance-Based Skills Assessment-Brief 
(UPSA-B) 
The UPSA-B assesses everyday functioning in persons with serious mental illness 
(Mausbach-2007). The UPSA-B consists of 2 subscales (communication and financial). The 
UPSA-Brief is a measure of functional capacity in which patients are asked to role-play tasks in 
2 areas of functioning: (1) communication and (2) finances. The UPSA-Brief requires 
approximately 10 – 15 minutes to complete and will be administered by a trained professional. 
The raw score of the financial subscale ranges from 0 to 11 and the raw score of communication 
subscale ranges from 0 to 9. Each subscale score is calculated by dividing the raw score by the 
highest possible raw score of that subscale and then multiplying by 50, so both subscale scores 
range from 0 to 50. The UPSA-B total score, calculated as the sum of two subscale scores, 
ranges from 0 to 100. Higher scores reflect better performance. 
11.4.8. 
Modified Specific Level of Functioning Scale (SLOF) 
The SLOF is designed to measure directly observable behavioral functioning and daily living 
skills of patients with chronic mental illness (Schneider-1983). The modified version of the 
SLOF used in this study consists of 24  items divided into 2 subscales (Social functioning 
[comprised of interpersonal relationships] and Community Living Skills [comprised of activities 
and work skills]). Each item is rated on a 5-point scale. Individual items are summed to 
determine scores for the total score and the 2 subscales. 
The scale will be completed by the Investigator or a member of the research site staff who is 
familiar with the subject. This assessment should include input from the subject’s informant 
(e.g., family member, friend or caregiver). However, if an informant is not available, the rating 
will still be administered. For each SLOF rating, the rater will record whether an informant was 
utilized or not.  
11.4.9. 
Medication Satisfaction Questionnaire (MSQ) 
The MSQ is a single-item, patient-rated, rater administered questionnaire that requires the 
subject to use a 7-point, Likert-type scale to rate how satisfied they are with their current 
antipsychotic medication (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 

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(5) Somewhat satisfied 
(6) Very satisfied 
(7) Extremely satisfied 
11.4.10. 
EuroQol 5D-5L (EQ-5D-5L) 
The EQ-5D is a self-administered, standardized measure of health states consisting of two parts: 
a) EQ-5D descriptive system consisting of one question in each of five dimensions (mobility, 
self-care, pain, usual activities, and anxiety), and b) a 20-cm visual analogue health status rating. 
In the descriptive system, respondents are asked to choose the level that reflects their "own 
health state today" for each of the five dimensions. Once the data have been collected and a 
database created, a scoring function is used to assign a value (ie, EQ-5D index score) to self-
reported health states from a set of population-based preference weights. Additionally, the 20-cm 
visual analog scale (EQ-VAS) has endpoints labeled "best imaginable health state" and "worst 
imaginable health state" that are anchored at 100 and 0, respectively. Respondents are asked to 
indicate how they rate their own health by drawing a line from an anchor box to that point on the 
EQ-VAS which best represents their own health on that day. 
11.4.11. 
Tobacco Use Information and Plasma Cotinine Concentrations 
Information on the use of tobacco at Baseline and during the Treatment Period will be recorded 
on the eCRF, including type of tobacco used and amount used. 
Blood samples taken at Baseline and Weeks 12, 24 and 52 for study drug concentration 
measurement will also be used for the measurement of cotinine levels. No separate blood 
samples will be collected for cotinine. 
11.5. 
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 Baseline or subsequently during study conduct. 
11.5.1. 
Adverse Events 
Adverse events will be collected for each subject. Subjects should be queried in a non-leading 
manner, without specific prompting (eg, “Has there been any change in your health status since 
your last visit?”). See Section 12, Safety Reporting. 
AEs and SAEs will be monitored throughout the study at all visits. 
11.5.2. 
Clinical Laboratory Tests 
The clinical laboratory tests required by protocol are listed in Section 21, Appendix II. 
Blood and urine samples will be collected for clinical laboratory tests. 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 

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Laboratory Improvement Amendments (CLIA) and/or other laboratory certifications or 
equivalent accreditation documents. 
Any POC (point of care) kits that are performed on site by study personnel rather than in a 
laboratory must be CLIA waived and the study center must possess a CLIA certificate of Waiver. 
11.5.3. 
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 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 should be obtained prior to clinical laboratory collection and performance of an ECG. 
Clinically significant changes from screening in vital sign parameters, as determined by the 
Investigator, will be noted as AEs in the CRF. 
11.5.4. 
Electrocardiograms (ECGs) 
All ECGs will be obtained in the supine position, after the subject has been resting supine for at 
least 5 minutes. ECGs will be 12-lead with a 10-second rhythm strip. ECGs should be obtained 
prior to drawing blood samples. All attempts should be made to use the same ECG recorder for 
all visits within individual subjects. ECGs will be centrally read at a core lab according to 
established quality assurance procedures for inter/intra reader variability. Additional information 
is provided in Section 20, Appendix I. 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 or continuance 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. 

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Any clinically significant changes after Screening, as determined by the Investigator, will be 
noted as AEs in the CRF. ECGs with possibly drug-related or clinically significant abnormal 
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. 
11.5.5. 
Physical and Neurological Examination 
Complete physical examinations (PE) as well as a neurological examination 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. 
Any clinically significant changes after Screening, as determined by the Investigator, will be 
noted as AEs in the CRF. 
11.5.6. 
Safety Scales 
11.5.7. 
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, and address rigidity, gait 
(bradykinesia), tremor, glabellar tap, and salivation (Siddiqui-2009; Simpson-1970). The SAS 
will be administered by a qualified rater at the site. 
11.5.8. 
Barnes Akathisia Rating Scale (BARS) 
The BARS is a rating scale geared toward assessment of neuroleptic-induced akathisia, though it 
can be used to measure akathisia associated with other drugs as well. The BARS consists of four 
items, including one item assessing objective restlessness, two items targeting subjective 
restlessness (awareness and related distress), and one global clinical assessment item. All items 
are anchored and utilize a 4-point scale, except for the global rating which has a 6-point scale 
(from absence of akathisia through severe akathisia). The subjective and objective items are 
summed to yield a total score. The BARS can be administered in about 10 minutes 
(Barnes-1989; Barnes-2003). The BARS will be administered by a qualified rater at the site. 
11.5.9. 
Abnormal Involuntary Movement Scale (AIMS) 
The AIMS is a clinician-rated assessment of abnormal movements consisting of unobtrusive 
observation of the subject at rest (with shoes removed) and several questions or instructions 
directed toward the subject. Using a severity scale ranging from 0 (none) to 4 (severe), clinicians 
rate dyskinesia in several body regions, including the facial area, extremities, and trunk. There 
are two items related to dental status, as well as three global impression items assessing overall 
severity, incapacitation, and the subject’s awareness of abnormal movements (Guy-1976; 
Munetz-1988). The AIMS raters will be required to meet specific credential and educational 
criteria before they are certified to rate for this study. The AIMS will be administered by a 
qualified rater at the site. 

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Protocol SEP361-304, Version 3.00 
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It is suggested that the rating scales be completed in the following order, if possible: 
1. PANSSa 
2. BNSS 
3. MADRS 
4. C-SSRS 
5. SAS/BARS/AIMS 
6. SLOF 
7. EQ-5D-5L 
8. ESS 
9. MSQ 
10. BACS 
11. UPSA-B 
12. HCRU 
13. CGI-S 
a When administering the PANSS, it is suggested that the informant interview and PANSS-IC be completed prior to the subject 
interview. 
Note: With the exception of the SCID-CT, UPSA-B, C-SSRS and the HCRU all rating assessments will be completed by the rater 
using an electronic tablet. In the event that the electronic tablet is not available, the rating assessments will be performed by the 
rater or subject using a paper version of the assessment, with the exception of the EQ-5D-5L which is licensed only for 
electronic use. 
 
11.7.1. 
Screening: Visit 1 (Day -21 to -1) 
After a subject provides consent, a unique subject number will be assigned at screening by the 
IWRS, 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 #005 will be 304005002). 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. 
Subjects will be evaluated at the Screening Visit to determine their eligibility for the study. The 
subject’s eligibility assessment will be reviewed by the contract research organization’s (CRO) 
oversight quality team along with the sponsor based on protocol specified inclusion and 
exclusion criteria. In the event the CRO/sponsor 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 upon leaving the study. 
Subjects who screen fail may be re-screened once, 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. 

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Protocol SEP361-304, Version 3.00 
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72 
14 January 2021 
• Urine pregnancy test (β-HcG), female subjects only 
• Adverse events monitoring 
• PANSS 
• BNSS 
• MADRS 
• C-SSRS 
• CGI-S 
• SAS 
• BARS 
• AIMS 
• ESS 
• SLOF 
• BACS 
• UPSA-B 
• HCRU 
11.7.11. 
Visit 11 (Week 28; Day 197 ± 3) 
The following procedures will be conducted during this visit: 
• Concomitant medication review 
• Study drug accountability 
• Dispense study drug 
• Vital signs 
• Urine pregnancy test (β-HcG), female subjects only 
• Adverse events monitoring 
• C-SSRS 
11.7.12. 
Visit 12 (Week 32; Day 225 ± 3) 
The following procedures will be conducted during this visit: 
• Concomitant medication review 
• Study drug accountability 
• Dispense study drug 
• Vital signs 
• Urine pregnancy test (β-HcG), female subjects only 

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Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
74 
14 January 2021 
• PANSS 
• BNSS 
• MADRS 
• C-SSRS 
• CGI-S 
11.7.15. 
Visit 15 (Week 44; Day 309 ± 3) 
The following procedures will be conducted during this visit: 
• Concomitant medication review 
• Study drug accountability 
• Dispense study drug 
• Vital signs 
• Urine pregnancy test (β-HcG), female subjects only 
• Adverse events monitoring 
• C-SSRS 
11.7.16. 
Visit 16 (Week 48; Day 337 ± 3) 
The following procedures will be conducted during this visit: 
• Concomitant medication review 
• Study drug accountability 
• Dispense study drug 
• Vital signs 
• Urine pregnancy test (β-HcG), female subjects only 
• Adverse events monitoring 
• PANSS 
• BNSS 
• MADRS 
• C-SSRS 
• CGI-S 
11.7.17. 
Visit 17 (Week 52; Day 365 ± 3) / End of Treatment (EOT) / Early Termination 
(ET) 
The following procedures will be conducted during this visit: 
• Concomitant medication review 

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Protocol SEP361-304, Version 3.00 
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76 
14 January 2021 
 
The following procedures will be conducted during this visit: 
• Concomitant medication review 
• Physical/neurological examination 
• Vital signs 
• Urine pregnancy test (β-HcG), female subjects only 
• Adverse events monitoring 
• C-SSRS 
11.7.19. 
Telephone contacts 
Telephone calls will be made by a member of the research staff to the subject between scheduled 
study visits at Weeks 3, 5, 6, 7, 9, 10, 11, 13, 14, 15, 17, 18, 19, 21, 22, 23, 25, 26, 27, 29, 30, 31, 
33, 34, 35, 37, 38, 39, 41, 42, 43, 45, 46, 47, 49, 50 and 51. The telephone calls will be used to 
collect AEs and concomitant medications, as well as to remind subject about adherence to study 
drug administration and upcoming visits. 
11.7.20. 
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 
• AE monitoring 
• Concomitant medication review 
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. 
 

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12. 
SAFETY REPORTING 
12.1. 
Definitions 
12.1.1. 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
Untoward medical occurrences that occur between the time of signing the informed consent form 
(ICF) and first drug administration are pre-treatment events. Those that occur after first 
administration of study drug are considered AEs. 
An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease occurring after the administration of a medicinal (investigational) 
product, whether or not considered related to the medicinal (investigational) product. AEs may 
include the onset of new illness and the exacerbation of pre-existing conditions. AEs will be 
collected from the signing of the ICF to the last study visit (Visit 18 [Follow-up Visit]). 
The Investigator should attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis should be documented as the AE 
and not the individual signs/symptoms. 
12.1.2. 
Serious Adverse Events 
A serious adverse event (SAE) is an AE that meets one or more of the following criteria: 
• Results in death. 
• Is life-threatening. 
• Requires hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly or birth defect. 
• Is an important medical event that may jeopardize the subject or may require a 
medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization. 
The term "severe" is often used to describe the severity of a specific event (as in mild, moderate, 
or severe myocardial infarction) (see Section 12.3); the event itself, however, may be of 
relatively minor medical significance (such as severe headache). This is not the same as 
"serious," which is based on subject/event outcome or action criteria usually associated with 
events that pose a threat to a subject's life or functioning as defined by the criteria above. 
During the study, if a subject has a hospitalization or procedure (eg, elective surgery) that was 
scheduled before the study entry, ie, before informed consent for an event/condition that 
occurred before the study, the hospitalization is considered a therapeutic intervention and not the 
result of a SAE. However, if the event/condition worsens during the study, it should be reported 

Protocol SEP361-304, Version 3.00 
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as an AE (or SAE, if the event/condition results in a serious outcome such as prolongation of 
hospitalization). 
Life-threatening means that the subject was, in the view of the Investigator, at immediate risk of 
death from the event as it occurred. This definition does not include an event that had it occurred 
in a more severe form might have caused death. 
SAE criteria information will be captured on the CRF. 
12.2. 
Objective Findings 
Clinically significant changes from signing of the ICF in objective findings (eg, clinical 
laboratory value, ECG value, and physical examination observation), as determined by the 
Investigator, will also be recorded as AEs. 
When a clear diagnosis is available that explains the objective findings, this diagnosis will be 
recorded as the AE, and not the abnormal objective finding (eg, viral hepatitis will be recorded as 
the AE, not transaminase elevation). If a definite diagnosis is not available, then record the sign 
(eg, clinically significant elevation of transaminase levels) or symptom (eg, abdominal pain) as 
the AE. 
Clinical laboratory test results 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; however, the Screening Period will not be extended to accommodate 
repeat laboratory / ECG tests unless repeat tests are needed due to a technical issue with 
laboratory sample processing, shipment or testing delay at the central laboratory. 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 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 AEs must be recorded in the subject’s study records/source documents in accordance with 
the Investigator’s normal clinical practice. All AEs that occur from the signing of the informed 
consent to the subject’s last visit must be recorded on the CRF. 
All AEs will be followed until resolution, stabilization of the condition, the event is otherwise 
explained, or the subject is lost to follow-up. 
Each AE is to be evaluated for duration, severity, frequency, seriousness, action taken with the 
study treatment, outcome, and causal relationship to the study treatment. Definitions for severity, 

Protocol SEP361-304, Version 3.00 
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frequency, action taken with the study treatment, outcome, and causal relationship to the study 
treatment are presented below. 
The severity of AE: 
• Mild - Ordinarily transient symptoms that do not influence performance of subject’s 
daily activities. Other treatment is not ordinarily indicated. 
• Moderate - Marked symptoms sufficient to make the subject uncomfortable. 
Moderate influence on performance of subject’s daily activities. Other treatment may 
be necessary. 
• Severe - Symptoms cause considerable discomfort. Substantial influence on subject’s 
daily activities. May be unable to continue the study, and other treatment may be 
necessary. 
The frequency of AE: 
• Once – an isolated episode. 
• Intermittent – occurs on two or more separate occasions. 
• Continuous – does not abate from date of onset to date of resolution. 
The action taken with the study treatment: 
• Drug Interrupted – Study drug stopped temporarily. 
• Drug Withdrawn – Study drug stopped permanently. 
• Dose Reduced 
• Dose Increased 
• Dose Not Changed 
• Not Applicable 
• Unknown 
The outcome of the AE: 
• Recovered/Resolved 
• Recovering/Resolving 
• Not Recovered/Not Resolved 
• Recovered/Resolved with Sequelae 
• Fatal 
• Unknown 
The causal relationship of the AE to the study treatment 
• Not related 
−  Not related - Improbable temporal relationship and is plausibly related to other 
drugs or underlying disease. 

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• Related 
− Possible - occurred in a reasonable time after study drug administration but could 
be related to concurrent drugs or underlying disease. 
− 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. 
− 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 that 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-pharmacovigilance (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. 
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 no more than 24 hours after the Investigator or 
study center staff become aware of the event. The SAE form must be signed by the Investigator 
or appropriate designee. The Sponsor provides the SAE form used to report SAEs. 
The Sponsor or designee will promptly notify all study centers and Investigators of a SAE that is 
determined to be expedited to the Regulatory Authorities in accordance with applicable law(s) 
and regulation(s). These SAEs must be promptly reported to the Institutional Review Board 

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(IRB) or Independent Ethics Committee (IEC) by the Investigator or the appropriate person at 
the study center if required per IRB/IEC guidelines. 
12.4.2. 
Pregnancy 
Pregnancies that occur from the time that informed consent is signed through 90 days following 
the last dose of the study drug will be collected and reported on the Pregnancy Event Form. 
If a subject becomes pregnant during the course of the study, she will be instructed to commence 
discontinuation of the study drug. Further, the subject 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 drug. All pregnancies, whether or not the subject received any additional study 
drug, will be followed until resolution (ie, termination [voluntary or spontaneous] or birth). 
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 
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. 
If the subject received blinded study drug, unblinding of the study drug will be offered to the 
subject when knowledge of such treatment may have an impact on further treatment decisions. 
Otherwise, information regarding to what treatment the subject was assigned may be provided 
when the study has ended. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study drug may have 
interfered with the effectiveness of a contraceptive medication or other AEs were detected. 
12.5. 
Data Monitoring Committee/Data and Safety Monitoring Board 
The Data and Safety Monitoring Board (DSMB) will review safety data including data on AEs 
and SAEs approximately 3 times annually. The DSMB will be independent of the Sponsor, study 
CRO, and the Investigators and will be empowered to recommend stopping the study due to 
safety concerns, but not for efficacy or futility. The DSMB may review blinded, unblinded, or 
partially unblinded data, but the Sponsor (with the exception of the relevant members of the 
pharmacovigilance team responsible for reporting Suspected Unexpected Serious Adverse 
Reactions [SUSARs]), study CRO, and the Investigators will remain blinded until the official 
unblinding of the database. The membership of the DSMB and its mandate will be described in a 
separate DSMB charter. 
 

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13. 
TERMINATION OF SUBJECT FROM 
STUDY/DISCONTINUATION OF STUDY DRUG 
13.1. 
Criteria for 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; eg, no improvement in underlying condition) 
• 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 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 prematurely discontinue from the study treatment 
(i.e., do not complete through Visit 17), every effort should be made to complete the final 
evaluation procedures, in accordance with the early termination (ET) visit described in 
Section 11.7.17. 
All subjects who discontinue from the study early will complete a follow up visit 7 (±2) days 
after the last dose of study drug as described in Section 11.7.18. 

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14. 
STUDY TERMINATION 
The Sponsor reserves the right to discontinue the study at this study center or at multiple centers 
for safety or administrative reasons at any time while safeguarding that early termination does 
not compromise subjects’ safety or well-being. In particular, a study center that does not recruit 
at an acceptable rate may be closed. Should the study be terminated and/or the study center 
closed for whatever reason, all documentation and study drugs pertaining to the study must be 
returned to the Sponsor or its representative. 
If, in the opinion of the Investigator, clinical observations suggest it may be unsafe to continue, 
the Investigator may terminate part or the entire study after consultation with the Sponsor. 
In the event of study or site termination, subjects will undergo final evaluation procedures, in 
accordance with the early termination (ET) visit described in Section 11.7.17 and safety 
Follow-up Visit as described in Section 11.7.18. 
 

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15. 
STATISTICS 
15.1. 
Sample Size  
A total of 300 subjects are expected to be enrolled from approximately 50 global sites, including 
the US and Europe. Subjects will be assigned randomly to receive SEP-363856 or active 
comparator in an allocation ratio of 2:1. The determination of sample size was based upon 
clinical considerations. The sample size of 300 subjects will provide approximately 80 subjects 
who are expected to complete 1 year of treatment with SEP-363856 to support sufficient long-
term safety data on SEP-363856. 
15.2. 
Analysis Populations 
15.2.1. 
Safety Population 
The safety population will consist of all subjects who were enrolled and receive at least one dose 
of study drug during the 52-week treatment period. The safety population will be used for the 
long-term safety and tolerability analyses. Subjects will be analyzed according to the actual 
treatment received. 
15.2.2. 
Efficacy Population 
The efficacy population will consist of all subjects who are randomized, have received at least 
one dose of study drug, and have a Baseline and at least one post-Baseline efficacy measurement 
in PANSS or CGI-S. Subjects will be included in the population regardless of any protocol 
deviation. The efficacy population will be the primary population for the efficacy analyses. 
Subjects will be analyzed according to the treatment to which they are randomized. 
15.2.3. 
Per Protocol Population 
The per protocol (PP) population will consist of all efficacy population subjects who satisfy the 
following conditions: 
• Have 14 days or more overall exposure to study drug 
• Have no important protocol deviations, determined by blinded data reviews prior to 
database lock 
Selected efficacy endpoints will be analyzed using the PP population. Subjects will be analyzed 
according to the treatment to which they are randomized. 
15.3. 
Data Analysis 
15.3.1. 
Subject Disposition  
Subject disposition will be summarized by the actual treatment group (if applicable) and overall 
for all subjects. The number and percent of subjects, who are screened, screen-failed, 
randomized, received study drug, and completed or discontinued early from the double-blind 
treatment period (including reasons for discontinuation) will be presented. 

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As exploratory analysis, the time-to-discontinuation (any reason) by treatment will be 
summarized descriptively and will also be tested with log-rank statistic and presented by a 
Kaplan-Meier plot. 
15.3.2. 
Study Drug Exposure and Compliance 
Duration of exposure and compliance will be summarized by treatment group for the safety 
population. 
Duration of exposure (in days) will be calculated as: last dose date - first study dose date + 1. 
Duration of exposure will be summarized both as a continuous variable and categorically: 
• Number and percentage of subjects with the study drug exposure ≥ 1, ≥ 14, ≥ 28, 
≥ 42, ≥ 90, ≥ 120, ≥ 150, ≥ 180, ≥ 270, and ≥ 360 days; 
• Number and percentage of subjects with the study drug exposure for 1 - 13, 14 - 27, 
28 - 41, 42 - 89, 90 - 119, 120 - 149, 150 - 179, 180 - 269, 270 - 359, and ≥ 360 days 
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 (i.e. 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 or quetiapine XR (depending upon randomization) 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 blinded review 
of data listings. The IPD categories may include, but may not be limited to: 
• Did not meet important inclusion and/or exclusion criteria. 
• Received prohibited medication. 
• Overall double-blind compliance rate < 75% or > 125%. 
IPDs will be identified for all randomized 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 (e.g. age, gender, race, ethnicity, etc.) will be summarized for all screened 
subjects by randomization status (i.e. randomized vs. not randomized). Demographic and 
baseline characteristics will be summarized for each defined analysis population by treatment 
group and overall.  

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Medical and psychiatric history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) and will be summarized by treatment for the safety population by 
presenting the number and percentage of subjects with at least one condition in each system 
organ class (SOC) and preferred term (PT). 
15.3.5. 
Efficacy Analyses 
Efficacy data will be summarized descriptively by treatment for the efficacy population. 
The observed values of PANSS total score and subscale scores (positive, negative, and general 
psychopathology), CGI-S score, BNSS total score, MADRS total score, BACS composite score, 
ESS total score, SLOF total and subscale scores, EQ-5D-5L VAS, index score and dimension 
score, UPSA-B total score, and MSQ score, at Baseline and each scheduled post-Baseline visit, 
will be summarized descriptively. Changes from Baseline in these efficacy measures as well as 
changes from baseline in tobacco use and cotinine concentrations, will be summarized at each 
scheduled post- Baseline visit. 
PANSS total score and CGI-S score data will also be summarized by age, sex, race, number of 
prior hospitalizations for treatment of schizophrenia, duration of schizophrenia, geographic 
region, and country. 
The proportion of subjects who achieve a response, defined as a 20% or greater improvement 
(i.e. decrease) in PANSS total score from the Baseline, will be calculated for each scheduled visit 
and the Week 52 last-observation-carried-forward (LOCF). The proportion of subjects who 
achieve a response, defined as a 30% or greater improvement (i.e. decrease) in PANSS total 
score from the Baseline, will be summarized similarly. As exploratory analyses, PANSS total 
score and subscale scores, CGI-S score, BNSS total score, and MADRS total score will be 
analyzed using a mixed model for repeated measures (MMRM) under the missing-at-random 
(MAR) assumption. Under this assumption, the efficacy outcome of subjects in each treatment 
group after early discontinuation will exhibit the same future evolution as subjects in the same 
group remaining in the study. The MMRM model will include fixed factors for treatment, visit as 
a categorical variable, country, and treatment-by-visit interaction, and include Baseline score as a 
covariate. An unstructured covariance matrix will be used to model the within-subject 
correlation. Kenward-Roger approximation will be used to calculate the denominator degrees of 
freedom. The main estimator of the efficacy estimand is the least squares (LS) mean difference 
in each score change from Baseline at Week 52 from the analysis model of observed repeated 
measures data. 
In case the model above fails to converge, a spatial exponential covariance structure and a spatial 
power covariance structure will be assumed sequentially. The first covariance structure to yield 
convergence will be used in the analysis. These analyses will be based on the observed data only. 
Missing data will not be imputed. 
Sensitivity analyses may be conducted to assess the impact of missing data on the PANSS total 
score and CGI-S score analysis results by deviating away from the MAR assumption; however, 
all efficacy analyses are exploratory in this safety study. 
Relapse 
Relapse will be identified programmatically and manual data review using the pre-defined 
criteria (specified below). The rate of relapse will be calculated as the proportion of subjects with 

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a relapse in the 52-week period out of the efficacy population, along with the 95% confidence 
interval. The time-to-relapse will be summarized descriptively and will also be presented by a 
Kaplan-Meier plot, with log rank test statistic. 
Relapse will be defined as the earliest occurrence of any of the following: 
• Worsening of > 30% PANSS total score from Baseline (Day 1) and a CGI-S 
score > 3. 
• Hospitalization for worsening of psychosis. 
• Emergence of suicidality, homicidality and/or risk of harm to self or others. 
• Discontinuation from the study due to exacerbation of the underlying illness of 
schizophrenia. 
The frequency of hospitalization due to relapse will be summarized descriptively by treatment. 
15.3.6. 
Safety Analyses 
15.3.6.1. Adverse Events 
Both AEs and pre-treatment events will be coded using MedDRA. 
The following summaries will be provided by treatment and 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 by treatment will also be 
provided. 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. 
As exploratory analyses, the odds ratios (OR) with 95% confidence intervals (CI) of all AEs, 
SAEs, AEs leading to discontinuation, and AEs relating to extrapyramidal symptoms (EPS) 
between the two treatment groups will be provided. 

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15.3.6.2. Clinical Laboratory Assessments 
Clinical laboratory parameters will be summarized by presenting shift tables and through by visit 
summaries of the observed values and the change from Baseline values by treatment. For 
parameters with categorical outcomes, the number and percentage of subjects with each outcome 
will be summarized by visit. The number 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. 
The change from Baseline values will be analyzed by nonparametric rank ANCOVA to compare 
between the SEP-363856 and quetiapine XR treatment groups for: lipid (total cholesterol, LDL 
cholesterol, HDL cholesterol, and triglycerides), glucose, HbA1c and prolactin levels. Details of 
the rank ANCOVA analysis will be provided in the SAP. 
15.3.6.3. ECGs 
ECG analysis will be based on the centrally read data. Observed values and changes from 
Baseline in ECG parameters will be summarized by treatment. 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 by 
treatment. Fridericia’s correction (QTcF) and Bazett’s correction (QTcB) will be used for QT 
interval correction. 
15.3.6.4. Vital Signs 
Vital sign parameters will be summarized by presenting by visit summaries of the observed 
values and the change from Baseline values by treatment. The change from Baseline values for 
weight and BMI will also be analyzed by nonparametric rank ANCOVA to compare between the 
SEP-363856 and quetiapine XR treatment groups. 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. 
15.3.6.5. 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. 

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Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
93 
14 January 2021 
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 SOPs, protocol, ICH GCP and local regulations. The 
Investigator or appropriate designee must also agree to inspection of all study documents by the 
regulatory authorities and the IEC. Should the Investigator or appropriate designee be notified of 
a regulatory inspection involving this study they should notify the Sponsor immediately. 
16.5. 
Study Documentation 
Study records are comprised of source documents, CRFs, and all other administrative 
documents, eg, IRB/IEC correspondence, clinical study materials and supplies shipment 
manifests, monitoring logs, Sponsor and CRO correspondence, etc. A study specific binder will 
be provided with instructions for the maintenance of study records. 
Source document is defined as any 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, e.g., 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, 
e.g., faxed laboratory reports and hard copy laboratory reports, faxed initial results and hard 
copy, final report. 
16.6. 
Clinical Laboratory Certification and Normal Values 
A central laboratory will be used for analysis for the clinical laboratory tests for this study. The 
central laboratory will provide the Investigator, Sponsor/CRO with laboratory certification(s), a 
dated copy of normal range values for the central clinical laboratory selected to analyze clinical 
specimens. If an exception is granted to use a local laboratory, the Investigator must supply the 
Sponsor/CRO with laboratory certification, lab director’s curricula vitae and a current, dated 
copy of normal range values. 

Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
94 
14 January 2021 
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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CCI

Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
97 
14 January 2021 
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 if the 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 SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
98 
14 January 2021 
18. 
REFERENCES 
American Psychiatric Association (APA). Diagnostic and Statistical Manual of Mental 
Disorders. 4th ed; 2000. 
Ascher-Svanum H, Zhu B, Faries DE, Salkever D, Slade EP, Peng X, Conley RR. The cost of 
relapse and the predictors of relapse in the treatment of schizophrenia. BMC Psychiatry. 
2010;10:2-7. 
Atkins AS, Tseng T, Vaughan A, Twamley EW, et al. Validation of the tablet-administered Brief 
Assessment of Cognition (BAC App). Schizophr Res. 2017;181:100-106. 
Barnes TRE. A rating scale for drug-induced akathisia. Br J Psychiatry 1989;154:672-676. 
Barnes TRE. The Barnes Akathisia Rating Scale – Revisited. J Psychopharmacology 2003; 
17(4): 365-370. 
Davis JM, Chen N. Dose response and dose equivalence of antipsychotics. J Clin 
Psychopharmacology. 2004;24:192-208. 
The Epworth Sleepiness Scale. https://epworthsleepinessscale.com/about-the-ess/ [website 
accessed 12-June-2019]. 
First MB, Williams JBW, Karg RS, Spitzer RL. Structured Clinical Interview for DSM-5-
Clinical Trials Version (SCID-5-CT); Arlington, VA, American Psychiatric Association, 2015. 
Guy W. EDCEU Assessment Manual for Psychopharmacology – Revised (DHEW Publ No 
ADM 76-338). Rockville, MD, U.S. Department of Health, Education, and Welfare, Public 
Health Service, Alcohol, Drug Abuse, and Mental Health Administration, NIMH 
Psychopharmacology Research Branch, Division of Extramural Research Programs, 1976:534-
537. 
Kay SR, Opler LA, Fisbein A. Positive and Negative Syndrome Scale Manual. North 
Tonawanda, NY: Multi-Health Systems, 1994. 
Kapur S, Remington G. Atypical antipsychotics: new directions and new challenges in the 
treatment of schizophrenia. Annu Rev Med 2001;52:503-517. 
Keefe RSE, Bilder RM, Harvey PD, Davis SM, Palmer BW, Gold JM, et al. Baseline 
neurocognitive deficits in the CATIE schizophrenia trial. Neuropsychopharmacology. 
2006;31:2033-2046. 
Kim DH, Maneen MJ, Stahl SM. Building a better antipsychotic: receptor targets for the 
treatment of multiple symptom dimensions of schizophrenia. Neurotherapeutics. 2009;6:78-85. 
Kirkpatrick B, Strauss GP, Nguyen L, et al. The Brief Negative Symptom Scale: Psychometric 
Properties. Schizophrenia Bulletin. 2011;37(2):300-305. doi:10.1093/schbul/sbq059. 
Kreyenbuhl J, Buchanan RW, Dickerson FB, Dixon LB. The Schizophrenia Patient Outcomes 
Research Team (PORT): updated treatment recommendations 2009. Schizophr Bull. 2010;36:94-
103. 
Kuroki T, Nagao N, Nakahara T. Neuropharmacology of second-generation antipsychotic drugs: 
a validity of the serotonin-dopamine hypothesis. Prog Brain Res. 2008;172:199-212. 

Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
99 
14 January 2021 
Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with 
schizophrenia, second edition. Am J Psychiatry. 2004;161(suppl 2):1-56. 
Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-
generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009;373:31-41. 
Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, et al. 
Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 
2005;353:1209-1223. 
Mausbach BT, Harvey PD, Goldman SR, Jeste DV, Patterson TL. Development of a brief scale 
of everyday functioning in persons with serious mental illness. Schizophr Bull. 2007;33:1364–
1372. 
Meltzer HY, Cucchiaro J, Silva R, Ogasa M, Philips D, Xu, J, Kalali, AH, Schweizer E, Pikalov 
A, Loebel A. Lurasidone in the treatment of schizophrenia: a randomized, double-blind, placebo-
and olanzapine-controlled study. Am J Psychiatry. 2011;168:957-967. 
Minzenberg, et al. Chapter 10: Schizophrenia. In: Hales RE, Yudofsky SC, Gabbard GO, eds. 
The American Psychiatric Publishing Textbook of Psychiatry. 5th edition. Arlington, VA: 
American Psychiatric Publishing, Inc; 2008. 
Morken G, Widen JH, Grawe RW. Non-adherence to antipsychotic medication, relapse and 
rehospitalization in recent-onset schizophrenia. BMC Psychiatry. 2008;8:32-37. 
Munetz MR, Benjamin S. How to examine subjects using the Abnormal Involuntary Movement 
Scale. Hospital and Community Psychiatry 1988; 39: 1172-1177. 
Munro J, Osborne S, Dearden L, Pascoe K, Gauthier A, Price M. Hospital treatment and 
management in relapse of schizophrenia in the UK: associated costs. The Psychiatrist. 
2011;35:95-100. 
Naber D, Lambert M. The CATIE and CUtLASS studies in schizophrenia: results and 
implications for clinicians. CNS Drugs. 2009;23:649-659. 
Nakamura M, Ogasa M, Guarino J, Phillips D, Severs J, Cucchiaro J, Loebel A. Lurasidone in 
the treatment of acute schizophrenia: a double-blind, placebo-controlled trial. J Clin Psychiatry. 
2009;70:829-836. 
Narrow WE, Rae DS, Robins LN, Regier DA. Revised prevalence estimates of mental disorders 
in the United States: using a clinical significance criterion to reconcile 2 surveys' estimates. Arch 
Gen Psychiatry. 2002;59:115-123. 
National Institute of Mental Health (NIMH). Schizophrenia. 
http://www.nimh.nih.gov/health/publications/schizophrenia/schizophrenia-booket-2009.pdf. 
Accessed October 20, 2010. 
Newcomer JW. Antipsychotic medications: metabolic and cardiovascular risk. J Clin Psychiatry. 
2007;68 (suppl 4):8-13. 
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. 

Protocol SEP361-304, Version 3.00 
SEP-363856 
 
Confidential and Proprietary 
100 
14 January 2021 
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. 
Schnieder LC, Struening EI. SLOF: A behavioral rating scale for assessing the mentally ill. 
Social Work Research and Abstracts, 1983; 41, 9-21. 
Schultz SK, Andreasen NC. Schizophrenia. Lancet. 1999;353:1425-1430. 
SEROQUEL XR® (package insert) https://www.seroquelxr.com/ [website accessed 
10-May-2019] 
Siddiqui O, Hung HM, O'Neil R. MMRM versus LOCF: A comprehensive comparison based on 
simulation study and 25 NDA datasets. Journal of Biopharmaceutical Statistics, 2009; 19: 227-
246. 
Simpson GM, Angus JWS. A rating scale for extrapyramidal side effects. Acta Psychiatrica 
Scandinavia, Suppl 1970; 212S: 11-19. 
Tandon R, Belmaker RH, Gattaz WF, et al. World Psychiatric Association Pharmacopsychiatry 
Section statement on comparative effectiveness of antipsychotics in the treatment of 
schizophrenia. Schizophrenia Res. 2008;100:20-38. 
Vernon MK, Revicki DA, George AG, et al. Psychometric evaluation of the Medication 
Satisfaction Questionnaire (MSQ) to assess satisfaction with antipsychotic medication among 
schizophrenia patients. Schizophrenia Research. 2010; 118:271-278. 
Webber MA, Marder SR. Better pharmacotherapy for schizophrenia: what does the future hold? 
Current Psychiatry Reports. 2008;10:352-358. 
Williams JBW, Kobak KA. Development and reliability of a structured interview guide for the 
Montgomery-Asberg Depression Rating Scale (SIGMA). Br J Psych. 2008; 192: 52-58. 
Wu EQ, Shi L, Birnbaum H, Hudson T, Kessler R. Annual prevalence of diagnosed 
schizophrenia in the USA: a claims data analysis approach. Psychol Med. 2006;36:1535-1540. 

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19. 
INVESTIGATOR APPROVAL 
I have read the protocol, SEP361-304, Version 3.00 “A Randomized, Double-blind, Active 
Comparator-Controlled Study to Evaluate the Long-term Safety and Tolerability of SEP-363856 
in Subjects with Schizophrenia,” and agree that it contains all necessary details for conducting 
the study and to conduct the study in strict accordance with the specifications outlined herein. 
I agree that no additional procedure(s) will be added during the conduct of the study except 
through protocol amendment by Sunovion Pharmaceuticals Inc. and after documentation of IRB 
approval. 
 
Investigator Signature: ____________________________________________________ 
Print Investigator Name: __________________________________________________ 
Date: ___________________________________________ 

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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 over-read 
will be retained at the study center. 
4. Data Standardization 
ECG data will be transmitted to a centralized cardiac safety vendor and centrally over-read 
and interpreted using standardized procedures. 
 

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21. 
APPENDIX II. 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, not calculated at Week 1), 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: Amphetamines, Barbiturates, Benzodiazepines, Cannabinoids, 
Cocaine, 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), 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. 

CCI

CCI