Clinical trial NCT04038957
Conditions: Schizophrenia
Keywords: schizophrenia
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Start date: 2019-08-07; Completion date: 2023-06-06
Enrollment: 22 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A clinical study to investigate the effect of an investigational drug as an added medication to an antipsychotic, in adults with schizophrenia, as measured positron emission tomography (PET) imaging . This study is accepting male and female participants between 18 years old -45 years old who have been diagnosed with schizophrenia. This study will be conducted in 2 locations in the UK. The study will last approximately 14 months.

Detailed description:
This is a single-site, open-label, flexibly-dosed study evaluating the effect on brain dopamine synthesis capacity as measured by 18F-DOPA PET imaging of adjunctive open-label administration of SEP-363856 (50 to 75 mg/day) over 2 weeks in adults with schizophrenia. The study will consist of 3 periods: Screening (up to 28 days), Treatment (2 weeks), and a Follow-up visit

Arms: arm 1: SEP-363856 50mg, 75mg flexible dosing, dosed once daily
Interventions: intervention 1: SEP-363856
Intervention descriptions: intervention 1: SEP-363856 50mg, 75mg flexable dosing, dosed once daily capsule

Protocol documents:
Prot_000.pdf: 


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RESTRICTED DISTRIBUTION OF PROTOCOLS 
This document contains information confidential and/or of proprietary interest to Sumitomo 
Dainippon Pharma Co. Ltd. and/or Sunovion Pharmaceuticals Inc. (including their 
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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1. 
SYNOPSIS 
Name of Sponsor/Company:  Sunovion Pharmaceuticals Inc. 
Name of Investigational Product: SEP-363856 
Title of Study: An Open-Label Positron Emission Tomography Study to Investigate the Effect of 
Adjunctive Administration of SEP-363856 on Brain Dopamine Synthesis Capacity Using 18F-DOPA 
in Adult Subjects with Schizophrenia 
Proposed Indication: Schizophrenia 
Study Centers: A single center in the United Kingdom (UK) 
Phase of Development: 1 
Study Objectives: 
Primary: To investigate the effect of open-label administration of SEP-363856 (50 or 75 mg/day) 
adjunctive to an antipsychotic, on brain dopamine synthesis capacity in adults with schizophrenia, as 
measured by 18F-DOPA positron emission tomography (PET) imaging. 
Safety Objective: 
• 
To evaluate the safety and tolerability of adjunctive administration with SEP-363856 (50 
or 75 mg/day) in adult subjects with schizophrenia. 
• 
To assess whether adjunctive administration of SEP-363856 is associated with 
extrapyramidal symptoms as measured by the Barnes Akathisia Rating Scale (BARS), the 
Abnormal Involuntary Movement Scale (AIMS), and the Simpson-Angus Scale (SAS). 
Other Objectives: 
• 
To characterize the relationship between brain dopamine synthesis capacity and plasma 
SEP-363856 and its N-desmethyl metabolite, SEP-363854 exposure. 
• 
To explore the effect of SEP-363856 on resting state functional magnetic resonance 
imaging (fMRI) as a biomarker of effects in circuits relevant to schizophrenia and 
cognitive function. 
• 
To explore the effect of SEP-363856 on neuromelanin and iron content (as well as other 
potential markers identifiable through MRI) and investigate the relationship of these 
markers with the 18F-DOPA PET measure of dopamine synthesis capacity. 
• 
To investigate the effect of adjunctive open-label administration of SEP-363856 (50 or 
75 mg/day) on psychiatric symptoms in adults with schizophrenia. 
Study Design: 
This is a single-site, open-label, flexibly dosed study evaluating the effect on brain dopamine 
synthesis capacity as measured by 18F-DOPA PET imaging of adjunctive open-label administration of 
SEP-363856 (50 to 75 mg/day) over 2 weeks in adults with schizophrenia. 
The study will consist of 3 periods: Screening (up to 49 days), Treatment (2 weeks), and a Follow-up 
visit as shown in Figure 1. 
Prior to each PET scan, there is a period of resting state fMRI collection. Two PET scans will be 
conducted during the study: 1 PET scan prior to dosing (between Day -44 to Day -2) and 1 PET scan 
following approximately 14 days of treatment (Day 14). 
Safety and tolerability will be monitored throughout the study by physical examination, 
electrocardiogram [ECGs], vital signs, body weight, BMI, collection of adverse events (AEs), clinical 


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laboratory parameters, and the Columbia-Suicide Severity Rating Scale (C-SSRS). Subjects who have 
significant findings for suicidal ideation assessed by the C-SSRS at any time during the study must be 
referred to the Investigator for follow-up evaluation. 
Population pharmacokinetic analyses will be performed using plasma SEP-363856 concentrations; the 
results of which will be reported separately. The relationship between dopamine synthesis capacity 
and plasma SEP-363856 exposure using population pharmacokinetic (PK)/pharmacodynamics (PD) 
methods will be explored. The plasma concentrations of the background antipsychotic medication will 
be examined based on bioanalytical determination, when available. 
Exploratory evaluation of the effects of SEP-363856 on psychiatric symptoms will be based on 
change from baseline to Week 2 on the PANSS, CGI-S, and BNSS rating scales. 
Screening Period (up to 49 days): 
Informed consent will be obtained from each subject before any study procedures are performed. No 
imaging procedures involving ionizing radiation will be performed within 12 hours of written consent. 
Screening procedures will occur over multiple days. Subjects must be on a stable dose of a single 
antipsychotic medication, dose within the labeled dose-range, for a minimum of 3 weeks or if above 
the maximum label dose (country specific) for at least 12 weeks prior to the PET scan at the screening 
visit, and the dose should remain fixed throughout the study. Subjects who meet entry criteria may be 
in-clinic for up to 7 days during the screening period, at the Investigator’s discretion. 
During the screening period, those subjects who are outpatients will report to the imaging center for 
their PET scan at screening (~2 hours duration) and those subjects who are in-clinic will be 
transferred to the imaging center accompanied by clinic personnel. The PET scan will be performed 
prior to dosing (Day -44 to Day -2), with administration of 18F-DOPA occurring at the start of the 
PET scan session. 
The screening MRI must occur prior to the PET scan at screening (Day -44 to Day -2). Prior to the 
PET scan at screening, a blood sample will be taken to determine antipsychotic plasma 
concentrations. 
Subjects who are not already in-clinic will check into the clinic on Day -2. 
Subjects who screen fail may be re-screened up to two times, if judged appropriate by the 
Investigator. Subjects who screen fail due to MRI or PET scan at screening or fMRI results may not 
be re-screened. 
Open-Label Treatment Period (2 weeks; Day 1 to Day 14+5 days): 
Treatment: At Visit 2 (Day 1), subjects who continue to meet all study inclusion criteria and none of 
the exclusion criteria (see below) will begin treatment with SEP-363856 as an adjunct to their 
background, stable antipsychotic treatment. Study drug dosing will begin on Day 1. Study drug 
(Days 1 – 13) should be taken approximately the same time each day with morning dosing 
recommended. Doses may be moved to the evening for reasons of tolerability. The final dose, on 
Day 14, should occur approximately 2 to 4 hours prior to the final PET scan. Treatment with 
SEP-363856 will occur once-daily during the treatment period with procedures outlined in Table 2 
(schedule of assessments). Subjects will receive SEP-363856 50 mg/day on Day 1 through Day 3. On 
Day 4, subjects will titrate up to a dose of 75 mg/day. A one-time dose reduction (from 75 mg to 
50 mg) for tolerability purposes is permitted and may occur at any time, at the Principal Investigator’s 
discretion. Subjects who have a dose reduction for tolerability will continue to receive the reduced 
dose for the remainder of the study. Subjects will remain in-clinic and on treatment through Week 2 
until all Day 14 assessments including the PET scan are complete. In the event of an unsuccessful 
PET scan on Day 14, additional days of dosing may be necessary up to, but not exceeding, Day 19. If 
any such additional days are necessary, subjects will remain in the clinic and continue their usual 
daily dosing. All Day 14 assessments are to be completed the same day as the PET scan. Subjects will 
be eligible for clinic discharge at the Week 2 visit, at the Investigator’s discretion. 


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Blood samples for determination of SEP-363856 and SEP-363854 plasma concentrations will be 
collected on Day 1 (predose), Day 2 (postdose), Day 7 (postdose), and Day 14 (prior to PET scan). 
Blood samples for antipsychotic plasma concentrations will be collected on Day -2, Day 1 (predose), 
Day 2 (postdose), Day 7 (postdose), and Day 14 (prior to PET scan). Blood samples for SEP-363856, 
SEP-363854 and antipsychotic plasma concentrations should be collected at approximately the same 
time as dosing for Day 2 (postdose) and Day 7 (postdose) while the Day 14 collection should occur 
immediately prior to the PET scan. 
Administration of 18F-DOPA will occur at the start of the PET scan session. Clinical assessments as 
described in the Schedule of Assessments (SOA) will be performed. 
Follow-up/End of Study (EOS) (7± 2 days after last day of study drug): 
A follow-up visit will occur 7 days (± 2 days) after last day of study drug. Clinical assessments as 
described in the Schedule of Assessments (SOA) will be performed. 
Early Termination: 
Subjects who discontinue early from the study will complete an early termination visit. Clinical 
assessments as described in the Schedule of Assessments (SOA) will be performed. 
Number of Subjects (planned): 22 subjects 
Diagnosis and Main Criteria for Subject Inclusion: 
See Section 8 of full protocol for the complete list of inclusion and exclusion criteria information. 
Main criteria include: 
• 
Male or female subject between 18 to 45 years of age (inclusive) at the time of consent. 
• 
Subject meets Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for 
a primary diagnosis of schizophrenia as established by clinical interview (using the 
DSM-5 as a reference and confirmed using the Structured Clinical Interview for DSM-V 
Clinical Trials Version [SCID-CT]). The duration of the subject's illness whether treated 
or untreated must be ≥ 6 months. 
• 
Subject must be on a stable dose of a single antipsychotic medication, dosed within the 
labeled dose-range, for a minimum of 3 weeks prior to the PET scan at the screening visit. 
Patients taking clozapine are not eligible to participate. 
Investigational Product, Dosage and Mode of Administration: 
SEP-363856 will be supplied as 50 mg or 75 mg tablets administered orally once daily. Study drug 
(Days 1 – 13) may be taken without regard to food at approximately the same time each day with 
morning dosing recommended. Doses may be moved to the evening for reasons of tolerability. The 
final dose, Day 14, should occur approximately 2 to 4 hours prior to the final PET scan.  
Duration of Treatment: Once daily open-label treatment for 2 weeks 
Reference Therapy, Dosage and Mode of Administration: not applicable 
Concomitant Medications: 
Following is a summary of allowed/disallowed concomitant medications. Further details are provided 
in Section 10.3. 
Concomitant use of CYP2D6 inhibitors is prohibited as SEP-363856 is a potential substrate for 
CYP2D6. 
Caution should be taken with concomitant use of CYP2D6 substrates with SEP-363856 as 
SEP-363856 is a weak inhibitor of CYP2D6 (see Section 25). 


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Concomitant Non-psychotropic Medications: 
Non-psychotropic medications used to treat mild, chronic medical conditions may be used during 
screening and after enrollment if the dose and regimen have been stable (± 25%) for at least 30 days 
prior to screening. The concomitant medication dose may change, as needed, after enrollment (or be 
discontinued). β-adrenergic antagonists used to treat stable hypertension may be continued through 
the screening phase and post-initiation. In addition, use of non-prescription pain medications (eg, 
aspirin, acetaminophen) are allowed during all phases of the study provided these medications do not 
have a propensity for psychotropic effects and do not interfere with the evaluation of study drug. 
Hydrocortisone 1% cream or ointment for treatment of contact dermatitis from ECG pads is allowed. 
Female subjects may use oral, patch, or intrauterine device (IUD) hormonal contraceptives, or 
progestin implant or injection (contraception requirements are defined in protocol Section 10.5). 
Medications for short-term treatment of a medical condition (no more than 10 days) may be allowed 
with consultation with the Medical Monitor. 
Prior Medications: 
Subjects must be on a stable dose of a single antipsychotic medication, dose within the labeled dose-
range, for a minimum of 3 weeks or if above the maximum label dose (country specific) for at least 
12 weeks prior to the PET scan at the screening visit, and the dose should remain fixed throughout the 
study. Depot neuroleptic dose must be stable for at least 2 treatment cycles or at least 30 days 
(whichever is longer) prior to the screening visit. 
Prior exposure to clozapine is allowed, as long as treatment is discontinued at least 120 days prior to 
PET scan at screening. All other psychotropic medication (with the exception of the single 
background antipsychotic, or medications listed below), must be discontinued, as tolerated and 
clinically appropriate, prior to PET scan at screening in a manner that is consistent with labeling 
recommendations and conventional medical practice. 
Concomitant Psychotropic Medications: 
Subjects who require treatment with a prohibited concomitant medication during the treatment period 
will be discontinued from the study. 
Treatment with benztropine (benzotropine outside the US) up to 6 mg/day will be permitted, as 
needed, for movement disorders. In cases where benztropine is not available or a subject has had an 
inadequate response or intolerability to benztropine treatment, the following medications may be used 
to treat acute extrapyramidal symptoms (EPS): biperiden (up to 16 mg/day) or trihexyphenidyl (up to 
15 mg/day) or diphenhydramine (up to 100 mg/day) or procyclidine (up to 30 mg/day). Treatment 
with propranolol (up to 120 mg/day) will be permitted as needed for akathisia. 
Concomitant use of lorazepam, temazepam, eszopiclone, zaleplon, zolpidem, and zolpidem CR 
(controlled release) is permitted at the discretion of the Investigator with the following restrictions: 
• 
lorazepam (or equivalent benzodiazepine) is permitted for clinically significant 
anxiety/agitation or as a sedative/hypnotic up to a maximum daily dose of 6 mg/day. 
Intramuscular lorazepam is permitted up to 4 mg/day for acute anxiety/agitation, as 
clinically indicated. Lorazepam should be used sparingly, when clinically required, per 
Investigator judgment. 
• 
temazepam (≤ 30 mg/day), eszopiclone (≤ 3 mg/day), zaleplon (≤ 20 mg/day), zolpidem 
(≤ 10 mg/day), and zolpidem CR (≤ 12.5 mg/day) may be administered at bedtime for 
insomnia, as needed. 
• 
hypnotic agents should be administered no more than once nightly and should not be used 
in combination. 


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The date and time of the last dose taken prior to scheduled efficacy assessments must be recorded at 
each visit. Subjects should be encouraged to avoid taking sedative/hypnotic medications within 
8 hours of scheduled efficacy assessments. 
Medications used for the treatment of anxiety/agitation and insomnia (eg, lorazepam and zolpidem) 
should not be used in close temporal proximity (defined as administration within 2 hours of each 
other). Similar drugs at equivalent dosages will be permitted as described in the Operations Manual or 
in consultation with the Medical Monitor. 
Subjects who require treatment with one or more of the prohibited concomitant medications 
(including antidepressants, mood stabilizers, or anxiolytics [lorazepam or equivalent at doses above 
protocol-specified limits]) will be discontinued (as appropriate) from the study. Continuation of 
subjects who require an increase in dose of their background antipsychotic during the study will be 
discussed with the Medical Monitor. A down-titration of the background antipsychotic due to 
tolerability may be allowable, after consultation with the Medical Monitor. All efforts will be made to 
complete the PET and resting state fMRI scans intended by the protocol even in cases of 
discontinuations of study drug or procedures. 
Study Endpoints: 
Primary Endpoint: Change from baseline in dopamine synthesis capacity at Week 2 using 
18F-DOPA. 
Safety Endpoints: 
• 
Incidence of treatment emergent adverse events (TEAEs), serious AEs (SAEs), and 
adverse events (AEs) (or SAEs) leading to discontinuation. 
• 
Absolute values and changes from baseline in clinical laboratory tests (hematology, 
serum chemistry, urinalysis), and clinical evaluations (vital signs, body weight, body 
mass index [BMI], 12-lead ECG parameters). 
• 
Frequency and severity of suicidal ideation or suicidal behavior as measured by the 
C-SSRS. 
• 
Change from Baseline in BARS, AIMS, and SAS scores at Week 2 and Week 3. 
Other Endpoints: 
• 
Change in baseline resting state BOLD fMRI signal at Week 2. 
• 
Change in exploratory MRI markers, including but not limited to neuromelanin signal as 
measured by neuromelanin sensitive MRI (NM-MRI) and iron signal as measured by an 
iron-sensitive MRI sequence (effective transverse relaxation rate [R2*] or Quantitative 
Susceptibility Mapping [QSM]), at Week 2. 
• 
Plasma concentrations of SEP-363856 and its metabolite SEP-363854 at each postdose 
timepoint. 
• 
Change from baseline to Week 2 in: 
− 
Positive and Negative Syndrome Scale (PANSS) score. 
− 
Brief Negative Symptom Scale (BNSS) Montgomery-Asberg Depression Rating 
Scale (MADRS) total score. 
− 
Clinical Global Impression-Severity (CGI-S) score. 
Statistical Methods: 
PET Analysis: The region of interest in the primary endpoint is the whole striatum. Exploratory 
analyses will be conducted in other regions and sub-regions of interest. The cerebellum will be used 


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as the reference region. Dopamine synthesis capacity will be calculated based on each individual PET 
images collected at each scan for each subject. 
Statistical Analysis: The analysis of brain dopamine synthesis capacity and fMRI analysis will use 
the PET population, which include subjects who were administered at least one dose of SEP-363856 
and have a baseline and a post-baseline PET assessment. The change from baseline in dopamine 
synthesis capacity at Week 2 will be calculated, together with 95% confidence interval from a paired 
sample t distribution. Changes in resting state BOLD fMRI signal at each post-dose time point from 
baseline will be summarized. Changes in exploratory MRI markers, including (but not limited to) 
neuromelanin and iron signal at each post-dose time point from baseline will be summarized. The 
efficacy population will include all subjects who have received at least one dose of SEP-363856, and 
have any postdose data for the PANSS, CGI-S, BNSS or MADRS. Efficacy data will be based on this 
population. Changes from baseline at each post-dose time point will be summarized, with 95% 
confidence intervals. 
Safety analyses will use the Safety population, which includes all subjects who have received at least 
one dose of study drug. Safety measures will be summarized descriptively. 
Treatment emergent adverse events (TEAEs) will be summarized by presenting the number and 
percentage of subjects with any TEAEs, and AEs by system organ class and preferred term. Adverse 
events will be further summarized by severity and by relationship to study drug. The summary of 
TEAEs will be limited to events occurring on or after the first dose of study drug. All AEs, as well as 
a listing of deaths, SAEs, or AEs leading to discontinuation, will be presented in listings. 
Vital signs, ECG parameters, and laboratory data will be summarized by presenting summary 
statistics of actual values and change from baseline values. The number and percentage of subjects 
with potentially clinically significant post-baseline values for selected parameters will be presented. 
The incidence of orthostatic hypotension and orthostatic tachycardia will be summarized. 
The BARS, AIMS, and SAS will be summarized descriptively by presenting summary statistics of 
actual values and change from baseline values. 
The relationship between dopamine synthesis capacity at baseline and measures of baseline symptom 
severity (PANSS, CGI-S, BNSS, and MADRS) and their change from baseline will be presented 
graphically. 
Sample Size: This study is designed to determine the magnitude of a possible pharmacological effect 
of SEP-363856 on dopamine synthesis capacity. Measurement of dopamine synthesis capacity has 
shown good test-retest reliability (Egerton-2010). Prior studies have reported a within-subject 
standard deviation of 0.00056/min in dopamine synthesis capacity. The absolute elevation in 
dopamine synthesis capacity for schizophrenia cases versus normal healthy controls is estimated to be 
approximately 0.001/min and to have a correlation of approximately 0.6 with symptoms. Given this 
relationship between dopamine synthesis capacity and symptoms, it is estimated that a decrease in 
dopamine synthesis capacity of 0.0005/min in patients is the smallest reduction likely to be clinically 
significant (anticipated to translate into > 20% reduction in symptoms, which is generally considered 
the smallest change readily detected in clinical practice). A sample size of 16 subjects treated with 
SEP-363856 will provide > 90% power to detect a treatment reduction of 0.0005/min (change from 
baseline) in dopamine synthesis capacity using a paired sample t-test with alpha set at the 0.05 level. 
Subjects who are initiated on treatment but discontinue from the study may not be replaced. The total 
sample size will be 22 subjects to allow for up to 25% drop-out to obtain complete PET scans on at 
least 16 subjects. 


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Table 2: Schedule of Assessments 
Study Visit Number 
Visit 1 
Visit 2 
Visit 3 
ET 
Study Visit Week 
Screeninga 
Check-in 
Day 1 
Week 2 
Week 3 
Follow-up/ 
EOS 
Early 
Termination 
Study Visit Type 
Outpatient or 
In-clinic up to 7 daysb 
In-clinic 
In-clinic 
In-clinic 
Outpatient 
- 
Study Visit Day  
-49 to -2 
-2 
-1 
1 
14 + 5 days 
7 ± 2 days post 
last dose of 
study drug 
- 
Obtain informed consent 
X 
 
 
 
 
 
 
Review inclusion/exclusion criteria  
X 
X 
X 
X 
 
 
 
Demography 
X 
 
 
 
 
 
 
Prior/concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
Dispensation of study drug (blister card) 
 
 
 
Xc 
 
 
 
Administration of Study Drugc 
 
 
 
X 
X 
 
 
Admit to Clinic, if not admitted during screening 
 
Xb 
 
 
 
 
 
Clinic Discharge 
 
 
 
 
X 
 
 
Medical history 
X 
 
 
 
 
 
 
Psychiatric history/mental status 
X 
 
 
 
 
 
 
SCID-CTd 
X 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
X 
X 
Height/BMI 
X 
 
 
 
 
 
 
Vital signse 
X 
X 
X 
X 
X 
X 
X 
Weight  
X 
X 
 
X 
X 
X 
X 
Electrocardiogram (ECG) 
X 
X 
 
X 
X 
X 
X 
Hematology, chemistry, and urinalysis  
X 
X 
 
 
X 
X 
X 
Coagulation Panel 
X 
 
 
 
 
 
 
Thyroid Panel 
X 
 
 
 
 
 
 


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Table 2: 
Schedule of Assessments (Continued) 
Study Visit Number 
Visit 1 
Visit 2 
Visit 3 
ET 
Study Visit Week 
Screeninga 
Check-in 
Day 1 
Week 2 
Week 3 
Follow-up/ 
EOS 
Early 
Termination 
Study Visit Type 
Outpatient or 
In-clinic up to 7 daysb 
In-clinic 
In-clinic 
In-clinic 
Outpatient 
- 
Study Visit Day  
-49 to -2 
-2 
 
 
-1 
1 
14 + 5 days 
7± 2 days post 
last dose of 
study drug 
- 
Serum prolactin 
X 
X 
 
 
X 
X 
X 
Hepatitis B/C, HIV-1/HIV-2 
X 
 
 
 
 
 
 
Glycosylated hemoglobin (HbA1c) 
X 
 
 
 
 
 
 
Glucose and lipid panelf 
X 
X 
 
 
X 
X 
X 
Follicle stimulating hormone (FSH), females onlyg 
X 
 
 
 
 
 
 
Serum human chorionic gonadotropin (β-hCG), females 
only 
X 
 
 
 
 
 
 
Urine β-hCGh, females only 
X 
X 
 
X (predose) 
X 
X 
X 
Blood sample for pharmacogenomics  
 
 
 
X 
 
 
 
Blood sample for SEP-363856 and SEP-363854 PKi 
 
 
 
X 
X 
X 
X 
Blood sample for antipsychotic levelsj 
X 
X 
 
X 
X 
X 
X 
Urine drug screenk 
X 
X 
 
X 
X 
X 
X 
Magnetic resonance imaging (MRI) Scan 
X 
 
 
 
 
 
 
PET/MR Scan including fMRIl 
X (Day -44 to -2) 
 
 
 
Xm 
 
Xn 
Positive and Negative Syndrome Scale (PANSS) 
X 
 
Xs 
 
Xm 
(±1 day of PET Scan) 
 
Xo 
Brief Negative Symptom Scale (BNSS) 
X 
 
Xs 
 
Xm 
(±1 day of PET Scan) 
 
Xo 
Montgomery-Asberg Depression Rating Scale (MADRS) 
 
 
Xs 
 
Xm 
(±1 day of PET Scan) 
 
Xo 


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Table 2: 
Schedule of Assessments (Continued) 
Study Visit Number 
Visit 1 
Visit 2 
Visit 3 
ET 
Study Visit Week 
Screeninga 
Check-in 
Day 1 
Week 2 
Week 3 
Follow-up/ 
EOS 
Early 
Termination 
Study Visit Type 
Outpatient or 
In-clinic up to 7 daysb 
In-clinic 
In-clinic 
In-clinic 
Outpatient 
- 
Study Visit Day 
-49 to -2 
-2 
-1 
1 
14 + 5 days 
7± 2 days post 
last dose of 
study drug 
- 
Columbia Suicide Severity Rating Scale (C-SSRS)p 
X 
Xs 
X 
X 
X 
Clinical Global Impression – Severity (CGI-S) 
X 
Xs 
Xm 
(±1 day of PET Scan) 
Xo 
Barnes Akathisia Rating Scale (BARS)q 
X (predose)t 
X 
X 
X 
Abnormal Involuntary Movement Scale (AIMS)q 
X (predose)t 
X 
X 
X 
Simpson-Angus Scale (SAS)q 
X (predose)t 
X 
X 
X 
Adverse events (AEs) monitoringr
X 
X 
X 
X 
X 
X 
X 
Abbreviations: BARS = Barnes Akathisia Rating Scale; BMI = body mass index; AIMS = Abnormal Involuntary Movement Scale; SAS = Simpson-Angus 
Scale; C-SSRS = Columbia-Suicide Severity Rating Scale; EOS = end of study; ET = early termination; fMRI = functional magnetic resonance imaging; 
PET = positron emission tomography; PK = pharmacokinetics; MR = magnetic resonance; SCID-CT = structured clinical interview for DSM-V, clinical trials 
version. 
a Subjects who screen fail may be re-screened up to two times, if judged appropriate by the Investigator. Subjects who screen fail due to MRI or PET or fMRI 
results may not be re-screened. Screening procedures will occur on multiple days. If subject re-screened, an MRI (without any abnormality) obtained at the 
study’s imaging center within 90 days prior to Day -1 check-in is acceptable for eligibility. 
b Extension of in-clinic stay during the screening phase to complete screening assessments may be allowed on a case-by-case basis with pre-approval of the 
Medical Monitor. Subject must be admitted to the clinic by Day -2. 
c Dispensation of study drug on Day 1 and Day 8. All study drug will be taken once daily by mouth from Day 1 through Week 2 (Day 14). After 3 days of 
treatment with 50 mg/day SEP-363856, subjects are required to titrate up to 75 mg/day. Subjects may dose reduce one time to 50 mg/day for tolerability 
reasons at any time. Subjects who have a dose reduction for tolerability will continue to receive the reduced dose for the remainder of the study. The final dose, 
on Day 14, should occur approximately 2 to 4 hours prior to the final PET scan. 
d The SCID-CT will be used to support the DSM-5 diagnosis and must be administered by a qualified rater with at least 2 years' experience with the population 
under study. 
e Vital signs will include supine and standing measurements of blood pressure and heart rate, respiratory rate, and oral body temperature. 
f Subjects must be fasted (no food or drink except water at least 8 hours prior to specified blood tests). Blood samples should be drawn in the morning followed 
by a snack or meal. 


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g Blood samples for follicle stimulating hormone (FSH) will be collected if menopause is suspected. 
h Any positive urine β-hCG test should be confirmed by a serum β-hCG test. Must be performed prior to PET scan on same day as screening scan and on Day 14 
scan. 
i Blood samples for determination of SEP-363856 and SEP-363854 concentrations will be collected on Day 1 (approximately 10 minutes prior to dosing), Day 2 
(2 – 4 hours postdose), Day 7 (2 – 4 hours postdose), Day 14 (prior to PET scan), and at Follow-up. 
j Blood samples for antipsychotic plasma concentrations will be collected at Screening, Day -2, Day 1 (approximately 10 minutes prior to dosing), Day 2 
(2 - 4 hours postdose), Day 7 (2 – 4 hours postdose), Day 14 (prior to PET scan), and at Follow-up. 
k Additional urine drug screen may be ordered as deemed clinically appropriate. These results should be discussed with the Medical Monitor. 
l Each PET scan will be accompanied by intravenous administration of radiotracer 18F-DOPA and oral pre-treatment (1 hour prior to tracer) with 150 mg 
carbidopa and 400 mg entacapone. If PET/MR scanner is unavailable for technical reasons separate PET and MR scans (on an alternate PET scanner without 
MR and alternate MR scanner) will be permitted. Prior to each PET scan, there is a period of resting state fMRI collection. In addition to fMRI scan sequences, 
exploratory MRI sequences may be performed during each of the MRI and PET/MR acquisition times and may include (but not limited to) a neuromelanin-
sensitive MRI (NM-MRI) sequence and an iron-sensitive MRI sequence (effective transverse relaxation rate [R2*] or Quantitative Susceptibility Mapping 
[QSM]).  Repeat MRI including exploratory MRI sequences may be performed where it is not possible to obtain complete measures during the PET-MRI scan. 
m In the event of unsuccessful PET scan on Day 14, additional days of dosing may be necessary up to, but not exceeding, Day 19. If any such additional days are 
necessary, subjects will continue their usual daily dosing. PANSS, BNSS, MADRS, and CGI-S may be assessed ±1 day of PET scan; other assessments are to 
be completed the same day as the PET scan. Participants will only receive 3 PET scans in the event that a scan is not able to be completed or is not suitable for 
analysis. It is expected that the majority of participants will receive up to 2 PET scans which would result in an effective dose of 7.4 mSv. 
n PET scan to be performed at early termination (ET) visit only if the subject terminates the study prior to Day 14 PET scan. 
o Only perform PANSS, BNSS, CGI-S, and MADRS if subject discontinues prior to Day 14 scan day. 
p At the screening visit, the “Baseline/Screening” version will be completed; the “Since Last Visit” version of the C-SSRS will be administered for all other 
visits. C-SSRS should be performed prior to PET scan on Day 14. 
q Unscheduled BARS, AIMS, and SAS scales should be administered if a subject develops extrapyramidal symptoms (EPS) requiring treatment. 
r All adverse events occurring after signing informed consent through the end of study will be collected. 
s PANSS, BNSS, MADRS, CGI-S, and C-SSRS to be completed on Day -2 or Day -1. 
t BARS, AMES, SAS to be collected on Day -1 or Day 1 (predose). 
 


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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
RESTRICTED DISTRIBUTION OF PROTOCOLS ......................................................................2 
EMERGENCY CONTACTS...........................................................................................................3 
1. 
SYNOPSIS ...................................................................................................................4 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............14 
TABLE OF CONTENTS ...............................................................................................................14 
LIST OF TABLES .........................................................................................................................19 
LIST OF FIGURES .......................................................................................................................19 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................20 
4. 
INTRODUCTION ......................................................................................................23 
4.1. 
Background .................................................................................................................23 
4.2. 
Study Conduct Rationale ............................................................................................23 
4.3. 
Risk-Benefit Assessment ............................................................................................24 
5. 
STUDY OBJECTIVES ..............................................................................................25 
5.1. 
Primary Objective .......................................................................................................25 
5.2. 
Safety Objectives ........................................................................................................25 
5.3. 
Other Objectives .........................................................................................................25 
6. 
STUDY ENDPOINTS ................................................................................................26 
6.1. 
Primary Endpoint ........................................................................................................26 
6.2. 
Safety Endpoints .........................................................................................................26 
6.3. 
Other Endpoints ..........................................................................................................26 
7. 
INVESTIGATIONAL PLAN .....................................................................................27 
7.1. 
Overall Study Design ..................................................................................................27 
7.2. 
Treatment Assignment and Blinding ..........................................................................29 
7.3. 
Rationale .....................................................................................................................29 
7.3.1. 
Rationale for the Study Design ...................................................................................29 
7.3.2. 
Rationale for the Dosages ...........................................................................................30 
7.3.3. 
Rationale for the Study Population .............................................................................31 
7.4. 
Prevention of Missing Data ........................................................................................32 
8. 
SELECTION OF SUBJECTS ....................................................................................33 


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8.1. 
Subject Inclusion Criteria ...........................................................................................33 
8.2. 
Subject Exclusion Criteria ..........................................................................................34 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................38 
9.1. 
Description of Study Drug ..........................................................................................38 
9.2. 
Study Drug Packaging and Labeling ..........................................................................38 
9.2.1. 
Package Description ...................................................................................................38 
9.2.2. 
Labeling Description ..................................................................................................38 
9.3. 
Study Drug Storage .....................................................................................................39 
9.4. 
Dispensing of Study Drug ..........................................................................................39 
9.5. 
Study Drug Accountability .........................................................................................39 
9.6. 
Study Drug Handling and Disposal ............................................................................39 
10. 
TREATMENT OF SUBJECTS ..................................................................................40 
10.1. 
Study Medication ........................................................................................................40 
10.1.1. 
Dose Adjustment Criteria ...........................................................................................40 
10.2. 
Treatment Compliance ................................................................................................40 
10.3. 
Concomitant Medications and Therapies ...................................................................40 
10.3.1. 
Prohibited Medications ...............................................................................................40 
10.3.2. 
Prohibited Therapies ...................................................................................................41 
10.3.3. 
Restricted Medications ...............................................................................................41 
10.3.4. 
Permitted Medications ................................................................................................42 
10.4. 
Restrictions .................................................................................................................42 
10.5. 
Contraception Requirements ......................................................................................42 
10.6. 
Dietary Guidelines ......................................................................................................43 
11. 
STUDY ASSESSMENTS ..........................................................................................44 
11.1. 
Demographics and Baseline Characteristics ...............................................................44 
11.2. 
Prior and Concomitant Medication Review ...............................................................44 
11.3. 
Structured Clinical Interview for DSM-5 Axis I Disorders-Clinical Trials 
version (SCID-CT) .....................................................................................................44 
11.4. 
PET/fMRI Assessments ..............................................................................................44 
11.5. 
Efficacy Assessments .................................................................................................45 
11.5.1. 
Positive and Negative Syndrome Scale (PANSS) ......................................................45 
11.5.2. 
Brief Negative Symptom Scale (BNSS) .....................................................................45 
11.5.3. 
Montgomery-Asberg Depression Rating Scale (MADRS) ........................................46 


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11.5.4. 
Clinical Global Impressions – Severity Scale (CGI-S) ..............................................46 
11.6. 
Safety Assessments .....................................................................................................46 
11.6.1. 
Adverse Events ...........................................................................................................46 
11.6.2. 
Clinical Laboratory Assessments ...............................................................................46 
11.6.3. 
Vital Signs ..................................................................................................................47 
11.6.4. 
Electrocardiograms (ECGs) ........................................................................................47 
11.6.5. 
Physical and Neurological Examination .....................................................................47 
11.6.6. 
Height, Weight, and BMI ...........................................................................................48 
11.6.7. 
Safety Scales ...............................................................................................................48 
11.6.7.1. 
Abnormal Involuntary Movement Scale (AIMS) .......................................................48 
11.6.7.2. 
Barnes Akathisia Rating Scale (BARS) .....................................................................48 
11.6.7.3. 
Simpson-Angus Scale (SAS) ......................................................................................48 
11.6.7.4. 
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................................48 
11.7. 
Pharmacokinetic Assessments ....................................................................................49 
11.8. 
Pharmacogenomic Assessments .................................................................................49 
11.9. 
Study Visits and Assessments ....................................................................................49 
11.9.1. 
Screening (Day -49 to Day -2): Visit 1 .......................................................................50 
11.9.2. 
In-Clinic (Day -2 to Day 14): Visit 2..........................................................................51 
11.9.2.1. 
Day -2, Check-in .........................................................................................................51 
11.9.2.2. 
Day -1 .........................................................................................................................51 
11.9.2.3. 
Day 1 ...........................................................................................................................52 
11.9.2.4. 
Day 2 ...........................................................................................................................52 
11.9.2.5. 
Day 7 ...........................................................................................................................53 
11.9.2.6. 
Day 14 (+5 Days)........................................................................................................53 
11.9.3. 
Outpatient Follow-up / End of Study (EOS) (7 ± 2 Days Post Last Dose of 
Study Drug): Visit 3....................................................................................................54 
11.9.4. 
Early Termination (ET) ..............................................................................................55 
12. 
SAFETY REPORTING ..............................................................................................56 
12.1. 
Definitions ..................................................................................................................56 
12.1.1. 
Adverse Events ...........................................................................................................56 
12.1.2. 
Serious Adverse Events ..............................................................................................56 
12.2. 
Objective Findings ......................................................................................................57 
12.3. 
Collection and Recording of Adverse Events .............................................................57 


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12.4. 
Immediately Reportable Events ..................................................................................59 
12.4.1. 
Serious Adverse Event ................................................................................................59 
12.4.2. 
Pregnancy ...................................................................................................................60 
13. 
TERMINATION OF SUBJECT FROM STUDY/DISCONTINUATION OF 
STUDY DRUG ...........................................................................................................61 
13.1. 
Criteria for Subject Termination .................................................................................61 
13.2. 
Clinical Assessments After Study Drug Discontinuation ...........................................61 
14. 
STUDY TERMINATION ..........................................................................................62 
15. 
STATISTICS ..............................................................................................................63 
15.1. 
Sample Size ................................................................................................................63 
15.2. 
Analysis Populations ..................................................................................................63 
15.3. 
Data Analysis ..............................................................................................................63 
15.3.1. 
Subject Disposition .....................................................................................................63 
15.3.2. 
Drug Exposure and Compliance .................................................................................64 
15.3.3. 
Important Protocol Deviations ....................................................................................64 
15.3.4. 
Demographic and Baseline Characteristics ................................................................64 
15.3.5. 
Medical History and Psychiatric History ....................................................................64 
15.3.6. 
Positron Emission Tomography (PET) and Functional Magnetic Resonance 
Imaging (fMRI) Analysis ...........................................................................................64 
15.3.7. 
Efficacy Analyses .......................................................................................................65 
15.3.7.1. 
Subgroup Analysis ......................................................................................................65 
15.3.8. 
Safety Analyses ..........................................................................................................65 
15.3.8.1. 
Adverse Events ...........................................................................................................65 
15.3.8.2. 
Clinical Laboratory Assessments ...............................................................................66 
15.3.8.3. 
Electrocardiograms .....................................................................................................66 
15.3.8.4. 
Vital Signs ..................................................................................................................67 
15.3.8.5. 
Physical/Neurological Examination ...........................................................................67 
15.3.8.6. 
Concomitant Medications ...........................................................................................67 
15.3.8.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................67 
15.3.8.8. 
Movement Disorder Measures ....................................................................................67 
15.3.8.9. 
Subgroup Analysis ......................................................................................................68 
15.3.9. 
Pharmacokinetic Analysis ..........................................................................................68 
15.3.10. 
Interim Analysis ..........................................................................................................68 


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15.3.11. 
Treatment of Missing Data .........................................................................................68 
16. 
PROCEDURE FOR CLINICAL STUDY QUALITY CONTROL /DATA 
COLLECTION, MANAGEMENT, AND QUALITY ASSURANCE ......................69 
16.1. 
Data Collection/Electronic Data Capture (EDC) ........................................................69 
16.2. 
Computerized Systems Used for Source Data ............................................................69 
16.3. 
Study Monitoring ........................................................................................................70 
16.4. 
Audits ..........................................................................................................................71 
16.5. 
Study Documentation .................................................................................................71 
16.6. 
Clinical Laboratory Certification and Normal Values ................................................71 
17. 
ETHICAL AND REGULATORY OBLIGATIONS..................................................72 
17.1. 
Study Conduct ............................................................................................................72 
17.2. 
Institutional Review Board/Independent Ethics Committee ......................................72 
17.3. 
Informed Consent .......................................................................................................73 
17.4. 
Subject Privacy ...........................................................................................................73 
17.5. 
Protocol Amendments and Emergency Deviations ....................................................74 
17.6. 
Records Retention .......................................................................................................74 
17.7. 
Inspection of Records .................................................................................................74 
17.8. 
Financial Disclosure ...................................................................................................74 
17.9. 
Publication Policy .......................................................................................................74 
18. 
REFERENCES ...........................................................................................................76 
19. 
INVESTIGATOR APPROVAL .................................................................................79 
20. 
APPENDIX I. CARDIAC SAFETY MONITORING (ECG) ....................................80 
21. 
APPENDIX II. CLINICAL LABORATORY TESTS ...............................................81 
22. 
APPENDIX III. PHARMACOKINETIC SAMPLING AND SAMPLE 
HANDLING GUIDELINE .........................................................................................82 
23. 
APPENDIX IV. SAMPLE COLLECTION AND HANDLING 
GUIDELINES FOR ANTIPSYCHOTIC LEVELS ...................................................83 
24. 
APPENDIX V. SAMPLE COLLECTION AND HANDLING 
GUIDELINES FOR PHARMACOGENOMICS ASSESSMENT .............................84 
25. 
APPENDIX VI. CYP2D6 INHIBITORS AND SUBSTRATES ...............................85 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Schedule of Assessments ............................................................................................10 
Table 3: 
List of Abbreviations ..................................................................................................20 
Table 4: 
Definition of Key Study Terms ..................................................................................22 
Table 5: 
Investigational Product ...............................................................................................38 
Table 6: 
Computerized Systems Used for Source Data ............................................................69 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................27 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The abbreviations and the definition of key study terms used in the clinical study protocol are 
shown in Table 3 and Table 4. 
Table 3: List of Abbreviations 
Abbreviation 
Full Form 
AE 
Adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BARS 
Barnes akathisia Rating Scale 
BMI 
Body mass index  
BNSS 
Brief Negative Symptom Scale 
CDR 
Clinical data repository 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global Impression-Severity 
Cmax 
Maximum observed plasma concentration 
CNS 
Central nervous system 
CRF 
Case report form 
CRO 
Contract research organization 
CS 
Clinically significant 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CV 
Coefficient of variation 
DSM-V, DSM-5 
Diagnostic and Statistical Manual of Mental Disorders 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EOS 
End of study 
ET 
Early termination 
ePRO 
Electronic patient reported outcomes 
FDA 
U.S. Food and Drug Administration 
fMRI 
Functional magnetic resonance imaging 
GCP 
Good Clinical Practice 
5-HT 
5-hydroxytryptamine (serotonin) 


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Table 3: 
List of Abbreviations (Continued) 
Abbreviation 
Full Form 
HIV 
Human immunodeficiency virus  
HRA 
Health Research Authority 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee  
IND 
Investigational New Drug 
IP 
Investigational product 
IPD 
Important protocol deviation 
IRB 
Institutional Review Board 
LIMS 
Laboratory information management system 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NCS 
Not clinically significant 
PANSS 
Positive and Negative Syndrome Scale 
PCS 
Potentially clinically significant 
PET 
Positron emission tomography 
PK 
Pharmacokinetic(s) 
PR 
Time between P wave and QRS in electrocardiography 
PT 
Preferred term 
PVG 
Pharmacovigilance 
QRS 
Electrocardiographic wave (complex or interval) 
QT 
Electrocardiographic interval from the beginning of the QRS complex to 
the end of the T wave 
QTc 
QT interval corrected for heart rate 
RR 
RR interval 
SAE 
Serious adverse event 
SAS 
Simpson-Angus scale 
SCID-CT 
Structured clinical interview for DSM, clinical trials version 
SOC 
System organ class 
TEAE 
Treatment emergent adverse event 
WBC 
White blood cells 
WHO-DD 
World Health Organization – Drug Dictionary 


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Table 4: Definition of Key Study Terms 
Terms 
Definition of terms 
CRF 
A printed, optical, or electronic document designed to record all 
of the protocol required information to report to the Sponsor for 
each study subject. 
Screened Subject 
Any subject who signed the study specific informed consent 
and completed at least one study related procedure. 
Screen Failures 
Any subject who signed the study specific informed consent but 
either failed to meet study requirements during screening or met 
study requirements at screening but was not 
enrolled/randomized. 
Study Drug (or 
Study medication) 
Term to cover investigational drug, placebo, and/or active 
control. 
Treatment Period 
The period of the study in which the study drug is administered. 
Completed 
Treatment 
Any subject who participated throughout the duration of the 
14-day treatment period, up to and including the Day 14 
PET/fMRI scan. 
Completed Study 
Any subject who completed treatment and the last planned visit. 
Early Termination 
Subject 
Any subject who was successfully screened and entered into the 
treatment period of the study but did not complete the study. 
End of Treatment 
The day that the subject receives protocol-defined last dose of 
the study drug. 
End of Study 
The day that the subject completes the study per the study 
design. 
 


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4. 
INTRODUCTION 
4.1. 
Background 
Schizophrenia is a chronic and disabling neurodegenerative disorder characterized by a mixture 
of positive symptoms (eg, hallucinations, delusions, and disordered thought), negative symptoms 
(eg, flat affect, anhedonia, alogia, and avolition), and cognitive deficits (eg, impaired memory, 
attention, and planning/organizing). Mood symptoms such as depression, anxiety, hostility, and 
excitement can also be present in patients with schizophrenia (Patel-2007; 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, and the side effects associated with 
current treatments. New treatments with greater efficacy and tolerability are needed to reduce the 
associated high rates of  morbidity and mortality (Lehman-2004; Tandon-2008; NIMH-2010). 
Schizophrenia has an estimated population prevalence of approximately 1% (estimated 
2.4 million adults), with a diagnosed prevalence of 0.51% in the United States (Narrow-2002; 
Wu-2006). It affects both genders equally (NIMH-2010) typically first manifesting in young 
adults, with the peak ages of onset in the early to mid 20s in men and late 20s in women 
(APA-2000). It is believed to be caused by a combination of genetic and environmental factors 
(Minzenberg-2008). Dopaminergic, serotonergic and glutamatergic systems are believed to play 
a role in schizophrenia (Kuroki-2008; Kim-2009). 
The current standard of care for the treatment of schizophrenia is the use of second generation 
antipsychotics or “atypical antipsychotics” (Lehman-2004; Kreyenbuhl-2009; NIMH-2010; 
Meltzer-2011; Nakamura-2009). These “atypicals” are thought to have fewer extrapyramidal 
side effects compared to first generation antipsychotics or “typical antipsychotics” (eg, 
haloperidol) (Leucht-2009; Naber-2009). However, some patients respond poorly to both 
atypical and typical antipsychotics and some continue to have symptoms and substantial 
functional/cognitive impairment (Keefe-2006; Webber-2008). Very few patients return to 
baseline (pre-psychosis) function (Schultz-1999; Pearlson-2000; Kapur-2001). In addition, some 
atypical agents have a variety of other side effects, including weight gain, metabolic syndrome, 
sedation, QT prolongation, extrapyramidal symptoms, and tardive dyskinesia (Davis-2004; 
Lieberman-2005; Newcomer-2007; Leucht-2009), which may lead to significant comorbid 
medical problems as well as contribute to poor compliance and treatment discontinuation. The 
large scale NIMH-CATIE schizophrenia study found that 70% to 80% of outpatients discontinue 
medications due to lack of efficacy or occurrence of side effects (Lieberman-2005), often leading 
to relapse of symptoms and the need for rehospitalization (Ascher-Svanum-2010; Munro-2011; 
Morken-2008). Clearly, an unmet need exists for new, effective, and well-tolerated treatments. 
4.2. 
Study Conduct Rationale 
SEP-363856 is currently being investigated in subjects with schizophrenia. One randomized, 
double-blind study (SEP361-201) evaluating efficacy and safety of flexible SEP-363856 doses 
(50 mg/day or 75 mg/day) in adult subjects with schizophrenia is complete. Subjects who 
completed this study were eligible to enroll in a 26-week-long-term open-label safety and 
tolerability study (SEP361-202). 


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The primary objective of the current study is to investigate the effect of open-label 
administration of SEP-363856 (50 or 75 mg/day) adjunctive to an antipsychotic, on brain 
dopamine synthesis capacity, as measured by 18F-DOPA positron emission tomography (PET) 
imaging, in adults with schizophrenia. 
4.3. 
Risk-Benefit Assessment 
Overall, in previous clinical studies, SEP-363856 was generally well-tolerated. The 
pharmacokinetic (PK) and safety profiles observed in healthy male subjects and male and female 
subjects with schizophrenia from completed Phase 1 clinical studies, as well as safety data from 
the completed Phase 2 double-blind and clinically complete open-label extension study in adults 
with schizophrenia, support the evaluation of SEP-363856 in the dose range of 50 to 75 mg/day 
in adults with schizophrenia. 
Schizophrenia is a life-long disorder and despite advances in drug treatment many patients 
continue to experience symptoms with impaired quality of life. SEP-363856 has a novel 
mechanism of action not related to direct antagonism of the D2 receptor. If proven effective and 
well-tolerated, it may provide an advance in the treatment of patients with schizophrenia by 
reducing the side-effect burden associated with direct D2 receptor antagonists. 


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5. 
STUDY OBJECTIVES 
5.1. 
Primary Objective 
To investigate the effect of open-label administration of SEP-363856 (50 or 75 mg/day) 
adjunctive to an antipsychotic, on brain dopamine synthesis capacity in adults with 
schizophrenia, as measured by 18F-DOPA positron emission tomography (PET) imaging. 
5.2. 
Safety Objectives 
• To evaluate the safety and tolerability of adjunctive administration with SEP-363856 
(50 or 75 mg/day) in adults with schizophrenia. 
• To assess whether adjunctive administration of SEP-363856 is associated with 
extrapyramidal symptoms as measured by the Barnes Akathisia Rating Scale 
(BARS), the Abnormal Involuntary Movement Scale (AIMS), and the 
Simpson-Angus Scale (SAS). 
5.3. 
Other Objectives 
• To characterize the relationship between brain dopamine synthesis capacity and 
plasma SEP-363856 and its N-desmethyl metabolite, SEP-363854, exposure. 
• To explore the effect of SEP-363856 on neuromelanin and iron content (as well as 
other potential markers identifiable through MRI) and investigate the relationship of 
these markers with the 18F-DOPA PET measure of dopamine synthesis capacity. 
• To explore the effect of SEP-363856 on resting state functional magnetic resonance 
imaging (fMRI) as a biomarker of effects in circuits relevant to schizophrenia and 
cognitive function. 
• To investigate the effect of adjunctive open-label administration of SEP-363856 
(50 or 75 mg/day) on psychiatric symptoms in adults with schizophrenia. 
 


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6. 
STUDY ENDPOINTS 
6.1. 
Primary Endpoint 
Change from baseline in dopamine synthesis capacity at Week 2 using 18F-DOPA. 
6.2. 
Safety Endpoints 
• Incidence of treatment emergent adverse events (TEAEs), serious AEs (SAEs) and 
AEs (or SAEs) leading to discontinuation. 
• Absolute values and changes from baseline in clinical laboratory tests (hematology, 
serum chemistry, urinalysis), and clinical evaluations (vital signs, body weight, body 
mass index [BMI], 12-lead electrocardiogram [ECG] parameters). 
• Frequency and severity of suicidal ideation or suicidal behavior as measured by the 
C-SSRS. 
• Change from Baseline in BARS, AIMS and SAS scores at Week 2 and Week 3. 
6.3. 
Other Endpoints 
• Change in baseline resting state BOLD fMRI signal at Week 2. 
• Change in exploratory MRI markers, including but not limited to neuromelanin signal 
as measured by neuromelanin sensitive MRI (NM-MRI) and iron signal as measured 
by an iron-sensitive MRI sequence (effective transverse relaxation rate [R2*] or 
Quantitative Susceptibility Mapping [QSM]), at Week 2. 
• Plasma concentrations of SEP-363856 and its metabolite SEP-363854 at each 
postdose timepoint. 
• Change from baseline to Week 2 in:  
− Positive and Negative Syndrome Scale (PANSS) scores. 
− Brief Negative Symptom Scale (BNSS). 
− Montgomery-Asberg Depression Rating Scale (MADRS) total score. 
− Clinical Global Impression-Severity (CGI-S) score. 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a single-site, open-label, flexibly dosed study evaluating the effect on brain dopamine 
synthesis capacity as measured by 18F-DOPA PET imaging of adjunctive open-label 
administration with SEP-363856 (50 to 75 mg/day) over 2 weeks in adults with schizophrenia.  
The study will consist of 3 periods: Screening (up to 49 days), Treatment (2 weeks), and a 
Follow-up visit as shown in Figure 1. 
Figure 1: 
Study Schematic 
 
 
 
 
Prior to each PET scan, there is a period of resting state fMRI collection. Two PET scans will be 
conducted during the study: 1 PET scan prior to dosing (between Day -44 to Day -2) and 1 PET 
scan following approximately 14 days of treatment (Day 14). 
Safety and tolerability will be monitored throughout the study by physical examination, ECGs, 
vital signs, body weight, BMI, collection of AEs, clinical laboratory parameters, and the 
Columbia-Suicide Severity Rating Scale (C-SSRS). Subjects who have significant findings for 
suicidal ideation assessed by the C-SSRS at any time during the study must be referred to the 
Investigator for follow-up evaluation. 
Population pharmacokinetic analyses will be performed using plasma SEP-363856 
concentrations; the results of which will be reported separately. The relationship between 
dopamine synthesis capacity and plasma SEP-363856 exposure using population 


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PK/pharmacodynamics (PD) methods will be explored. The plasma concentrations of the 
background antipsychotic medication will be examined based on bioanalytical determination, 
when available. 
Exploratory evaluation of the effects of SEP-363856 on psychiatric symptoms will be based on 
change from baseline to Week 2 on the PANSS, CGI-S, and BNSS rating scales. 
Screening Period (up to 49 days): 
Informed consent will be obtained from each subject before any study procedures are performed. 
No imaging procedures involving ionizing radiation will be performed within 12 hours of written 
consent. Screening procedures will occur over multiple days. Subjects must be on a stable dose 
of a single antipsychotic medication, dose within the labeled dose-range, for a minimum of 
3 weeks or if above the maximum label dose (country specific) for at least 12 weeks prior to the 
PET Scan at the screening visit, and the dose should remain fixed throughout the study. Subjects 
who meet entry criteria may be in-clinic for up to 7 days during the screening period, at the 
Investigator’s discretion. 
During the screening period, those subjects who are outpatient will report to the imaging center 
for their PET scan at screening (~2 hours duration) and those subjects who are in-clinic will be 
transferred to the imaging center accompanied by clinic personnel. The PET scan will be 
performed prior to dosing (Day -44 to Day -2), with administration of 18F-DOPA occurring at the 
start of the PET scan session. 
The screening MRI must occur prior to the PET scan at screening (Day -44 to Day -2). Prior to 
the PET scan at screening, a blood sample will be taken to determine antipsychotic plasma 
concentrations. 
Subjects will check into the clinic on Day -2. 
Subjects who screen fail may be re-screened up to two times, if judged appropriate by the 
Investigator. Subjects who screen fail due to MRI or PET or fMRI results may not be 
re-screened. 
Open-Label Treatment Period (2 weeks; Day 1 to Day 14 + 5 days): 
Treatment: At Visit 2 (Day 1), subjects who continue to meet all study inclusion criteria and 
none of the exclusion criteria (see below) will begin treatment with SEP-363856 as an adjunct to 
their background, stable antipsychotic treatment. Study drug dosing will begin on Day 1. Study 
drug (Days 1 – 13) should be taken approximately the same time each day with morning dosing 
recommended. Doses may be moved to the evening for reasons of tolerability. The final dose, on 
Day 14, should occur approximately 2 to 4 hours prior to the final PET scan. Treatment with 
SEP-363856 will continue once-daily during the treatment period with procedures outlined in 
Table 2 (schedule of assessments). Subjects will receive SEP-363856 50 mg/day on Day 1 
through Day 3. On Day 4, subjects will titrate up to a dose of 75 mg/day. A one-time dose 
reduction (from 75 mg to 50 mg) for tolerability purposes is permitted and may occur at any 
time, at the principal Investigator’s discretion. Subjects who have a dose reduction for 
tolerability will continue to receive the reduced dose for the remainder of the study. Subjects will 
remain in-clinic and on treatment through Week 2 until all Day 14 assessments including the 
PET scan are complete. In the event of an unsuccessful PET scan on Day 14, additional days of 
dosing may be necessary up to, but not exceeding, Day 19. If any such additional days are 


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necessary, subjects will remain in the clinic and continue their usual daily dosing. All Day 14 
assessments are to be completed the same day as the PET scan. Subjects will be eligible for 
clinic discharge at the Week 2 visit, at the Investigator’s discretion. 
Blood samples for determination of SEP-363856 and SEP-363854 plasma concentrations will be 
collected on Day 1 (predose), Day 2 (postdose), Day 7 (postdose), and Day 14 (prior to PET 
scan). Blood samples for antipsychotic plasma concentrations will be collected on Day -2, Day 1 
(predose), Day 2 (postdose), Day 7 (postdose), and Day 14 (prior to PET scan). Blood samples 
for SEP-363856, SEP-363854 and antipsychotic plasma concentrations should be collected at 
approximately the same time as dosing for Day 2 (postdose) and Day 7 (postdose) while the 
Day 14 collection should occur immediately prior to the PET scan. 
Administration of 18F-DOPA will occur at the start of the PET scan session. Clinical assessments 
as described in the Schedule of Assessments (SOA) will be performed. 
Follow-up/End of Study (EOS) (7± 2 days after last dose of study drug): A follow-up visit 
will occur 7 days (± 2 days) after last dose of study drug. Clinical assessments as described in the 
Schedule of Assessments (SOA) will be performed. 
Early Termination: Subjects who discontinue early from the study will complete an early 
termination visit. Clinical assessments as described in the Schedule of Assessments (SOA) will 
be performed. 
7.2. 
Treatment Assignment and Blinding 
This is a non-randomized study. All subjects will receive SEP-363856 50 mg/day on Day 1 
through Day 3. On Day 4, subjects will titrate up to a dose of 75 mg/day. A one-time dose 
reduction (from 75 mg to 50 mg) for tolerability purposes is permitted and may occur at any 
time, at the principal Investigator’s discretion. 
7.3. 
Rationale 
7.3.1. 
Rationale for the Study Design 
This is an open-label, flexibly-dosed, study evaluating the effect on brain dopamine synthesis 
capacity as measured by 18F-DOPA PET imaging of adjunctive open-label administration with 
SEP-363856 (50 to 75 mg/day) over 2 weeks in adults with schizophrenia. The 2-weeks of 
treatment will provide an adequate timeframe within which to evaluate the effects of 
SEP-363856 in this subject population. 
Patients with schizophrenia and other psychotic disorders show altered presynaptic dopaminergic 
function, as supported by the use of PET-imaging techniques (Jauhar-2017). The radiotracer 
18F-DOPA has been commonly used to measure dopamine turnover in PET studies and has 
consistently reported elevated Ki values in patients with schizophrenia with a summary effect 
size of 0.8 on meta-analysis, and effect sizes of 1.1 - 1.3 with the current high-resolution PET 
scanners. Several lines of evidence suggest that increased presynaptic dopamine synthesis 
capacity and greater baseline dopamine dysfunction are associated with responsiveness to 
D2-based antipsychotic treatments (Howes-2014). On the other hand, it has been hypothesized 
that treatment resistance may be linked to a different underlying neurobiology which is more 
glutamatergic and less dopaminergic. This is supported by the finding that pre-synaptic 


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dopamine synthesis capacity has been shown to be reduced in treatment resistant schizophrenia 
(Demjaha-2012, Kim-2017). Given that up to 30% of the schizophrenic population is 
treatment-resistant, this is an area of significant unmet need, and treatments focused on 
alternative targets to the D2 receptor are therefore of great interest. 
Trace Amine-Associated Receptor 1 (TAAR1) agonists have come to light in recent years as 
potential targets for the treatment of schizophrenia and related psychotic disorders. With the 
development of highly selective ligands, there is evidence to suggest that TAAR1 agonists may 
act as negative modulators of dopaminergic signaling within the mesolimbic system where they 
are predominantly expressed (Rutigliano-2018). On the basis of PET imaging experiments in 
animal models, Study SEP361-118 is designed to investigate the effect of SEP-363856 
administration adjunctive to an antipsychotic on striatal dopamine synthesis capacity, as 
measured using 18F-DOPA PET imaging. 
18F-DOPA has been used in clinical PET studies to reliably detect dopamine synthesis capacity 
and therefore will be used as the imaging ligand in this study. 
7.3.2. 
Rationale for the Dosages 
Study SEP361-118 will employ a flexible dosing regimen. After initiation at aSEP-363856 dose 
of 50 mg/day for 3 days, subjects are required to titrate up to 75 mg/day. Subjects may reduce the 
dose once to 50 mg/day for tolerability reasons at any time. Subjects who have a dose reduction 
for tolerability will continue to receive the reduced dose for the remainder of the study. This 
dosing scheme is nearly identical to the dosing regimen utilized in the current, clinically 
complete Phase 2 study in patients with schizophrenia (Study SEP361-201). 
SEP-363856 50 mg/day and 75 mg/day were selected based on the safety and tolerability 
observed profiles for single and multiple oral doses of SEP-363856 given to healthy adult male 
subjects and adult subjects with schizophrenia during the clinical development program. Results 
of completed studies demonstrated that the maximum tolerated single SEP-363856 dose was 
50 mg for healthy adult volunteer subjects and 100 mg for adults with schizophrenia. Single 
doses of SEP-363856 were also shown to have robust central nervous system (CNS) activity in 
completed fMRI study (SEP361-104). Dose selection is further supported by safety and 
tolerability results after dosing with SEP-363856 10 mg - 100 mg/day for 7 days and dosing with 
SEP-363856 75 mg/day for 28 days in adults with schizophrenia (Study SEP361-106, Parts 1 
and 2). 
The PET ligand 18F-DOPA will be used at each of the PET scans in this study. Up to 150 MBq 
of 18F-DOPA will be intravenously administered at the start of each PET scan. The total radiation 
exposure from each PET scan is up to 3 mSv, and each PET scan will be accompanied by up to 
2 low dose CT scans resulting in up to 0.7 mSV. The total effective dose from this study is 
therefore up to 3 * (3.0 + 0.7) = 11.1 mSv, placing it in the III category of the International 
Commission on Radiological Protection (ICRP) classification, suitable for research studies in 
human subjects. The effective dose of 11.1 mSv is equivalent to 4.8 years of naturally occurring 
background radiation. For an adult in good health, this is calculated to result in a risk of 
approximately 1 in 1800 in induction of fatal cancer. This dose has been selected as it provides 
images of suitable quality while minimizing the radiation exposure to participants. The majority 
of participants will receive up to 2 PET scans, which would result in an effective dose of 


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7.4 mSv. Participants will only receive 3 PET scans in the event that a scan is not able to be 
completed or is not suitable for analysis. 
One hour prior to each PET scan, single doses of 150 mg carbidopa and 400 mg entacapone will 
be given orally to reduce the peripheral metabolism of 18F-DOPA, and the formation 18F-DOPA 
metabolites, thereby improving the quality of the acquired brain images. Both drugs are 
approved at the doses administered for human use and will be administered approximately one 
hour before the scan. No drug interaction concerns are anticipated with the limited exposure to 
carbidopa and entacapone. 
7.3.3. 
Rationale for the Study Population 
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 these effects has not been completely elucidated but may 
include actions at 5-HT1A and trace amine associated 1 (TAAR1) receptors. Rat 
electroencephalogram (EEG) studies showed that SEP-363856 suppressed rapid eye movement 
(REM) sleep in a dose dependent manner. In nonhuman primate fMRI experiments, pretreatment 
with SEP-363856 reduced the ketamine brain fMRI response in rhesus monkey, similar to 
risperidone, supporting an antipsychotic-like profile. 18F-DOPA PET imaging showed that 
SEP-363856 reduces striatal dopamine synthesis capacity to a greater extent in mice with a state 
of hyperdopaminergia (induced by sub-chronic ketamine administrations) than in control 
animals. Taken together, these data demonstrate that SEP-363856 exhibits CNS 
pharmacodynamic signals in rodents and nonhuman primates consistent with antipsychotic 
activity, and that SEP-363856 has a pharmacological effect on presynaptic dopamine synthesis 
capacity. 
As of 24 Sept 2018, a total of 246 subjects have received oral doses of SEP-363856 in 
8 completed Phase 1 studies. An additional 199 subjects received oral doses of SEP-363856 in 
ongoing phase 2 studies (placebo-controlled study SEP361-201 and open label extension 
SEP361-202) and 24 subjects in an ongoing phase 1 study (multiple ascending dose study 
DA801004 in Japanese subjects) in subjects diagnosed with schizophrenia. 
Single doses of SEP-363856 were shown to have robust CNS activity in a completed fMRI 
Study (SEP361-104) in healthy adult subjects. 
The treatment emergent AEs (TEAEs) that were reported in the Phase 1 clinical trials involving 
SEP-363856 having two-fold higher incidence with SEP-363856 compared with placebo and that 
were at least possibly related to SEP-363856 in ≥ 2 subjects were classified as adverse drug 
reactions (ADRs). ADRs to SEP-363856 included nausea, dizziness, and orthostatic hypotension 
(very common ≥ 10%); and dry mouth, fatigue, lethargy, and sedation (common ≥ 1% and 
< 10%). 
One randomized, double-blind study (SEP361-201) evaluating efficacy and safety of flexible 
SEP-363856 doses (50 mg/day or 75 mg/day) in adult subjects with schizophrenia is clinically 
complete clinical study report pending. Subjects completing this study are eligible to enroll in an 
ongoing 26-week-long-term open-label safety and tolerability study (SEP361-202, ongoing). 


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7.4. 
Prevention of Missing Data 
In an effort to minimize the number of subjects who withdraw consent prior to study completion, 
the number of visits and assessments has been limited to those required to collect the information 
needed to address the objectives of the study. The number of PET scans and collection of blood 
samples are essential components of the study, therefore, subjects will remain in the overnight 
confinement unit until the completion of the postdose PET scans and blood sample collection (all 
assessments will be performed in the clinic). 
Day pass may be granted during the study due to emergency unavoidable personal reasons with 
prior approval from the Medical Monitor. The pass must be of limited duration. The subject must 
be considered by the Investigator to be clinically stable and Investigators should follow standard 
facility or institutional procedures to ensure subject safety during the pass. The reason for and 
duration of the day pass as well as Medical Monitor approval must be documented. Subjects will 
receive an unscheduled urine drug screen upon return to site. 
A concerted effort by the clinical team will be made to enroll subjects with good venous access. 
In addition, every effort will be made to have subjects return for the end of study visit to collect 
follow-up safety data. In the case of failure to obtain adequate data from a measure (eg due scan 
failure due to technical reasons), the measure may be repeated if feasible (total radiation dose to 
remain within guidelines for exposure for research purposes). 


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8. 
SELECTION OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
To qualify for participation, subjects must meet all of the following inclusion criteria at 
screening and Day 1 (including all available predose assessments): 
1. Subject must give written informed consent and privacy authorization prior to 
participation in the study. 
2. Subject must be willing and able to comply with the study procedures and visit schedule, 
including required minimum 2-week in-clinic treatment period, and must be able to 
understand and follow verbal and written instructions. 
3. Male or female subject between 18 to 45 years of age (inclusive) at the time of consent. 
4. Subject meets Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria 
for a primary diagnosis of schizophrenia as established by clinical interview (using the 
DSM-5 as a reference and confirmed using the Structured Clinical Interview for DSM-V 
Clinical Trials Version [SCID-CT]). The duration of the subject's illness whether treated 
or untreated must be ≥ 6 months. 
5. Subject must be on a stable dose of a single antipsychotic medication, dosed within the 
labeled dose-range, for a minimum of 3 weeks prior to the PET scan at the screening 
visit. Patients taking clozapine are not eligible to participate. 
6. Subject must have a Clinical Global Impression-Severity (CGI-S) score ≥ 3 (mild or 
greater). 
7. Subject must have a Positive and Negative Syndrome Scale (PANSS) total score ≥ 70. 
8. Subject’s BMI must be at least 18 kg/m2 but no more than 35 kg/m2. 
9. Female subjects must have a negative serum pregnancy test at screening; as well as a 
negative urine pregnancy test prior to the PET scan on each day PET scans are 
performed, as well as prior to the MRI scan. 
a. Female subject of childbearing potential and male subject with female partner of 
childbearing potential must agree to use a highly effective form of birth control (refer 
to Section 10.5) from at least 30 days prior to administration of the first dose of study 
drug, during the treatment period, and 60 days after completion or premature 
discontinuation from the study drug. Male subjects must also refrain from 
semen/sperm donation 30 days prior to administration of the first dose of study drug, 
during the treatment period, and 60 days after completion or premature 
discontinuation from the study drug. 
In the Investigator's judgment, the subject will adhere to this requirement. 
b. Female subjects who are of non-childbearing potential are not required to abide by 
birth control requirements. 
− Non-childbearing potential is defined as subject who is surgically sterile 
(hysterectomy, bilateral salpingectomy or bilateral oophorectomy) or is 
postmenopausal (defined as at least 12 months of spontaneous amenorrhea 


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[follicle stimulating hormone [FSH] concentrations may be used to confirm a 
post-menopausal state at the discretion of the investigator, but 12 months of 
amenorrhea is still required]). 
10. Subject is, in the opinion of the Investigator, generally healthy based on screening 
medical history, PE, neurological examination, vital signs, clinical laboratory values 
(hematology, serum chemistry, urinalysis, lipid panel, coagulation panel, thyroid panel, 
and serum prolactin). 
11. Subject has had a stable living arrangement at the time of screening and agrees to return 
to a similar living arrangement after discharge. This criterion is not meant to exclude 
subjects who have temporarily left a stable living arrangement (eg, due to psychosis). 
Such subjects remain eligible to participate in this study. Chronically homeless subjects 
should not be enrolled. 
12. Subject must agree to comply with all medication restrictions for the required length of 
time (see Concomitant Medication section below). 
8.2. 
Subject Exclusion Criteria 
To qualify for participation, subjects must not meet any of the following exclusion criteria at 
Screening and Day 1 (including all available predose assessments): 
1. Subject answers “yes” to “Suicidal Ideation” Items 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 at or during the Screening period (ie, in the past one month) 
and/or Day 1 (ie, since last visit). 
2. Subject does not tolerate venipuncture or has poor venous access that would cause 
difficulty for administration of the radioisotope and for collecting blood samples. 
3. Subject is currently participating in, or has participated in, a study with an investigational 
or marketed compound or device within 3 months prior to signing the informed consent, 
or has participated in more than 2 studies of investigational compounds within 24 months 
prior to signing the informed consent. 
4. Subject has participated in a research and/or PET or radiological investigations with 
radiation exposure that, when combined with the dose from the present study, would 
exceed 10 mSv in addition to natural background radiation, in the previous 12 months. 
5. Subject has previously received SEP-363856. 


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6. 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. Clinically significant hematological (including deep vein thrombosis) or bleeding 
disorder, renal, metabolic, endocrine, pulmonary, gastrointestinal, urological, 
cardiovascular, hepatic, neurologic, or allergic disease (except for untreated, 
asymptomatic, seasonal allergies at time of dosing). 
b. 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. Subject has a pituitary tumor of any duration. 
c. Disorder or history of a condition, or previous gastrointestinal surgery 
(eg, cholecystectomy, vagotomy, bowel resection) that may interfere with drug 
absorption, distribution, metabolism, excretion, gastrointestinal motility, or pH, or a 
history of clinically significant abnormality of the hepatic or renal system, or a history 
of malabsorption. 
d. Subject currently has or has had within the last 6 months a diagnosis of Alcohol or 
Substance Abuse Disorder (DSM-5 criteria). The only exceptions include caffeine or 
nicotine. 
e. Subject has a clinically significant abnormal 12-lead ECG that may jeopardize the 
subject’s ability to complete the study as determined by the Investigator or a 
screening 12-lead ECG demonstrating any one of the following: heart rate 
> 100 beats per minute, QRS > 120 ms, QT interval corrected for heart rate using 
Fridericia’s formula (QTcF) > 450 ms (males), QTcF > 470 ms (females), or PR 
> 220 ms. 
f. Subjects with known history of human immunodeficiency virus (HIV) seropositivity. 
g. Subject has a history of clinically significant hypotensive disorder, systolic blood 
pressure ≤ 80 mmHg or diastolic blood pressure ≤ 40 mmHg at any measurement 
prior to dosing on Day 1, or any clinically significant symptoms associated with 
hypotension at any time during participation prior to dosing on Day 1 
7. Female subject who is pregnant or lactating. 
8. Subject has a presence or history of a medically diagnosed, clinically significant 
psychiatric disorder (including intellectual disability, major depressive disorder with 
psychosis, and bipolar disorder) other than schizophrenia (medically diagnosed 
schizoaffective disorder or schizophreniform disorder will be allowed). 
9. Subject tests positive for drugs of abuse at screening, however, a positive test for 
barbiturates, opiates, benzodiazepines or methadone may not result in exclusion of 
subjects if the Investigator determines that the positive test is as a result of prescription 
medicine(s). In the event a subject tests positive cannabinoids (tetrahydrocannabinol), the 
Investigator will evaluate the subject’s ability to abstain from using this substance during 
the study. This information will be discussed with the Medical Monitor prior to study 
enrollment. 
10. Subject is at significant risk of harming him/herself or others according to the 
Investigator’s judgment. 
11. Subject has attempted suicide within 6 months prior to screening. 


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12. Subject is involuntarily hospitalized. 
13. Subject is judged in the opinion of the Investigator to be severely resistant to 
antipsychotic treatment defined as a failure to respond to 4 or more marketed 
antipsychotic agents, given at an adequate dose as per labeling and for an adequate 
duration (lifetime). 
14. Subject is receiving an antipsychotic medication at a dose above the maximum labeled 
dose (country-specific) for less than 12 weeks prior to the PET scan at the screening visit. 
15. Subject has received clozapine treatment within 120 days of planned PET scan at 
screening. 
16. Subject has received electroconvulsive therapy treatment within the 3 months prior to 
screening or is expected to require ECT during the study. 
(Note: Criteria 17 intentionally skipped) 
18. Subject has a history of allergy or hypersensitivity to more than 2 distinct chemical 
classes of drug (eg, sulfonylureas and penicillins) or suspected sensitivity to any 
substance that is contained in the study drug formulation or to carbidopa or entacapone. 
19. Subject has any clinically significant abnormal laboratory values as determined by the 
Investigator (hematology, serum chemistry, urinalysis, lipid panel, coagulation panel, 
thyroid panel, and serum prolactin). (Note: abnormal findings of questionable 
significance will be discussed with the Medical Monitor prior to including subject). 
20. Subject demonstrates evidence of acute hepatitis, clinically significant chronic hepatitis, 
or evidence of clinically significant impaired hepatic function through clinical and 
laboratory evaluation. 
Note: Subjects with serum alanine transaminase (ALT) or aspartate transaminase (AST) 
≥ 3 times the upper limit of the reference ranges provided by the laboratory require 
retesting. If on retesting, the laboratory value remains ≥ 3 times the upper limit, the 
subject will be excluded. 
21. Subject has bilirubin ≥ 1.5 x upper limit of normal (ULN) with the exception that isolated 
bilirubin > 1.5 x ULN is acceptable if bilirubin is fractioned and direct bilirubin < 35% at 
screening. 
22. Subject has a serum blood urea nitrogen (BUN) or serum creatinine (Cr) value ≥ 1.5 
times the upper limit of normal for the reference range. 
23. Subject has experienced significant blood loss (≥ 473 mL), has donated blood within 
60 days prior to first dose of study drug, has donated plasma within 72 hours prior to the 
first dose of study drug or intends to donate plasma or blood or undergo elective surgery 
during study participation or within 60 days after the last study visit. 
24. Subject consumes more than 300 mg of caffeine per day (5 cups of coffee or equivalent 
in caffeinated beverages). 
25. Subject has used disallowed prescription or disallowed nonprescription drugs, or dietary 
or herbal supplements as specified within the Concomitant Medications and Restrictions 
(Section 10.3) for at least 5 half-lives or 14 days prior to dosing, whichever is longer, or 


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anticipates the need for any disallowed medication during their participation in this study 
(exception: female subjects who are taking oral, patch, or intrauterine device [IUD] 
hormonal contraceptives, or progestin implant or injection). Further details to be provided 
in Section 10.3. 
26. Subject is a staff member or the relative of a staff member. 
27. Subject is in the opinion of the Investigator, unsuitable in any other way to participate in 
this study. 
28. Subject has contraindications to undergoing MRI/fMRI examination including, but not 
limited to claustrophobia, metal foreign bodies or implanted devices incompatible with 
the MRI/fMRI exposure. 


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9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
9.1. 
Description of Study Drug 
Table 5: 
Investigational Product 
Attribute 
Investigational Product 
Product name 
SEP-363856 
SEP-363856 
Dosage form 
Tablet 
Tablet 
Unit dose 
50 mg 
75 mg 
Route of administration 
Oral 
Oral 
Physical description 
Yellow oval tablet 
Yellow oval tablet 
Active Pharmaceutical 
ingredient (API) 
SEP-363856-01(hydrochloride salt) 
SEP-363856-01 (hydrochloride salt) 
Excipients  
-Microcrystalline cellulose  
-Mannitol 
-Sodium starch glycolate 
-Magnesium stearate 
Film coating:  
-Hydroxypropyl methylcellulose 
-Hydroxypropyl cellulose 
-Titanium dioxide 
-Yellow iron oxide 
Carnauba wax 
-Microcrystalline cellulose  
-Mannitol 
-Sodium starch glycolate 
-Magnesium stearate 
Film coating:  
-Hydroxypropyl methylcellulose 
-Hydroxypropyl cellulose 
-Titanium dioxide 
-Yellow iron oxide 
Carnauba wax 
9.2. 
Study Drug Packaging and Labeling 
9.2.1. 
Package Description 
Study drug will be provided in one-week blister cards containing 9 tablets (7 days + 2 extra days) 
SEP-363856 50 mg or 75 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 for subject identifiers 


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• Period of use (as required) 
• Unique medication/kit ID number 
• Investigator information (if needed) 
9.3. 
Study Drug Storage 
All SEP-363856 tablets are to be stored at controlled room temperature, between 15°C and 25°C 
(59°F and 77°F). 
9.4. 
Dispensing of Study Drug 
Study drug will be administered on an in-patient basis as open-label 50 mg or 75 mg dosage 
strengths of SEP-363856. Subjects will take one tablet of study drug per day at approximately 
the same time each day with morning dosing recommended. Dosing may be moved to the 
evening for reasons of tolerability; except for the day of post dose fMRI scanning where dosing 
will occur approximately 2 to 4 hours before fMRI scanning. Study drug may be taken without 
regard to food. 
Appropriate guidelines should be followed in proper dispensation to the study participant. Study 
drug will not be dispensed to any person who is not a study subject under this protocol. 
9.5. 
Study Drug Accountability 
The Investigator or designee is responsible for maintaining adequate and up to date records of 
drug disposition that include the dates, quantities received and dispensed, and use by subjects. 
Upon receipt of study drug, the Investigator or designee will inspect the supplies and confirm 
receipt of the shipment.  The Investigator or designee will review the contents of each drug 
shipment against the provided packing list and confirm date of receipt, completeness of shipment 
and condition of study drug received. 
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 
storage and handling guidelines should be followed. An Investigational Product (IP) Manual will 
be supplied. In the event that study drug expires while at the site before it is returned to the 
depot, the Investigator or designee should store the expired study drug separately. 
If the study is stopped for any reason or completed, all used and unused supplies of drug 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 unused study drug to the Sponsor or 
designee as instructed. The Investigator or designee is required to maintain copies of study drug 
shipping receipts, drug accountability records, and records of return of the study drug in 
accordance with local regulatory requirements. 


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10. 
TREATMENT OF SUBJECTS 
10.1. 
Study Medication 
All study drug doses will consist of tablet(s) containing SEP-363856 administered orally. 
Subjects may take study drug with or without food. Study drug (Days 1 – 13) should be taken at 
approximately the same time each day with morning dosing recommended. Dosing may be 
moved to the evening for reasons of tolerability; except for the day of post dose fMRI scanning 
where dosing will occur approximately 2 to 4 hours before fMRI scanning.  
10.1.1. 
Dose Adjustment Criteria 
Subjects will receive SEP-363856 50 mg/day on Day 1 through Day 3. On Day 4, subjects will 
titrate up to a dose of 75 mg/day. Subjects may dose reduce one time to 50 mg/day for 
tolerability reasons at any time. Subjects who have a dose reduction for tolerability will continue 
to receive the reduced dose for the remainder of the study. 
10.2. 
Treatment Compliance 
Study drug will be administered in-clinic. The Investigator will record the dose of the study drug 
and the dates of the initial and final administration for each dose. 
10.3. 
Concomitant Medications and Therapies 
The following information on all medication administered between screening and end of study or 
at discontinuation will be recorded on the case report form (CRF): Medication name, dose, 
frequency, route, start date, stop date, and indication. 
Prior treatment with antipsychotic agents including depot neuroleptics will be recorded for at 
least 6 months prior to the screening visit. All other prior treatments will be recorded for at least 
3 months prior to screening. 
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). 
Subjects who require treatment with a prohibited concomitant medication will be discontinued 
from the study. 
10.3.1. 
Prohibited Medications 
Concomitant use of CYP2D6 inhibitors is prohibited as SEP-363856 is a potential substrate for 
CYP2D6. 
All psychotropic medications and herbal supplements (with the exception of the single, 
background antipsychotic, or medications listed in Section 10.3.4) are prohibited during the 
study and must be discontinued, as tolerated and clinically appropriate (for at least 5 half-lives or 
14 days, whichever is longer), prior to the first dose of study drug in a manner that is consistent 
with labeling recommendations and conventional medical practice. 


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Clozapine is prohibited. Prior exposure to clozapine is allowed, as long as treatment is 
discontinued at least 120 days prior to PET scan at screening. 
Subjects who require treatment with one or more of the prohibited concomitant medications 
(including antidepressants, mood stabilizers, or anxiolytics [lorazepam or equivalent at doses 
above protocol-specified limits]) will be discontinued (as appropriate) from the study. 
All efforts will be made to complete the PET and resting state fMRI scans intended by the 
protocol even in cases of discontinuations of study drug or procedures. 
The majority of participants will receive up to 2 PET scans. Participants will only receive 3 PET 
scans in the event that a scan is not able to be completed or is not suitable for analysis. 
10.3.2. 
Prohibited Therapies 
Electroconvulsive therapy (ECT) is prohibited within 3 months prior to screening and during the 
study. 
10.3.3. 
Restricted Medications 
Caution should be taken with concomitant use of CYP2D6 substrates with SEP-363856 as 
SEP-363856 is a weak inhibitor of CYP2D6 (see to Section 25). 
Concomitant Non-psychotropic Medications: 
Non-psychotropic medications used to treat mild, chronic medical conditions may be used during 
screening and after enrollment if the dose and regimen have been stable (± 25%) for at least 
30 days prior to screening. The concomitant medication dose may change, as needed, after 
enrollment (or be discontinued). β-adrenergic antagonists used to treat stable hypertension may 
be continued through the screening phase and post-initiation. Medications for short-term 
treatment of a medical condition (no more than 10 days) are allowed during the study with 
consultation with the Medical Monitor. 
Concomitant Psychotropic Medications: 
Treatment with benztropine up to 6 mg/day will be permitted, as needed, for movement 
disorders. In cases where benztropine is not available or a subject has had an inadequate response 
or intolerability to benztropine treatment, the following medications may be used to treat acute 
extrapyramidal symptoms (EPS): biperiden (up to 16 mg/day) or trihexyphenidyl (up to 
15 mg/day) or diphenhydramine (up to 100 mg/day) or procyclidine (up to 30 mg/day). 
Treatment with propranolol (up to 120 mg/day) will be permitted as needed for akathisia. 
Concomitant use of lorazepam, temazepam, eszopiclone, zaleplon, zolpidem, and zolpidem CR 
is permitted at the discretion of the Investigator with the following restrictions:  
1. 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 
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2. temazepam (≤ 30 mg/day), eszopiclone (≤ 3 mg/day), zaleplon (≤ 20mg/day), zolpidem 
(≤ 10 mg/day), and zolpidem CR (≤ 12.5 mg/day) may be administered at bedtime for 
insomnia, as needed. 
3. hypnotic agents should be administered no more than once nightly and should not be used 
in combination. 
The date and time of the last dose taken prior to scheduled efficacy assessments must be 
recorded at each visit. Subjects should be encouraged to avoid taking sedative/hypnotic 
medications within 8 hours of scheduled efficacy assessments. 
Medications used for the treatment of anxiety/agitation and insomnia (eg, lorazepam and 
zolpidem) should not be used in close temporal proximity (defined as administration within 
2 hours of each other). 
Similar drugs at equivalent dosages will be permitted as described in the Operations Manual or 
in consultation with the Medical Monitor. 
10.3.4. 
Permitted Medications 
Subjects must be on a stable dose of a single antipsychotic medication, dose within the labeled 
dose-range, for a minimum of 3 weeks or if above the maximum label dose (country specific) for 
at least 12 weeks prior to the PET scan at the screening visit, and the dose should remain fixed 
throughout the study. Depot neuroleptic dose must be stable for at least 2 treatment cycles or at 
least 30 days (whichever is longer) prior to the screening visit. 
Subjects who require an increase in dose of their background antipsychotic during the study will 
be discussed with the Medical Monitor. A down-titration of the background antipsychotic due to 
tolerability may be allowable, after consultation with the study medical monitor. 
Use of non-prescription pain medications (eg, aspirin, acetaminophen) are allowed during all 
phases of the study provided these medications do not have a propensity for psychotropic effects 
and do not interfere with the evaluation of study drug. Hydrocortisone 1% cream or ointment for 
treatment of contact dermatitis from ECG pads is allowed. Female subjects may use oral, patch, 
or intrauterine device (IUD) hormonal contraceptives, or progestin implant or injection (detailed 
information on allowed contraceptives provided in Section 10.5). 
10.4. 
Restrictions 
Subjects must abstain from alcohol from clinic admission through the end of the study. 
10.5. 
Contraception Requirements 
Female subject of childbearing potential and male subject with female partner of childbearing 
potential must agree to use a highly effective form of birth control from 30 days prior to 
administration of the first dose of study drug, during the treatment period, and 60 days after 
completion or premature discontinuation from the 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 60 days after completion or premature discontinuation from the 
study drug. Continued use of a highly effective form of birth control for males and females is 
recommended for 2 months after study completion or discontinuation from the study. 


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Methods that can achieve a failure rate of less than 1% per year when consistently and correctly 
used are considered as highly effective. Such methods are: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal, transdermal). 
• Progestogen-only hormonal contraception (oral, injectable, implantable) associated 
with inhibition of ovulation 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner (with surgical success confirmed by medical assessment) 
• Sexual abstinence if part of the volunteers preferred lifestyle 
Hormonal contraceptives have the following timeframe requirements:  
a) Contraceptive implant implanted at least 90 days prior to screening;  
b) Injectable contraception given at least 14 days prior to screening; or  
c) Oral contraception taken as directed for at least 30 days prior to screening. 
Female subjects who are of non-childbearing potential are not required to abide by birth control 
requirements. 
Non-childbearing potential is defined as a subject who is surgically sterile (hysterectomy, 
bilateral salpingectomy or bilateral oophorectomy) or is postmenopausal (defined as at least 
12 months of spontaneous amenorrhea) are not required to remain abstinent or use adequate 
contraception. 
10.6. 
Dietary Guidelines 
While subjects are confined to the clinic, meals will be provided. Subjects will receive meals 
according to the study site procedures. 


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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). 
11.2. 
Prior and Concomitant Medication Review 
See Section 10.3 for a complete description of medications permitted during the study. Site study 
staff will record all medications used to treat schizophrenia taken within 6 months prior to 
screening visit in the eCRF. Also, the following parameters will be recorded for all concomitant 
medications: drug name, route of administration, total daily dose, unit, frequency, start/stop 
dates, indication, and whether the medication was started after last dose of study medication. The 
prior and concomitant medications will subsequently be coded using the World Health 
Organization Drug Dictionary (WHO-DD). 
11.3. 
Structured Clinical Interview for DSM-5 Axis I Disorders-Clinical 
Trials version (SCID-CT) 
The SCID-5-CT is a modified version of the SCID developed for use in clinical trials. It is a 
semi-structured interview for the purpose of making a DSM-5 diagnosis (First-2015). Clinicians 
administering the SCID should be familiar with the DSM-5 classification and diagnostic criteria. 
The SCID-5-CT will be administered by a qualified rater at the research site listed on Form 
FDA 1572 with at least 2 years of experience with the population under study. The 
administration time is approximately 30 - 40 minutes. 
11.4. 
PET/fMRI Assessments 
It is important that the participant is examined under the same conditions at baseline and 
subsequent scan, including scanning at the same time of day where possible (scanning time of 
day should be ± 3h from the time of day of the baseline scan where possible), and head motion 
monitored and minimised. The post-dose scan should be timed to occur so that the start is 
approximately at the time in which maximum observed plasma concentration (Cmax) occurs. Post 
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Prior to entry into the scanner, subjects will complete the site’s standard radiography screening 
questionnaire to ensure they are safe to enter the scanner environment (eg, no history of surgery 
involving metal implants). Females will undergo urine pregnancy test to exclude pregnancy. 
Scan date as well as start and stop time will be collected. 
Approximately 1 hour before the scan participants will receive 150 mg of carbidopa and 400 mg 
of entacapone orally. This inhibits the formation of radiolabeled metabolites of F-DOPA that 
may cross the blood-brain barrier, and boosts the signal to noise ratio. Subjects will have an 
IV canula placed in the ante-cubital fossa for administration of F-DOPA. Prior to scanning they 
will be asked to go to the toilet. 
Striatal dopamine synthesis capacity (DSC) assessment (Ki) using 18F-DOPA kinetic analysis 
will be performed. 
In addition to fMRI scan sequences, exploratory MRI sequences may be performed during each 
of the MRI and PET/MR acquisition times and may include (but not limited to) a neuromelanin-
sensitive MRI (NM-MRI) sequence and an iron-sensitive MRI sequence (effective transverse 
relaxation rate [R2*] or Quantitative Susceptibility Mapping [QSM]).  Repeat MRI including 
exploratory MRI sequences may be performed where it is not possible to obtain complete 
measures during the PET-MRI scan. 
The majority of participants will receive up to 2 PET scans. Participants will only receive 3 PET 
scans in the event that a scan is not able to be completed or is not suitable for analysis. 
11.5. 
Efficacy Assessments 
11.5.1. 
Positive and Negative Syndrome Scale (PANSS) 
The PANSS is an interview-based measure of the severity of psychopathology in adults with 
psychotic disorders. The measure is comprised of 30 items and 3 scales: the Positive scale 
assesses hallucinations, delusions, and related symptoms; the Negative scale assesses emotional 
withdrawal, lack of motivation, and similar symptoms; and the General Psychopathology scale 
addresses other symptoms such as anxiety, somatic concern, and disorientation. An anchored 
Likert scale from 1 - 7, where values of 2 and above indicate the presence of progressively more 
severe symptoms, is used to score each item. Individual items are then summed to determine 
scores for the 3 scales, as well as a total score. A Composite scale score (Positive scale score 
minus Negative scale score) can also be calculated to show the relative valence of positive and 
negative symptoms. Total time required for the PANSS interview and scoring is approximately 
30 - 40 minutes (Kay-1994, Opler-1992; Perkins-2000). PANSS raters will be required to meet 
specific training and education criteria before they are certified to rate for this study. In addition, 
raters will receive specific training and education regarding all of the assessments prior to study 
initiation. 
11.5.2. 
Brief Negative Symptom Scale (BNSS) 
The BNSS is a rating scale to measure the current level of severity of negative symptoms in 
schizophrenia and schizoaffective disorder. The measure is comprised of 13 individual items and 
5 domain scores (blunted affect, alogia, avolition, anhedonia, and asociality). The 5 domain 
scores provide a summary score and the 13 individual items provide a composite total score 
(ranging from 0 to 78). Each of the items are scored on a Likert-type 7-point scale from 0 - 6, 


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where values of 0 indicates symptom is absent and a value of 6 means the symptom is a severe 
form. The number of items varies per domain. BNSS raters will be required to meet specific 
training and education criteria before they are certified to rate for this study. In addition, raters 
will receive specific training and education regarding all of the assessments prior to study 
initiation. 
11.5.3. 
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. 
11.5.4. 
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. 
11.6. 
Safety Assessments 
The Investigator or appropriate designee will review results of safety assessments on a regular 
basis and the Sponsor must be kept fully informed of any clinically significant findings either at 
Screening or subsequently during study conduct. 
11.6.1. 
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. 
 
11.6.2. 
Clinical Laboratory Assessments 
The clinical laboratory tests required by protocol are listed in Section 21, Appendix II. 
Blood and urine samples will be collected for clinical laboratory tests. All clinical laboratory 
tests will be performed locally. For detailed instructions regarding clinical laboratory procedures, 
sampling, and shipping guidelines refer to the study center and local clinical laboratory 
guidelines. Samples will be processed at a local laboratory.Out of range laboratory results 
assessed as clinically significant by the investigator will be reported as adverse events. 


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11.6.3. 
Vital Signs 
Vital sign measurements consist of systolic and diastolic blood pressures, respiratory rate, pulse 
rate, and oral temperature. 
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. Vital signs results assessed as clinically significant by the investigator will be 
reported as adverse events. Vital signs will be obtained prior to clinical laboratory collection and 
performance of an ECG. 
11.6.4. 
Electrocardiograms (ECGs) 
Subjects will be supine for at least 10 minutes prior to and 5 minutes after the ECG is obtained. 
ECGs will be 12-lead with a 10-second rhythm strip. ECGs should be obtained prior to drawing 
blood samples. All attempts should be made to use the same ECG recorder for all visits within 
individual subjects. Refer to Section 20, Appendix I for additional information. ECG parameters 
to be collected include ventricular heart rate (beats/min), QT interval (msec), PR interval (msec), 
QRS interval (msec), RR interval (msec), and overall ECG interpretation (Normal, Abnormal 
NCS, Abnormal CS). 
It is the responsibility of the Investigator to perform a safety review of the ECG data for changes 
from previous assessments and/or emergent cardiac dysfunction, and to determine subjects’ 
eligibility for or continuance in the study. Abnormalities require comment as not clinically 
significant (NCS) or clinically significant (CS). Typically, CS designated events will be reported 
as adverse events. 
ECGs will be reviewed, signed and dated by the Investigator after each ECG collection. The 
same physician should review all ECG reports for a given subject whenever possible. 
The original ECG tracing will be kept with subject’s source documentation. A copy may be 
collected by the Sponsor. 
11.6.5. 
Physical and Neurological Examination 
A full PE as well as a neurological will be performed. The PE includes an assessment of general 
appearance and a review of systems (dermatologic, head, eyes, ears, nose, mouth/throat/neck, 
thyroid, lymph nodes, respiratory, cardiovascular, gastrointestinal, extremities, musculoskeletal, 
neurologic, and psychiatric systems). 
All PE and neurological exam findings at screening will be captured in the medical history in the 
CRF. Any clinically significant changes from screening, as determined by the Investigator, will 
be noted as AEs in the CRF. 


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11.6.6. 
Height, Weight, and BMI 
Weight will be measured in kilograms as specified in the schedule of assessments (Table 2). 
Height in meters will be recorded only at Screening. 
Height will be measured without shoes. 
Weight will be measured in street clothes, without shoes and coat/jacket. 
BMI will be calculated by site staff using the equation BMI = weight [kg]/height [m]² at 
Screening only. BMI for all other visits will be derived within the Electronic Data Capture 
(EDC) system. 
11.6.7. 
Safety Scales 
11.6.7.1. Abnormal Involuntary Movement Scale (AIMS) 
The AIMS is a clinician-rated assessment of abnormal movements consisting of unobtrusive 
observation of the subject at rest (with shoes removed) and several questions or instructions 
directed toward the subject. Using a severity scale ranging from 0 (none) to 4 (severe), clinicians 
rate dyskinesia in several body regions, including the facial area, extremities, and trunk. There 
are two items related to dental status, as well as three global impression items assessing overall 
severity, incapacitation, and the subject’s awareness of abnormal movements (Guy-1976; 
Munetz-1988). The AIMS raters will be required to meet specific credential and educational 
criteria before they are certified to rate for this study. The AIMS will be administered by a 
qualified rater at the site. 
11.6.7.2. Barnes Akathisia Rating Scale (BARS) 
The BARS is a rating scale geared toward assessment of neuroleptic-induced akathisia, though it 
can be used to measure akathisia associated with other drugs as well. The BARS consists of four 
items, including one item assessing objective restlessness, two items targeting subjective 
restlessness (awareness and related distress), and one global clinical assessment item. All items 
are anchored and utilize a 4-point scale, except for the global rating which has a 6-point scale 
(from absence of akathisia through severe akathisia). The subjective and objective items are 
summed to yield a total score. The BARS can be administered in about 10 minutes 
(Barnes-1989; Barnes-2003). The BARS will be administered by a qualified rater at the site. 
11.6.7.3. Simpson-Angus Scale (SAS) 
The SAS is a clinician-rated assessment of neuroleptic-induced Parkinsonism consisting of 
10 items. Items are anchor-based, rated on a 5-point scale of severity, and address rigidity, gait 
(bradykinesia), tremor, akathisia, shoulder shaking, glabellar tap, and salivation (Siddiqui-2009; 
Simpson-1970). The SAS will be administered by a qualified rater at the site. 
11.6.7.4. Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a tool designed to systematically assess and track suicidal adverse events 
(suicidal behavior and suicidal ideation) throughout the trial. The strength of this suicide 
classification system is in its ability to comprehensively identify suicidal events while limiting 
the over-identification of suicidal behavior. The scale takes approximately 5 minutes to 


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administer. The C-SSRS will be administered by a trained rater at the site. Subjects with Type 4 
or Type 5 suicidal ideation during the study will be discontinued from the study and referred to a 
mental health professional (Posner-2007). At screening visit, “Baseline/Screening” version of 
C-SSRS will be used including assessment for lifetime and previous 1 month. For all visits from 
Visit 2 onward, the “Since Last Visit” version of the C-SSRS will be used. 
11.7. 
Pharmacokinetic Assessments 
All blood samples for determination of plasma SEP-363856 and SEP-363854 concentrations will 
be obtained at the same time that other blood samples are taken whenever possible. The time and 
date of doses of study drug, date, and clock time of sampling must be recorded. Date and clock 
time of food intake must be recorded when blood samples are collected for determination of 
plasma SEP-363856 and SEP-363854 concentrations. Plasma SEP-363856 and SEP-363854 
concentrations will be determined by a validated liquid chromatography-tandem mass 
spectrometry (LC-MS/MS) method. Population pharmacokinetic (POP-PK) analysis will be 
performed using plasma SEP-363856 concentrations; the results of which will be reported 
separately. The relationship between PANSS total score and plasma SEP-363856 exposure will 
be explored using population PK/pharmacodynamics (PD) methods, and reported separately. The 
impact of cytochrome (CYP) P450 CYP2D6 metabolizer status on SEP-363856 plasma exposure 
will be explored and reported separately. See Section 22 Appendix III for details including 
instructions of processing blood samples for determination of plasma SEP-363856 and 
SEP-363854 concentrations. 
All blood samples for determination of plasma antipsychotic concentrations will be obtained at 
the same time that other blood samples are taken whenever possible. The time and date of doses 
of antipsychotic medication, date, and clock time of sampling must be recorded. See Section 23 
Appendix IV for details including instructions of processing blood samples for determination of 
plasma concentrations. 
11.8. 
Pharmacogenomic Assessments 
If a subject has consented to have a deoxyribo nucleic acid (DNA) sample taken for genetic 
analysis (and is eligible for randomization), a blood sample (approximately 4 mL) for 
pharmacogenetic (PGx) analysis will be taken. Samples should not be collected if the subject has 
not consented to PGx sampling. If samples are collected for analysis, this analysis must be 
performed. The timing of the analysis may be following completion of this study and as such can 
be reported separately. Blood samples will be shipped to the central laboratory where they will 
be stored frozen until shipment to the PGx laboratory (contact details provided in the general 
study information section of the protocol). Following shipment, DNA will be extracted and the 
PGx laboratory will remain blinded to the identity of the subject, but will have access to 
information relating to demographics of the subject (ethnic origin and gender). See Section 24 
Appendix V for details including instructions of PGx sample handling. 
11.9. 
Study Visits and Assessments 
See Table 2 Schedule of Assessments, for a summary of procedures at each study visit. 


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11.9.1. 
Screening (Day -49 to Day -2): Visit 1 
A unique screening number will be assigned to each subject. 
Subjects will be evaluated at the Screening Visit to determine their eligibility to enroll in the 
study. No imaging procedures involving ionizing radiation will be performed within 12 hours of 
written consent. 
Procedures may be completed in any order unless specified otherwise. 
The following study-related procedures will be performed at Screening (procedures will occur 
over multiple days): 
• Obtain signed informed consent and privacy authorization from the subject before 
conducting any other visit procedures. 
• Inclusion and exclusion criteria 
• Obtain demographic information. 
• Prior/concomitant medications 
• Medical history 
• Psychiatric history/mental status 
• SCID-CT 
• Physical examination. 
• Height and weight; clinical site staff to calculate and record BMI. 
• Vital sign measurements. 
• Perform ECG. 
• Collect blood sample for clinical laboratory evaluation (hematology, chemistry, 
serum prolactin, glycosylated hemoglobin [HbA1c], Hepatitis B/C, HIV-1/HIV-2, and 
fasted glucose panel and lipid panel). 
• Collect blood samples for serum pregnancy test (serum human chorionic 
gonadotropin [β-hcG]) for female subjects and serum follicle stimulating hormone 
(FSH) for female subjects if menopause is suspected. 
• Collect blood sample for antipsychotic levels. 
• Collect urine sample for urinalysis and urine drug screen (UDS). 
• Perform MRI (MRI at screening must occur prior to the PET scan at screening). 
• Perform psychiatric assessments in the following order: PANSS, BNSS, C-SSRS, 
CGI-S. 
• Collect adverse events. 
• Perform PET/MR Scan including fMRI (Day -44 to Day -2). Approximately 1 hour 
before the scan participants will receive 150 mg of carbidopa and 400 mg of 
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• Female subjects only, collect urine samples for pregnancy test (any positive test must 
be followed up with a serum β-hcG test). Urine pregnancy test to be performed on the 
same day as, but prior to, screening PET/MR Scan. 
Subjects who screen fail may be re-screened up to two times, if judged appropriate by the 
Investigator. Subjects who screen fail due to MRI or PET or fMRI results may not be 
re-screened. 
Re-screened subjects will be re-consented and all screening procedures will be repeated except:  
• SCID results from the original screening will be reviewed and updated if necessary. 
• MRI (without any abnormality) obtained at the study’s imaging center within 90 days 
prior to Day -1 check-in is acceptable for eligibility. 
11.9.2. 
In-Clinic (Day -2 to Day 14): Visit 2 
11.9.2.1. Day -2, Check-in 
The following procedures will be conducted for this Visit Day: 
• Review Inclusion/exclusion criteria. 
• Concomitant medications. 
• Vital sign measurements 
• Weight 
• Perform ECG. 
• Collect blood sample for clinical laboratory evaluation (hematology, chemistry, 
serum prolactin, and fasted glucose panel and lipid panel). 
• Collect blood sample for antipsychotic levels. 
• Collect urine sample for urinalysis and urine drug screen (UDS). 
• Female subjects only, collect urine samples for pregnancy test (any positive test must 
be followed up with a serum β-hcG test). 
• Collect adverse events. 
If the subject still qualifies for the study after completion of study day procedures; the subject 
will be checked into the clinic. 
11.9.2.2. Day -1 
The following procedures will be conducted for this Visit Day: 
• Review Inclusion/exclusion criteria. 
• Concomitant medications 
• Vital sign measurements 


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• Perform psychiatric assessments in the following order: PANSS, BNSS, MADRS, 
CGI-S. (May be collected on Day -2) 
• Perform C-SSRS. (May be collected on Day -2) 
• Collect adverse events. 
11.9.2.3. Day 1 
All procedures should occur prior to dosing unless specified otherwise. 
The following procedures will be conducted for this Visit Day: 
• Review Inclusion/exclusion criteria. 
• Collect concomitant medications. 
• Vital sign measurements 
• Weight 
• Perform ECG 
• Female subjects only, collect urine samples for pregnancy test (any positive test must 
be followed up with a serum β-hcG test) (must be performed predose). 
• Collect blood sample for determination of plasma SEP-363856 and SEP-363854 
concentration. 
• Collect blood sample for antipsychotic levels. 
• Collect blood sample for pharmacogenomics. 
• Collect urine sample for urine drug screen (UDS). 
• BARS (May be collected on Day -1) 
• AIMS (May be collected on Day -1) 
• SAS (May be collected on Day -1) 
• Collect adverse events. 
• Dispensation of blister card 
• Administer study drug. 
11.9.2.4. Day 2 
The following procedures will be conducted for this Visit Day: 
• Collect blood sample for determination of plasma SEP-363856 and SEP-363854 
concentration. (collected approximately 2-4 hours postdose) 
• Collect blood sample for antipsychotic levels. (collected approximately 2-4 hours 
postdose) 
• Concomitant medications 


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• Collect adverse events 
• Administer study drug 
Daily administration of study drug, monitoring of adverse events and concomitant medications 
will continue for Days 3 through 6. 
11.9.2.5. Day 7 
The following procedures will be conducted for this Visit Day: 
• Collect blood sample for determination of plasma SEP-363856 and SEP-363854 
concentration. (collected approximately 2-4 hours) 
• Collect blood sample for antipsychotic levels. (collected approximately 2-4 hours 
postdose) 
• Concomitant medications 
• Collect adverse events. 
• Administer study drug. 
 
Daily administration of study drug, monitoring of adverse events and concomitant medications 
will continue for Days 8 through Day 13. 
Note: Dispensation of blister card on Day 8. 
11.9.2.6. Day 14 (+5 Days) 
All Day 14 assessments are to be completed the same day as the PET scan, unless otherwise 
noted. The following procedures will be conducted on the Day 14 PET scan day: 
• Collect concomitant medications. 
• Vital sign measurements. 
• Weight 
• Perform ECG. 
• Collect blood sample for clinical laboratory evaluation (hematology, chemistry, 
serum prolactin, and fasted glucose panel and lipid panel). 
• Female subjects only, collect urine samples for pregnancy test (any positive test must 
be followed up with a serum β-hcG test) (must be performed predose). 
• Collect urine sample for urine drug screen (UDS). 
• Perform psychiatric assessments in the following order: PANSS, BNSS, MADRS 
C-SSRS, CGI-S. 
Note: PANSS, BNSS, MADRS, and CGI-S assessments may be collected ± 1 day of 
PET Scan; however, C-SSRS must be performed same day as PET Scan. 
• BARS 


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• AIMS 
• SAS 
• Collect adverse events. 
• Administer study drug. 
• Collect blood sample for determination of plasma SEP-363856 and SEP-363854 
concentration immediately prior to fMRI scan. 
• Collect blood sample for antipsychotic levels immediately prior to fMRI scan. 
• Perform PET/MR Scan including fMRI. Approximately 1 hour before the scan 
participants will receive 150 mg of carbidopa and 400 mg of entacapone orally. 
• Discharge subject from clinic after all Day 14 assessments are complete. 
In the event of an unsuccessful PET scan on Day 14, additional days of dosing may be necessary 
up to, but not exceeding, Day 19. If any such additional days of dosing are necessary, subjects 
will continue their usual daily dosing with monitoring of adverse events and concomitant 
medications. All Day 14 assessments are to be completed again occurring on the same day as the 
PET scan, unless otherwise noted above. 
11.9.3. 
Outpatient Follow-up / End of Study (EOS) (7 ± 2 Days Post Last Dose of Study 
Drug): Visit 3 
The following procedures will be at this visit: 
• Collect concomitant medications. 
• Physical examination 
• Vital sign measurements 
• Weight 
• Perform ECG. 
• Collect blood sample for clinical laboratory evaluation (hematology, chemistry, 
serum prolactin, and fasted glucose panel and lipid panel). 
• Collect blood sample for determination of plasma SEP-363856 and SEP-363854 
concentration. 
• Collect blood sample for antipsychotic levels. 
• Female subjects only, collect urine samples for pregnancy test (any positive test must 
be followed up with a serum β-hcG test). 
• Collect urine sample for urine drug screen (UDS). 
• C-SSRS 
• BARS 
• AIMS 


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• SAS 
• Collect adverse events. 
11.9.4. 
Early Termination (ET) 
The following procedures will be at this visit: 
• Collect concomitant medications. 
• Physical examination 
• Vital sign measurements 
• Weight 
• Perform ECG. 
• Collect blood sample for clinical laboratory evaluation (hematology, chemistry, 
serum prolactin, and fasted glucose panel and lipid panel). 
• Collect blood sample for determination of plasma SEP-363856 and SEP-363854 
concentration. 
• Collect blood sample for antipsychotic levels. 
• Female subjects only, collect urine samples for pregnancy test (any positive test must 
be followed up with a serum β-hcG test). 
• Collect urine sample for urine drug screen (UDS). 
• Perform psychiatric assessments in the following order: PANSS, BNSS, MADRS, 
C-SSRS, CGI-S. (Only perform PANSS, BNSS, MADRS, CGI-S if early termination 
occurs prior to Day 14 PET/MR scan.) 
• BARS 
• AIMS 
• SAS 
• Collect adverse events 
• Perform PET/MR Scan including fMRI (only perform if the subject terminates the 
study prior to the Day 14 PET/MR Scan). 
 


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12. 
SAFETY REPORTING 
12.1. 
Definitions 
12.1.1. 
Adverse Events 
An adverse event (AE) can be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease occurring after signing the informed consent form 
(ICF), whether or not considered related to the medicinal (investigational) product. AEs may 
include the onset of new illness and the exacerbation of pre-existing conditions. AEs will be 
collected from the time of signing the ICF to the last study visit/EOS visit. 
New signs and symptoms of underlying disease, or signs and symptoms of emerging disease 
must be recorded as AEs. 
The Investigator should attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis should be documented as the AE 
and not the individual signs/symptoms. 
12.1.2. 
Serious Adverse Events 
A serious adverse event (SAE) is an AE that meets one or more of the following criteria: 
• Results in death. 
• Is life-threatening. 
• Requires hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly or birth defect. 
• Is an important medical event that may jeopardize the subject or may require a 
medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization. 
The term "severe" is often used to describe the severity of a specific event (as in mild, moderate, 
or severe myocardial infarction) (see Section 12.3); the event itself, however, may be of 
relatively minor medical significance (such as severe headache). This is not the same as 
"serious," which is based on subject/event outcome or action criteria usually associated with 
events that pose a threat to a subject's life or functioning as defined by the criteria above. 
During the study, if a subject has a hospitalization or procedure (eg, elective surgery) that was 
scheduled before the study entry, ie, before informed consent for an event/condition that 
occurred before the study, the hospitalization is considered a therapeutic intervention and not the 
result of a SAE. However, if the event/condition worsens during the study, it should be reported 
as an AE (or SAE, if the event/condition results in a serious outcome such as prolongation of 
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Life-threatening means that the subject was, in the view of the Investigator, at immediate risk of 
death from the event as it occurred. This definition does not include an event that had it occurred 
in a more severe form might have caused death. 
SAE criteria information will be captured on the CRF. 
12.2. 
Objective Findings 
Clinically significant abnormal objective findings (eg, clinical laboratory value, ECG value, and 
physical examination observation) will also be recorded as AEs. 
When a clear diagnosis is available that explains the objective findings, this diagnosis will be 
recorded as the AE, and not the abnormal objective finding (eg, viral hepatitis will be recorded as 
the AE, not transaminase elevation). If a definite diagnosis is not available, then record the sign 
(eg, clinically significant elevation of transaminase levels) or symptom (eg, abdominal pain) as 
the AE. 
Clinical laboratory test results will be reviewed by the Investigator. The Investigator must 
determine the clinical significance of all out of range values. Clinical laboratory test with 
possibly drug-related or clinically relevant abnormal values of uncertain causality may be 
repeated. Any abnormal values that persist should be followed at the discretion of the 
Investigator. Laboratory reports will be initialed and dated on all pages by the Investigator. 
Clinical Laboratory Tests Outside the Normal Range: Any value outside the normal range will be 
flagged for the attention of the Investigator or appropriate designee at the study center. The 
Investigator or appropriate designee will indicate whether or not the value is of clinical 
significance. If the result of any test (or repeat test, if done) from the samples taken during 
Screening is indicated as clinically significant and is not covered by the inclusion criteria in 
Section 8.1, the subject will not be allowed into the study. Additional testing during the study 
may be done if medically indicated. If a clinically significant abnormality is found in the samples 
taken after dosing, during the study, and/or at the Follow-Up Visit, this should be recorded as an 
AE and the subject will be followed until the test(s) has (have) normalised or stabilised. 
All on-site ECG tracings and ECG over-read reports will be reviewed by the Investigator. The 
Investigator must determine the clinical significance of all abnormal ECGs. ECG with possibly 
drug-related or clinically relevant abnormal findings of uncertain causality may be repeated. Any 
abnormal ECGs that persist should be followed at the discretion of the Investigator. ECG 
tracings will be initialed and dated on all pages by the Investigator. 
12.3. 
Collection and Recording of Adverse Events 
All AEs must be recorded in the subject’s study records/source documents in accordance with 
the Investigator’s normal clinical practice. All pre-treatment events and AEs/all AEs must be 
recorded on the CRF. 
All AEs will be followed until resolution, stabilization of the condition, the event is otherwise 
explained, or the subject is lost to follow-up. 
Each AE is to be evaluated for duration, severity, frequency, seriousness, action taken with the 
study treatment, outcome, and causal relationship to the study treatment. Definitions for severity, 


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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 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 
o  Not related - Improbable temporal relationship and is plausibly related to 
other drugs or underlying disease. 
• Related 


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o Possible - occurred in a reasonable time after study drug administration, but 
could be related to concurrent drugs or underlying disease. 
o Probable - occurred in a reasonable time after study drug administration, is 
unlikely to be attributable to concurrent drugs or underlying disease, and there 
is a plausible mechanism to implicate the study drug. 
o Definite - occurred in a reasonable time after study drug administration and 
cannot be explained by concurrent drugs or underlying disease. The adverse 
event should respond to dechallenge/rechallenge, however, this is not 
mandatory before assigning a definite causality. 
The Medical Monitor is the initial contact person for protocol related questions or discussion of 
AEs. The contact information for the Medical Monitor as well as other emergency contact 
information can be found in Table 1 of this protocol. 
12.4. 
Immediately Reportable Events 
The following medical events must be immediately reported to the Sponsor: 
• SAE 
• Pregnancy 
Emergency contact information can be found in Table 1. 
12.4.1. 
Serious Adverse Event 
If the Investigator or study center staff becomes aware of a SAE that occurs in a study subject 
from the time of informed consent through 30 days following the last dose of the study 
medication, this must be reported immediately to the Sponsor whether considered related or 
unrelated to the study drug. SAEs must be recorded on the CRF and the data recorded should 
agree with that on the SAE form. 
Following the end of subject participation in the study, the Investigator or an authorized delegate 
should report SAEs “spontaneously” to the 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 not more than 24 hours after the Investigator 
or study center staff becomes aware of the event. The SAE form must be signed by the 
Investigator or appropriate designee. The Sponsor provides the SAE form used to report SAEs. 
The Sponsor or designee will promptly notify all study centers and Investigators of a SAE that is 
determined to be expedited to the Regulatory Authorities in accordance with applicable law(s) 
and regulation(s). These SAEs must be promptly reported to the Institutional Review Board 
(IRB) or Independent Ethics Committee (IEC) by the Principal Investigator or the appropriate 
person at the study center if required per IRB/IEC guidelines. 


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12.4.2. 
Pregnancy 
Subject 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 pregnancy is reported for a study subject’s partner following the subject’s discharge 
through 90 days following the last dose of study drug, 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. 
If a subject becomes pregnant during the course of the study, she will be instructed to not take 
any more study drug. Further, the subject will be instructed to return promptly/within 48 hours of 
the first notification of pregnancy to the study center and undergo a serum/urine pregnancy test, 
as confirmation of pregnancy. If positive, the female pregnant subject will not receive any 
additional study medication. All pregnancies, whether or not the subject received any additional 
study medication, will be followed until resolution (ie, termination [voluntary or spontaneous] or 
birth). 
To report a pregnancy, the Pregnancy Event Form must be completed and sent via fax to 
PPD-PVG within 24 hours of the Investigator or study center staff becoming aware of the 
pregnancy. The Sponsor provides the Pregnancy Event Form. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study drug may have 
interfered with the effectiveness of a contraceptive medication or other AEs were detected. 


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13. 
TERMINATION OF SUBJECT FROM 
STUDY/DISCONTINUATION OF STUDY DRUG 
13.1. 
Criteria for Subject Termination 
Subjects may terminate the study participation at any time for any reason. 
The possible reasons for the termination of study participation are as follows: 
• Adverse event. 
• Lost to follow-up (specify). 
• Withdrawal by subject (specify). 
• Non-compliance with study drug (specify). 
• Protocol deviation (specify). 
• Pregnancy. 
• Death. 
• 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 treatment. 
The reason for discontinuation and information on the epoch 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 study drug will not be followed up on leaving the study. 
For subjects who have received study drug and who prematurely discontinue from the study 
treatment (ie, do not complete all visits through Follow-up), every effort should be made to 
complete the final evaluation procedures, in accordance with the early termination (ET) visit 
described in Section 11.9.4. 


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14. 
STUDY TERMINATION 
The Sponsor reserves the right to discontinue the study at this study center for safety or 
administrative reasons at any time while safeguarding that early termination does not 
compromise subjects’ safety or well-being. In particular, a study center that does not recruit at an 
acceptable rate may be closed. Should the study be terminated, and/or the study center closed for 
whatever reason, all documentation and study medications pertaining to the study must be 
returned to the Sponsor or its representative. 
If, in the opinion of the Investigator, clinical observations suggest it may be unsafe to continue, 
the Investigator may terminate part or the entire study after consultation with the Sponsor. 
In the event of study or site termination, subjects will be required to undergo final evaluation 
procedures, in accordance with the early termination (ET) visit described in Section 11.9.4. 


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15. 
STATISTICS 
15.1. 
Sample Size 
This study is designed to determine the magnitude of a possible pharmacological effect of 
SEP-363856 on dopamine synthesis capacity. Dopamine synthesis capacity has shown good test-
retest reliability (Egerton-2010). Prior studies have reported a within-subject standard deviation 
of 0.00056/min in dopamine synthesis capacity. The absolute elevation in dopamine synthesis 
capacity for schizophrenia cases versus normal healthy controls is estimated to be approximately 
0.001/min, and to have a correlation of approximately 0.6 with symptoms. Given this 
relationship between dopamine synthesis capacity and symptoms, it is estimated that a decrease 
in dopamine synthesis capacity of 0.0005/min in patients is the smallest reduction likely to be 
clinically significant (anticipated to translate into > 20% reduction in symptoms which is 
generally considered the smallest change readily detected in clinical practice). A sample size of 
16 subjects treated with SEP-363856 will provide > 90% power to detect a treatment reduction 
of 0.0005/min (change from baseline) in dopamine synthesis capacity using a paired sample 
t-test and alpha set at the 0.05 level. 
Subjects who are initiated on treatment but discontinue from the study may not be replaced. The 
total sample size will be 22 subjects to allow for up to 25% drop-out to obtain complete PET 
scans on at least 16 subjects. 
15.2. 
Analysis Populations 
The following populations will be defined: 
• Safety Population: The safety population will consist of all subjects who receive at 
least one dose of study drug. 
• PET Population: The PET population is defined as all subjects who took at least one 
dose of SEP-363856 and have a baseline and a post-baseline PET assessment. 
• Efficacy population: the efficacy population is defined as all subjects who have 
received at least one dose of study drug, and have any postdose data for the PANSS, 
CGI-S, BNSS or MADRS. 
• Per Protocol Population: The Per Protocol Population is defined as all subjects in the 
PET population, the subject completed the study, and the subject had NO important 
protocol deviations. 
15.3. 
Data Analysis 
15.3.1. 
Subject Disposition 
The number and percentage of subjects screened, screen failed, enrolled, dosed, and completing 
the study will be summarized. The number and percentage of subjects who terminate early will 
also be summarized, with reasons for early termination. 


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15.3.2. 
Drug Exposure and Compliance 
A data listing, by subject, containing the study medication dosing and dosing errors, if any, will 
be provided. Treatment compliance will not be summarized as all dosing will occur in-clinic. 
The total number of days of exposure will be summarized categorically (N [%]). 
15.3.3. 
Important Protocol Deviations 
Important protocol deviations (IPDs) will be identified and documented based on a review of 
potential IPDs. The potential IPDs will be identified through programmatic checks of study data, 
as well as through review of selected data listings. The potential IPDs to be reviewed include, but 
are not limited to, subjects who: 
• Did not meet inclusion/exclusion criteria. 
• Received any disallowed concomitant medication. 
Individual IPDs will be presented in a data listing. The number and percentage of subjects with 
IPDs will be summarized by type of deviation and dose group. 
15.3.4. 
Demographic and Baseline Characteristics 
Basic demographics (e.g. age, gender, race, ethnicity, etc.) will be summarized descriptively. 
Medical history will be coded using MedDRA, and will be summarized for the safety population 
by presenting the number and percentage of subjects with at least one condition in each system 
organ class (SOC) and preferred term (PT). 
15.3.5. 
Medical History and Psychiatric History 
Medical and psychiatric history will be coded using MedDRA. The count and percentage of 
subjects under each history term, coded by SOC and PT, will be summarized. 
15.3.6. 
Positron Emission Tomography (PET) and Functional Magnetic Resonance 
Imaging (fMRI) Analysis 
The analysis of brain dopamine synthesis capacity and fMRI analysis will use the PET 
population. 
The region of interest in the primary endpoint is the whole striatum. Exploratory analyses will be 
conducted in other regions and sub-regions of interest. The cerebellum will be used as the 
reference region. The regions of interest will be delineated on the subjects structural MR based 
on using the Hammersmith Atlas, and this will be co-registered to the subject’s dynamic PET 
images. Dopamine synthesis capacity will be calculated based on each individual PET images 
collected at each scan for each subject using a Patlak Graphical Analysis. For the fMRI image 
pre-processing will be performed via the CONN toolbox (version 17.b)(65) for Statistical 
Parametric Mapping software (SPM 12 (6906)). For each participant, BOLD signal time-series 
will be extracted from the nodes in the Gordon cortical atlas, and functional connectivity 
determined within primary networks of interest (the default mode network, the salience network) 
and the visual network (a control network), and additional networks guided by the PET analysis. 
The primary endpoint is the change from baseline in dopamine synthesis capacity at Week 2 will 
be calculated, together with 95% confidence interval from a paired sample t distribution. 


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Changes in resting state BOLD fMRI signal within the salience, default mode, and visual 
networks at each post-dose time point from baseline will be summarized. 
Changes in exploratory MRI markers, including (but not limited to) neuromelanin and iron signal 
at each post-dose time point from baseline will be summarized. 
15.3.7. 
Efficacy Analyses 
Efficacy parameters include PANSS, CGI-S, BNSS, and MADRS. Tabular and graphical 
summaries will be based on the Efficacy Population. 
The actual and changes from baseline at each post-dose time point will be summarized, with 
95% confidence intervals. The relationship between dopamine synthesis capacity at baseline and 
measures of baseline symptom severity (PANSS, CGI-S, BNSS, and MADRS) and their change 
from baseline will be presented graphically. 
15.3.7.1. Subgroup Analysis 
Subgroup analyses are not planned for the efficacy parameters. 
15.3.8. 
Safety Analyses 
15.3.8.1. Adverse Events 
All AEs will be coded using MedDRA.  
Treatment emergent AEs (TEAEs) are untoward medical occurrences: 
• that occurred on or after the first dose of study medication, 
•  with a missing start date and a stop date on or after the first dose of study medication, 
or 
•  with both a missing start and stop date. 
TEAEs will be summarized by MedDRA system organ class (SOC) and Preferred Term (PT). 
The following TEAEs will be summarized and presented by MedDRA SOC and PT for the 
Safety population: 
• All TEAEs (including number of events and subject incidence). 
• TEAEs by severity (mild, moderate, severe). 
• TEAEs by relationship to the study treatment (related, or not related). 
The following conventions will be followed in summarizing TEAEs: 
• For subject incidence summaries, each subject will be counted only once within each 
SOC and within each preferred term. 
• If a subject reports more than one TEAE within a preferred term and/or a body 
system, the AE with the highest known severity within each body system and within 
each preferred term will be included in the summaries by severity. 


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• For summaries by relationship to the study medication, TEAEs will be grouped as 
“related” or “not related.” TEAEs assessed as “possible,” “probable,” or “definite,” 
will be grouped as “related.” If a subject reports more than one TEAE within the 
same treatment regimen, SOC and PT, and any are related, it will be summarized as 
related. 
Untoward medical occurrences that occur between the time of signing the ICF and first drug 
administration are pretreatment events. 
A listing of all AEs, as well as a listing of deaths, SAEs, or AEs leading to discontinuation, will 
be presented. 
15.3.8.2. Clinical Laboratory Assessments 
Laboratory data will be summarized overall for the safety population. 
For laboratory parameters with continuous outcomes, descriptive statistics (number of subjects, 
mean, SD, median, minimum, and maximum) for the observed values and for changes from 
baseline will be presented and overall at each visit. For laboratory parameters with categorical 
outcomes, the number and percentage of subjects with each outcome will be presented for each 
dose cohort and overall at each visit. 
The number and percentage of subjects with Sponsor defined potentially clinically significant 
(PCS) laboratory values (defined in the SAP) will be summarized for each dose cohort and 
overall at each visit. The data listings for laboratory parameters will flag values outside of the 
reference range. Clinically significant laboratory findings will be displayed in a separate data 
listing. 
15.3.8.3. Electrocardiograms 
Electrocardiogram parameters to be collected include ventricular heart rate, QT interval, PR 
interval, QRS duration, and RR interval (ms). The corrected QT interval will be derived 
according to the Fridericia formula (QTcF) as well as Bazett’s formula (QTcB). 
ECG data will be summarized overall for the safety population. 
Electrocardiogram parameters and changes in these parameters from baseline, as determined by 
the central over-read, will be summarized using descriptive statistics (number of subjects, mean, 
standard deviation, median, minimum, and maximum) at each visit. 
The number and percentage of subjects with QTcF values in the following categories will be 
summarized: 
• QTcF ≥ 500 ms at any postdose timepoint and not present at baseline. 
• QTcF ≥ 480 ms at any postdose time point and not present at baseline. 
• QTcF ≥ 450 ms at any postdose timepoint and not present at baseline. 
• Change from baseline in QTcF ≥ 60 ms for at least one postdose measurement. 
• Change from baseline in QTcF ≥ 30 ms for at least one postdose measurement, but 
≤ 60 ms for all postdose measurements. 


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For these categorical analyses, the percent of subjects will be based on the number of subjects 
with at least one non-missing post treatment value. Any early termination visit or unscheduled 
ECG that occurs after the single dose will be included for these posttreatment summaries. 
The number and percentage of subjects with potentially clinically significant post-baseline 
values (defined in the SAP) will be presented. 
15.3.8.4. Vital Signs 
Oral body temperature, respiration rate, pulse (supine and standing) and systolic and diastolic 
blood pressure (supine and standing) will be summarized overall using descriptive statistics at 
each visit. Changes from baseline will be summarized in the same manner. The number and 
percentage of subjects with Sponsor defined PCS vital sign values (defined in the SAP) will be 
presented overall at each visit. 
The number and percentage of subjects with orthostatic hypotension will be summarized by dose 
cohort by timepoint and overall. Orthostatic hypotension is defined as a decrease of ≥ 20 mmHg 
in systolic blood pressure or ≥ 10 mmHg in diastolic blood pressure after the subject had been 
standing for at least 2 to 4 minutes, compared to the systolic and diastolic blood pressures 
measured in the supine position, respectively. 
15.3.8.5. Physical/Neurological Examination 
Findings from the physical and neurological examination will be presented as follows: 
pre-existing clinically significant conditions recorded as medical history, and new clinically 
significant conditions recorded as AEs. Physical and neurological examination findings will also 
be provided in a data listing (date/time of examination and yes/no [was examination performed]). 
15.3.8.6. Concomitant Medications 
All medications will be coded using WHO-DD. 
Medication taken between screening and the follow-up visit will be reported as concomitant. The 
number and percentage of subjects using each concomitant medication will be summarized 
overall according to the WHODRUG Anatomic Therapeutic Class (ATC) Level and preferred 
term. Subjects with multiple uses of a concomitant medication will be counted once by the 
WHODRUG class and preferred term. 
15.3.8.7. Columbia-Suicide Severity Rating Scale (C-SSRS) 
A listing of all C-SSRS responses will be provided. 
Frequency and severity of suicidal ideation and suicidal behavior as measured by the C-SSRS 
scale will be summarized for each visit/study day. 
15.3.8.8. Movement Disorder Measures 
Movement disorder measures include AIMS, BARS, and SAS. The BARS, AIMS, and SAS will 
be summarized descriptively by presenting summary statistics of actual values and change from 
baseline values. 


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15.3.8.9. Subgroup Analysis 
No subgroup analyses are planned for the safety parameters. 
15.3.9. 
Pharmacokinetic Analysis 
Plasma concentrations of SEP-363856 and its metabolite SEP-363854 will be summarized 
descriptively at each scheduled sample collection time point. 
15.3.10. 
Interim Analysis 
No interim analysis is planned. 
15.3.11. 
Treatment of Missing Data 
No imputation will be performed for missing data. Missing data will be considered as missing at 
random. 


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16. 
PROCEDURE FOR CLINICAL STUDY QUALITY CONTROL 
/DATA COLLECTION, MANAGEMENT, AND QUALITY 
ASSURANCE 
16.1. 
Data Collection/Electronic Data Capture (EDC) 
The results from Screening and data collected during the study (except clinical laboratory test 
results,) will be recorded in the subject’s electronic CRF. The study centers will use an EDC 
system that is compliant with relevant FDA regulatory requirements per 21 Code of Federal 
Regulation (CFR) Part 11. Password protected access to the EDC system will be via a secure 
website. Data queries and data corrections will be handled through the same system. All 
transactions within the EDC system are fully documented within an electronic audit trail. Each 
set of completed CRFs must be reviewed and electronically signed and dated by the Investigator. 
16.2. 
Computerized Systems Used for Source Data 
A list of the computerized systems that will be used to create, modify, maintain, archive, retrieve, 
or transmit source data are presented below, pursuant to the Guidance for Industry Computerized 
Systems Used in Clinical Investigations, May 2007. 
 
Table 6: 
Computerized Systems Used for Source Data 
Protocol Step 
Computerized System 
Type or Description 
Obtain informed consent 
A 
Review inclusion/exclusion criteria  
A 
Demography 
A 
Prior/concomitant medication review 
A 
Dispensation of study drug 
NA 
Administration of Study Drug 
A 
Admit to Clinic, if not admitted during screening 
NA 
Clinic Discharge 
NA 
Medical history 
A 
Psychiatric history/mental status 
A 
SCID-CT 
A 
Physical examination 
A 
Height/BMI 
A 
Vital signs 
A 
Weight  
A 


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Table 6: 
Computerized Systems Used for Source Data (Continued) 
Protocol Step 
Computerized System 
Type or Description 
Electrocardiogram (ECG) 
C 
Hematology, chemistry, and urinalysis  
B 
Serum prolactin 
B 
Hepatitis B/C, HIV-1/HIV-2 
B 
Glycosylated hemoglobin (HbA1c) 
B 
Glucose and Lipid panel 
B 
Follicle stimulating hormone (FSH), females only 
B 
Serum human chorionic gonadotropin (β-hCG)  
B 
Urine β-hCG 
A 
Blood sample for pharmacogenomics 
D 
Blood sample for SEP-363856 and SEP-363854 PK 
D 
Blood sample for antipsychotic levels 
D 
Urine drug screen 
B 
Magnetic resonance imaging (MRI) Scan 
A 
PET/MR Scan including fMRI 
E 
Positive and Negative Syndrome Scale (PANSS) 
A 
Clinical Global Impression – Severity (CGI-S) 
A 
Montgomery-Asberg Depression Rating Scale (MADRS) 
A 
Columbia Suicide Severity Rating Scale (C-SSRS) 
A 
Barnes Akathisia Rating Scale (BARS) 
A 
Abnormal Involuntary Movement Scale (AIMS) 
A 
Simpson-Angus Scale (SAS) 
A 
Brief Negative Symptom Scale (BNSS) 
A 
Adverse events (AEs) monitoring 
A 
Statistical analysis 
SAS®, version 9.1.3 or higher 
 A = EDC (company name); B = LIMS; C = Core Lab Over-read; D = LIMS/ASCII; E = Computerized 
Assessment System (Imanova). 
 Abbreviations: EDC = electronic data capture; CDR = clinical data repository; ePRO = electronic patient reported 
outcomes; LIMS = laboratory information management system; NA = not applicable; PK = pharmacokinetic. 
16.3. 
Study Monitoring 
This study will be monitored from initiation to completion by the Sponsor or its representative. 
Monitoring will include personal visits and telephone communication to assure that the 


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investigation is conducted according to protocol and in order to comply with International 
Council for Harmonization (ICH) Good Clinical Practice (GCP). On-site review of CRFs will 
include a review of forms for completeness and clarity, and consistency with source documents 
available for each subject. 
16.4. 
Audits 
The study may be subject to audit by the Sponsor/designee. If such an audit occurs, the 
Investigator must agree to allow access to required subject records. This is dependent on the 
subject granting consent by signing the ICF. By signing this protocol, the Investigator grants 
permission to personnel from the Sponsor or its representatives for on-site monitoring and 
auditing of all appropriate study documentation, as well as on-site review of the procedures 
employed in CRF generation, where clinically appropriate. 
In accordance with ICH GCP the Sponsor may select this study for audit. During the audit the 
Sponsor representative will carry out an inspection of center facilities (eg, pharmacy, drug 
storage areas, laboratory) and review study related records in order to evaluate the study 
compliance with the Sponsor/center SOPs, protocol, ICH GCP and local regulations. The PI or 
appropriate designee must also agree to inspection of all study documents by the regulatory 
authorities and the IEC. Should the PI or appropriate designee be notified of a regulatory 
inspection involving this study they should notify the Sponsor immediately. 
16.5. 
Study Documentation 
Study records are comprised of source documents, CRFs, and all other administrative 
documents, eg, IRB/IEC correspondence, clinical study materials and supplies shipment 
manifests, monitoring logs, Sponsor and CRO correspondence, etc. A study specific binder will 
be provided with instructions for the maintenance of study records. 
Source document is defined as any handwritten or computer generated document that contains 
medical information or test results that have been collected for or are in support of the protocol 
specifications, eg, clinical laboratory reports, clinic notes, drug disbursement log, subject sign in 
sheets, subject completed questionnaires if applicable, telephone logs, ECGs, etc. All draft, 
preliminary and pre-final iterations of a final report are also considered to be source documents, 
eg, faxed laboratory reports and hard copy laboratory reports, faxed initial results and hard copy, 
final report. 
16.6. 
Clinical Laboratory Certification and Normal Values 
A local/site laboratory will be used for analysis for most of the clinical laboratory tests for this 
study. The local/site laboratory will provide the Investigator, Sponsor/CRO with laboratory 
certification(s), a dated copy of normal range values for the local/site clinical laboratory selected 
to analyze clinical specimens. 
 


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


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


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17.5. 
Protocol Amendments and Emergency Deviations 
All revisions and/or amendments (substantial or non-substantial) to this protocol must be 
approved in writing by the Sponsor, the appropriate IRB/IEC, and the Health Research Authority 
(HRA). The Investigator will not make any changes to the conduct of the study or the protocol 
without first obtaining written approval from the Sponsor, IRB/IEC, and HRA, except where 
necessary to eliminate an apparent immediate hazard to a study subject. 
Emergency deviations or modifications may be initiated without Sponsor, IRB/IEC, or HRA 
approval or favorable opinion, only in cases where the deviation or modification is necessary to 
eliminate or avoid an immediate apparent hazard to subjects. Emergency deviations or 
modifications must be reported to the Sponsor/CRO, IRB/IEC, and HRA immediately/within 
five business days of the occurrence, or in accordance with applicable regulatory requirements. 
17.6. 
Records Retention 
The Investigator/the study center must arrange for retention of study records at the study center 
for at least 25 years from time of participation in the study or longer in accordance with 
applicable regulations and Sponsor SOPs. The Investigator/site should take measures to prevent 
accidental or premature destruction of these documents. Documents cannot be destroyed without 
written Sponsor authorization. The Sponsor will inform the Investigator/the study center when 
the destruction of documents is permitted. 
17.7. 
Inspection of Records 
In the event of an inspection, the Investigator agrees to allow representatives of the Sponsor and 
its representative and, the regulatory authorities’ access to all study records. The Investigator will 
promptly notify the Sponsor/CRO of all requests to inspect a Sunovion-sponsored study by 
government agencies and will promptly forward a copy of all such inspection reports. 
17.8. 
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 


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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. 


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18. 
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Kapur S, Remington G. Atypical antipsychotics: new directions and new challenges in the 
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Kim E, Howes OD, Veronese M, Beck K, Seo S, Park JW, Lee JS, Lee YS, Kwon JS. 
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19. 
INVESTIGATOR APPROVAL 
I have read the protocol, SEP361-118, Version 5.00 “An Open-Label Positron Emission 
Tomography Study to Investigate the Effect of Adjunctive Administration of SEP-363856 on 
Brain Dopamine Synthesis Capacity Using 18F-DOPA in Adult Subjects With Schizophrenia”; 
and agree that it contains all necessary details for conducting the study and to conduct the study 
in strict accordance with the specifications outlined herein. 
I agree that no additional procedure(s) will be added during the conduct of the study except 
through protocol amendment by Sunovion Pharmaceuticals Inc. and after documentation of IRB 
approval. 
Investigator Signature: ____________________________________________________ 
Print Investigator Name: __________________________________________________ 
Date: ___________________________________________ 


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20. 
APPENDIX I. CARDIAC SAFETY MONITORING (ECG) 
1. Requirements for Testing 
ECG equipment and supplies will be provided to the site and should be used for all in-clinic 
protocol ECG assessments. 
• All 12-lead ECGs will be recorded in the same manner. 
• The site personnel must be adequately trained in performing ECGs on the specific 
ECG equipment used in this protocol that is provided by the cardiac safety vendor. 
• To the extent possible, the same ECG machine and personnel should be used to 
acquire a subject’s ECGs throughout the period of their participation in the study. 
• Indelible ink may be used to mark the placement of the leads on the skin to ensure 
consistent placement throughout 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, Subjects will be supine for at least 10 minutes prior to and 
5 minutes after 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 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 
Clinical Safety Panel 
HEMATOLOGY: (Differential reported as % and absolute value) 
Hemoglobin, Hematocrit, Platelet Count, red blood cell (RBC) Count, White blood cells (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), CPK, Creatinine, Glucose, HbA1c, 
Magnesium (Mg), Phosphorus (P), Potassium (K), Prolactin, Protein (Total), Sodium (Na), Uric 
Acid 
 
URINALYSIS: Blood, Glucose, Ketones, Leukocyte esterase, Microscopic examination, 
Nitrites, pH, Protein 
 
LIPID PANEL: LDL-Cholesterol, HDL-Cholesterol, Triglycerides 
 
THYROID PANEL: Free T3, Free T4, Thyroid stimulating hormone (TSH) 
 
URINE DRUG SCREENING: Alcohol test, Amphetamines, Barbiturates, Benzodiazepines, 
Cannabinoids, Cocaine, Cotinine, Methamphetamines, Methadone, 
Methylenedioxymethamphetamine (MDMA), Phencyclidine (PCP), Opiates, Oxycodone 
 
SEROLOGY PANEL: Hepatitis B Ag, Hepatitis C Ab, HIV-1 Ab, HIV-2 Ab (screening only) 
 
COAGULATION PANEL: International Normalized Ratio (INR), activated Partial 
Thromboplastin time (aPTT), Prothrombin time (PT) 
 
OTHER TESTS: Serum Pregnancy (β-hCG) (in female subjects only), Urine Pregnancy Test 
(in female subjects only), follicle stimulating hormone (FSH) (in female subjects only) 
 
Laboratory reports will be initialed and dated on all pages by the Investigator listed on the Form 
FDA 1572 (MD or DO). Laboratory test results will be reviewed by the Investigator as they 
become available. The Investigator must determine the clinical significance of all out-of-range 
lab values (except drug screens). Possibly drug-related or clinically relevant abnormal values of 
uncertain causality must be repeated. Any abnormal values that persist should be followed at the 
discretion of the Investigator. 
 


Protocol SEP361-118, Version 5.00 
 
SEP-363856 
 
Confidential and Proprietary 
82 
18 Mar 2020 
22. 
APPENDIX III. PHARMACOKINETIC SAMPLING AND 
SAMPLE HANDLING GUIDELINE 
 
Please refer to the Laboratory Investigator Manual for all collection and shipping instructions. 
 
When blood sample for PK assessment and clinical lab sample collections share the same 
designated time points (including predose sample), the blood samples should be collected during 
the same venipuncture. 
For each defined PK sampling time point, collect 6 mL blood sample into a K2-EDTA treated 
tube. Invert gently 8 to 10 times. Keep the blood collection tube on wet ice upon blood draw, and 
centrifuge for 20 minutes at ca. x 1300 g to isolate plasma within 30 minutes of blood draw. To 
ensure a more homogenous sample, all plasma samples should first be transferred to 1 tube, 
capped and mixed well. Split the harvest plasma sample with approximately equal volume into 
2 polypropylene tubes, and label as Primary and Back-up. Freeze plasma tubes in a freezer set at 
approximately -20°C or lower. The date and clock time of blood collection must be recorded. 
Blood must be collected from all subjects at the time points indicated below. 
All samples will be shipped with sufficient dry ice protection. 
 
Study Day 
Collection Time 
Volume 
Collected 
Day 1 
Pre-dose (approximately 10 minutes prior to dosing) 
6 mL 
Day 2 
2-4 hours Post-dose (Actual date and clock time will be 
recorded) 
6 mL 
Day 7 
2-4 hours Post-dose (Actual date and clock time will be 
recorded) 
6 mL 
Day 14 
Prior to PET scan (Actual date and clock time will be recorded) 
6 mL 
7 days post last day 
of study drug 
administration 
Actual date and clock time will be recorded 
6 mL 
 


Protocol SEP361-118, Version 5.00 
 
SEP-363856 
 
Confidential and Proprietary 
83 
18 Mar 2020 
23. 
APPENDIX IV. SAMPLE COLLECTION AND HANDLING 
GUIDELINES FOR ANTIPSYCHOTIC LEVELS 
Please refer to the Laboratory Investigator Manual for all collection and shipping instructions. 
BLOOD SAMPLES FOR ANTIPSYCHOTIC LEVELS 
 
When blood sample for antipsychotic levels and clinical lab sample collections share the same 
designated time points (including predose sample), the blood samples should be collected during 
the same venipuncture. 
For each defined sampling time point, collect 6 mL blood sample into a K2-EDTA treated tube. 
Invert gently 8 to 10 times. Keep the blood collection tube on wet ice upon blood draw, and 
centrifuge for 20 minutes at ca. x 1300 g to isolate plasma within 30 minutes of blood draw. To 
ensure a more homogenous sample, all plasma samples should first be transferred to 1 tube, 
capped and mixed well. Split the harvest plasma sample with approximately equal volume into 
2 polypropylene tubes, and label as Primary and Back-up. Freeze plasma tubes in a freezer set at 
approximately -20°C or lower. The date and clock time of blood collection must be recorded. 
Blood must be collected from all subjects at the time points indicated below. 
All samples will be shipped with sufficient dry ice protection. 
 
Study Day 
Collection Time 
Volume 
Collected 
-49 to -2 
Screening 
6 mL 
Day -2 
Actual date and clock time will be recorded 
6 mL 
Day 1 
Pre-dose (approximately 10 minutes prior to dosing) 
6 mL 
Day 2 
2-4 hours Post-dose (Actual date and clock time will be recorded) 
6 mL 
Day 7 
2-4 hours Post-dose (Actual date and clock time will be recorded) 
6 mL 
Day 14 
Prior to PET scan (Actual date and clock time will be recorded) 
6 mL 
7 days post last day 
of study drug  
Actual date and clock time will be recorded 
6 mL 
 


Protocol SEP361-118, Version 5.00 
 
SEP-363856 
 
Confidential and Proprietary 
84 
18 Mar 2020 
24. 
APPENDIX V. SAMPLE COLLECTION AND HANDLING 
GUIDELINES FOR PHARMACOGENOMICS ASSESSMENT 
Please refer to the Laboratory Investigator Manual for all collection and shipping instructions. 
BLOOD SAMPLES FOR PHARMACOGENOMICS 
• A blood sample (approximately 4.0 mL) will be collected predose on Day 1 using a 
4-mL Vacutainer® (or equivalent) collection tube containing K2-EDTA as an 
anticoagulant. 
• The tubes containing blood samples will be labeled with the following information: 
unique barcode (if possible), protocol number, subject number, and sample date of 
collection. 
• Blood samples will be kept upright on wet ice upon blood draw and will be stored 
frozen at approximately -70°C within 10 min of collection until shipment to the 
appropriate laboratory. 
• The blood samples for pharmacogenomics will be shipped in leak-proof double-
plastic sealed bags with approximately 20 pounds of dry ice placed in insulated 
shipping containers labeled on the outside with “Human Specimens/Non-infectious”. 
Packing material such as bubble-wrap or other cushioning material will be placed 
around the samples to prevent breakage during shipping. Samples will be shipped in 
conformance with International Air Transport Association (IATA) regulations 
relating to the handling and shipping of hazardous goods. 
• Samples will be shipped via Sponsor-specified overnight courier service on Monday 
through Wednesday (should be shipped at least 2 days prior to National Holiday). 
 
 


Protocol SEP361-118, Version 5.00 
 
SEP-363856 
 
Confidential and Proprietary 
85 
18 Mar 2020 
25. 
APPENDIX VI. CYP2D6 INHIBITORS AND SUBSTRATES  
 
The following tables provide examples of CYP2D6 inhibitors (prohibited during participation) 
and CYP2D6 substrates (concomitant use requires caution) but are not intended to be fully 
comprehensive lists. Therefore, use of medications for which the potential for interactions 
mediated by CYP2D6 is in question should be discussed with the medical monitor prior to use. 
 
CYP2D6 Inhibitors 
Strong Inhibitors 
Moderate Inhibitors 
Weak Inhibitors 
CYP2D6 
bupropion, fluoxetine, 
paroxetine, quinidine, 
terbinafine 
cimetidine, cinacalcet, 
duloxetine, fluvoxamine, 
mirabegron 
abiraterone, amiodarone, 
celecoxib, cimetidine, clobazam, 
cobicistat, desvenlafaxine, 
escitalopram, labetalol, 
lorcaserin, ritonavir, sertraline, 
vemurafenib 
Reference: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-
substrates-inhibitors-and-inducers#table3-2 [accessed 29-May-2019]. 
 
CYP2D6 Substrates 
Sensitive Substrates 
Moderate Sensitive Substrates 
CYP2D6 
Substrates 
atomoxetine, desipramine, dextromethorphan, 
eliglustat, nebivolol, nortriptyline, 
perphenazine, tolterodine, venlafaxine 
amitriptyline, encainide, imipramine, 
metoprolol, propafenone, propranolol, 
tramadol, trimipramine, 
Reference: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-
substrates-inhibitors-and-inducers#table2-1 [accessed 29-May-2019]. 
 
 

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STATISTICAL ANALYSIS PLAN 
CLINICAL STUDY PROTOCOL SEP361-118 
AN OPEN-LABEL POSITRON EMISSION TOMOGRAPHY STUDY TO 
INVESTIGATE THE EFFECT OF ADJUNCTIVE ADMINISTRATION OF 
SEP-363856 ON BRAIN DOPAMINE SYNTHESIS CAPACITY USING 
18F-DOPA IN ADULT SUBJECTS WITH SCHIZOPHRENIA 
VERSION NUMBER AND DATE: FINAL V1.0, 26JUL2023 








 
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MODIFICATION HISTORY 
 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ......................................................................................................... 10 
2. 
STUDY OBJECTIVES ................................................................................................. 10 
2.1. 
Primary Objective ................................................................................................................................... 10 
2.2. 
Safety Objectives ..................................................................................................................................... 10 
2.3. 
Other Objectives ..................................................................................................................................... 11 
3. 
STUDY ENDPOINT...................................................................................................... 11 
3.1. 
Primary Endpoint ................................................................................................................................... 11 
3.2. 
Safety Endpoints ..................................................................................................................................... 11 
3.3. 
Other Endpoints ...................................................................................................................................... 11 
4. 
STUDY DESIGN ........................................................................................................... 12 
4.1. 
General Description ................................................................................................................................ 12 
4.2. 
Changes to Analysis from Protocol ......................................................................................................... 13 
5. 
PLANNED ANALYSES ................................................................................................ 15 
5.1. 
Data Monitoring Committee (DMC) ...................................................................................................... 15 
5.2. 
Interim Analysis ...................................................................................................................................... 15 
5.3. 
Final Analysis .......................................................................................................................................... 16 
6. 
ANALYSIS POPULATIONS ........................................................................................ 16 
6.1. 
Safety Population [SAF].......................................................................................................................... 16 
6.2. 
Efficacy Population [EFF] ...................................................................................................................... 16 


 
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7. 
STATISTICAL CONSIDERATIONS .......................................................................... 16 
7.1. 
Reference Start Date and Study Day ...................................................................................................... 16 
7.2. 
Baseline ................................................................................................................................................... 17 
7.3. 
Retests, Unscheduled Visits and Early Termination Data ..................................................................... 17 
7.4. 
Windowing Conventions ......................................................................................................................... 17 
7.5. 
Statistical Tests........................................................................................................................................ 17 
7.6. 
Common Calculations ............................................................................................................................. 18 
7.7. 
Software Version ..................................................................................................................................... 18 
7.8. 
Missing Data............................................................................................................................................ 18 
7.9. 
Examination of Subgroups...................................................................................................................... 18 
8. 
OUTPUT PRESENTATIONS ...................................................................................... 18 
9. 
DISPOSITION AND WITHDRAWALS ...................................................................... 19 
9.1. 
Important Protocol Deviations ............................................................................................................... 19 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ....................... 19 
10.1. 
Derivations .......................................................................................................................................... 20 
11. 
MEDICAL AND PSYCHIATRIC HISTORY ............................................................. 20 
12. 
PRIOR AND CONCOMITENT MEDICATIONS ...................................................... 20 
13. 
STUDY MEDICATION EXPOSURE .......................................................................... 21 
14. 
STUDY MEDICATION COMPLIANCE .................................................................... 21 
15. 
EFFICACY OUTCOMES ............................................................................................. 21 


 
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15.1. 
Efficacy Variables ............................................................................................................................... 22 
15.2. 
Missing Data Method for Efficacy Variables ...................................................................................... 26 
16. 
SAFETY OUTCOMES ................................................................................................. 26 
16.1. 
Adverse Events .................................................................................................................................... 26 
16.1.1. 
All AEs ............................................................................................................................................. 28 
16.1.3. 
AEs Leading to Discontinuation from Study ...................................................................................... 28 
16.1.4. 
Severity of AEs ................................................................................................................................. 28 
16.1.5. 
Relationship to Study Medication ...................................................................................................... 28 
16.1.6. 
Serious  Adverse Events .................................................................................................................... 29 
16.1.7. 
Adverse Events Leading to Death ...................................................................................................... 29 
16.1.8. 
Adverse Events of Potential Drug Abuse and Dependence.................................................................. 29 
16.2. 
Laboratory Evaluations ...................................................................................................................... 29 
16.2.1. 
Laboratory Reference Ranges and Potentially Clinically Significant Criteria ...................................... 30 
16.3. 
ECG Evaluations ................................................................................................................................. 31 
16.4. 
Vital Signs............................................................................................................................................ 32 
16.4.1. 
Vital Signs  Potentially  Clinically Significant (PCS) Criteria ............................................................. 33 
16.4.2. 
Orthostatic Effects ............................................................................................................................. 33 
16.5. 
Physical and Neurological Examinations ............................................................................................ 34 
16.6. 
Columbia Suicide Severity Rating Scale (C-SSRS) ............................................................................ 34 
16.7. 
Movement Disorder Measures ............................................................................................................ 36 
16.8. 
Subgroup Analysis .............................................................................................................................. 37 
16.9. 
Pharmacokinetic Analysis ................................................................................................................... 37 
16.10. 
Interim Analysis .................................................................................................................................. 38 
17. 
REFERENCES .............................................................................................................. 38 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS ............................. 39 
APPENDIX 2. PARTIAL DATE CONVENTIONS ............................................................ 40 
Algorithm for Prior / Concomitant / Post-treatment Medications: ................................................................... 42 


 
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APPENDIX 3. CLINICAL LABOROTORY PARAMETERS .......................................... 47 
APPENDIX 4. POTENTIALLY CLINICALLY SIGNIFICANT (PCS) LABORATORY 
CRITERIA 
49 
APPENDIX 5. PRECISION PRESENTATION OF STATISTICAL RESULTS .............. 51 
 
 


 
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1. INTRODUCTION 
Schizophrenia is a chronic and disabling neurodegenerative disorder characterized by a mixture of positive 
symptoms, negative symptoms, and cognitive deficits. SEP-363856 is currently being investigated in subjects with 
schizophrenia. One randomized, double-blind study (SEP361-201) evaluating efficacy and safety of flexible SEP-
363856 doses (50 mg/day or 75 mg/day) in adult subjects with schizophrenia is clinically complete. Subjects who 
completed this study are eligible to enroll in a 26-week open-label safety and tolerability study of SEP-363856 
(SEP361-202). 
The primary objective of the current study is to investigate the effect of open-label administration of SEP-363856 
(50 or 75 mg/day) adjunctive to an antipsychotic, on brain dopamine synthesis capacity, as measured by 18F-DOPA 
positron emission tomography (PET) imaging, in adults with schizophrenia. 
Overall, in previous clinical studies, SEP-363856 was generally well-tolerated. The pharmacokinetic (PK) and 
safety profiles observed in healthy male subjects and male and female subjects with schizophrenia from completed 
Phase 1 clinical studies, as well as accumulating safety data from the clinically complete Phase 2 double-blind and 
ongoing open-label extension studies in adults with schizophrenia, support the evaluation of SEP-363856 in the dose 
range of 50 to 75 mg/day in adults with schizophrenia. 
Schizophrenia is a life-long disorder and despite advances in drug treatment many patients continue to experience 
symptoms with impaired quality of life. SEP-363856 has a novel mechanism of action not related to direct 
antagonism of the D2 receptor. If proven effective and well-tolerated, it may provide an advance in the treatment of 
patients with schizophrenia by reducing the side-effect burden associated with direct D2 receptor antagonists. 
This document describes the rules and conventions to be used in the presentation and analysis of efficacy, safety and 
pharmacokinetic (PK) data for Protocol SEP361-118. It describes the data to be summarized and analyzed, including 
specifics of the statistical analyses to be performed.  
This statistical analysis plan (SAP) is based on Sumitomo Pharma America, Inc. (formerly Sunovion 
Pharmaceuticals Inc.; herein referred to as SMPA) Protocol version 5.00, dated 18MAR2020. 
2. STUDY OBJECTIVES 
2.1. PRIMARY OBJECTIVE 
The primary objective is to investigate the effect of open-label administration of SEP-363856 (50 or 75 mg/day) 
adjunctive to an antipsychotic, on brain dopamine synthesis capacity in adults with schizophrenia, as measured by 
18F-DOPA positron emission tomography (PET) imaging. 
2.2. SAFETY OBJECTIVES 
The safety objectives are: 
• 
To evaluate the safety and tolerability of adjunctive administration with SEP-363856 (50 or 75 mg/day) in 
adults with schizophrenia. 


 
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• 
To assess whether adjunctive administration of SEP-363856 is associated with extrapyramidal symptoms as 
measured by the Barnes Akathisia Rating Scale (BARS), the Abnormal Involuntary Movement Scale (AIMS), 
and the Simpson-Angus Scale (SAS). 
2.3.  OTHER OBJECTIVES 
The other objectives are: 
• 
To characterize the relationship between brain dopamine synthesis capacity and plasma SEP-363856 and its 
N-desmethyl metabolite, SEP-363854 exposure. 
• 
To explore the effect of SEP-363856 on neuromelanin and iron content (as well as other potential markers 
identifiable through MRI) and investigate the relationship of these markers with the 18F-DOPA PET measure 
of dopamine synthesis capacity. 
• 
To explore the effect of SEP-363856 on resting state functional magnetic resonance imaging (fMRI) as a 
biomarker of effects in circuits relevant to schizophrenia and cognitive function. 
• 
To investigate the effect of adjunctive open-label administration of SEP-363856 (50 or 75 mg/day) on 
psychiatric symptoms in adults with schizophrenia. 
3. STUDY ENDPOINT 
3.1. PRIMARY ENDPOINT 
Change from baseline in dopamine synthesis capacity at Week 2 using 18F-DOPA. 
3.2. SAFETY ENDPOINTS 
• 
Incidence of treatment emergent adverse events (TEAEs), serious AEs (SAEs) and AEs (or SAEs) leading to 
discontinuation. 
• 
Absolute values and changes from baseline in clinical laboratory tests (hematology, serum chemistry, 
urinalysis), and clinical evaluations (vital signs, body weight, body mass index [BMI], 12-lead 
electrocardiogram [ECG] parameters). 
• 
Frequency and severity of suicidal ideation or suicidal behavior as measured by the C-SSRS. 
• 
Change from Baseline in BARS, AIMS and SAS scores at Week 2 and Week 3. 
3.3. OTHER ENDPOINTS 
• 
Change in baseline resting state BOLD fMRI signal at Week 2. 


 
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• 
Change in exploratory MRI markers, including but not limited to neuromelanin signal as measured by 
neuromelanin sensitive MRI (NM-MRI) and iron signal as measured by an iron-sensitive MRI sequence 
(effective transverse relaxation rate [R2*] or Quantitative Susceptibility Mapping [QSM]), at Week 2. 
• 
Plasma concentrations of SEP-363856 and its metabolite SEP-363854 at each post-dose timepoint. 
• 
Change from baseline to Week 2 in: 
• 
Positive and Negative Syndrome Scale (PANSS) scores. 
• 
Brief Negative Symptom Scale (BNSS).  
• 
Montgomery-Asberg Depression Rating Scale (MADRS) total score. 
• 
Clinical Global Impression-Severity (CGI-S) score. 
4. STUDY DESIGN 
4.1. GENERAL DESCRIPTION 
This is a single-site, open-label, flexibly dosed study evaluating the effect on brain dopamine synthesis capacity as 
measured by 18F-DOPA PET imaging of adjunctive open-label administration of SEP-363856 (50 to 75 mg/day) 
over 2 weeks in adults with schizophrenia. 
The study will consist of 3 periods: Screening (up to 49 days), Treatment (2 weeks), and a Follow-up visit as shown 
in Figure 1. 
During each PET scan, there will be two periods of resting state fMRI collection, and one period for NM-MRI and 
iron-sensitive MRI collection. Two PET scans will be conducted during the study: 1 PET scan prior to dosing 
(between Day -44 to Day -2) and 1 PET scan following approximately 14 days of treatment (Day 14). 
Safety and tolerability will be monitored throughout the study by physical examination, electrocardiogram [ECGs], 
vital signs, body weight, BMI, collection of adverse events (AEs), clinical laboratory parameters, and the Columbia-
Suicide Severity Rating Scale (C-SSRS). Subjects who have significant findings for suicidal ideation assessed by the 
C-SSRS at any time during the study must be referred to the Investigator for follow-up evaluation. 
Population pharmacokinetic analyses will be performed using plasma SEP-363856 concentrations; the results of 
which will be reported separately. The relationship between dopamine synthesis capacity and plasma SEP-363856 
exposure using population pharmacokinetic (PK)/pharmacodynamics (PD) methods will be explored. The plasma 
concentrations of the background antipsychotic medication will be examined based on bioanalytical determination, 
when available. 
Exploratory evaluation of the effects of SEP-363856 on psychiatric symptoms will be based on change from 
baseline to Week 2 on the PANSS, CGI-S, and BNSS rating scales. 


 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
Figure 1: Study Schematic
 
  Schedule of Events 
Schedule of events can be found in Section 1 Table 2 of the Protocol. 
4.2. CHANGES TO ANALYSIS FROM PROTOCOL 
No changes to the planned analyses are due to COVID-19. 
Protocol:  
15.2. Analysis Populations 
The Per Protocol Population defined in the Protocol will not be utilized for either safety analysis covered by this 
SAP or imaging analysis covered by a separate SAP. Therefore, a per protocol population will not be determined for 
this study. 
15.3.3. Important Protocol Deviations 
“The number and percentage of subjects with IPDs will be summarized by type of deviation and dose group.”  
Change to “The number and percentage of subjects with IPDs will be summarized by category of deviation for SEP-
363856 (Overall) for the safety population.” 


 
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15.3.8.2. Clinical Laboratory Assessments 
“For laboratory parameters with continuous outcomes, descriptive statistics (number of subjects, mean, SD, median, 
minimum, and maximum) for the observed values and for changes from baseline will be presented and overall at 
each visit. For laboratory parameters with categorical outcomes, the number and percentage of subjects with each 
outcome will be presented for each dose cohort and overall at each visit. 
The number and percentage of subjects with Sponsor defined potentially clinically significant (PCS) laboratory 
values (defined in the SAP) will be summarized for each dose cohort and overall at each visit. The data listings for 
laboratory parameters will flag values outside of the reference range. Clinically significant laboratory findings will 
be displayed in a separate data listing.” 
Change to “For laboratory parameters with continuous outcomes, descriptive statistics (number of subjects, mean, 
SD, median, Q1, Q3, minimum, and maximum) for the observed values and for changes from baseline will be 
presented for SEP-363856 (Overall) [which refers to the overall treatment group] at each visit. For laboratory 
parameters with categorical outcomes, the number and percentage of subjects with each outcome will be presented 
for SEP-363856 (Overall) at each visit. 
The number and percentage of subjects with Sponsor defined potentially clinically significant (PCS) laboratory 
values (defined in the SAP) will be summarized for SEP-363856 (Overall) at each visit. The data listings for 
laboratory parameters will flag values outside of the reference range. PCS laboratory findings will be displayed in a 
separate data listing.” 
 
15.3.8.3. Electrocardiograms 
“The number and percentage of subjects with QTcF values in the following categories will be summarized:  
• 
QTcF ≥ 500 ms at any postdose timepoint and not present at baseline.  
• 
QTcF ≥ 480 ms at any postdose time point and not present at baseline.  
• 
QTcF ≥ 450 ms at any postdose timepoint and not present at baseline.  
• 
Change from baseline in QTcF ≥ 60 ms for at least one postdose measurement.  
• 
Change from baseline in QTcF ≥ 30 ms for at least one postdose measurement, but ≤ 60 ms for all postdose 
measurements.”  
Change to “The number and percentage of subjects with QTcF values in the following categories will be 
summarized: 
• 
QTcF > 500 ms at any postdose timepoint (including unscheduled visits) and not present at baseline 
• 
QTcF > 480 ms at any postdose timepoint (including unscheduled visits) and not present at baseline 
• 
QTcF > 450 ms at any postdose timepoint (including unscheduled visits) and not present at baseline 
• 
Change from baseline in QTcF ≥ 60 ms for at least one postdose measurement (including unscheduled visits) 
• 
Change from baseline in QTcF ≥ 30 ms for at least one postdose measurement (including unscheduled visits) 
and < 60 ms for all postdose measurements (including unscheduled visits)” 
 


 
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15.3.8.4. Vital Signs 
“The number and percentage of subjects with orthostatic hypotension will be summarized by dose cohort by 
timepoint and overall. Orthostatic hypotension is defined as a decrease of ≥ 20 mmHg in systolic blood pressure or ≥ 
10 mmHg in diastolic blood pressure after the subject had been standing for at least 2 to 4 minutes, compared to the 
systolic and diastolic blood pressures measured in the supine position, respectively.” 
Change to “The number and percentage of subjects with orthostatic hypotension will be summarized by timepoint 
and for the overall post-dose period for SEP-363856 (Overall). Orthostatic hypotension is defined as a decrease of ≥ 
20 mmHg in systolic blood pressure or ≥ 10 mmHg in diastolic blood pressure after the subject had been standing 
for at least 2 to 4 minutes, compared to the systolic and diastolic blood pressures measured in the supine position, 
respectively.” 
 
15.3.8.6 Concomitant Medications 
Change “Medication taken between screening and the follow-up visit will be reported as concomitant.” to “Other 
than the study drug, any medication taken during the course of the study, with a start date/time on or after the first 
dose of study drug and on or before the last dose of study drug; or with a start date/time prior to, and an end 
date/time on or after, the first dose of study drug, or marked as ongoing, will be considered concomitant.” 
 
Appendix II Clinical Laboratory Tests 
“HEMATOLOGY: (Differential reported as % and absolute value)” changed to “HEMATOLOGY: (Differential 
reported as fraction of 1 and absolute value)”. 
5. PLANNED ANALYSES 
The following analyses will be performed for this study: 
• 
Final Analysis  
5.1. DATA MONITORING COMMITTEE (DMC)  
There will be no DMC for this study. 
5.2. INTERIM ANALYSIS  
No interim analysis is planned. 


 
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5.3. FINAL ANALYSIS  
All final, planned analyses identified in this SAP (which does not include PET and fMRI analysis) will be performed 
by IQVIA Biostatistics following database lock. 
6. ANALYSIS POPULATIONS 
Enrolled subjects are subjects who signed the ICF and did not screen fail at their final screening. 
Three analysis populations will be defined in this study.  The population for PET and fMRI analyses will be 
specified in a separate Statistical Analysis Plan. 
6.1. SAFETY POPULATION [SAF] 
The safety population will consist of all subjects who receive at least one dose of study drug. 
6.2. EFFICACY POPULATION [EFF] 
The efficacy population is defined as all subjects who have received at least one dose of study drug and have any 
postdose data for the PANSS, CGI-S, BNSS or MADRS.  
 
7. STATISTICAL CONSIDERATIONS 
7.1. REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date and will be used to show the start/ stop day of assessments 
and events.  
Reference start date is defined as the date of the first dose of study medication (Day 1 is the study day of the first 
dose of study medication).  
• 
If the date of the assessment or event is on or after the reference start date then:  
Study Day = (date of assessment or event – reference start date) + 1. 
 
• 
If the date of the assessment or event is prior to the reference start date then:  
Study Day = (date of assessment or event – reference start date). 
 


 
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In the situation where the assessment or event date is partial or missing, Study Day and any corresponding durations 
will appear missing in the listings. Partial assessment or event dates will however be presented as is in the listings.  
7.2. BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior to the first dose of 
study medication (including unscheduled assessments). Whenever available, the time information should be 
accounted for in the derivation of baseline values. In the case where time is not available and the date of the last 
non-missing measurement and the date of the first dose of study medication coincide, that measurement will be 
considered baseline. 
7.3. RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION 
DATA 
In general, for by-visit summaries, data recorded at the nominal visit will be presented.  
In the case of a retest, the assessment recorded under the planned visit will be used for by-visit summaries, and the 
assessment(s) recorded under unscheduled visit(s) will be presented in listings only.  
Early termination data will be mapped to the next scheduled or planned timepoint where an assessment is expected 
to be performed as specified by the Schedule of Assessment table in the Protocol for by-visit summaries. This 
applies to all efficacy, safety, and PK data. 
Listings will include scheduled, unscheduled, retest and early discontinuation data. 
Unscheduled measurements will not be included in by-visit summaries. Unscheduled measurements collected prior 
to the first dose of study medication will contribute to the derivation of the baseline value. Unscheduled 
measurements collected post baseline will contribute to the derivation of potentially clinically significant (PCS) 
post-baseline value and worst case value where required. 
7.4. WINDOWING CONVENTIONS  
No visit windowing will be performed for this study. 
7.5. STATISTICAL TESTS 
The default significance level will be 5%; confidence intervals (CIs) will be 95%. All p-values and CIs will be two-
sided, unless otherwise specified in the description of the analyses. 


 
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7.6. COMMON CALCULATIONS 
For quantitative measurements, change from baseline will be calculated as: 
 
Test Value at Visit X – Baseline Value 
For PK computations, the Percentage Coefficient of Variation (CV%), Geometric Mean (GM), and Percentage 
Geometric Coefficient of Variation (GCV% or ‘Geometric CV%’) will be computed as below: 
𝐶𝑉% = 100 
𝑆𝐷
𝑀𝑒𝑎𝑛 
𝐺𝑀= 𝑒𝑀𝑒𝑎𝑛𝐿𝑜𝑔 
𝐺𝐶𝑉% = (100)√(𝑒𝑆𝐷𝐿𝑂𝐺
2
) −1 
Where SD is the sample standard deviation, Mean is the sample mean, MeanLog is the sample mean of the 
log transformed data, and SDLog is the sample standard deviation of the log transformed data.  Note that 
when the data are lognormally distributed, CV% and GCV% are equal. 
7.7. SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.4 or higher  
7.8. MISSING DATA 
No imputation will be performed for missing data.  
7.9.  EXAMINATION OF SUBGROUPS 
No subgroup analyses will be performed for the analysis defined in this SAP. 
8. OUTPUT PRESENTATIONS 
APPENDIX 1 shows conventions for presentation of data in outputs.  
The templates provided with this SAP describe the presentations for this study and therefore the format and content 
of the summary tables, figures, and listings to be provided by IQVIA Biostatistics. 
 


 
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9. DISPOSITION AND WITHDRAWALS 
All subjects screened will be accounted for in this study.  
The number and percentage of subjects screened, screen failed, and enrolled will be summarized for SEP-363856 
(Overall) based on the number of all subjects screened. The number and percentage of subjects under each reason 
for screen failure will be presented based on the number of subjects screened. Number and percentage of subjects 
completing the study or terminating early will also be summarized (with reasons for early termination), based on the 
number of enrolled subjects. The number and percentage of subjects included in the safety and efficacy populations 
will be presented, based on the number of enrolled subjects. 
The number of subjects who failed screening due to COVID-19 related reasons and who discontinued early due to 
COVID-19 related reasons will be summarized in the disposition table. Subjects who failed screening or 
discontinued due to COVID-19 related AEs are identified by the following AEs with preferred terms (PTs) and 
codes: 
• 
Coronavirus test positive (PT code = 10070255), or 
• 
Corona virus infection (PT code = 10053983). 
Disposition data will be provided in a listing for screen failures and all subjects enrolled. 
9.1. IMPORTANT PROTOCOL DEVIATIONS 
Important Protocol Deviations (IPDs) will be identified and documented based on a review of data listings and the 
protocol deviations log.  
The IPD categories may include, but may not be limited to: 
• 
Did not meet inclusion/exclusion criteria.  
• 
Received any disallowed concomitant medication.  
IPDs will be identified for all enrolled subjects and presented in a data listing. The number and percentage of 
subjects with IPDs will be summarized by category of deviation for SEP-363856 (Overall) for the safety population.  
In addition, a listing of all protocol deviations reported by the clinical team during the study, including impact by 
COVID-19, will be provided for all subjects enrolled. 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be presented for the safety population and efficacy 
population. No statistical testing will be carried out for demographic or other baseline characteristics. 
The number and percentage of subjects by gender, racial group and ethnicity will be summarized. Age, baseline 
height, baseline weight, baseline BMI, baseline efficacy parameters (PANSS total score, PANSS subscale scores 
(positive, negative, and general psychopathology), CGI-S score, BNSS total score, and MADRS total score) and 
baseline movement disorder measures (AIMS total score, BARS total score, and SAS mean score) will be 
summarized using descriptive statistics (number of subjects, mean and standard deviation, median, Q1, Q3, 


 
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minimum, and maximum).  
Individual subject demographics and baseline characteristics will be presented in listings for all subjects enrolled. 
10.1. DERIVATIONS 
• 
BMI (kg/ m2) = weight (kg)/ height (m)2 
11. MEDICAL AND PSYCHIATRIC HISTORY 
The medical history as well as psychiatric history of subjects will be coded by System Organ Class (SOC) and 
Preferred Term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA), version 22.0. The number 
and percentage of subjects in each SOC and each PT will be summarized for the safety population for SEP-363856 
(Overall). 
Each subject’s medical and psychiatric history will be listed by SOC and PT for all subjects enrolled. 
12. PRIOR AND CONCOMITENT MEDICATIONS 
Subjects may not take any disallowed prescription or disallowed non-prescription medications, or dietary or herbal 
supplements, for at least 5 half-lives or 14 days prior to dosing, whichever is longer or anticipate the need for any 
disallowed medication during their participation in this trial. Concomitant use of CYP2D6 inhibitors is prohibited. 
Subjects may not use Clozapine for at least 120 days prior to PET scan at screening. Antidepressants, mood 
stabilizers, or anxiolytics [lorazepam or equivalent at doses above protocol-specified limits] are prohibited 
concomitant medications. Electroconvulsive therapy is prohibited within 3 months prior to screening and during the 
study. 
Other than the study drug, any medication taken during the course of the study, with a start date/time on or after the 
first dose of study drug and on or before the last dose of study drug; or with a start date/time prior to, and an end 
date/time on or after, the first dose of study drug, or marked as ongoing, will be considered concomitant. 
Medications that stopped prior to the first dose of study drug will not be considered concomitant but prior 
medications. Post treatment medications are medications which started after the last dose of study drug. 
Antipsychotic agents including depot neuroleptics taken within at least 6 months prior to screening, and any other 
medications taken within at least 3 months prior to screening, through the End of Study visit will be recorded and 
reported. All medications will be provided in a listing for all subjects enrolled. 
All medications will be coded using the World Health Organization Drug Dictionary (WHODRUG version 
01MAR2019). The number and percentage of subjects using each prior/concomitant medication will be summarized 
for safety population for SEP-363856 (Overall) according to the WHODRUG Anatomic Therapeutic Class (ATC) 
Level III and preferred name. Subjects with multiple uses of a prior/concomitant medication will be counted once 
for a given ATC class and preferred name. 
Similarly, the number and percentage of subjects using background antipsychotics, including typical, atypical, oral 
and depot antipsychotics, will be summarized for safety population for SEP-363756 (Overall) according to the 


 
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Version Number: 
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WHODRUG Anatomic Therapeutic Class (ATC) Level III and preferred name. Background antipsychotics, 
including typical, atypical, oral and depot antipsychotics, are identified based on all prior/concomitant medications 
with “Started prior to study?” = “Yes” and “Ongoing”=”Yes”. The definitions of those medications are as below: 
 
Category 
Definition 
Antipsychotics 
ATC3 Code = N05A 
Typical Antipsychotics 
ATC4 Code = N05AA, N05AB, N05AC, N05AD, 
N05AF or N05AG 
Atypical Antipsychotics 
ATC4 Code = N05AE, N05AH, N05AL or N05AX 
Oral Antipsychotics 
ATC3 Code = N05A and “Route” = “oral” 
Depot Antipsychotics 
ATC3 Code = N05A and (“Route” = “intramuscular”, 
“subcutaneous” or “other”) and (“Frequency” = “As 
needed” or “other”) 
 
13. STUDY MEDICATION EXPOSURE  
The total number of days of exposure to study drug by dose level and for SEP-363856 (Overall) will be summarized 
categorically (N [%]) for the safety population. The total number of doses of exposure to radiotracer will be 
summarized categorically (N [%]) for the safety population as well. 
A data listing, by subject, containing the study medication dosing data will be provided for all subjects enrolled.  
14. STUDY MEDICATION COMPLIANCE  
Treatment compliance will not be summarized as all dosing will occur in-clinic. 
15. EFFICACY OUTCOMES  
The analyses of the efficacy variables will be performed on the efficacy population, unless otherwise specified. 


 
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15.1. EFFICACY VARIABLES 
Efficacy parameters include PANSS total score, PANSS subscale scores (positive, negative, and general 
psychopathology), PANSS factor scores (Marder factor scores and UPSM factor scores), CGI-S score, BNSS total 
score, BNSS subscale scores and MADRS total score. Tabular summaries will be based on the Efficacy Population. 
The actual values and changes from baseline at each post-dose time point will be summarized, with 95% confidence 
intervals. 
Efficacy parameters for each individual subject will be listed for all enrolled subjects. 
 
PANSS 
PANSS is used to measure the psychopathology in adults with psychotic disorders, comprising 30 items and 3 
subscales. The positive subscale assesses hallucinations, delusions and related symptoms (7 items), the negative 
subscale assesses emotional withdrawal, lack of motivation and related symptoms (7 items), and the general 
psychopathology subscale assesses other symptoms such as anxiety, somatic concern and disorientation (16 
items). An anchored Likert scale from 1 to 7 (1 = absent, 7 = extreme, with values of 2 and above indicating the 
presence of progressively more severe symptoms) is used to score each item. Individual items are summed to derive 
the following scores:  
 
• 
Total score = sum of all 30 items. Total score ranges from 30 to 210. 
 
• 
Subscale scores = sum of items within each of the following subscales: 
o 
Positive subscale: delusions, conceptual disorganization, hallucinatory behavior, excitement, 
grandiosity, suspiciousness/persecution, hostility. This subscale score ranges from 7 to 49. 
o 
Negative subscale: blunted affect, emotional withdrawal, poor rapport, passive/apathetic social 
withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, 
stereotyped thinking. This subscale score ranges from 7 to 49. 
o 
General psychopathology subscale: somatic concern, anxiety, guilt feelings, tension, mannerisms 
and posturing, depression, motor retardation, uncooperativeness, unusual thought content, 
disorientation, poor attention, lack of judgment and insight, disturbance of volition, poor impulse 
control, preoccupation, active social avoidance. This subscale score ranges from 16 to 112. 
 
• 
Marder factor scores – sum of items within each of the following factors (Marder, Davis, Chouinard. 1997): 
o 
Negative symptoms: blunted affect, emotional withdrawal, poor rapport, passive/apathetic social 
withdrawal, lack of spontaneity and flow of conversation, motor retardation, active social 
avoidance 
o 
Positive symptoms: delusions, hallucinatory behavior, grandiosity, suspiciousness/persecution, 
stereotyped thinking, somatic concern, unusual thought content, lack of judgment and insight 


 
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o 
Disorganized thought: conceptual disorganization, difficulty in abstract thinking, mannerisms and 
posturing, disorientation, poor attention, disturbance of volition, preoccupation 
o 
Uncontrolled hostility/excitement: excitement, hostility, uncooperativeness, poor impulse control 
o 
Anxiety/depression: anxiety, guilt feelings, tension, depression 
 
• 
UPSM factor scores 
The PANSS item scores of each subject at each visit will be transformed using the uncorrelated PANSS 
score matrix (UPSM), to obtain the scores of 7 transformed PANSS factors (Hopkins et al. 2018): 
o 
POS: Positive 
o 
DIS: Disorganized 
o 
NAA: Negative apathy/avolition 
o 
NDE: Negative deficit of expression 
o 
HOS: Hostility 
o 
ANX: Anxiety 
o 
DEP: Depression 
The transformation will be done as follows: 
[PANSS Data](N×30) ∗[UPSM](30×7) = [Transformed PANSS Factor Data](N×7) 
where 
[PANSS Data](N×30) is matrix with N PANSS assessments and 30 columns containing the scores of 30 
PANSS items ordered in the same way as shown in UPSM. 
[𝑈𝑃𝑆𝑀](30×7) is a matrix with 30 rows (one for each PANSS item) and 7 columns (one for each of the 7 
transformed PANSS factors). This matrix is presented in Table 1. 
[Transformed PANSS Factor Data](N×7) is the transformed matrix with N sets of scores for the 7 
transformed PANSS factors


 
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Table 1 - Uncorrelated PANSS Score Matrix (UPSM) for Generating Transformed PANSS Factor Scores 
PANSS 
UPSM-POS 
UPSM-DIS 
UPSM-NAA 
UPSM-NDE 
UPSM-HOS 
UPSM-ANX 
UPSM-DEP 
PANSS01 
0.5792730597 
-0.1547126840 
-0.0828932650 
0.0071927220 
-0.0593031510 
-0.0735449620 
0.0020484408 
PANSS02 
0.0292444390 
0.1975824582 
-0.0260173260 
-0.0234753800 
-0.0368756010 
-0.0012396240 
-0.0361645050 
PANSS03 
0.2065788330 
-0.0179419820 
-0.0250663450 
-0.0133031880 
-0.0300507070 
0.0001506005 
0.0293001724 
PANSS04 
-0.0336790630 
0.0115284348 
0.0011652392 
-0.0723891460 
0.1379358628 
0.1108194656 
-0.1045224460 
PANSS05 
-0.0341508580 
-0.0301875430 
-0.0041019560 
-0.0233459100 
-0.0069204000 
-0.0313277060 
0.0308288417 
PANSS06 
0.3537254634 
-0.0626270750 
0.0477329954 
0.0012126712 
0.0192067437 
-0.0161398140 
0.0063264235 
PANSS07 
-0.0383468990 
-0.1767919370 
-0.0299340700 
0.0314652864 
0.5025411101 
-0.0997121200 
0.0573604084 
PANSS08 
-0.0054230270 
-0.0291400280 
0.0568702938 
0.2474176209 
-0.0388464000 
0.0188235393 
-0.0091524870 
PANSS09 
-0.0315765690 
-0.0243925850 
0.3317907576 
-0.0228204580 
-0.0507096280 
-0.0145653830 
0.0112689069 
PANSS10 
-0.0742072890 
-0.0401313020 
-0.0097485120 
0.0161513666 
0.0245536353 
-0.0176161520 
-0.0172218040 
PANSS11 
-0.0943532590 
-0.0856364190 
0.4611503804 
-0.0286825100 
-0.0189062390 
-0.0185825180 
-0.0130433890 
PANSS12 
0.0043338689 
0.1062496353 
0.0255910591 
-0.0301470410 
-0.0133497570 
0.0096065791 
-0.0686802390 
PANSS13 
0.0041274699 
0.0051521898 
0.0009558861 
0.2576813501 
-0.0085004640 
0.0194235006 
-0.1037459520 
PANSS14 
-0.0111267300 
0.1462268689 
-0.0276416260 
0.0023017188 
-0.0055291270 
-0.0118427800 
0.0040128786 
PANSS15 
-0.0356272010 
0.0552508287 
-0.0382627720 
0.0110152489 
-0.0309176290 
0.0444944076 
0.1059845189 
PANSS16 
-0.0331052830 
-0.0821894470 
-0.0327376640 
-0.0533178140 
-0.0386473380 
0.4576579818 
0.1197800301 
PANSS17 
-0.0368854600 
-0.0004363100 
-0.0020681500 
-0.0407976460 
-0.0272172130 
-0.0253163640 
0.2459654614 
PANSS18 
-0.0931367690 
-0.0332617600 
-0.0132943930 
0.0231904701 
-0.0287529750 
0.5123850161 
-0.0312522560 
PANSS19 
-0.0455199430 
0.0494113554 
-0.0324174560 
0.1026255664 
-0.0136676190 
0.0293507269 
-0.0441735260 
PANSS20 
-0.0344751890 
-0.0688197670 
-0.0412738350 
0.0381793764 
0.0042219619 
-0.0635101090 
0.4514426846 
PANSS21 
-0.0348890020 
-0.0366137810 
-0.0779782830 
0.4409895205 
-0.0073240410 
-0.0192655290 
0.0464131877 


 
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PANSS22 
-0.0803690920 
0.0334025939 
-0.0088488890 
-0.0200483170 
0.2858700784 
-0.0567167860 
-0.0531076130 
PANSS23 
0.1428966744 
0.0939213700 
-0.0326143600 
-0.0367524640 
-0.0675856980 
-0.0209072840 
-0.0177890070 
PANSS24 
-0.0383047770 
-0.0324584080 
-0.0255393890 
-0.0180115340 
-0.0266180700 
-0.0210068530 
-0.0176029110 
PANSS25 
-0.1036311520 
0.2814367260 
-0.0478918640 
0.0029986238 
0.0037656449 
-0.0226520240 
0.0401351054 
PANSS26 
0.0142987589 
0.1548635741 
-0.0306089330 
-0.0331581690 
0.0262295986 
-0.0576293550 
-0.0626180490 
PANSS27 
-0.0573513270 
0.1867914227 
-0.0143489160 
0.0581534153 
-0.0145494330 
-0.0371788310 
0.0455412078 
PANSS28 
-0.0748387810 
0.0166272025 
-0.0267498020 
-0.0031632780 
0.2546669938 
-0.0201249190 
-0.0076420280 
PANSS29 
-0.0520812460 
0.2912295497 
0.0029775475 
-0.0324350460 
-0.0442337350 
-0.0047991290 
0.0567191230 
PANSS30 
-0.0112030990 
-0.0007246980 
0.2860136812 
-0.0606201430 
0.0183598393 
-0.0302347770 
0.0370748725 


 
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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. The CGI-S score takes one of the following values: 1 (normal, not at 
all ill), 2 (borderline mentally ill), 3 (mildly ill), 4 (moderately ill), 5 (markedly ill), 6 (severely ill), 7 (among the 
most extremely ill patients). 
BNSS 
The BNSS is a rating scale to measure the current level of severity of negative symptoms in schizophrenia and 
schizoaffective disorder. The measure is comprised of 13 individual items organized in 6 subscales (blunted affect 
(items 9, 10, 11), alogia (items 12, 13), avolition (items 7, 8), anhedonia (items 1, 2, 3), asociality (items 5, 6), and 
distress (item 4)). The 13 individual items provide a composite total score (ranging from 0 to 78). Each of the items 
is scored on a Likert-type 7-point scale from 0 - 6, where a value of 0 indicates symptom is absent and a value of 6 
means the symptom is a severe form. In addition, BNSS subscale scores will be calculated by summing the item 
scores under each subscale. 
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. MADRS total score will be calculated by the sum of all 10 item 
scores. 
15.2. MISSING DATA METHOD FOR EFFICACY VARIABLES 
The PANSS total score, PANSS subscale scores (positive, negative, and general psychopathology), PANSS factor 
scores (Marder factor scores and UPSM factor scores), BNSS total score, BNSS subscale scores and MADRS total 
score will be set to missing if any one item contributing to the total/subscale/factor score is missing. The change 
from baseline in PANSS total score, PANSS subscale scores (positive, negative, and general psychopathology), 
PANSS factor scores (Marder factor scores and UPSM factor scores), CGI-S score, BNSS total score, BNSS 
subscale scores and MADRS total score at Week 2 (Day 14 or ET), will be set to missing if such scores at baseline 
or at Week 2 (Day 14 or ET) is missing. Missing data will not be imputed. 
16. SAFETY OUTCOMES 
All tabular summaries for safety outcomes will be based on the safety population.  
16.1. ADVERSE EVENTS 
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) central coding dictionary, 
Version 22.0. 
An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 


 
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occurring after signing the informed consent form (ICF), whether or not considered related to the medicinal 
(investigational) product. AEs may include the onset of new illness and the exacerbation of pre-existing conditions. 
AEs will be collected from the time of signing the ICF to the last study visit/EOS visit. 
TEAEs are untoward medical occurrences: 
• 
that occurred on or after the first dose of study medication, 
• 
with a missing start date and a stop date on or after the first dose of study medication, or 
• 
with both a missing start date and a missing stop date. 
The following TEAEs will be summarized and presented by MedDRA SOC and PT for the Safety population:  
• 
All TEAEs (including number of events and subject incidence).  
• 
TEAEs by severity (mild, moderate, severe).  
• 
TEAEs by relationship to the study treatment (related, or not related).  
• 
TEAEs by dose at onset (including number of events and subject incidence) 
• 
TEAEs leading to study medication discontinuation (including number of events and subject incidence) 
• 
Serious TEAEs (including number of events and subject incidence) 
• 
TEAEs leading to study discontinuation (including number of events and subject incidence) 
The following conventions will be followed in summarizing TEAEs:  
• 
For subject incidence summaries, each subject will be counted only once within each SOC and within each 
preferred term.  
• 
If a subject reports more than one TEAE within a preferred term and/or a body system, the adverse event 
with the highest known severity within each body system and within each preferred term will be included 
in the summaries by severity. Any TEAE with a missing severity will be treated as “severe” and counted in 
the severe category.  
• 
For summaries by relationship to study drug, TEAEs assessed as “possible,” “probable,” or “definite” will 
be grouped as “related.” If a subject reports more than one TEAE within the same treatment regimen, SOC 
and PT, and any are related, it will be summarized as related. Any TEAE with a missing relationship to 
study medication will be regarded as “related” to study medication. 
• 
For summaries by dose at AE onset, TEAEs will be summarized by the last actual dose level the subject 
was on before the onset of event. If a subject reports more than one TEAE within the same dose level, SOC 
and PT, it will be counted only once. 
Untoward medical occurrences that occur between the time of signing the ICF and first drug administration are 
pre-treatment events. 
A listing of AEs (TEAEs and pre-treatment events), as well as a listing of Serious TEAEs, TEAEs leading to 
discontinuation of study medication and discontinuation from study, TEAEs of potential drug abuse and dependence 
(see APPENDIX 6), and a listing of treatment emergent deaths will be presented. 
See APPENDIX 2 for handling of partial dates for AEs.  In the case where it is not possible to determine whether an 
AE began before or after dosing, the AE will be classified by the worst case; i.e. treatment emergent.  


 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
Presentations regarding each of the categories described in the sub-sections below, will be provided as described and 
specified in the templates. 
16.1.1. 
ALL AES 
TEAEs will be summarized by System Organ Class (SOC) and Preferred Term (PT) for SEP-363856 (Overall).  
Listings of pre-treatment events and TEAEs will also be presented for all subjects enrolled. A listing of pre-
treatment events will also be presented for screen failures. 
TEAEs will also be summarized by SOC, PT and dose at event onset for SEP-363856 (Overall). 
16.1.2. 
AES LEADING TO DISCONTINUATION OF STUDY MEDICATION 
AEs leading to permanent discontinuation of study medication will be identified by using the AE page of the 
electronic case report form [eCRF], where “Action Taken with Study Treatment” is answered as “Drug Withdrawn”. 
TEAEs will be summarized by SOC and PT for SEP-363856 (Overall). A listing of TEAEs leading to permanent 
discontinuation of study medication will be presented for all subjects enrolled. 
16.1.3. 
AES LEADING TO DISCONTINUATION FROM STUDY 
AEs leading to permanent discontinuation from the study will be identified by using the AE page of the electronic 
case report form [eCRF], where “Caused Study Discontinuation” is answered as “Yes”. TEAEs will be summarized 
by SOC and PT for SEP-363856 (Overall). A listing of TEAEs leading to permanent discontinuation from the study 
will be presented for all subjects enrolled. 
16.1.4. 
SEVERITY OF AES 
Severity is classed as mild/moderate/severe (increasing severity). AEs with a missing severity will be classified as 
severe. If a subject reports an AE more than once within a SOC/ PT, the AE with the worst case severity (i.e., 
maximum severity) will be used in the summary. 
TEAEs by severity will be summarized by SOC and PT for SEP-363856 (Overall). 
16.1.5. 
RELATIONSHIP TO STUDY MEDICATION 
Relationship, as indicated by the Investigator, is classed as not related, possible, probable, or definite (increasing 
strength of relationship). A related AE is defined as an AE with a relationship to study medication as possible or 
probable or definite. AEs with a missing relationship to study medication will be regarded as related to study 
medication. If a subject reports an AE more than once within a SOC/ PT, the AE with the strongest relationship to 
study medication will be used in the summary.  
TEAEs by relationship to study medication will be summarized by SOC and PT for SEP-363856 (Overall). 


 
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16.1.6. 
SERIOUS  ADVERSE EVENTS 
Serious adverse events (SAEs) are those events recorded as “Serious” on the Adverse Events page of the (e)CRF. 
Serious TEAEs will be summarized by SOC and PT for SEP-363856 (Overall). A listing of serious TEAEs will be 
presented for all subjects enrolled. 
16.1.7. 
ADVERSE EVENTS LEADING TO DEATH 
AEs leading to death are those events which are recorded with an AE outcome of “Fatal” on the Adverse Events 
page of the (e)CRF. A listing of TEAEs leading to death will be presented for all subjects enrolled. 
16.1.8. 
ADVERSE EVENTS OF POTENTIAL DRUG ABUSE AND DEPENDENCE 
AEs of potential drug abuse and dependence are defined as the following PT: All PTs within the FDA Guidance for 
Industry: Assessment of Abuse Potential of Drugs (CDER 2017), all PTs listed in the MedDRA version 22.0 broad 
SMQ for Drug abuse and dependence [20000101], and all Pts listed in the FDA FMQ: Study Agent Abuse Potential, 
Broad (2022). The list of such PTs are found in APPENDIX 6. A listing of TEAEs of potential drug abuse and 
dependence will be presented for all subjects enrolled. 
16.2. LABORATORY EVALUATIONS 
Results from the local laboratory will be included in the reporting of this study for hematology, serum chemistry, 
urinalysis, lipid panel, thyroid panel, urine drug screening, serology panel (hepatitis B Ag, hepatitis C Ab, and HIV 
Ab), coagulation panel and other tests [Serum Pregnancy (β-hCG) (in female subjects only), urine pregnancy test (in 
female subjects only), follicle stimulating hormone (FSH) (in female subjects only)]. A list of laboratory 
assessments to be included in the tables and listings is included in 0. 
Hematology, serum chemistry (except HbA1c), urinalysis, and lipid panel laboratory tests data are collected at Visit 
1 (screening), Visit 2 (Day -2), Visit 2 (Week 2), Visit 3 (follow-up) and ET (early termination). Urine drug 
screening is performed at Visit 1(screening), Visit 2 (Day -2), Visit 2 (Day 1), Visit 2 (Week 2), Visit 3 (follow-up) 
and ET (early termination). Serology panel, thyroid panel, HbA1c, and coagulation panel are collected at screening 
only. 
Presentations will use standard international (SI) Units. Quantitative laboratory measurements reported as “< X”, i.e. 
below the lower limit of quantification (BLQ), or “> X”, i.e. above the upper limit of quantification (ULQ), will be 
converted to X for the purpose of quantitative summaries, but will be presented as recorded, i.e. as “< X” or “> X” 
in the listings. 
The following summaries and listings will be provided for laboratory data: 
• 
For laboratory parameters with continuous outcomes (serum chemistry, hematology, urinalysis and lipid 
panel), descriptive statistics (number of subjects, mean, standard deviation, median, Q1, Q3, minimum, and 
maximum) for the actual values and for changes from baseline (when post-baseline assessments are 
scheduled) will be presented at each scheduled timepoint for SEP-363856 (Overall). For thyroid panel and 
coagulation panel, descriptive statistics (number of subjects, mean, standard deviation, median, Q1, Q3, 


 
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minimum, and maximum) for the actual values will be presented at each scheduled timepoint for SEP-
363856 (Overall). Glucose and lipid panel results will be summarized separately by fasting status: fasting 
only and overall (fasting, non-fasting, or fasting status unknown combined). Change from baseline for 
glucose and lipid panel results will only be calculated if post-baseline fasting status is matching baseline 
fasting status. 
• 
For laboratory parameters with categorical outcomes (urinalysis and urine drug screening), the number and 
percentage of subjects with each outcome will be presented at each scheduled timepoint for SEP-363856 
(Overall). 
• 
Shift in lab results (serum chemistry (except HbA1c), hematology, urinalysis and lipid panel) from baseline 
to each post-baseline visit according to the reference range criteria provided by the local laboratory.  
• 
The number and percentage of subjects with Sponsor-defined potentially clinically significant (PCS) 
laboratory values (serum chemistry, hematology, urinalysis and lipid panel) will be summarized for SEP-
363856 (Overall) at each visit and overall post-baseline. For the individual visits, percentages will be 
calculated based on the number of safety population subjects with data available for the given parameter 
and at the given visit. For the overall post-baseline period, percentages will be calculated based on the 
number of safety population subjects who had at least one non-missing post treatment test results for a 
particular laboratory parameter. Any early termination visit, follow-up visit or unscheduled visit that occurs 
after first dose will be included in the period of evaluation for PCS post-baseline. 
Data listings for all laboratory parameters (serum chemistry, hematology, urinalysis, lipid panel, thyroid panel, urine 
drug screening, serology panel, coagulation panel and other tests) will be provided for all subjects enrolled. Results 
outside of the reference range will be flagged. 
A listing of Potentially Clinically Significant (PCS) laboratory findings (serum chemistry, hematology, urinalysis, 
lipid panel, thyroid panel and coagulation panel) will be presented for all laboratory parameters with PCS criteria 
defined for all subjects enrolled. 
16.2.1. 
LABORATORY REFERENCE RANGES AND POTENTIALLY CLINICALLY SIGNIFICANT 
CRITERIA 
Laboratory reference range indicators provided by the local lab will be used in statistical analyses. Only if a 
reference range indicator is missing in the data transfer will it be derived in the analysis step as described below. 
• 
Quantitative laboratory measurements (that are not urinalysis erythrocytes or urinalysis leukocytes) will be 
compared with the relevant laboratory reference ranges in original units and categorized as: 
o 
Low: Below the lower limit of the laboratory reference range.  
o 
Normal: Within the laboratory reference range (upper and lower limit included). 
o 
High: Above the upper limit of the laboratory reference range. 
• 
For qualitative laboratory measurements as well as urinalysis erythrocytes and urinalysis leukocytes, if the 
result is within the reference range, the indicator is “NORMAL”; if the result is not within range, the indicator 
is “ABNORMAL”. 
In addition, PCS laboratory values will also be identified in accordance with the Sponsor defined PCS criteria as 
presented in APPENDIX 4. 


 
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16.3. ECG EVALUATIONS 
Results from the central ECG (Electrocardiogram) Reading Centre will be included in the reporting of this study.  
The following ECG parameters will be reported for this study: 
• 
PR Interval (msec) 
• 
QRS Duration (msec) 
• 
QRS Axis (deg) 
• 
RR interval (msec). 
• 
QT Interval (msec) 
• 
QTcF Interval (msec)  
• 
QTcB Interval (msec)  
• 
HR (bpm) 
• 
Overall assessment of ECG as determined by central over-read: 
• 
Normal 
• 
Abnormal, Insignificant 
• 
Abnormal, Significant 
• 
Not Evaluable 
• 
ECG findings 
Electrocardiogram parameters and changes in these parameters from baseline, as determined by the central over-
read, will be summarized using descriptive statistics (number of subjects, mean, standard deviation, median, Q1, Q3, 
minimum, and maximum) at each timepoint for SEP-363856 (Overall) for the safety population. For overall 
assessment, the number and percentage of subjects will be presented at each timepoint for SEP-363856 (Overall) for 
the safety population. 
Shift in ECG overall assessments from baseline to each post-baseline visit will also be presented. 
The number and percentage of subjects with QTcF/QTcB values in the following categories will be summarized: 
• 
QTcF/QTcB > 500 ms at any postdose timepoint (including unscheduled visits) not present at baseline 
• 
QTcF/QTcB > 480 ms at any postdose timepoint (including unscheduled visits) not present at baseline 
• 
QTcF/QTcB > 450 ms at any postdose timepoint (including unscheduled visits) not present at baseline 
• 
Change from baseline in QTcF/QTcB ≥ 60 ms for at least one postdose measurement (including unscheduled 
visits) 
• 
Change from baseline in QTcF/QTcB ≥ 30 ms for at least one postdose measurement (including unscheduled 
visits) and < 60 ms for all postdose measurements (including unscheduled visits) 


 
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Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
For the post-baseline summaries, the percent of subjects will be based on the number of safety population subjects 
with at least one non-missing post treatment value. For the change from baseline summaries, percentages will be 
based on the number of subjects with both baseline and at least one post-baseline result available. Any early 
termination visit, follow-up visit or unscheduled ECG that occurs after first dose will be included for these post 
treatment summaries. 
Data listings for all ECG parameters will be provided for all subjects enrolled. 
16.4. VITAL SIGNS 
Vital sign data is collected at Visit 1 (Screening), Visit 2 (Day -2), Visit 2  (Day -1), Visit 2  (Day 1 – predose), Visit 
2  (Week 2), Visit 3  (follow-up) and ET (Early termination).  Weight is collected at Visit 1 (Screening), Visit 2 
(Day -2), Visit 2 (Day 1 – predose), Visit 2 (Week 2), Visit 3 (follow-up) and ET (Early Termination). Height and 
BMI are collected at Visit 1 (Screening) only. Baseline height will be reported with demographics.   
The following Vital Signs measurements will be reported for this study: 
• 
Standing/ Supine Systolic Blood Pressure (mmHg) 
• 
Standing/ Supine Diastolic Blood Pressure (mmHg) 
• 
Standing/ Supine Pulse Rate (bpm) 
• 
Respiratory Rate (breaths/min) 
• 
Oral Body Temperature (⁰C) 
• 
Weight (kg) 
• 
BMI (kg/m2) 
These vital signs will be summarized using descriptive statistics at each time point for SEP-363856 (Overall). 
Changes from baseline will be summarized in the same manner. The number and percentage of subjects with 
Sponsor defined PCS vital sign values (defined in the Section 16.4.1) will be presented for SEP-363856 (Overall) at 
each visit and for the overall post baseline period. For the individual visits, percentages will be calculated based on 
the number of safety population subjects with data available for the given parameter and time point. For the overall 
post-baseline period, percentages will be calculated based on the number of safety population subjects who had at 
least one non-missing post treatment test result for a particular parameter. Any early termination visit, follow-up 
visit or unscheduled visit that occurs after first dose will be included in the period of evaluation for PCS 
post-baseline. 
The following summaries and listings will be provided for vital signs data: 
• 
Actual value and change from baseline presented at each time point for SEP-363856 (Overall) 
• 
Incidence of PCS values presented for SEP-363856 (Overall) 
• 
Listing of vital signs data for all enrolled subjects. 
• 
Listing of vital signs data meeting PCS criteria for all enrolled subjects 


 
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Version Number: 
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Version Date:  
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Effective Date: 01Apr2018 
 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
• 
The number and percentage of subjects with orthostatic hypotension and orthostatic tachycardia will be 
summarized for SEP-363856 (Overall), by time point and for the overall post-baseline period. Orthostatic 
hypotension and orthostatic tachycardia are defined in Section 16.4.2. 
16.4.1. 
VITAL SIGNS  POTENTIALLY  CLINICALLY SIGNIFICANT (PCS) CRITERIA 
Potentially clinically significant vital signs measurements will be identified in accordance with the following 
predefined PCS criteria: 
Parameter Name 
PCS Low 
PCS High 
Standing/ Supine Systolic Blood 
Pressure (mmHg) 
Value ≤ 90 and ≥ 20 decrease from 
baseline 
Value ≥ 180 and ≥ 20 increase from 
baseline 
Standing/ Supine Diastolic Blood 
Pressure (mmHg) 
Value ≤ 50 and ≥ 15 decrease from 
baseline 
Value ≥ 105 and ≥ 15 increase from 
baseline 
Standing/ Supine Pulse Rate 
(beats/min) 
Value ≤ 50 and ≥ 15 decrease from 
baseline 
Value ≥ 120 and ≥ 15 increase from 
baseline 
Weight (kg) 
≥ 7% decrease from baseline 
≥ 7% increase from baseline 
Temperature (°C) 
NA 
Value ≥ 38.3°C and ≥ 0.8°C 
increase from baseline 
. 
16.4.2. 
ORTHOSTATIC EFFECTS 
Orthostatic hypotension is defined as a decrease of ≥ 20 mmHg in systolic blood pressure or ≥ 10 mmHg in diastolic 
blood pressure after the subject had been standing for at least 2 to 4 minutes, compared to the systolic and diastolic 
blood pressures measured in the supine position, respectively. 
Orthostatic tachycardia is defined as a heart rate increase of >= 20 beats per minute (bpm) and a heart rate of >100 
bpm after the subject had been standing for at least 2 to 4 minutes, compared to the heart rate measured in the supine 
position. 
The number and percentage of subjects with orthostatic hypotension and orthostatic tachycardia will be summarized 
at each scheduled timepoint and for the overall post-baseline period for SEP-363856 (Overall). Any early 
termination visit, follow-up visit or unscheduled visit that occurs after first dose will be included in the period of 
evaluation for overall post-baseline incidence summary. For orthostatic hypotension, percentages will be calculated 
based on the number of safety population subjects who were assessed for both supine and standing blood pressure at 
the given timepoint. For orthostatic tachycardia, percentages will be calculated based on the number of safety 
population subjects who were assessed for both supine and standing heart rate at the given timepoint. For overall 
post-baseline incidence summary, if a subject experienced more than 1 episode of orthostatic 
hypotension/tachycardia, the subject was counted only once for the corresponding parameter. Systolic and diastolic 
BP values showing orthostatic hypotension will be flagged in the listing of vital signs data. Heart rate values 
showing orthostatic tachycardia will be flagged in the listing of vital signs data. 


 
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Version Number: 
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16.5. PHYSICAL AND NEUROLOGICAL EXAMINATIONS 
Findings from the physical examination will be presented as follows:  
Pre-existing clinically significant conditions recorded as medical history (at screening). Refer to Section 11 for 
data display of medical history. 
 
New clinically significant conditions recorded as AEs (post baseline). Refer to Section 16.1 for data display of 
AEs. 
16.6. COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS) 
The C-SSRS is a tool designed to systematically assess and track suicidal behavior and suicidal ideation for lifetime, 
one month prior to the screening visit, and throughout the study. The strength of this suicide classification system is 
in its ability to comprehensively identify suicidal events while limiting the over-identification of suicidal behavior. 
The C-SSRS Baseline/Screening Version is used at the screening visit and the C-SSRS Since Last Visit Version is 
used from Visit 2 onward. Subjects with Type 4 (active suicidal ideation with some intent to act, without specific 
plan) or Type 5 (active suicidal ideation with specific plan and intent) suicidal ideation during the study will be 
discontinued from the study and referred to a mental health professional.  
C-SSRS includes four sections: Suicidal Ideation, Intensity of Ideation, Suicidal Behavior, and Answer for Actual 
Suicide Attempts. 
C-SSRS Categories 
The following outcomes are C-SSRS categories and have binary responses (yes/no). The categories have been re-
ordered from the actual scale to facilitate the definitions of the C-SSRS endpoints, and to provide clarity in the 
presentation of the results.  
Category 1 – Wish to be Dead 
Category 2 – Non-specific Active Suicidal Thoughts 
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Category 5 – Active Suicidal Ideation with Specific Plan and Intent 
Category 6 – Preparatory Acts or Behavior 
Category 7 – Aborted Attempt 
Category 8 – Interrupted Attempt 
Category 9 – Actual Attempt (non-fatal) 
Category 10 – Completed Suicide 
The categories of the C-SSRS are not mutually exclusive. Subjects will be counted in each category for which they 
have an event. 
Self-injurious behavior without suicidal intent is a non-suicide-related C-SSRS outcome, and also has a binary 
response (yes/no). 
 
 


 
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Version Number: 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
C-SSRS Analyses 
For the purpose of C-SSRS analysis, “baseline” and “post-baseline” are defined as follows. 
 
C-SSRS composite endpoints will be derived for each time point of interest (i.e. baseline, post baseline, and each 
study visit) as follows: 
• 
Any suicidal ideation: A “yes” answer to any one of the 5 suicidal ideation questions on C-SSRS 
(Categories 1-5). 
• 
Any suicidal behavior: A “yes” answer to any one of the 5 suicidal behavior questions on the C-SSRS 
(Categories 6-10). 
• 
Any suicidality: A “yes” answer to any one of the 10 suicidal ideation and/or behavior questions on the C-
SSRS (Categories 1-10). 
For each subject, the suicidal ideation score at each time point of interest (i.e. baseline, post baseline, each study 
visit) is defined as the maximum suicidal ideation category (1-5) present for the time of interest. If no ideation is 
present a score of 0 is assigned. A suicidal ideation score of 4 or 5 is considered serious. 
The number and percentage of subjects with any suicidality, any suicidal ideation and subtypes of ideation, any 
suicidal behavior and subtypes of behavior, and any non-suicidal self-injurious behavior will be presented for: 
• 
Baseline (as defined above) 
• 
Post-baseline (as defined above) 
• 
Each scheduled study visit: Screening (Lifetime; Past 1 Month), Day -1, Week 2, Week 3 (Follow-up) 
Shift in suicidal ideation score from baseline to the post-baseline time point and to each of the following study visits 
will be presented: Week 2, Week 3 (Follow-up) 
Intensity of ideation for the most severe ideation subtype is measured in terms of frequency, duration, 
controllability, deterrents, and reasons for ideation. Each is measured with responses ranging from 1 to 5 for 
frequency and duration, and from 0 to 5 for controllability, deterrents, and reasons for ideation. The ideation 
intensity total score is the sum of responses to the five items and can range from 2 to 25 for subjects with endorsed 
suicidal ideation. For subjects with endorsed suicidal ideation, if one or more of these five items are missing at an 
assessment, the total score will be set to missing. If a subject did not endorse any suicidal ideation, a score of 0 for 
the ideation intensity total score will be given. 
Actual lethality associated with actual attempts is rated on a 6-point scale from 0 = ‘No physical damage or very 
minor physical damage’ to 5 = ‘Death’. Potential lethality of actual attempts (if actual lethality = 0) is rated on a 3-
Time point 
Study Visit 
C-SSRS Version 
Derivation Rule 
Baseline 
Screening 
Baseline/Screening – Past 1 Month 
Most severe outcome 
Day -1 
Since Last Visit 
Post-baseline 
All post-baseline visits up to 
and including Week 3/Follow-
up/End of Study, including 
unscheduled visits 
Since Last Visit 
Most severe outcome 


 
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Author: 
 
Version Number: 
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Version Date:  
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
point scale from 0 = ‘Behavior not likely to result in injury’ to 2 = ‘Behavior likely to result in death despite 
available medical care. 
All C-SSRS responses will be listed for all subjects enrolled. The ideation intensity total score and the actual 
lethality and potential lethality of actual attempts will only be presented in data listings. 
16.7. MOVEMENT DISORDER MEASURES 
Movement disorder measures include AIMS, BARS, and SAS. The BARS, AIMS, and SAS will be summarized 
descriptively by presenting summary statistics of actual values and change from baseline values. All data from the 
three scales will be presented in the data listings for all subjects enrolled. 
 
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). AIMS total score will be calculated as the sum of items 1 through 7 (ranging from 0 to 28).  If any 
item score contributing to the calculation of AIMS total score is missing, the total score will be set to missing. Items 
8 through 12 will not be used in total score calculation. The global severity score (item 8) will be summarized 
separately.  
AIMS total score (observed value and change from baseline) will be summarized numerically by visit. In addition, 
the AIMS total score at each visit will be classified as “abnormal” if: either at least two items (out of items 1 - 7) 
have a response of “mild” or higher, or at least one item (out of items 1 - 7) has a response of “moderate” or higher. 
Otherwise, the non-missing total score will be classified as “normal”. This is a modification of the Schooler-Kane 
criteria for tardive dyskinesia. Shifts from baseline in AIMS total score classification will be summarized by visit 
and for the overall post-baseline period. Any early termination visit, follow-up visit or unscheduled visit that occurs 
after first dose will be included in the overall post-baseline period. 
The AIMS global severity score will be summarized both numerically and categorically by visit. 
The post-baseline AIMS global severity assessment will be classified as “worsened” (score is higher than baseline), 
“unchanged” (score is equal to baseline), or “improved” (score is lower than baseline), relative to a subject’s 
baseline response. These post-baseline changes will be summarized by visit. 
 
Barnes Akathisia Rating Scale (BARS) 
The BARS is a 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 (ranging from 0 to 9). If any item score contributing to the calculation of BARS total 


 
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Version Number: 
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Version Date:  
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Effective Date: 01Apr2018 
 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
score is missing, the total score will be set to missing.  
BARS total score (observed value and change from baseline) will be summarized numerically by visit. In addition, 
the BARS item scores for the four items will be summarized both numerically and categorically by visit.  
The post-baseline BARS global clinical assessment of akathisia will be classified as “worsened” (score is higher 
than baseline), “unchanged” (score is equal to baseline), or “improved” (score is lower than baseline), relative to a 
subject’s baseline response. These post-baseline changes will be summarized by visit. 
 
Simpson-Angus Scale (SAS) 
The SAS is a clinician-rated assessment of neuroleptic-induced Parkinsonism consisting of 10 items. Items are 
anchor-based, rated on a 5-point scale of severity, and address rigidity, gait (bradykinesia), tremor, akathisia, 
shoulder shaking, glabellar tap, and salivation (Siddiqui-2009; Simpson-1970). SAS mean score is calculated as the 
average of all 10 item scores.  If any item score is missing, the mean score will be set to missing.  
SAS mean score (observed value and change from baseline) will be summarized numerically by visit. In addition, 
SAS mean score at each visit will be classified as “abnormal” if it exceeds 0.3. Otherwise, non-missing mean scores 
will be classified as “normal”. Shifts from baseline in SAS mean score classification will be summarized by visit 
and for the overall post-baseline period. Any early termination visit, follow-up visit or unscheduled visit that occurs 
after first dose will be included in the overall post-baseline period. 
16.8. SUBGROUP ANALYSIS 
No subgroup analyses are planned for the safety parameters. 
16.9. PHARMACOKINETIC ANALYSIS 
Plasma concentrations of SEP-363856 and its metabolite SEP-363854 will be summarized descriptively at each 
scheduled sample collection time point. 
Plasma SEP-363856 and SEP-363854 concentrations that are below the limit of quantitation (BLQ) will be treated 
as zero for the computation of descriptive statistics. However, if there is at least one BLQ value for a time point, the 
geometric mean and geometric coefficient of variation% will not be calculated for that time point. Missing 
concentrations will not be imputed.  
Descriptive statistics (n, mean, standard deviation, CV%, geometric mean, geometric coefficient of variation% 
[GCV%], median, minimum, maximum) will be used to summarize plasma SEP-363856 and SEP-363854 
concentration data.  
A subject listing of all plasma concentration-time data for SEP-363856 and SEP-363854 will be presented for all 
subjects enrolled. 
 


 
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Version Number: 
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Version Date:  
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16.10. 
INTERIM ANALYSIS 
No interim analysis is planned. 
17. REFERENCES  
1.  Sunovion SEP-363856 Clinical Study Protocol SEP3611-118 
2.  International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for 
Human Use, ICH Harmonised Tripartite Guideline, Statistical Principles for Clinical Trials (E9), 5 February 1998. 
3.  International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for 
Human Use, ICH Harmonised Tripartite Guideline, Structure and Content of Clinical Study Reports (E3), 30 
November 1995. 
4.  Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York, NY: Marcel Dekker, Inc.; 1982. 
5.  Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five dimensions of schizophrenia derived 
by factor analysis: combined results of the North American trials. J Clin Psychiatry 1997;58:538–46. 
6.  Hopkins SC, Ogirala A, Loebel A, Koblan KS. Transformed PANSS factors intended to reduce pseudospecificity 
among symptom domains and enhance understanding of symptom change in antipsychotic-treated patients with 
schizophrenia. Schizophr Bull 2018;44(3):593-602. 
 
 


 
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Author: 
 
Version Number: 
Final 1.0 
 
Version Date:  
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Template No.:  CS_TP_BS016 Revision 5 
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Effective Date: 01Apr2018 
 
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APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
IQVIA OUTPUT CONVENTIONS 
Outputs will be presented according to the following output conventions: 
DATES & TIMES 
Depending on data available, dates and times will take the form yyyy-mm-ddThh:mm:ss. 
PRESENTATION OF TREATMENT GROUPS 
For outputs, treatment groups will be represented as follows and in that order unless shown otherwise in the output 
templates: 
Treatment Group 
For Tables and Graphs 
For Listings 
SEP-363856 (Overall) 
SEP-363856 (Overall) 
SEP-363856 (Overall) 
PRESENTATION OF VISITS 
For all outputs, including tables and listings, visits will be represented as follows and in that order unless shown 
otherwise in the output templates: 
Long Name (default) 
Short Name  
Screening  
Scr  
Day -2 
D-2 
Day-1 
D-1 
Day1 
D1 
Baseline 
BL 
Week 2 
W2 
Week 3/Follow-up/End of Study 
W3 
Early Termination  
ET 
Early termination only applies to listings. Unscheduled visits will be presented in listings, if any. 
LISTINGS 
All listings will be ordered by the following (unless otherwise indicated in the template): 
Subject ID 
Date/Time (where applicable) 








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


 
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Author: 
 
Version Number: 
Final 1.0 
 
Version Date:  
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Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
START DATE 
STOP DATE 
ACTION 
Partial 
Partial 
Impute start date as earliest possible date: 
CRF questions: ‘Started prior to study?’ = Yes; ‘Started after last dose of 
study medication?’ = No. 
• 
If only day unknown, impute as the later of (first day of the month; 
date of birth [if full date is available]). 
• 
If month and day unknown, impute as the later of (1st January; date 
of birth [if full date is available]). 
CRF questions: ‘Started prior to study?’ = No; ‘Started after last dose of 
study medication?’ = Yes. 
• 
If only day unknown, impute as the later of (first day of the month; 
end of treatment + 1). 
• 
If month and day unknown, impute as the later of (1st January; end 
of treatment + 1). 
CRF questions: ‘Started prior to study?’ = No; ‘Started after last dose of 
study medication?’ = No. 
• 
If only day unknown, impute as the later of (first day of the month; 
date of ICF). 
• 
If month and day unknown, impute as the later of (1st January; date 
of ICF). 
 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown). 
 
Then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study med start date and start date > end of treatment, assign 
as post treatment 




 
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Version Number: 
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Version Date:  
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Effective Date: 01Apr2018 
 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
START DATE 
STOP DATE 
ACTION 
Missing 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown). 
 
Then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and CRF question ‘Started after last 
dose of study medication?’ = No, assign as concomitant 
If stop date >= study med start date and CRF question ‘Started after last 
dose of study medication?’ = Yes, assign as post treatment.  
Missing 
Missing 
If CRF question ‘Started after last dose of study medication?’ = No, assign 
as concomitant. 
If CRF question ‘Started after last dose of study medication?’ = Yes, assign 
as post treatment.  
 
 
 


 
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Version Number: 
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Version Date:  
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APPENDIX 3. CLINICAL LABOROTORY PARAMETERS 
• HEMATOLOGY: (Differential reported as fraction of 1 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), CPK, Creatinine, Glucose, HbA1c, 
Magnesium (Mg), Phosphorus (P), Potassium (K), Prolactin, Protein (Total), Sodium 
(Na), Uric Acid 
• URINALYSIS: 
Blood, Glucose, Ketones, Leukocyte esterase, Microscopic Examination, Nitrites, pH, 
Protein 
• URINE DRUG SCREENING: 
Alcohol test, Amphetamines, Barbiturates, Benzodiazepines, Cannabinoids, Cocaine, 
Cotinine, Methamphetamines, Methadone, Methylenedioxymethamphetamine 
(MDMA), Phencyclidine (PCP), Opiates, Oxycodone 
• LIPID PANEL 
Low Density Lipoprotein (LDL) - Cholesterol, High Density Lipoprotein (HDL) - 
Cholesterol, Triglycerides 
• THYROID PANEL: 
Free T3, Free T4, Thyroid stimulating hormone (TSH) 
• SEROLOGY PANEL: 
Hepatitis B Ag, Hepatitis C Ab, HIV-1 Ab, HIV-2 Ab (screening only) 
Note: The lab will report results for HIV Ab, which detects both HIV-1 Ab and HIV-2 
Ab. 
• COAGULATION PANEL: 
International Normalized Ratio (INR), activated Partial Thromboplastin time (aPTT), 
Prothrombin time (PT). 


 
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Version Number: 
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Version Date:  
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
• OTHER TESTS: 
Serum Pregnancy (β-hCG) (in female subjects only), Urine Pregnancy Test (in female 
subjects only), follicle stimulating hormone (FSH) (in female subjects only) 
Laboratory reports will be initialled and dated on all pages by the Investigator listed on the Form 
FDA 1572 (MD or DO). Laboratory test results will be reviewed by the Investigator as they 
become available. The Investigator must determine the clinical significance of all out-of-range 
lab values (except drug screens). Possibly drug-related or clinically relevant abnormal values of 
uncertain causality must be repeated. Any abnormal values that persist should be followed at the 
discretion of the Investigator. 
 
 


 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
APPENDIX 4. POTENTIALLY CLINICALLY SIGNIFICANT (PCS) 
LABORATORY CRITERIA 
Category 
PCS Range (SI units) – 
Low 
PCS Range (SI units) – 
High 
Parameter Name  
Age/Gender Restriction, 
if any 
 
 
HEMATOLOGY 
 
 
WBC 
≤ 2.8 x 109/L 
≥ 16 x 109/L 
Neutrophils (abs) 
< 0.5 x 109/L 
> 13.5 x 109/L 
Lymphocytes (abs) 
N/A 
> 12 x 109/L 
Monocytes (abs) 
N/A 
> 2.5 x 109/L 
Eosinophils (abs) 
N/A 
> 1.6 x 109/L 
Basophils (abs) 
N/A 
> 1.6 x 109/L 
Neutrophils (relative) 
≤ 0.15 
> 0.85 
Lymphocytes (relative) 
N/A 
≥ 0.75 
Monocytes (relative) 
N/A 
≥ 0.15 
Eosinophils (relative) 
N/A 
≥ 0.10 
Basophils (relative) 
N/A 
≥ 0.10 
Hemoglobin 
 
 
  Male 
≤ 115 g/L 
≥ 190 g/L 
  Female 
≤ 95 g/L 
≥ 175 g/L 
Hematocrit 
 
 
   Male 
≤ 0.37 
≥ 0.60 
   Female 
≤ 0.32 
≥ 0.54 
RBC 
≤ 3.5 x 1012/L 
≥ 6.4 x 1012/L 
Platelet Count 
≤ 75 x 109/L 
≥ 700 x 109/L 
 
 
SERUM CHEMISTRY 
 
 
Sodium 
< 130 mmol/L 
> 150 mmol/L 
Potassium 
< 3 mmol/L 
> 5.5 mmol/L 
Chloride 
≤ 90 mmol/L 
≥ 118 mmol/L 
Calcium 
< 1.75 mmol/L 
≥ 3.1 mmol/L 
Phosphate 
< 0.65 mmol/L 
> 1.65 mmol/L 
Bicarbonate 
< 15.1 mmol/L 
> 34.9 mmol/L 
Magnesium 
< 0.4 mmol/L 
> 1.23 mmol/L 
AST 
N/A 
≥ 3 x ULN 
ALT 
N/A 
≥ 3 x ULN 
Alkaline Phosphatase 
N/A 
≥ 1.5 x ULN 
CK 
N/A 
> 2.5 x ULN 
Creatinine 
N/A 
≥ 177 umol/L 
BUN 
N/A 
≥ 10.7 mmol/L 
Total bilirubin 
N/A 
≥ 34.2 umol/L OR > 2 x ULN 
Total protein 
≤ 45 g/L 
≥ 100 g/L 
Albumin 
≤ 25 g/L 
N/A 


 
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Author: 
 
Version Number: 
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Version Date:  
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Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
Category 
PCS Range (SI units) – 
Low 
PCS Range (SI units) – 
High 
Parameter Name  
Age/Gender Restriction, 
if any 
HDL-Cholesterol 
< 0.78 mmol/L 
N/A 
LDL-Cholesterol 
N/A 
> 4.9 mmol/L 
Triglycerides 
N/A  
> 3.42 mmol/L 
Uric acid 
 
 
  Male 
N/A 
> 595 umol/L 
  Female 
N/A 
> 476 umol/L 
Glucose 
< 2.78 mmol/L 
> 13.9 mmol/L 
HbA1c 
N/A 
≥ 0.075 
Prolactin 
N/A 
≥ 5 x ULN 
 
 
URINALYSIS 
 
 
RBC 
N/A 
> 25 hpf 
WBC 
N/A 
> 25 hpf 
 
 
 
COAGULATION 
 
 
aPTT 
N/A 
> 1.5 x ULN 
INR 
N/A 
> 1.5 x ULN 
PT 
N/A 
> 1.5 x ULN 
 
 
 


 
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Version Number: 
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Version Date:  
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Effective Date: 01Apr2018 
 
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APPENDIX 5. PRECISION PRESENTATION OF STATISTICAL 
RESULTS 
Univariate Statistics: 
• 
Statistics should be presented in the same order across tables (i.e., n, Mean, SD, Median, Q1, Q3, Minimum, 
Maximum) 
• 
Table statistics should line up under the N part of the (N=XXX) in the table header. All decimal points should 
line up. If the minimum and maximum are output on one line as Minimum, Maximum then the comma should 
line up with the decimal point. 
• 
If the original data has N decimal places, then the summary statistics should have the following decimal places: 
o 
Minimum and maximum: N 
o 
Mean, median, and 95% CI: N + 1 
o 
SD: N + 2 
o 
25th percentile (Q1): N+1 
o 
75th percentile (Q3): N+1 
• 
For CGI-S score, 2 decimal places will be presented for mean, median, Q1, Q3 and 95% CI; 3 decimal places 
will be presented for SD; 0 decimal places will be presented for minimum and maximum. 0 decimal places will 
be presented in listings. 
• 
For the calculated UPSM scores: No rounding will be applied in the ADaM datasets. 3 decimal places will be 
presented for mean, median, Q1, Q3; 4 decimal places will be presented for SD; 2 decimal places will be 
presented for min and max. 2 decimal places will be presented in listings.  
• 
For the calculated parameter of BMI: No rounding will be applied in the ADaM datasets. 2 decimal places will 
be presented for mean, median, Q1, Q3; 3 decimal places will be presented for SD; 1 decimal places will be 
presented for min and max. 1 decimal place will be presented in listings. 
• 
For the calculated parameter of SAS mean score: No rounding will be applied in ADaM datasets. 2 decimal 
places will be presented for mean, median, Q1, Q3; 3 decimal places will be presented for SD; 1 decimal places 
will be presented for min and max. 1 decimal place will be presented in listings. 
• 
For lab data only: in the rare case where raw data has more than 3 decimal places, summary statistics will be 
presented for the scenario of N = 3. All decimals will be presented in listings. 
• 
For plasma concentration data: No rounding will be applied in the ADaM datasets. Summary statistics 
(arithmetic mean, SD, 95% CI for the mean, CV%, geometric mean, geometric CV%, median, min, max) will 
be presented to 3 significant figures. All decimals will be presented in listings. 
 
 
 


 
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Version Number: 
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Effective Date: 01Apr2018 
 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
Frequencies and percentages (n and %): 
• 
Percent values should be reported inside parentheses, with one space between the count and the left parenthesis 
of the percentage. Parentheses should be justified to accept a maximum of 100.0 as a value and padded with 
blank space if the percent is less than 100.0. An example is given below: 
o 
77 (100.0%) 
o 
50 ( 64.9%) 
o 
0 (  0.0%) 
• 
• Percentages will be reported to one decimal place, except percents <100.0% but >99.9% will be presented as 
‘>99.9%’ (e.g., 99.99% is presented as >99.9%); and percents < 0.1% will be presented as ‘<0.1%’ (e.g., 0.08% 
is presented as <0.1%). Rounding will be applied after the <0.1% and >99.9% rule. E.g.,  
o 
 ( <0.1%) 
o 
( 6.8%) 
o 
(>99.9%) 
• 
Percentages may be reported to 0 decimal places as appropriate (for example, where the denominator is 
relatively small). 
• 
Where counts are zero, no percentages should appear in the output. 
 
Confidence Intervals: 
• 
As a rule confidence intervals are output to one place more than the raw data, and standard deviations and 
standard errors to two places more than the raw data 
• 
Confidence intervals should be justified so that parentheses displayed on consecutive lines of a table “line up”. 
• 
Boundary values of confidence intervals should be separated by a comma. 
• 
Boundary values should be padded as necessary to accept negative values and to allow alignment of the decimal 
place. 
• 
An example is given below: 
o 
(-0.12, -0.10) 
o 
( 9.54, 12.91) 
 
P-values: 
• 
P-values should be reported to 4 decimal places. P-values less than 0.0001 will be displayed as <0.0001 in the 
tables, and P-values greater than 0.9999 will be displayed as >0.9999. 
 


 
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Author: 
 
Version Number: 
Final 1.0 
 
Version Date:  
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Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
Ratios: 
• 
Ratios should be reported to one more decimal place than the original data. 
 
Spacing: 
• 
There must be a minimum of 1 blank space between columns (preferably 2) 
 
Denominators: 
• 
If a different count other than the population count is used for a denominator (within the table) to calculate 
percentages, there should be a row in the table that identifies that number “n”. 
• 
Alternatively, a footnote should be included in each table with percentages to indicate the denominator for 
percentages. 
 
Missing values: 
• 
A “0” should be used to indicate a zero frequency. 
• 
A blank will be used to indicate missing data in an end-of-text table or subject listing. 
 
 
 
 


 
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Author: 
 
Version Number: 
Final 1.0 
 
Version Date:  
26JUL2023 
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Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
APPENDIX 6. ADVERSE EVENTS OF POTENTIAL DRUG ABUSE  AND 
DEPENDENCE  
To ensure comprehensive and consistent selection of terminology used for analyses of drug abuse and dependence in 
ongoing / planned studies of SEP-363856, MedDRA PTs were identified from the following sources: 
• 
FDA Guidance for Industry: Assessment of Abuse Potential of Drugs (CDER, 2017; noted that the Guidance 
reflects MedDRA version 20.0 terminology) 
• 
MedDRA version 22.0 SMQ: Drug abuse and dependence [20000101], Broad 
• 
FDA FMQ: Study Agent Abuse Potential, Broad (released at FDA public workshop “Advancing Premarket 
Safety Analytics”, held September 14, 2022) 
Description: 
Preferred terms were tabulated using MedDRA version 22.0 from the sources listed above. All PTs within the FDA 
Abuse Potential Guidance were included. All PTs listed in the MedDRA version 22.0 SMQ for Drug abuse and 
dependence [20000101] were included. For the FDA Study Agent Abuse Potential FMQ: No associated MedDRA 
PT was found for the term “Hypnogogic hallucination”, and this is therefore not included.  SMPA evaluates ‘Drug 
withdrawal’ as a unique medical concept using MedDRA version 22.0 SMQ for Drug withdrawal [20000102] 
(Broad); any overlapping PTs from the Drug withdrawal SMQ which are listed in the FDA Study Agent Abuse 
Potential FMQ are not included. All other PTs listed in the FDA FMQ were included. 
The table below depicts the preferred terms by source. 
FDA Guidance 2017  
SMQ 20000101 
FDA FMQ 
PT 
Code 
PT 
Code 
PT 
Code 
- 
- 
Accidental overdose 
10000381 
Accidental overdose 
10000381 
- 
- 
- 
- 
Acute psychosis 
10001022 
Aggression 
10001488 
- 
- 
- 
- 
Behavioural addiction 
10081939 
- 
- 
- 
- 
Confusional state 
10010305 
- 
- 
- 
- 
- 
- 
- 
- 
Delusion of grandeur 
10012241 
- 
- 
- 
- 
Delusional perception 
10012258 
Dependence 
10012335 
Dependence 
10012335 
Dependence 
10012335 
- 
- 
- 
- 
Depersonalisation 
10012357 
- 
- 
- 
- 
Derealisation disorder 
10077810 
- 
- 
- 
- 
Detoxification 
10061814 
- 
- 
- 
- 
Disinhibition 
10013142 
Disorientation 
10013395 
- 
- 
- 
- 
- 
- 
Disturbance in social 
behaviour 
10061108 
- 
- 
Dizziness 
10013573 
- 
- 
- 
- 
Dopamine 
dysregulation 
syndrome 
10067468 
Dopamine 
dysregulation 
syndrome 
10067468 
- 
- 
- 
- 
Drug abuse 
10013654 
Drug abuse 
10013654 
- 
- 
Drug abuser 
10061111 
Drug abuser 
10061111 


 
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Version Number: 
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Version Date:  
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Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
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to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
FDA Guidance 2017  
SMQ 20000101 
FDA FMQ 
PT 
Code 
PT 
Code 
PT 
Code 
- 
- 
Drug dependence 
10013663 
Drug dependence 
10013663 
Drug dependence, 
antepartum 
10013675 
Drug dependence, 
antepartum 
10013675 
Drug dependence, 
antepartum 
10013675 
Drug dependence, 
postpartum 
10013676 
Drug dependence, 
postpartum 
10013676 
Drug dependence, 
postpartum 
10013676 
- 
- 
Drug detoxification 
10052237 
Drug detoxification 
10052237 
- 
- 
Drug diversion 
10066053 
Drug diversion 
10066053 
- 
- 
Drug level above 
therapeutic 
10061132 
- 
- 
- 
- 
Drug level increased 
10013722 
- 
- 
- 
- 
Drug screen 
10050837 
- 
- 
- 
- 
Drug screen positive 
10049177 
- 
- 
Drug tolerance 
10052804 
Drug tolerance 
10052804 
- 
- 
Drug tolerance 
decreased 
10052805 
Drug tolerance 
decreased 
10052805 
- 
- 
Drug tolerance 
increased 
10052806 
Drug tolerance 
increased 
10052806 
- 
- 
Drug use disorder 
10079381 
Drug use disorder 
10079381 
Drug use disorder 
10079381 
- 
- 
Drug use disorder, 
antepartum 
10079382 
Drug use disorder, 
antepartum 
10079382 
- 
- 
Drug use disorder, 
postpartum 
10079383 
Drug use disorder, 
postpartum 
10079383 
- 
- 
- 
- 
Energy increased 
 
Euphoric mood 
10015535 
- 
- 
Euphoric mood 
10015535 
Feeling abnormal 
10016322 
- 
- 
- 
- 
Feeling drunk 
10016330 
- 
- 
Feeling drunk 
10016330 
- 
- 
- 
- 
Feeling jittery 
10016338 
Feeling of relaxation 
10016352 
- 
- 
Feeling of relaxation 
10016352 
- 
- 
- 
- 
Flight of ideas 
10016777 
Hallucination 
10019063 
- 
- 
Hallucination 
10019063 
Hallucination, 
auditory 
10019070 
- 
- 
Hallucination, 
auditory 
10019070 
Hallucination, 
gustatory 
10019071 
- 
- 
Hallucination, 
gustatory 
10019071 
Hallucination, 
olfactory 
10019072 
- 
- 
Hallucination, 
olfactory 
10019072 
Hallucination, 
synaesthetic 
10062824 
- 
- 
Hallucination, 
synaesthetic 
10062824 
Hallucination, tactile 
10019074 
- 
- 
Hallucination, tactile 
10019074 
Hallucination, visual 
10019075 
- 
- 
Hallucination, visual 
10019075 
Hallucinations, mixed 
10019079 
- 
- 
Hallucinations, mixed 
10019079 
Inappropriate affect 
10021588 
- 
- 
Hallucination, 
gustatory 
10019071 
- 
- 
- 
- 
Hypersomnia 
10020765 
- 
- 
- 
- 
Hypervigilance 
10048533 


 
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Author: 
 
Version Number: 
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Version Date:  
26JUL2023 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
FDA Guidance 2017  
SMQ 20000101 
FDA FMQ 
PT 
Code 
PT 
Code 
PT 
Code 
- 
- 
- 
- 
Hypnagogic 
hallucination 
10020927 
- 
- 
- 
- 
Hypnogogic 
hallucination 
No such code 
- 
- 
- 
- 
Hypnopompic 
hallucination 
10020928 
- 
- 
- 
- 
Inappropriate affect 
10021588 
- 
- 
- 
- 
Infant sedation 
10082187 
- 
- 
- 
- 
Intentional misuse of 
drug delivery system 
10081675 
- 
- 
Intentional overdose 
10022523 
Intentional overdose 
10022523 
- 
- 
Intentional product 
misuse 
10074903 
Intentional product 
misuse 
10074903 
- 
- 
Intentional product 
use issue 
10076308 
- 
- 
- 
- 
- 
- 
Mania 
10026749 
- 
- 
Maternal use of illicit 
drugs 
10026938 
- 
- 
- 
- 
Medication overuse 
headache 
10072720 
- 
- 
- 
- 
- 
- 
Mixed delusion 
10076429 
Mood altered 
10027940 
- 
- 
Mood altered 
10027940 
Mood swings 
10027951 
- 
- 
- 
- 
- 
- 
Narcotic bowel 
syndrome 
10072286 
- 
- 
- 
- 
Needle track marks 
10028896 
- 
- 
- 
- 
Neonatal 
complications of 
substance abuse 
10061862 
- 
- 
- 
- 
- 
- 
Neonatal 
oversedation 
10050395 
- 
- 
Overdose 
10033295 
- 
- 
- 
- 
- 
- 
Paranoia 
10033864 
- 
- 
- 
- 
Post-injection 
delirium sedation 
syndrome 
10072851 
- 
- 
Prescription drug 
used without a 
prescription 
10076639 
- 
- 
- 
- 
Prescription form 
tampering 
10067669 
Prescription form 
tampering 
10067669 
- 
- 
- 
- 
Psychomotor 
hyperactivity 
10037211 
Psychotic disorder 
10061920 
- 
- 
- 
- 
 
 
Reversal of opiate 
activity 
10039004 
- 
- 


 
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363856\BZA44200\Biostatistics\Documentation\SAP\V1\SEP361-301 SAP Final V1.0_26JUL2023  
Author: 
 
Version Number: 
Final 1.0 
 
Version Date:  
26JUL2023 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
FDA Guidance 2017  
SMQ 20000101 
FDA FMQ 
PT 
Code 
PT 
Code 
PT 
Code 
- 
- 
- 
- 
Sedation 
10039897 
- 
- 
- 
- 
Sedation 
complication 
10079741 
Somnolence 
10041349 
- 
- 
Somnolence 
10041349 
- 
- 
- 
- 
Somnolence neonatal 
10041350 
- 
- 
- 
- 
Stupor 
10042264 
- 
- 
Substance abuse 
10066169 
Substance abuse 
10066169 
- 
- 
Substance abuser 
10067688 
Substance abuser 
10067688 
- 
- 
Substance 
dependence 
10076595 
Substance 
dependence 
10076595 
- 
- 
Substance use 
10070964 
- 
- 
Substance use 
disorder 
10079384 
Substance use 
disorder 
10079384 
Substance use 
disorder 
10079384 
- 
- 
Substance-induced 
mood disorder 
10072387 
Substance-induced 
mood disorder 
10072387 
- 
- 
Substance-induced 
psychotic disorder 
10072388 
Substance-induced 
psychotic disorder 
10072388 
- 
- 
- 
- 
Suspected product 
tampering 
10079404 
Thinking abnormal 
10043431 
- 
- 
- 
- 
- 
- 
Toxicity to various 
agents 
10070863 
- 
- 
- 
- 
- 
- 
Transient psychosis 
10056326 
- 
- 
- 
- 
Withdrawal 
hypertension 
10048007 
 
 
 
 
 


 
PROTOCOL SEP361-118 
Statistical Analysis Plan 
Page 58 of 58 
 
Document: 
\\quintiles.net\enterprise\Apps\sasdata\SASa\sas\Sunovion\SEP-
363856\BZA44200\Biostatistics\Documentation\SAP\V1\SEP361-301 SAP Final V1.0_26JUL2023  
Author: 
 
Version Number: 
Final 1.0 
 
Version Date:  
26JUL2023 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 IQVIA. All rights reserved. The contents of this document are confidential and proprietary 
to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
APPENDIX 7. INTERNATIONALLY AGREED ORDER FOR SYSTEM 
ORGAN CLASS 
Internationally Agreed Order 
Infections and infestations 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) 
Blood and lymphatic system disorders 
Immune system disorders 
Endocrine disorders 
Metabolism and nutrition disorders 
Psychiatric disorders 
Nervous system disorders 
Eye disorders 
Ear and labyrinth disorders 
Cardiac disorders 
Vascular disorders 
Respiratory, thoracic and mediastinal disorders 
Gastrointestinal disorders 
Hepatobiliary disorders 
Skin and subcutaneous tissue disorders 
Musculoskeletal and connective tissue disorders 
Renal and urinary disorders 
Pregnancy, puerperium and perinatal conditions 
Reproductive system and breast disorders 
Congenital, familial and genetic disorders 
General disorders and administration site conditions 
Investigations 
Injury, poisoning and procedural complications 
Surgical and medical procedures 
Social circumstances 
Product issues