Clinical trial NCT05227209
Conditions: Depressive Episodes, Bipolar I Depression
Keywords: Depression, Depressive episode, Bipolar, Bipolar 1, Bipolar 1 depression
Sponsor: Sumitomo Pharma America, Inc.
Start date: 2022-03-17; Completion date: 2023-11-17
Enrollment: 64 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a clinical trial to determine the long-term safety and tolerability of an investigational drug in people with Major Depressive Episode Associated with Bipolar I Disorder (Bipolar I Depression). Participants in the study will receive the drug being studied. This study is accepting male and female participants between 18 and 65 years old who have completed Study SEP380-301. This study will be conducted in approximately 90 study centers worldwide. The treatment duration for this study is one (1) year.

Detailed description:
This is a 12-month open-label safety extension study to evaluate the long-term safety, tolerability, and effectiveness of SEP-4199 CR 200-400 mg/day in the treatment of subjects with bipolar I depression who previously completed a lead-in study of SEP-4199 CR.

The study will consist of a 12-month open-label flexible-dose treatment period, and a safety follow-up period. There are 15 scheduled visits, including a Baseline visit, 13 visits during the open-label treatment period, and 1 safety follow-up visit 7 (± 2) days after the last dose of study drug. If necessary, subjects may return to the clinic at anytime for an unscheduled visit

Arms: arm 1: SEP-4199 CR either 200 mg (one 200 mg tablet) or 400 mg (two 200 mg tablets) once daily during open-label flexible-dose treatment period.
Interventions: intervention 1: SEP-4199 CR
Intervention descriptions: intervention 1: SEP-4199 CR either 200 mg (one 200 mg tablet) or 400 mg (two 200 mg tablets) once daily

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 
Pharma Co., Ltd. (SMP) 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 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: Sunovion Pharmaceuticals Inc.; Sponsor in Japan: Sumitomo Pharma Co., Ltd. 
(SMP) 
Name of Investigational Product: SEP-4199 CR 
Name of Active Ingredient: aramisulpride (85%), esamisulpride (15%) 
Proposed Indication: Major depressive episode associated with bipolar I disorder (bipolar I 
depression) 
Title of Study: A 12-Month Open-label Extension Study to Evaluate the Long-term Safety, 
Tolerability, and Effectiveness of SEP-4199 Controlled Release (CR) for the Treatment of Major 
Depressive Episode Associated with Bipolar I Disorder (Bipolar I Depression) 
Study Centers: Up to 90 sites in Europe (EUR), Japan (JP), North America, and Latin America that 
have completed a 6-week double-blind placebo-controlled lead-in study of SEP-4199 CR (hereinafter 
referred to as lead-in study of SEP-4199 CR) 
Phase of Development: 3 
Study Objectives:  
To evaluate the long-term safety, tolerability, and effectiveness of SEP-4199 CR formulation at a 
flexible daily dose of 200 mg/day or 400 mg/day in subjects who previously completed a lead-in 
study of SEP-4199 CR for the treatment of major depressive episode associated with bipolar I 
disorder (bipolar I depression). 
Primary Objective:  
The primary objective of the current study is to evaluate the long-term safety and tolerability of 
treatment with SEP-4199 CR 200-400 mg/day, as reflected in rates of adverse events (AEs), 
discontinuations due to an AE, serious AEs (SAEs), and adverse events of special interest (AESI). 
Additional Safety Objectives:  
Long-term safety and tolerability of flexible-dose SEP-4199 CR treatment will be evaluated as 
follows: 
• 
Measurements including 12-lead electrocardiogram (ECG), clinical laboratory values, vital 
signs, body weight, and metabolic parameters 
• 
Prolactin levels 
• 
Manic symptoms using the Young Mania Rating Scale (YMRS) 
• 
Suicidality using the Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
Movement disorders using the Barnes Akathisia Rating Scale (BARS), Abnormal Involuntary 
Movement Scale (AIMS), and modified Simpson-Angus Scale (SAS) 
• 
Potential for withdrawal symptoms after discontinuation, using the Physician’s Withdrawal 
Checklist (PWC). 
Effectiveness Objectives:  
Long-term effectiveness of flexible-dose SEP-4199 CR treatment will be evaluated as follows: 
• 
Severity of depression symptoms as measured by the Montgomery-Asberg Depression Rating 
Scale (MADRS) 
• 
Overall bipolar depression severity assessed using the Clinical Global Impression-Bipolar 
Version-Severity of Illness (CGI-BP-S), Depression scale 


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• 
Anxiety symptoms severity assessed using the clinician-administered Hamilton Anxiety 
Rating Scale (HAM-A) 
• 
Severity of subject-reported depression symptoms as measured by the Quick Inventory of 
Depressive Symptomatology, Self-Report (QIDS-SR16) 
• 
Functional impairment, as measured by the Sheehan Disability Scale (SDS) 
• 
Quality of life, as measured by the EuroQol - 5 Dimension - 5 Level (EQ-5D-5L) 
• 
Anhedonia symptoms, as measured by the Snaith-Hamilton Pleasure Scale (SHAPS). 
Pharmacokinetics and Pharmacodynamics Objectives: 
• 
Perform population pharmacokinetic (Pop-PK) analysis using plasma SEP-4199 
concentrations. 
• 
Explore the relationship between MADRS score and plasma SEP-4199 exposure using 
population PK/pharmacodynamics (PD) methods. 
• 
Explore the relationship between safety outcomes and plasma SEP-4199 exposure. 
Study Design: SEP380-303 is a 12-month open-label safety extension study to evaluate the long-term 
safety, tolerability, and effectiveness of SEP-4199 CR 200-400 mg/day in the treatment of subjects 
with bipolar I depression who previously completed a lead-in study of SEP-4199 CR. 
The study will consist of a 12-month open-label flexible-dose treatment period, and a safety follow-up 
period, as shown in the following figure. There are 15 scheduled visits including a Baseline visit, 
13 visits during the open-label treatment period, and 1 safety follow-up visit 7 (± 2) days after the last 
dose of study drug. If necessary, subjects may return to the clinic at any time for an unscheduled visit. 
Study Schematic 
 
Note: All subjects are to take SEP-4199 CR 200 mg beginning on Day 1, the day following Baseline (Visit 1E). 
Abbreviations: BL = Baseline; CR = controlled release; EOT = end of treatment 
V = visit; E = extension; W = Week; M = Month 
 


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Baseline (Visit 1E; Day -1) 
Visit 6/End of Treatment (EOT) (Day 42) of the lead-in study of SEP-4199 CR will serve as the 
Baseline visit of the current open-label extension study. Subjects who completed 6 weeks of 
double-blind treatment in a lead-in study of SEP-4199 CR and who meet eligibility criteria to 
continue into the current extension study may be enrolled. Baseline values for safety and effectiveness 
measures for this study will be carried over from Visit 6/EOT (Day 42) of the lead-in study of 
SEP-4199 CR for each subject. Subjects should continue dosing with SEP-4199 CR in the current 
open-label study without dosing interruption. 
Open-Label Treatment Period (Day 1 to Visit 14E/Month 12) 
Subjects will self-administer the study drug on an outpatient basis once daily beginning on Day 1 and 
continue for 12 months. Subjects will be instructed to administer study drug as a single oral dose in 
the morning at approximately the same time each day. The last dose of study drug will be self-
administered by the subject at home on the morning of Visit 14E (Month 12). 
During the open-label treatment period, subjects will have clinic visits at Week 2/Day 14 and 
Months 1 to 12. In order to facilitate scheduling of clinic visits and telephone calls, a window of ± 2 
days will be allowed for Visits 2E (Week 2/Day 14) and 3E (Month 1); a window of ± 5 days will be 
allowed for Visits 4E (Month 2) to 13E (Month 11), and a window of +5 days will be allowed for 
Visit 14E (Month 12). Between study visits, subjects will be contacted weekly by telephone. 
All subjects will initiate treatment with SEP-4199 CR 200 mg/day. The dose may be increased to 
400 mg/day at Visit 2E (Week 2/Day 14) or later, based on the Investigator’s judgment. However, if 
clinically indicated, the dose may be increased as early as Day 7 at an unscheduled visit. The dose 
may be decreased to 200 mg/day at any time thereafter for tolerability. If a dose decrease is needed 
between study visits, subjects will return to the clinic for an unscheduled visit for drug dispensation. 
Dose increases will occur only at scheduled or unscheduled clinic visits. Prior to a dose increase, 
safety assessments will be completed, including but not limited to evaluation of AEs, concomitant 
medications, vital signs, and ECGs. Subjects whose ECG results, based on machine reading, show 
increase from Baseline in QT interval corrected for heart rate using Fridericia’s formula (QTcF) 
interval ≥ 30 milliseconds (msec) or whose QTcF interval is ≥ 480 msec at the 200 mg/day dose are 
not allowed to have their dose increased to 400 mg/day. Subjects with hyperprolactinemia-related 
AESI are not allowed to have the dose increased to 400 mg/day. 
End of Treatment (EOT)/Early Termination (ET) (Visit 14E: Month 12) 
Subjects will have Visit 14E at Month 12 (+ 5 days) for EOT assessments of safety and effectiveness. 
Subjects who prematurely discontinue from the study will undergo an ET visit to include all Visit 14E 
assessments and procedures. 
Follow-up Period (Visit 15E, 7 [± 2] days after last dose) 
All subjects will have a follow-up visit for safety and tolerability assessments 7 (± 2) days after their 
last dose of study drug. Assessment of potential withdrawal effects will also be made during the 
follow-up period. 
Safety Assessments 
Safety and tolerability will be monitored throughout the study by physical and neurological 
examinations, vital signs, AE monitoring, ECGs, and clinical laboratory tests. Body weight, body 
mass index (BMI), and waist circumference will also be recorded. AESI will include, but are not 
limited to, hyperprolactinemia-related AEs. AEs associated with extrapyramidal symptoms (EPS) will 
be summarized; and movement disorders and akathisia will be assessed by AIMS, BARS, and the 
modified SAS. Manic symptoms will be monitored using the YMRS. Suicidality will be monitored 
using the C-SSRS. Subjects who have significant findings for suicidal ideation upon completion of the 
C-SSRS at any time during the study must be discontinued from the study, referred to the Investigator 
for follow-up evaluation, and followed until the event resolves; in addition, an associated AE must be 


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reported. Potential withdrawal effects will be assessed using the PWC. A Data and Safety Monitoring 
Board (DSMB) will review safety data at regular intervals during the study. Details of these safety 
assessments are provided in Section 11.4 and Table 2. 
Effectiveness Assessments 
Effectiveness will be evaluated for depression symptoms using the clinician-rated MADRS, 
CGI-BP-S Depression scale, and the QIDS-SR16. Anxiety symptoms will be evaluated using the 
HAM-A. Functional disability will be assessed using the SDS. Quality of life will be assessed using 
the EQ-5D-5L. Anhedonia symptoms will be evaluated using the SHAPS. Details of these 
effectiveness assessments are provided in Section 11.3 and in Table 2. 
Pharmacokinetic Assessments 
Blood samples will be collected for population pharmacokinetics and plasma prolactin at the 
following visits: Visit 2E (Week 2/Day 14), Visit 4E (Month 2), Visit 6E (Month 4), Visit 8E 
(Month 6), Visit 10E (Month 8), V12E (Month 10), Visit 14E (Month 12), and Follow-up (Visit 15E, 
7 ± 2 days after last dose). 
Prior to PK blood sample collection, subjects will record the date and time of their 3 most-recent 
study drug doses; the clinical site staff will record the dates and times of the 3 doses in the eCRF for 
each of the PK collection visits during the treatment period. 
Plasma samples will be analyzed for concentrations of aramisulpride and esamisulpride using a 
validated enantioselective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. 
Plasma samples will also be analyzed for prolactin concentrations by an enzyme-linked 
immunosorbent assay (ELISA). 
Remaining plasma samples after amisulpride PK and prolactin analysis may also be used for the 
additional bioanalytical method development and/or characterization of putative metabolites of 
amisulpride and for other exploratory measurements, if needed. 
Number of Subjects (planned): Approximately 355 
Diagnosis and Criteria for Subject Inclusion:  
Inclusion Criteria: 
1. Subject provides written informed consent and is willing and able to comply with the protocol in 
the opinion of the Investigator. 
2. Subject has completed 6 weeks of double-blind treatment and all scheduled assessments from 
Visit 6/EOT (Day 42) of the lead-in study of SEP-4199 CR. 
3. Subject is medically appropriate for long-term open-label treatment with SEP-4199 CR in the 
opinion of the Investigator. 
4. Female subjects of childbearing potential must agree to use effective and reliable contraception 
throughout the study and for at least 30 days after the last dose of study drug has been taken. In 
the Investigator’s judgment, the subject will adhere to this requirement. Contraception 
requirements are detailed in Section 10.4. 
5. Male subjects agree to avoid fathering a child and to use effective methods of birth control 
throughout the study and until at least 90 days after the last study drug administration. 
Contraception requirements are detailed in Section 10.4. 
Exclusion Criteria: 
1. Subject is at high risk of non-compliance in the opinion of the Investigator. 
2. Subject plans to initiate treatment with a prohibited psychotropic medication during the study. 


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3. Subject plans to initiate treatment with transcranial magnetic stimulation (TMS), 
electroconvulsive therapy (ECT), vagus nerve stimulation (VNS), or deep brain stimulation 
(DBS) during the study. 
4. Subject experienced a moderate or severe hyperprolactinemia-related AESI in the lead-in study of 
SEP-4199 CR. 
5. Subject will require treatment with a drug that is associated with increases in QTc interval (see 
Section 23, Appendix IV for a list of medications, not all inclusive). 
6. Subject had any of the following at Visit 6/EOT (Day 42) of the lead-in study of SEP-4199 CR 
based on machine reading:  
• 
increase in QTcF interval of ≥ 30 msec from Baseline of the lead-in study of SEP-4199 CR 
AND a QTcF interval ≥ 480 msec 
• 
increase in QTcF interval ≥ 60 msec from Baseline of the lead-in study of SEP-4199 CR 
• 
QTcF interval > 500 msec 
• 
treatment-emergent clinically significant ECG abnormality. 
7. Subject is considered by the Investigator to be at imminent risk of suicide or injury to self or 
others, has a MADRS item 10 (suicidal ideation) score ≥ 4, or answers “yes” to “suicidal 
ideation” item 4 (active suicidal ideation with some intent to act, without specific plan) or item 5 
(active suicidal ideation with specific plan and intent) on the C-SSRS assessment at Visit 6/EOT 
(Day 42) of the lead-in study of SEP-4199 CR. 
8. Female subject of childbearing potential has a positive urine pregnancy test at Visit 6/EOT 
(Day 42) of the lead-in study of SEP-4199 CR or plans to become pregnant during the current 
study. 
9. Subject tests positive for any drug of abuse or cannabis at Visit 6/EOT (Day 42) of the lead-in 
study of SEP-4199 CR. 
Investigational Product, Dosage and Mode of Administration:  
SEP-4199 CR will be supplied as 200 mg film-coated tablets and containing a fixed 85:15 ratio of 
aramisulpride:esamisulpride. 
• 
For the SEP-4199 CR 200 mg/day dose, study drug will consist of 1 x 200 mg tablet. 
• 
For the SEP-4199 CR 400 mg/day dose, study drug will consist of 2 x 200 mg tablets. 
Study drug tablets will be self-administered by the subject orally once daily in the morning at 
approximately the same time each day beginning on Day 1. 
Duration of Treatment:  
Open-label treatment will be self-administered by the subject once daily for 12 months.  
Reference Therapy, Dosage and Mode of Administration:  
Not applicable.  
Prior and Concomitant Medications: 
Any medication, vaccination, or non-pharmacological therapy that is taken by or administered to the 
subject between the signing of informed consent and final visit or discontinuation will be recorded in 
the electronic case report form (eCRF). 
Concomitant medications in the lead-in study of SEP-4199 CR that were ongoing at Visit 6/EOT 
(Day 42) will be entered into the eCRF for this study (SEP380-303). All changes in concomitant 
medications or new medications administered during the study up to the Follow-up Visit (Visit 15E, 
7 ± 2 days after last dose) will be recorded. 


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Treatment with other psychotropic medications (eg, antipsychotic agents, antidepressants, and mood 
stabilizers) is prohibited except as noted below. 
Ongoing treatment or initiation of treatment with non-pharmacologic psychotherapy is allowed. 
Non-psychotropic medications may be used to treat mild, chronic medical conditions. β-adrenergic 
antagonists used to treat stable hypertension may be continued. In addition, non-prescription pain 
medications (eg, aspirin, acetaminophen/paracetamol, ibuprofen) are allowed during the study 
provided these medications do not have a propensity for psychotropic effects and do not interfere with 
the evaluation of study medication. 
Medications for the short-term (no more than 10 days) treatment of an acute medical condition are 
allowed provided that the medications do not prolong the QTc interval. Section 23, Appendix IV 
provides a representative, but not exhaustive, list of medications that prolong the QT interval and are 
not allowed during the study. Routine vaccines (ie, seasonal influenza, pneumonia, COVID-19, etc.) 
are allowed based on Investigator judgement. 
Medications for treatment of movement disorders may be administered if symptoms emerge. 
Benztropine (≤ 6 mg/day), biperiden (≤ 16 mg/day), trihexyphenidyl (≤ 15 mg/day), or 
diphenhydramine (≤ 100 mg/day) are permitted as needed to treat extrapyramidal symptoms. 
Propranolol (≤ 120 mg/day) or amantadine (≤ 300 mg/day) are permitted as needed to treat akathisia. 
Concomitant use of anxiolytics, sedatives, and hypnotics is permitted with the following restrictions: 
Lorazepam is permitted up to 2 mg/day for intolerable anxiety/agitation. Lorazepam (≤ 2 mg/day), 
eszopiclone (≤ 3 mg/day), zopiclone (≤ 7.5 mg/day), zolpidem (≤ 10 mg/day), zolpidem CR 
(≤ 12.5 mg/day), and temazepam (≤ 30 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. 
In regions that do not have the above specified medications available, similar medications at 
equivalent dosages may be permitted after consultation with and approval by the Medical Monitor. 
Opiates may be allowed in rare cases for a limited period of time with prior authorization from the 
Medical Monitor. 
The use of herbal supplements or other complementary or alternative medications during the trial is 
not permitted. Further details are provided in Section 10.3. 
Study Endpoints: 
Safety Endpoints: 
• 
The incidence of overall AEs, discontinuation due to AEs, and SAEs 
• 
The incidence of AESI including but not limited to hyperprolactinemia-related AEs 
• 
Clinical laboratory evaluations (chemistry, hematology, urinalysis),  
• 
Clinical evaluation (vital signs including orthostatic effects, and 12-lead ECG measurements) 
• 
Changes in prolactin values 
• 
Changes in metabolic parameters (insulin, glucose, hemoglobin A1c (HbA1c), lipid panel) 
• 
Change and percent change in body weight 
• 
Change in BMI 
• 
Incidence of treatment-emergent mania, defined as a YMRS total score ≥ 16 at post-Baseline visit 
(scheduled or unscheduled), or an adverse event of hypomania or mania 
• 
Changes from Baseline in movement disorders scales: AIMS, BARS, and modified SAS  
• 
Frequency and severity of suicidal ideation and suicidal behavior using the C-SSRS 
• 
Change from Week 52/EOT (end of treatment) visit to the safety follow-up visit on the PWC 


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Effectiveness Endpoints: 
• 
Changes in MADRS total score 
• 
Changes in CGI-BP-S depression score 
• 
The proportion of subjects with treatment response, defined as ≥ 50% reduction from Baseline in 
MADRS total score 
• 
The proportion of subjects meeting criteria for remission, defined as MADRS total score ≤ 12 
• 
Changes in HAM-A total score 
• 
Changes in QIDS-SR16 total score 
• 
Changes in SDS total and subscale scores (work/school, family, and social function) 
• 
The proportion of subjects meeting criteria for functional remission, defined as having a score ≤ 2 
on each of the SDS subscale scores (work/school, family, and social function) 
• 
Changes in the EQ-5D-5L VAS and Index scores 
• 
Changes in the SHAPS total score 
Pharmacokinetic and Pharmacodynamic Endpoints: 
• 
Plasma concentrations of aramisulpride and esamisulpride 
• 
Plasma concentrations of prolactin 
Statistical Methods:  
The safety population will include all subjects who receive at least one dose of study medication. The 
follow-up population includes all subjects who receive at least one dose of study medication and have 
at least 1 assessment after the last study drug administration for any evaluation. 
A total of 4 analysis groups will be formed based on a subject’s previous participation in the  lead-in 
study of SEP-4199 CR (previously randomized to SEP-4199 CR 200 mg/day, previously randomized 
to SEP-4199 CR 400 mg/day, previously randomized to any SEP-4199 CR dose group, previously 
randomized to placebo). A group that combines all of these analysis groups will also be presented. 
Summary tables, wherever applicable, will be presented by analysis group. Where changes are 
reported, the reference will be to the pretreatment Baseline from the lead-in study of SEP-4199 CR 
and indicated as “Double-blind (DB) Baseline”. Where relevant, changes from Baseline for the 
open-label study, defined as the Week 6 assessment in the double-blind study or the last assessment 
prior to the first dose of study medication in the open-label study, will also be reported, and will be 
referred to as the open-label study Baseline or "OL Baseline". Continuous variables will be 
summarized using descriptive statistics (N, mean, standard deviation, median, first quartile [Q1], third 
quartile [Q3], range, 95% confidence interval [CI] as needed) and categorical variables will be 
reported as frequencies and percentages at DB Baseline, OL Baseline, each of post-OL visit, and 
endpoint. No statistical comparisons will be conducted and no inferential statistics on effectiveness 
and safety will be presented. 
The safety data will be summarized by analysis group based on the safety population. In addition, for 
a few selected safety assessments (ie, AE, ECG, laboratory results, and vital signs), descriptive 
summary by analysis group will be provided based on the follow-up population, separately. 
A treatment-emergent adverse event (TEAE) is an adverse event with onset data on or after the first 
day of the open-label treatment period through 7 days after study drug discontinuation (14 days for 
serious adverse events). The start of the open-label treatment period is defined as the first dose day for 
subjects previously randomized to placebo group and the OL Baseline visit date for subjects 
previously randomized to SEP-4199 CR groups. 
The incidence of AEs, SAEs, and AEs leading to discontinuation due to AEs (or SAEs) will be 
summarized by analysis group (by presenting the number and percentage of subjects with one or more 


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AEs in each category). The number and proportion of subjects with one or more AEs within a system 
organ class (SOC) and by preferred term will be presented by analysis group as well. The incidence of 
AEs of special interest, including but not limited to hyperprolactinemia related AEs, will be 
summarized for overall and by gender, as appropriate. Incidence of post-treatment adverse events 
(defined as an AE with a start date after the date of last dose of study drug through the last 
contact/visit in the follow-up period) will be summarized separately for subjects in the follow-up 
population. 
For safety assessments, descriptive statistics will be provided for observed values and changes from 
DB Baseline and OL Baseline, respectively, by study visit and analysis group for the continuous 
variables. Frequencies and percentages will be reported for categorical variables by study visit and 
analysis group. The markedly abnormal values for selected safety parameters will be summarized, as 
appropriate. 
The number and percentage of subjects with suicidal ideation and/or suicidal behavior, emergence or 
worsening of suicidal ideation or suicidal behavior will be summarized by analysis group for the 
open-label treatment period. 
The PWC score will be summarized by presenting descriptive statistics of observed values and 
changes from Week 52/EOT by analysis group based on the follow-up population. 
Descriptive statistics of observed values and changes from DB Baseline and OL Baseline will be 
summarized by study visit and analysis group for effectiveness parameters (continuous). At a visit in 
the extension study, responders relative to DB Baseline are defined as those who show a 50% or more 
reduction (ie, improvement) from DB Baseline in MADRS total score. At a post-OL Baseline visit, 
responders relative to OL Baseline are defined as those who show a 50% or more reduction (ie, 
improvement) from OL Baseline. Remitters at any visit are defined as subjects with a MADRS total 
score of ≤ 12. Frequencies and percentages of MADRS responders relative to both DB Baseline and 
OL Baseline, and frequencies and percentages of remitters will be summarized over time by analysis 
group. 
Sample Size Consideration: Assuming a completion rate of 85% in the lead-in study of SEP-4199 
CR and an 80% rollover rate of completers from that study to the current extension study, it is 
estimated that approximately 355 subjects will be enrolled. 
 


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Table 2: Schedule of Assessments 
 
 
12-Month Open-Label Treatment Period 
Study Visit Numbera 
V1E 
V2E 
V3E 
V4E 
V5E 
V6E 
V7E 
V8E 
V9E 
Study Week or Month 
Baselineb 
Week 2 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 
Month 7 
Study Day 
-1 
14 (± 2) 
30 (± 2) 
60 (± 5) 
90 (± 5) 
120 (± 5) 
150 (± 5) 
180 (± 5) 
210 (± 5) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Informed Consent for 
Duplicate Subject Check 
(where local regulations 
allow)  
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
Dispense Study Drug  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Accountability 
 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
Physical Examination 
Core 
 
 
 
 
 
 
X 
 
Neurological Examination 
Core 
 
 
 
 
 
 
X 
 
Prior/Concomitant 
Medicationsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Schedule Next Visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Schedule Telephone Check-in 
With Subjectd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SAFETY ASSESSMENTS 
 
 
 
 
 
 
 
 
 
Vital Sign Measurements 
Core 
X 
X 
X 
X 
X 
X 
X 
X 
Weight and Body Mass Indexe 
Core 
X 
X 
X 
X 
X 
X 
X 
X 
Waist Circumference 
Core 
 
 
 
 
 
 
X 
 
Adverse Eventsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGg 
Core 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistryh 
Core 
X 
 
X 
 
X 
 
X 
 


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Table 2: 
Schedule of Assessments (Continued) 
 
 
12-Month Open-Label Treatment Period 
Study Visit Numbera 
V1E 
V2E 
V3E 
V4E 
V5E 
V6E 
V7E 
V8E 
V9E 
Study Week or Month 
Baselineb 
Week 2 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 
Month 7 
Study Day 
-1 
14 (± 2) 
30 (± 2) 
60 (± 5) 
90 (± 5) 
120 (± 5) 
150 (± 5) 
180 (± 5) 
210 (± 5) 
Hematology 
Core 
X 
 
X 
 
X 
 
X 
 
Urinalysis 
Core 
X 
 
X 
 
X 
 
X 
 
Serum Prolactini 
Core 
X 
 
X 
 
X 
 
X 
 
Blood Sampling for Plasma 
PK and Plasma Prolactinj 
Core 
X 
 
X 
 
X 
 
X 
 
Hemoglobin A1c (HbA1c) 
Core 
 
 
X 
 
X 
 
X 
 
Lipid Panelh 
Core 
 
 
X 
 
X 
 
X 
 
Serum Insulinh 
Core 
 
 
X 
 
X 
 
X 
 
High-sensitivity C-Reactive 
Protein (hs-CRP) 
Core 
 
 
 
 
 
 
X 
 
Thyroid Panel 
Core 
 
 
X 
 
X 
 
X 
 
Urine Pregnancy Test (females 
of childbearing potential)k,l 
Core 
 
X 
X 
X 
X 
X 
X 
X 
Rapid Urine Drug Testl 
Core 
X 
X 
X 
X 
X 
X 
X 
X 
Young Mania Rating Scale 
(YMRS) 
Core 
X 
X 
X 
X 
X 
X 
X 
X 
Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
Core 
X 
X 
X 
X 
X 
X 
X 
X 
Abnormal Involuntary 
Movement Scale (AIMS) 
Core 
X 
 
X 
 
X 
 
X 
 
Barnes Akathisia Scale 
(BARS) 
Core 
X 
 
X 
 
X 
 
X 
 
Modified Simpson-Angus 
Scale (SAS) 
Core 
X 
 
X 
 
X 
 
X 
 


Protocol SEP380-303, Version 2.02 
 
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Table 2: 
Schedule of Assessments (Continued) 
 
 
12-Month Open-Label Treatment Period 
Study Visit Numbera 
V1E 
V2E 
V3E 
V4E 
V5E 
V6E 
V7E 
V8E 
V9E 
Study Week or Month 
Baselineb 
Week 2 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 
Month 7 
Study Day 
-1 
14 (± 2) 
30 (± 2) 
60 (± 5) 
90 (± 5) 
120 (± 5) 
150 (± 5) 
180 (± 5) 
210 (± 5) 
Physician’s Withdrawal 
Checklist (PWC) 
 
 
 
 
 
 
 
 
 
EFFECTIVENESS 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
Montgomery-Asberg 
Depression Rating Scale 
(MADRS) 
Core 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Global Impression-
Bipolar Version-Severity of 
Illness (CGI-BP-S)  
Core 
X 
X 
X 
X 
X 
X 
X 
X 
Hamilton Anxiety Rating 
Scale (HAM-A) 
Core 
 
 
X 
 
X 
 
X 
 
Quick Inventory of Depressive 
Symptomatology, Self-Report 
(QIDS-SR16) 
Core 
 
 
X 
 
X 
 
X 
 
Sheehan Disability Scale 
(SDS) 
Core 
 
 
X 
 
X 
 
X 
 
EuroQoL - 5 Dimension - 
5 Level (EQ-5D-5L) 
Core 
 
 
X 
 
X 
 
X 
 
Snaith-Hamilton Pleasure 
Scale (SHAPS) 
Core 
 
 
X 
 
X 
 
X 
 
 
 


Protocol SEP380-303, Version 2.02 
 
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Table 2: 
Schedule of Assessments (Continued) 
 
12-Month Open-Label Treatment Period 
Follow-Up 
Study Visit Numbera 
V10E 
V11E 
V12E 
V13E 
V14E (EOT/ET) 
V15Eo 
Study Week or Month 
Month 8 
Month 9 
Month 10 
Month 11 
Month 12m,n 
(Week 52) 
7 (± 2) days 
after last dose 
Study Day 
240 (± 5) 
270 (± 5) 
300 (± 5) 
330 (± 5) 
360 (+ 5) 
Informed Consent 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
 
 
 
 
 
Dispense Study Drug  
X 
X 
X 
X 
 
 
Study Drug Accountability 
X 
X 
X 
X 
X 
 
Physical Examination 
 
 
 
 
X 
 
Neurological Examination 
 
 
 
 
X 
 
Prior/Concomitant Medications 
X 
X 
X 
X 
X 
X 
Schedule Next Visit 
X 
X 
X 
X 
X 
 
Schedule Telephone Check-in With Subjectd 
X 
X 
X 
X 
 
 
SAFETY ASSESSMENTS 
 
 
 
 
 
 
Vital Sign Measurements 
X 
X 
X 
X 
X 
X 
Weight and Body Mass Indexe 
X 
X 
X 
X 
X 
 
Waist Circumference 
 
 
 
 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
X 
X 
X 
X 
X 
Serum Chemistryh 
X 
 
X 
 
X 
 
Hematology 
X 
 
X 
 
X 
 
Urinalysis 
X 
 
X 
 
X 
 
Serum Prolactini 
X 
 
X 
 
X 
X 
Blood Sampling for Plasma PK and Plasma 
Prolactini,j 
X 
 
X 
 
X 
X 
Hemoglobin A1c (HbA1c) 
X 
 
X 
 
X 
 
Lipid Panelh 
X 
 
X 
 
X 
 
Serum Insulinh 
X 
 
X 
 
X 
 
High-sensitivity C-Reactive Protein (hs-CRP) 
 
 
 
 
X 
 


Protocol SEP380-303, Version 2.02 
 
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Confidential and Proprietary 
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06 Dec 2022 
Table 2: 
Schedule of Assessments (Continued) 
 
12-Month Open-Label Treatment Period 
Follow-Up 
Study Visit Numbera 
V10E 
V11E 
V12E 
V13E 
V14E (EOT/ET) 
V15Eo  
Study Week or Month 
Month 8 
Month 9 
Month 10 
Month 11 
Month 12m,n 
(Week 52) 
7 (± 2) days 
after last dose 
Study Day 
240 (± 5) 
270 (± 5) 
300 (± 5) 
330 (± 5) 
360 (+ 5) 
Thyroid Panel 
X 
 
X 
 
X 
 
Urine Pregnancy Test (females of childbearing 
potential)k,l 
X 
X 
X 
X 
X 
X 
Rapid Urine Drug Testl 
X 
X 
X 
X 
X 
X 
Young Mania Rating Scale (YMRS) 
X 
X 
X 
X 
X 
X 
Columbia-Suicide Severity Rating Scale 
(C-SSRS) 
X 
X 
X 
X 
X 
X 
Abnormal Involuntary Movement Scale 
(AIMS) 
X 
 
X 
 
X 
 
Barnes Akathisia Scale (BARS) 
X 
 
X 
 
X 
 
Modified Simpson-Angus Scale (SAS) 
X 
 
X 
 
X 
 
Physician’s Withdrawal Checklist (PWC) 
 
 
 
 
X 
X 
EFFECTIVENESS ASSESSMENTS 
 
 
 
 
 
 
Montgomery-Asberg Depression Rating Scale 
(MADRS) 
X 
X 
X 
X 
X 
 
Clinical Global Impression-Bipolar Version-
Severity of Illness (CGI-BP-S) 
X 
X 
X 
X 
X 
 
Hamilton Anxiety Rating Scale (HAM-A) 
X 
 
X 
 
X 
 
Quick Inventory of Depressive 
Symptomatology, Self-Report (QIDS-SR16) 
X 
 
X 
 
X 
 
Sheehan Disability Scale (SDS) 
X 
 
X 
 
X 
 
EuroQoL - 5 Dimension - 5 Level (EQ-5D-5L) 
X 
 
X 
 
X 
 
Snaith-Hamilton Pleasure Scale (SHAPS) 
X 
 
X 
 
X 
 


Protocol SEP380-303, Version 2.02 
 
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Abbreviations: BL = Baseline; eCRF = electronic case report form; E = extension; ECG = electrocardiogram; EOT = End of Treatment; ET = Early Termination; 
hCG = human chorionic gonadotropin; PK = pharmacokinetic 
Note: To ensure subject safety and data integrity, should circumstances warrant and with Sponsor approval, remote site/subject visits may be conducted. 
a Visit windows are as follows: ± 2 days for Visits 2E (Week 2/Day 14) and 3E (Month 1), ± 5 days for monthly visits between Visit 4E (Month 2) and Visit 13E 
(Month 11), + 5 days for Visit 14E (Month 12), and ± 2 days for the Follow-up Visit (Visit 15E). 
b Visit 6/ End of Treatment (EOT) (Day 42) of the lead-in study of SEP-4199 CR serves as the Baseline visit (Day -1) for the present study. “Core” indicates 
assessments that were conducted at Visit 6/EOT (Day 42) in the lead-in study of SEP-4199 CR and do not need to be repeated for this study. 
c Medications taken during the lead-in study of SEP-4199 CR that are ongoing at the start of the current extension study will be entered into the eCRF. 
d Between study visits, subjects will be contacted weekly by telephone. 
e BMI does not need to be calculated by the clinical site staff as it will be calculated in the analysis. 
f Adverse events with onset during the lead-in study of SEP-4199 CR and ongoing at the start of the current extension study will be entered into the eCRF. 
g ECG machine measurements are to be considered for subject eligibility at Baseline. 
h Subjects are required to fast for at least 8 hours prior to sample collection for laboratory testing at Visit 2E, Visit 4E, Visit 6E, Visit 8E, Visit 10E, Visit 12E, 
and Visit 14E (EOT/ET); fasting is also required at Week 6 (EOT) in the lead-in study of SEP-4199 CR, which serves as baseline (Visit 1E) in this long-term 
safety study. 
i Prolactin values at open-label Baseline visit (including any repeat testing) will be masked. Prolactin values after the first dose of study drug in the extension 
study will not be masked. 
j Blood sample for SEP-4199 population pharmacokinetic analysis for R- and S-enantiomers and/or plasma prolactin measurement will be collected at Visit 2E 
(Week 2/Day 14), Visit 4E (Month 2), Visit 6E (Month 4), Visit 8E (Month 6), Visit 10E (Month 8), V12E (Month 10), Visit 14E (Month 12), and Follow-up 
(Visit 15E, 7  ± 2 days after last dose), with a record of the time of last 3 administered doses on the eCRF for PK sampling visits during the treatment period. 
The blood sample will be collected at time of clinical safety laboratory test sample collection. Plasma concentrations of aramisulpride and esamisulpride and 
plasma prolactin levels will be measured. Remaining plasma from samples may also be used for the additional bioanalytical method development and/or 
characterization of putative metabolites of amisulpride and for other exploratory measurements, if needed. 
k For females of childbearing potential, any positive urine β- hCG test should be confirmed by a serum β-hCG test. 
l Unscheduled urine pregnancy (females of childbearing potential) and urine drug tests may be administered based on Investigator discretion. Point of care (POC) 
testing will be used for the urine pregnancy test and the rapid urine drug test. A urine drug screen should be submitted to the central lab for any positive rapid 
urine drug test throughout the study. Positive results for any of these assessments should be discussed with the Medical Monitor. 
m Visit 14E (Month 12) is the End of Treatment/Early Termination visit. Subjects who discontinue the study prior to Visit 14E will have all Visit 14E procedures 
performed at the time of discontinuation. 
n For subjects completing the 12-month treatment period, a visit window of + 5 days is strongly preferred. 
o Follow-up visit to be scheduled 7 (± 2) days after last dose of study drug. 


Protocol SEP380-303, Version 2.02 
 
 
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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 ...............18 
TABLE OF CONTENTS ...............................................................................................................18 
LIST OF TABLES .........................................................................................................................23 
LIST OF FIGURES .......................................................................................................................23 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................24 
4. 
INTRODUCTION ......................................................................................................28 
4.1. 
Background .................................................................................................................28 
4.2. 
Study Conduct Rationale ............................................................................................28 
4.3. 
Risk-Benefit Assessment ............................................................................................28 
5. 
STUDY OBJECTIVES ..............................................................................................30 
5.1. 
Primary Objective .......................................................................................................30 
5.2. 
Additional Safety Objectives ......................................................................................30 
5.3. 
Effectiveness Objectives .............................................................................................30 
5.4. 
Pharmacokinetic and Pharmacodynamic Objectives ..................................................31 
6. 
STUDY ENDPOINTS ................................................................................................32 
6.1. 
Safety Endpoints .........................................................................................................32 
6.2. 
Effectiveness Endpoints ..............................................................................................32 
6.3. 
Pharmacokinetic and Pharmacodynamic Endpoints ...................................................33 
7. 
INVESTIGATIONAL PLAN .....................................................................................34 
7.1. 
Overall Study Design ..................................................................................................34 
7.2. 
Treatment Assignment and Blinding ..........................................................................35 
7.3. 
Rationale .....................................................................................................................36 
7.3.1. 
Rationale for the Study Design ...................................................................................36 
7.3.2. 
Rationale for the Dosages ...........................................................................................36 
7.3.3. 
Rationale for the Study Population .............................................................................37 
7.3.4. 
Rationale for the Endpoints ........................................................................................37 


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7.4. 
Prevention of Missing Data ........................................................................................37 
8. 
SELECTION OF SUBJECTS ....................................................................................38 
8.1. 
Subject Inclusion Criteria ...........................................................................................38 
8.2. 
Subject Exclusion Criteria ..........................................................................................38 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................40 
9.1. 
Description of Study Drug ..........................................................................................40 
9.2. 
Study Drug Packaging and Labeling ..........................................................................40 
9.2.1. 
Package Description ...................................................................................................40 
9.2.2. 
Labeling Description ..................................................................................................40 
9.3. 
Study Drug Storage .....................................................................................................41 
9.4. 
Dispensing of Study Drug ..........................................................................................41 
9.5. 
Study Drug Accountability .........................................................................................41 
9.6. 
Study Drug Handling and Disposal ............................................................................41 
10. 
TREATMENT OF SUBJECTS ..................................................................................43 
10.1. 
Study Medication ........................................................................................................43 
10.1.1. 
Dose Adjustment Criteria ...........................................................................................43 
10.2. 
Treatment Compliance ................................................................................................43 
10.3. 
Concomitant Medications and Therapies ...................................................................43 
10.3.1. 
Prohibited Medications ...............................................................................................44 
10.3.2. 
Concomitant Non-psychotropic Medications .............................................................44 
10.3.3. 
Concomitant Psychotropic Medications .....................................................................44 
10.4. 
Contraception Requirements ......................................................................................45 
10.5. 
Guidance for Overdose ...............................................................................................46 
11. 
STUDY ASSESSMENTS ..........................................................................................47 
11.1. 
Duplicate Subject Check .............................................................................................47 
11.2. 
Demographics and Baseline Characteristics ...............................................................47 
11.3. 
Effectiveness Assessments .........................................................................................47 
11.3.1. 
Montgomery-Asberg Depression Rating Scale (MADRS) ........................................47 
11.3.2. 
Clinician Global Impression-Bipolar Version-Severity of Illness (CGI-BP-S) .........47 
11.3.3. 
Hamilton Anxiety Rating Scale (HAM-A) .................................................................48 
11.3.4. 
Quick Inventory of Depressive Symptomatology – Self Report (QIDS-SR16) .........48 
11.3.5. 
Sheehan Disability Scale (SDS) .................................................................................48 
11.3.6. 
EuroQol - 5 Dimension - 5 Level (EQ-5D-5L) ..........................................................48 


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11.3.7. 
Snaith-Hamilton Pleasure Scale (SHAPS) .................................................................49 
11.4. 
Safety Assessments .....................................................................................................49 
11.4.1. 
Adverse Events ...........................................................................................................49 
11.4.2. 
Clinical Laboratory Tests ...........................................................................................49 
11.4.3. 
Vital Signs ..................................................................................................................50 
11.4.4. 
Centrally-read ECG ....................................................................................................50 
11.4.5. 
Neurological and Physical Examination .....................................................................50 
11.4.6. 
Safety Scales ...............................................................................................................51 
11.4.6.1. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................51 
11.4.6.2. 
Young Mania Rating Scale (YMRS) ..........................................................................51 
11.4.6.3. 
Abnormal Involuntary Movement Scale (AIMS) .......................................................51 
11.4.6.4. 
Barnes Akathisia Rating Scale (BARS) .....................................................................52 
11.4.6.5. 
Modified Simpson-Angus Scale (SAS) ......................................................................52 
11.4.6.6. 
Physician’s Withdrawal Checklist (PWC) ..................................................................52 
11.5. 
Pharmacokinetic Assessments ....................................................................................52 
11.6. 
Study Visits and Assessments ....................................................................................53 
11.6.1. 
Visit 1E: Baseline (Day -1) .........................................................................................53 
11.6.2. 
Visit 2E (Week 2/Day 14 [± 2 days]) .........................................................................55 
11.6.3. 
Visit 3E (Month 1/Day 30 [± 2 days]) ........................................................................56 
11.6.4. 
Visit 4E (Month 2/Day 60 [± 5 days]) ........................................................................56 
11.6.5. 
Visit 5E (Month 3/Day 90 [± 5 days]) ........................................................................58 
11.6.6. 
Visit 6E (Month 4/Day 120 [± 5 days]) ......................................................................59 
11.6.7. 
Visit 7E (Month 5/Day 150 [± 5 days]) ......................................................................60 
11.6.8. 
Visit 8E (Month 6/Day 180 [± 5 days]) ......................................................................61 
11.6.9. 
Visit 9E (Month 7/Day 210 [± 5 days]) ......................................................................62 
11.6.10. 
Visit 10E (Month 8/Day 240 [± 5 days]) ....................................................................63 
11.6.11. 
Visit 11E (Month 9/Day 270 [± 5 days]) ....................................................................64 
11.6.12. 
Visit 12E (Month 10/Day 300 [± 5 days]) ..................................................................65 
11.6.13. 
Visit 13E (Month 11/Day 330 [± 5 days]) ..................................................................66 
11.6.14. 
Visit 14E (Month 12/Day 360 [+ 5 days]; End of Treatment/Early 
Termination) ...............................................................................................................67 
11.6.15. 
Follow-up: Visit 15E (7 ± 2 days after last dose) .......................................................68 
11.6.16. 
Telephone Contacts ....................................................................................................69 


Protocol SEP380-303, Version 2.02 
 
 
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06 Dec 2022 
11.6.17. 
Unscheduled Visit for Dose Adjustment ....................................................................69 
11.6.17.1. Unscheduled Visit for Dose Increase .........................................................................69 
11.6.17.2. Unscheduled Visit for Dose Decrease ........................................................................70 
12. 
SAFETY REPORTING ..............................................................................................71 
12.1. 
Definitions ..................................................................................................................71 
12.1.1. 
Adverse Events ...........................................................................................................71 
12.1.2. 
Serious Adverse Events ..............................................................................................71 
12.1.3. 
Adverse Events of Special Interest .............................................................................72 
12.2. 
Objective Findings ......................................................................................................72 
12.3. 
Collection and Recording of Adverse Events .............................................................73 
12.4. 
Immediately Reportable Events ..................................................................................74 
12.4.1. 
Serious Adverse Event ................................................................................................75 
12.4.2. 
Pregnancy ...................................................................................................................75 
12.5. 
Data and Safety Monitoring Board .............................................................................76 
13. 
TERMINATION OF SUBJECT FROM STUDY/DISCONTINUATION OF 
STUDY DRUG ...........................................................................................................77 
13.1. 
Criteria for Subject Termination .................................................................................77 
14. 
STUDY TERMINATION ..........................................................................................79 
15. 
STATISTICS ..............................................................................................................80 
15.1. 
Sample Size ................................................................................................................80 
15.2. 
Statistical Hypotheses .................................................................................................80 
15.3. 
Analysis Populations and Analysis Groups ................................................................80 
15.4. 
Data Analysis ..............................................................................................................80 
15.4.1. 
Study Subject ..............................................................................................................80 
15.4.2. 
Effectiveness Analyses ...............................................................................................81 
15.4.3. 
Safety Analyses ..........................................................................................................81 
15.4.3.1. 
Adverse Events ...........................................................................................................81 
15.4.3.2. 
Treatment-Emergent Mania ........................................................................................82 
15.4.3.3. 
Clinical Laboratory Assessments ...............................................................................82 
15.4.3.4. 
ECGs ...........................................................................................................................82 
15.4.3.5. 
Vital Signs ..................................................................................................................83 
15.4.3.6. 
Movement Disorder Measures ....................................................................................83 
15.4.3.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................83 


Protocol SEP380-303, Version 2.02 
 
 
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15.4.3.8. 
Physician’s Withdrawal Checklist (PWC) ..................................................................84 
15.4.4. 
Pharmacokinetic and Pharmacodynamic Analysis .....................................................84 
15.4.5. 
Interim Analysis ..........................................................................................................84 
15.4.6. 
Treatment of Missing Data .........................................................................................84 
16. 
PROCEDURE FOR CLINICAL STUDY QUALITY CONTROL /DATA 
COLLECTION, MANAGEMENT, AND QUALITY ASSURANCE ......................85 
16.1. 
Data Collection/Electronic Data Capture (EDC) ........................................................85 
16.2. 
Computerized Systems Used for Source Data ............................................................85 
16.3. 
Study Monitoring ........................................................................................................86 
16.4. 
Audits ..........................................................................................................................86 
16.5. 
Study Documentation .................................................................................................87 
16.6. 
Clinical Laboratory Certification and Normal Values ................................................87 
17. 
ETHICAL AND REGULATORY OBLIGATIONS..................................................88 
17.1. 
Study Conduct ............................................................................................................88 
17.2. 
Institutional Review Board/Independent Ethics Committee ......................................88 
17.3. 
Informed Consent .......................................................................................................89 
17.4. 
Subject Privacy ...........................................................................................................89 
17.5. 
Protocol Amendments and Emergency Deviations ....................................................90 
17.6. 
Records Retention .......................................................................................................90 
17.7. 
Inspection of Records .................................................................................................90 
17.8. 
Financial Disclosure ...................................................................................................90 
17.9. 
Publication Policy .......................................................................................................90 
17.10. 
Compensation .............................................................................................................91 
18. 
REFERENCES ...........................................................................................................92 
19. 
INVESTIGATOR APPROVAL .................................................................................93 
20. 
APPENDIX I. CARDIAC SAFETY MONITORING (ECG) ....................................94 
21. 
APPENDIX II. CLINICAL LABORATORY TESTS ...............................................95 
22. 
APPENDIX III. BLOOD SAMPLE COLLECTION AND HANDLING 
GUIDELINES FOR PHARMACOKINETIC AND PLASMA PROLACTIN 
ASSESSMENTS.........................................................................................................96 
23. 
APPENDIX IV. PROHIBITED DRUGS KNOWN TO PROLONG THE QT 
INTERVAL ................................................................................................................97 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Schedule of Assessments ............................................................................................12 
Table 3: 
List of Abbreviations ..................................................................................................24 
Table 4: 
Definition of Key Study Terms ..................................................................................27 
Table 5: 
Investigational Product ...............................................................................................40 
Table 6: 
Computerized Systems Used for Source Data ............................................................85 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................34 
 


Protocol SEP380-303, Version 2.02 
 
 
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Confidential and Proprietary 
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06 Dec 2022 
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 
AESI 
Adverse event of special interest 
AIMS 
Abnormal Involuntary Movement Scale 
BARS 
Barnes Akathisia Rating Scale 
BMI 
Body mass index  
CFR 
Code of Federal Regulations 
CGI-BP-S 
Clinical Global Impression – Bipolar Version-Severity of Illness 
CI 
Confidence interval 
Cmax  
Maximum concentration of drug 
COVID-19 
Coronavirus disease 2019 
CR 
Controlled release 
CRO 
Contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DB 
Double-blind 
DBP 
Diastolic blood pressure 
DBS 
Deep brain stimulation 
DMP 
Data Management Plan 
DSMB 
Data and Safety Monitoring Board 
E 
Extension 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ECT 
Electroconvulsive therapy 
EDC 
Electronic Data Capture 
EOT 
End of treatment 
EPS 
Extrapyramidal symptoms 
EQ-5D-5L 
EuroQoL - 5 Dimension – 5 Level 
EQ-VAS 
EuroQol Visual Analogue Scale 
ET 
Early termination 


Protocol SEP380-303, Version 2.02 
 
 
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Table 3: 
List of Abbreviations (Continued) 
Abbreviation 
Full Form 
EU or EUR 
European Union / Europe 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
HAM-A 
Hamilton Anxiety Rating Scale 
HbA1c 
Hemoglobin A1c 
hCG 
Human chorionic gonadotropin 
HR 
Heart rate 
Hs-CRP 
High-sensitivity C-Reactive Protein 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IPD 
Important protocol deviation 
IR 
Immediate release 
IRB 
Institutional Review Board 
ITT 
Intention-to-treat 
IXRS 
Interactive Web Response System 
M 
Month 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
msec 
Millisecond 
OL 
Open-label 
PCS 
Potentially clinically significant 
PD 
Pharmacodynamics 
PET 
Positron emission tomography 
PK 
Pharmacokinetic(s) 
POC 
Point of care 
Pop-PK 
Population pharmacokinetics 
PR 
Time between P wave and QRS in electrocardiography 
PRN 
As needed 
PT 
Preferred term 
PVG 
Pharmacovigilance 


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Table 3: 
List of Abbreviations (Continued) 
Abbreviation 
Full Form 
PWC 
Physician’s Withdrawal Checklist 
Q1 
First quartile (25th percentile) 
Q3 
Third quartile (75th percentile) 
QIDS-SR16 
Quick Inventory of Depressive Symptomatology – Self-Report 
QRS 
Electrocardiographic wave (complex or interval) 
QT 
Electrocardiographic interval from the beginning of the QRS 
complex to the end of the T wave 
QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RR 
RR interval 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Simpson-Angus Scale 
SBP 
Systolic blood pressure 
SDS 
Sheehan Disability Scale 
SHAPS 
Snaith-Hamilton Pleasure Scale 
SIGH-A 
Structured Interview Guide for the HAM-A 
SOC 
System organ class 
SOPs 
Standard operating procedures 
TEAE 
Treatment-emergent adverse event 
TMS 
Transcranial magnetic stimulation 
US 
United States 
V 
Visit 
VAS 
Visual Analog Scale 
VNS 
Vagus nerve stimulation 
W 
Week 
WHO-DD 
World Health Organization drug dictionary 
YMRS 
Young Mania Rating Scale 


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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. 
Enrolled Subject 
Any subject who signed the study specific informed consent and 
was dispensed study drug. 
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 Subject 
Any subject who participated throughout the duration of the 
treatment period, up to and including Visit 15E. 
Early Termination  
Any subject who was successfully enrolled into the open-label 
treatment period of the study but did not complete the study. 
End of Treatment 
The day that the subject receives the protocol-defined last dose of 
the study drug. 


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4. 
INTRODUCTION 
4.1. 
Background 
The treatment of bipolar depression is challenging, due to the complexity of clinical 
presentations, which may include mixed symptoms with depression predominating. Although the 
pharmacologic treatment of bipolar depression is dominated by 3 major classes of drugs, the 
atypical antipsychotics, anticonvulsants, and serotonergic antidepressants, these treatments have 
significant limitations including undesirable side effects such as metabolic derangement, weight 
gain, sedation, sexual dysfunction, akathisia, and extrapyramidal effects (Kemp 2014). 
Amisulpride has been shown in a large meta-analysis of 32 oral antipsychotics, to be associated 
with relatively little weight gain (Huhn 2019). The clinical efficacy of amisulpride on depressive 
symptoms in mood disorders (Montgomery 2002) has been demonstrated at dose levels 
associated with relatively low dopamine D2 receptor occupancy. Racemic amisulpride is 
approved in Italy, Czech Republic, and Portugal for the treatment of dysthymia at a low dose of 
50 mg/day (Lecrubier 1997), which is substantially lower than the 400-800 mg/day dose 
recommended for the treatment of schizophrenia (Solian SMPC 2021). In vitro radioligand 
binding studies show that racemic amisulpride has high affinity for serotonin 5-HT7 receptors in 
addition to dopamine D2 receptors (Abbas 2009). Preclinical pharmacology studies using 5-HT7 
knockout mice suggest that the antidepressant-like effects of amisulpride are mediated by 5-HT7 
receptor antagonism (Abbas 2009). 
SEP-4199 is a non-racemic mixture of aramisulpride and esamisulpride enantiomers in an 85:15 
ratio. Aramisulpride is stereoselective for antagonism of serotonin 5-HT7 receptors. 
Esamisulpride is stereoselective for antagonism of dopamine D2 receptors. The 85:15 ratio of 
R:S enantiomers of SEP-4199 is optimal for maximizing serotonergic 5-HT7 receptor 
antagonism in a dose range that retains < 50% D2 receptor occupancy. SEP-4199 leverages the 
potential antidepressant activity of racemic amisulpride, driven by 5-HT7 receptor antagonism, 
from the D2 receptor-mediated antipsychotic activity by discovering that each enantiomer favors 
a different receptor (Hopkins 2021). Therefore, the pharmacology of SEP-4199 is designed to 
treat depressive symptoms via 5-HT7 antagonism, and to confer some of the mood stabilizing 
benefits of limited D2 antagonism while reducing the risk of side effects such as extrapyramidal 
symptoms and akathisia which are associated with higher levels of D2 antagonism. 
4.2. 
Study Conduct Rationale 
This study is being conducted to evaluate the long-term safety, tolerability, and effectiveness of 
open-label treatment with SEP-4199 controlled release (CR) dosed flexibly at 200 mg/day or 
400 mg/day, in subjects who previously completed a 6-week double-blind placebo-controlled 
lead-in study of SEP-4199 CR (hereinafter referred to as lead-in study of SEP-4199 CR) for the 
treatment of major depressive episode associated with bipolar I disorder (bipolar I depression). 
4.3. 
Risk-Benefit Assessment 
To date, one completed Phase 2 6-week clinical study (SEP380-201) evaluated fixed doses of 
SEP-4199 Immediate Release (IR) formulation at doses of 200 mg/day and 400 mg/day vs. 
placebo in subjects with bipolar I depression. In the full global intention-to-treat (ITT) 


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population, including North American, Latin American, European, and Japanese subjects 
(N = 337), both SEP-4199 IR 200 mg/day and 400 mg/day doses demonstrated significantly 
greater improvement compared to placebo (post-hoc adjusted p = 0.025 for both treatment 
groups using the same multiplicity adjustment approach as for the primary analysis). Based on 
the full global safety population, SEP-4199 IR was well tolerated in this study, with an overall 
adverse event (AE) rate (< 50%) in both dose groups that was comparable to that in the placebo 
group and a low rate (< 9% in either group) of discontinuations due to an AE. These results 
demonstrated proof of concept for the efficacy of SEP-4199 IR in the treatment of bipolar I 
depression and support further development of the SEP-4199 compound. However, safety and 
tolerability data for SEP-4199 IR in patients with bipolar I depression are currently limited to 
those collected over the 6-week treatment duration. Longer-term exposure to clinical doses of 
SEP-4199 is needed to fully evaluate safety, tolerability, and effectiveness. 
A novel CR formulation of SEP-4199 has been developed. SEP-4199 CR was well tolerated in 
the PK and positron emission tomography (PET) imaging study in healthy volunteers 
(SEP380-105). Administration of SEP-4199 CR resulted in the same degree of dopamine D2 
receptor occupancy after multiple doses as did SEP-4199 IR at the same dosages, while 
exhibiting lower serum concentrations at Cmax. The lower Cmax of SEP-4199 CR was associated 
with substantially less QT interval corrected for heart rate (QTc) interval prolongation than was 
observed with SEP-4199 IR. Therefore, SEP-4199 CR is hypothesized to be therapeutically 
equivalent to SEP-4199 IR, but with an improved therapeutic index due to improved cardiac 
safety. For this reason, the SEP-4199 CR formulation will be evaluated in the current long-term 
open-label study. 
 


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5. 
STUDY OBJECTIVES 
The objective of Study SEP380-303 is to evaluate the long-term safety, tolerability, and 
effectiveness of SEP-4199 CR at a flexible daily dose of 200 mg/day or 400 mg/day in subjects 
who previously completed a lead-in study of SEP-4199 CR for the treatment of major depressive 
episode associated with bipolar I disorder (bipolar I depression). 
5.1. 
Primary Objective 
The primary objective of the current study is to evaluate the long-term safety and tolerability of 
treatment with SEP-4199 CR 200-400 mg/day, as reflected in rates of adverse events (AEs), 
discontinuations due to an AE, serious AEs (SAEs), and adverse events of special interest 
(AESI). 
5.2. 
Additional Safety Objectives 
Long-term safety and tolerability of flexible-dose SEP-4199 CR treatment will be evaluated as 
follows: 
• Measurements including 12-lead electrocardiogram (ECG), clinical laboratory values, 
vital signs, body weight, and metabolic parameters 
• Prolactin levels 
• Manic symptoms using the Young Mania Rating Scale (YMRS) 
• Suicidality using the Columbia-Suicide Severity Rating Scale (C-SSRS) 
• Movement disorders using the Barnes Akathisia Rating Scale (BARS), Abnormal 
Involuntary Movement Scale (AIMS), and modified Simpson-Angus Scale (SAS) 
• Potential for withdrawal symptoms after discontinuation, using the Physician’s 
Withdrawal Checklist (PWC). 
5.3. 
Effectiveness Objectives 
Long-term effectiveness of flexible-dose SEP-4199 CR treatment will be evaluated as follows: 
• Severity of depression symptoms as measured by the Montgomery-Asberg 
Depression Rating Scale (MADRS) 
• Overall bipolar depression severity assessed using the Clinical Global Impression-
Bipolar Version-Severity of Illness (CGI-BP-S) Depression scale 
• Anxiety symptoms severity assessed using the clinician-administered Hamilton 
Anxiety Rating Scale (HAM-A) 
• Severity of subject-reported depression symptoms as measured by the Quick 
Inventory of Depressive Symptomatology, Self-Report (QIDS-SR16) 
• Functional impairment, as measured by the Sheehan Disability Scale (SDS) 
• Quality of life, as measured by the EuroQol - 5 Dimension - 5 Level (EQ-5D-5L) 
• Anhedonia symptoms, as measured by the Snaith-Hamilton Pleasure Scale (SHAPS). 


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5.4. 
Pharmacokinetic and Pharmacodynamic Objectives 
• Perform population pharmacokinetic (Pop-PK) analysis using plasma SEP-4199 
concentrations. 
• Explore the relationship between MADRS score and plasma SEP-4199 exposure 
using population PK/pharmacodynamics (PD) methods. 
• Explore the relationship between safety outcomes and plasma SEP-4199 exposure. 


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6. 
STUDY ENDPOINTS 
6.1. 
Safety Endpoints 
• The incidence of overall AEs, discontinuation due to AEs, and SAEs 
• The incidence of AESI including but not limited to hyperprolactinemia-related AEs 
• Clinical laboratory evaluations (serum chemistry, hematology, thyroid panel, 
urinalysis) 
• Clinical evaluation (vital signs including orthostatic effects, and 12-lead ECG 
measurements) 
• Changes in prolactin values 
• Changes in metabolic parameters (insulin, glucose, hemoglobin A1c (HbA1c), lipid 
panel) 
• Change and percent change in body weight 
• Change in body mass index (BMI) 
• Incidence of treatment-emergent mania, defined as a YMRS total score ≥ 16 at 
post-Baseline visit (scheduled or unscheduled), or an adverse event of hypomania or 
mania 
• Changes from Baseline in movement disorders scales: AIMS, BARS, and modified 
SAS 
• Frequency and severity of suicidal ideation and suicidal behavior using the C-SSRS 
• Change from Week 52/EOT (end of treatment) visit to the safety follow-up visit on 
the PWC 
6.2. 
Effectiveness Endpoints 
• Changes in MADRS total score 
• Changes in CGI-BP-S depression score 
• The proportion of subjects with treatment response, defined as ≥ 50% reduction from 
Baseline in MADRS total score 
• The proportion of subjects meeting criteria for remission, defined as MADRS total 
score ≤ 12 
• Changes in HAM-A total score 
• Changes in QIDS-SR16 total score 
• Changes in SDS total and subscale scores (work/school, family, and social function) 
• The proportion of subjects meeting criteria for functional remission, defined as 
having a score ≤ 2 on each of the SDS subscale scores (work/school, family, and 
social function) 


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• Changes in the EQ-5D-5L Visual Analog Scale (VAS) and Index scores 
• Changes in the SHAPS total score 
6.3. 
Pharmacokinetic and Pharmacodynamic Endpoints 
• Plasma concentrations of aramisulpride and esamisulpride 
• Plasma concentrations of prolactin 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
SEP380-303 is a 12-month open-label safety extension study to evaluate the long-term safety, 
tolerability, and effectiveness of SEP-4199 CR 200-400 mg/day in the treatment of subjects with 
bipolar I depression who previously completed a lead-in study of SEP-4199 CR. 
The study will consist of a 12-month open-label flexible-dose treatment period, and a safety 
follow-up period, as shown in the following figure. There are 15 scheduled visits, including a 
Baseline visit, 13 visits during the open-label treatment period, and 1 safety follow-up visit 
7 (± 2) days after the last dose of study drug. If necessary, subjects may return to the clinic at any 
time for an unscheduled visit. 
Figure 1: 
Study Schematic 
 
 
 
Note: All subjects are to take SEP-4199 CR 200 mg beginning on Day 1, the day following Baseline (Visit 1E). 
Abbreviations: BL = Baseline; CR = controlled release; EOT = end of treatment 
V = visit; E = extension; W = Week; M = Month 
 
Baseline (Visit 1E; Day -1) 
Visit 6/End of Treatment (EOT) (Day 42) of the lead-in study of SEP-4199 CR will serve as the 
Baseline visit of the current open-label extension study. Subjects who completed 6 weeks of 
double-blind treatment in a lead-in study of SEP-4199 CR and who meet eligibility criteria to 
continue into the current extension study may be enrolled. Baseline values for safety and 


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effectiveness measures for this study will be carried over from Visit 6/EOT (Day 42) of the 
lead-in study of SEP-4199 CR for each subject. Subjects should continue dosing with SEP-4199 
CR in the current open-label study without dosing interruption. 
Open-Label Treatment Period (Day 1 to Visit14E/Month 12) 
Subjects will self-administer the study drug on an outpatient basis once daily beginning on Day 1 
and continue for 12 months. Subjects will be instructed to administer study drug as a single oral 
dose in the morning at approximately the same time each day. The last dose of study drug will be 
self-administered by the subject at home on the morning of Visit 14E (Month 12). 
During the open-label treatment period, subjects will have clinic visits at Week 2/Day 14 and 
Months 1 to 12. In order to facilitate scheduling of clinic visits and telephone calls, a window of 
± 2 days will be allowed for Visits 2E (Week 2/Day 14) and 3E (Month 1); a window of ± 5 days 
will be allowed for Visits 4E (Month 2) to 13E (Month 11), and a window of +5 days will be 
allowed for Visit 14E (Month 12). Between study visits, subjects will be contacted weekly by 
telephone. 
All subjects will initiate treatment with SEP-4199 CR 200 mg/day. The dose may be increased to 
400 mg/day at Visit 2E (Week 2/Day 14) or later, based on the Investigator’s judgment. 
However, if clinically indicated, the dose may be increased as early as Day 7 at an unscheduled 
visit. The dose may be decreased to 200 mg/day at any time thereafter for tolerability. If a dose 
decrease is needed between study visits, subjects will return to the clinic for an unscheduled visit 
for drug dispensation. Dose increases will occur only at scheduled or unscheduled clinic visits. 
Prior to a dose increase, safety assessments will be completed, including but not limited to 
evaluation of AEs, concomitant medications, vital signs, and ECGs. Subjects whose ECG results, 
based on machine reading, show increase from Baseline in QT interval corrected for heart rate 
using Fridericia’s formula (QTcF) interval ≥ 30 milliseconds (msec) or whose QTcF interval is 
≥ 480 msec at the 200 mg/day dose are not allowed to have their dose increased to 400 mg/day. 
Subjects with hyperprolactinemia-related AESI are not allowed to have their dose increased to 
400 mg/day. 
End of Treatment (EOT)/Early Termination (ET) (Visit 14E: Month 12) 
Subjects will have Visit 14E at Month 12 (+ 5 days) for EOT assessments of safety and 
effectiveness. 
Subjects who prematurely discontinue from the study will undergo an ET visit to include all 
Visit 14E assessments and procedures. 
Follow-up Period (Visit 15E, 7 [± 2] days after last dose) 
All subjects will have a follow-up visit for safety and tolerability assessments 7 (± 2) days after 
their last dose of study drug. Assessment of potential withdrawal effects will also be made during 
the follow-up period. 
7.2. 
Treatment Assignment and Blinding 
This is an open-label study; therefore, randomization and blinding will not be employed. All 
subjects will receive flexible dosing with SEP-4199 CR 200 mg/day or 400 mg/day. 


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Prolactin values at open-label Baseline visit (including any repeat testing) will be masked in the 
lab data transfer until the study database of the lead-in study of SEP-4199 CR is locked and 
treatment is unblinded for all subjects. Prolactin values assessed after the first dose of study drug 
of the open-label treatment period will not be masked and will appear in the regular lab data 
transfer. 
Plasma concentrations of aramisulpride, esamisulpride, and total amisulpride will not be 
disclosed before the study database of the lead-in study of SEP-4199 CR is locked and treatment 
is unblinded for all subjects. 
7.3. 
Rationale 
7.3.1. 
Rationale for the Study Design 
This study is being conducted to evaluate the long-term safety, tolerability, and effectiveness of 
open-label treatment with SEP-4199 CR dosed flexibly at 200 mg/day or 400 mg/day, in subjects 
who previously completed a lead-in study of SEP-4199 CR for the treatment of major depressive 
episode associated with bipolar I disorder (bipolar I depression). 
To date, one completed Phase 2 6-week clinical study (SEP380-201) evaluated fixed doses of 
SEP-4199 IR formulation at doses of 200 mg/day and 400 mg/day vs. placebo in subjects with 
bipolar I depression. In the full global ITT population, including North American, Latin 
American, European, and Japanese subjects (N = 337), both SEP-4199 IR 200 mg/day and 
400 mg/day doses demonstrated significantly greater improvement compared to placebo (post-
hoc adjusted p = 0.025 for both treatment groups using the same multiplicity adjustment 
approach as for the primary analysis). Based on the full global safety population, SEP-4199 IR 
was well tolerated in this study, with an overall AE rate (< 50%) in both dose groups that was 
comparable to that in the placebo group and a low rate (< 9% in either group) of discontinuations 
due to an AE. These results demonstrated proof of concept for the efficacy of SEP-4199 IR in the 
treatment of bipolar I depression and support further development of the SEP-4199 compound. 
However, safety and tolerability data for SEP-4199 IR in patients with bipolar I depression are 
currently limited to those collected over the 6-week treatment duration. Longer-term exposure to 
clinical doses of SEP-4199 is needed to fully evaluate safety, tolerability, and effectiveness. 
A novel CR formulation of SEP-4199 has been developed. SEP-4199 CR was well tolerated in 
the PK and PET imaging study in healthy volunteers (SEP380-105). Administration of SEP-4199 
CR resulted in the same degree of dopamine D2 receptor occupancy after multiple doses as did 
SEP-4199 IR at the same dosages, while exhibiting lower serum concentrations at Cmax. The 
lower Cmax of SEP-4199 CR was associated with substantially less QTc interval prolongation 
than was observed with SEP-4199 IR. Therefore, SEP-4199 CR is hypothesized to be 
therapeutically equivalent to SEP-4199 IR, but with an improved therapeutic index due to 
improved cardiac safety. For this reason, the SEP-4199 CR formulation will be evaluated in the 
current long-term open-label study. 
7.3.2. 
Rationale for the Dosages 
The current extension study will enroll subjects who previously completed a lead-in study that 
evaluated SEP-4199 CR monotherapy at fixed doses 200 mg/day or 400 mg/day vs. placebo. 
Therefore, this study will continue to evaluate the longer-term safety, tolerability, and 


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effectiveness of open-label SEP-4199 CR monotherapy, flexibly dosed at 200 mg/day or 
400 mg/day. 
7.3.3. 
Rationale for the Study Population 
Only subjects who complete a lead-in study that evaluates SEP-4199 CR monotherapy at fixed 
doses of 200 mg/day or 400 mg/day vs. placebo will be included in this extension study. 
7.3.4. 
Rationale for the Endpoints 
The standard safety assessments and their timing are appropriate to assess the safety of 
SEP-4199 CR in adults with bipolar I depression. The symptom, functional, and quality of life 
assessments were selected to address the potential effectiveness of SEP-4199 CR on these 
parameters. 
7.4. 
Prevention of Missing Data 
In an effort to minimize the number of subjects who are terminated from the study before the end 
of treatment, the following study design and conduct elements are implemented: 
• Specific medications for the as needed (PRN) treatment of movement disorders and 
acute extrapyramidal symptoms (EPS) are permitted. 
• Specific medications for the PRN treatment of anxiety/agitation and insomnia are 
permitted. 
• Training the sites on the importance of continued follow-up and on the informed 
consent process, ensuring subjects understand the commitment they are making, 
including the intent to complete the trial. 
• The Sponsor will use study centers with a good track record of enrolling and 
following eligible subjects. 
• Monitor data collection for adherence during the study. 
Details for data handling rules of missing data will be provided in the Statistical Analysis Plan 
(SAP). 


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8. 
SELECTION OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
The subjects who fulfill the following criteria will be included in the study: 
1. Subject provides written informed consent and is willing and able to comply with the 
protocol in the opinion of the Investigator. 
2. Subject has completed 6 weeks of double-blind treatment and all scheduled assessments 
from Visit 6/EOT (Day 42) of the lead-in study of SEP-4199 CR. 
3. Subject is medically appropriate for long-term open-label treatment with SEP-4199 CR in 
the opinion of the Investigator. 
4. Female subjects of childbearing potential must agree to use effective and reliable 
contraception throughout the study and for at least 30 days after the last dose of study 
drug has been taken. In the Investigator’s judgment, the subject will adhere to this 
requirement. Contraception requirements are detailed in Section 10.4. 
5. Male subjects agree to avoid fathering a child and to use effective methods of birth 
control throughout the study and until at least 90 days after the last study drug 
administration. Contraception requirements are detailed in Section 10.4. 
8.2. 
Subject Exclusion Criteria 
The subjects who meet any of the following criteria will be excluded from the study: 
1. Subject is at high risk of non-compliance in the opinion of the Investigator. 
2. Subject plans to initiate treatment with a prohibited psychotropic medication during the 
study. 
3. Subject plans to initiate treatment with transcranial magnetic stimulation (TMS), 
electroconvulsive therapy (ECT), vagus nerve stimulation (VNS), or deep brain 
stimulation (DBS) during the study. 
4. Subject experienced a moderate or severe hyperprolactinemia-related AESI in the lead-in 
study of SEP-4199 CR. 
5. Subject will require treatment with a drug that is associated with increases in QTc 
interval (see Section 23, Appendix IV for a list of medications, not all inclusive). 
6. Subject had any of the following at Visit 6/EOT (Day 42) of the lead-in study of 
SEP-4199 CR based on machine reading:  
• increase in QTcF interval of ≥ 30 msec from Baseline of the lead-in study of 
SEP-4199 CR AND a QTcF interval ≥ 480 msec 
• increase in QTcF interval ≥ 60 msec from Baseline of the lead-in study of 
SEP-4199 CR 
• QTcF interval > 500 msec 
• treatment-emergent clinically significant ECG abnormality. 


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7. Subject is considered by the Investigator to be at imminent risk of suicide or injury to self 
or others, has a MADRS item 10 (suicidal ideation) score ≥ 4, or answers “yes” to 
“suicidal ideation” item 4 (active suicidal ideation with some intent to act, without 
specific plan) or item 5 (active suicidal ideation with specific plan and intent) on the 
C-SSRS assessment at Visit 6/EOT (Day 42) of the lead-in study of SEP-4199 CR. 
8. Female subject of child-bearing potential has a positive urine pregnancy test at Visit 
6/EOT (Day 42) of the lead-in study of SEP-4199 CR or plans to become pregnant during 
the current study. 
9. Subject tests positive for any drug of abuse or cannabis at Visit 6/EOT (Day 42) of the 
lead-in study of SEP-4199 CR. 


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9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
9.1. 
Description of Study Drug 
SEP-4199 CR will be supplied as 200 mg tablets containing a fixed 85:15 ratio of 
aramisulpride:esamisulpride.  
• For the SEP-4199 CR 200 mg/day dose, study drug will consist of 1 x 200 mg tablet. 
• For the SEP-4199 CR 400 mg/day dose, study drug will consist of 2 x 200 mg tablets. 
A description of the investigational product is provided in Table 5. 
Table 5: 
Investigational Product 
Attribute 
Investigational Product 
Product name 
SEP-4199 CR 200 mg 
Dosage form 
Tablets 
Unit dose 
Tablet 
Route of administration 
Oral 
Physical description 
Pale orange round film-coated unmarked tablets 
Excipients  
D-Mannitol, partly pregelatinized starch, partially hydrolyzed polyvinyl 
alcohol, hypromellose, light anhydrous silicic acid, sodium stearyl 
fumarate, Macrogol 400, titanium oxide, talc, ferric oxide yellow, red 
ferric oxide, and carnauba wax 
9.2. 
Study Drug Packaging and Labeling 
9.2.1. 
Package Description 
Study drug will be provided in one-week blister cards (7 days + 2 extra days) containing 9 or 
18 tablets of SEP-4199 CR 200 mg tablets. The 200 mg blister cards will contain 9 tablets; 
subjects will be instructed to take a column of one tablet per day, according to dosing 
instructions. The 400 mg blister cards will contain 18 tablets; subjects will be instructed to take a 
column of two tablets each day, according to dosing instructions. 
9.2.2. 
Labeling Description 
All packaging for the study medications will be labeled with: 
• Protocol number 
• Sponsor’s name and address 
• Compound/Code or name of investigational drug and dosage form 
• Content (eg, number of tablets) 
• Investigational New Drug statement/caution statement 
• Instructions for use and storage 


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• Batch number 
• Period of use (as required) 
• Blank space to record visit number 
• Blank space for subject identifiers 
• Unique medication number/kit ID number 
• Investigator information (if needed) 
9.3. 
Study Drug Storage 
All study drug should be stored at 15°C to 25°C (59°F to 77°F) and away from light. Excursions 
of 9°C to 30°C (48°F to 86°F) are permitted during shipment of study drug to investigational 
sites. The subject will be instructed to store the medication at room temperature. 
9.4. 
Dispensing of Study Drug  
An Interactive Web Response System (IXRS) will be used to manage subject enrollment. The 
IXRS is an integrated web-based subject and drug management system. 
Study drug blister cards will be assigned by the IXRS based on the treatment schedule. The 
IXRS will generate instructions for which blister card ID(s) to dispense to a subject. Each subject 
will be dispensed two or four 9-day (7 days + 2 extra days) blister cards per scheduled visit, 
depending on the timing of the next scheduled visit (see Table 2). 
The first study drug dose will be taken on Day 1. Subjects will take one or two tablets of study 
drug according to dosing instructions once a day in the morning at approximately the same time 
each day. Study drug may be taken with or without food. 
9.5. 
Study Drug Accountability 
The Investigator or designee is responsible for maintaining adequate and up to date records of 
drug disposition that includes dates, quantities, and use by subjects. 
Upon receipt of study drug, the Investigator or designee will inspect the supplies and verify 
receipt of the shipment in the IXRS, confirming the date of receipt, inventory, and condition of 
study drug received. 
The IXRS will also be used for the accountability of the study drug at the clinical site. The 
Investigator or designee will maintain records for accountability within the IXRS, including 
study drug dispensation, return, and availability of study drug received. The Investigator or 
designee will collect and document all used and unused study drug from study subjects at 
appropriate study visits. 
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 staff at all times. Proper handling 
and storage guidelines should be followed. 


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If the study is stopped for any reason or completed, all unused supplies will be returned to the 
Sponsor, unless other instructions are provided in writing by the Sponsor/contract research 
organization (CRO). 
The Investigator or designee is required to return all used and unused study drug and packaging 
to the Sponsor or designee as instructed. The Investigator or designee is required to maintain 
copies of study drug shipping receipts, drug accountability records, and records of return or final 
disposal of the study drug in accordance with local regulatory requirements. 
Study drug will not be dispensed to any person who is not a study subject under this protocol. 


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10. 
TREATMENT OF SUBJECTS 
10.1. 
Study Medication 
SEP-4199 CR 200 mg tablets for 200 mg and 400 mg doses will be supplied as described in 
Section 9.1. 
Study drug will be self-administered by the subject once daily as a single oral dose in the 
morning at approximately the same time, beginning on Day 1 and continuing through Visit 14E 
(Month 12). 
10.1.1. 
Dose Adjustment Criteria 
All subjects will initiate treatment with SEP-4199 CR 200 mg/day. The dose may be increased to 
400 mg/day at Visit 2E (Week 2/Day 14) or later, based on the Investigator’s judgment. 
However, if clinically indicated, the dose may be increased as early as Day 7 at an unscheduled 
visit. The decision to increase the dose and dispense additional study drug will be made by the 
Investigator at a scheduled or unscheduled study visit. A dose decrease can occur at any time for 
safety or tolerability concerns (minimum dose of 200 mg/day). If a dose decrease is needed 
between study visits, subjects will return to the clinic for an unscheduled visit for drug 
dispensation. Temporary interruption of the study drug is allowed at the Investigator’s discretion 
for specific hyperprolactinemia-related AESI (see Section 13.1). 
Prior to a dose increase, safety assessments will be completed, including but not limited to 
evaluation of adverse events, concomitant medications, vital signs, and ECGs. Subjects whose 
ECG results, based on machine reading, show increase from Baseline in QTcF interval 
≥ 30 msec or whose QTcF interval is ≥ 480 msec at the 200 mg/day dose are not allowed to have 
their dose increased to 400 mg/day. Subjects with hyperprolactinemia-related AESI are not 
allowed to have their dose increased to 400 mg/day. IXRS drug dispensing guidelines should be 
followed for dispensing the drug to subjects. A specific user manual will be provided. 
10.2. 
Treatment Compliance 
Compliance must be monitored closely and evaluated by the Investigator at each visit. Subjects 
will be instructed to bring all used blister cards and unused study drug with them to each visit. 
The number of tablets lost, if any, needs to be reported and recorded. Compliance for a study 
visit period will be assessed by counting the number of returned tablets, calculated by dividing 
the actual number of doses taken (= number of tablets dispensed – number of tablets returned – 
number of tablets lost per tablet count) by the number of doses the subject should have taken and 
multiplying by 100. All subjects will be reminded of the importance of strict compliance with 
taking study drug. 
Subjects who miss more than 25% of scheduled doses or take more than 125% of the scheduled 
doses will be considered noncompliant. Evidence of noncompliance must be immediately 
reported to the Clinical Research Associate (CRA) and/or Medical Monitor. 
10.3. 
Concomitant Medications and Therapies 
Any medication, vaccination, or non-pharmacological therapy that is taken by or administered to 
the subject between signing of informed consent and final visit will be recorded in the electronic 


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case report form (eCRF). The entry must include the dose, frequency, route, indication, and dates 
of use. 
Concomitant medications in the lead-in study of SEP-4199 CR that were ongoing at Visit 6/EOT 
(Day 42) will be entered into the eCRF for this study (SEP380-303). All changes in concomitant 
medications or new medications administered during the study up to the Follow-up Visit (7 ± 2 
days after last dose) will be recorded. 
Information on the format and version of coding dictionary is provided in the Data Management 
Plan (DMP). All medications will be coded using the World Health Organization drug dictionary 
(WHO-DD). 
Ongoing treatment or initiation of treatment with non-pharmacologic psychotherapy is allowed. 
10.3.1. 
Prohibited Medications 
Treatment with other psychotropic medications (eg, antipsychotic agents, antidepressants, and 
mood stabilizers) is prohibited except as noted below. 
The use of herbal supplements or other complementary or alternative medications during the trial 
is not permitted. 
10.3.2. 
Concomitant Non-psychotropic Medications 
Medications for the short-term (no more than 10 days) treatment of an acute medical condition 
are allowed, provided that the medications do not prolong the QTc interval. Section 23, 
Appendix IV provides a representative, but not exhaustive, list of medications that prolong the 
QT interval and are not allowed during the study. Non-psychotropic medications may be used to 
treat mild, chronic medical conditions. β-adrenergic antagonists used to treat stable hypertension 
may be continued. In addition, non-prescription pain medications (eg, aspirin, 
acetaminophen/paracetamol, ibuprofen) are allowed during the study provided these medications 
do not have a propensity for psychotropic effects and do not interfere with the evaluation of 
study medication. Routine vaccines (ie, seasonal influenza, pneumonia, COVID-19, etc.) are 
allowed based on Investigator judgement. 
10.3.3. 
Concomitant Psychotropic Medications 
Medications for treatment of movement disorders may be administered if symptoms emerge. 
Benztropine (≤ 6 mg/day), biperiden (≤ 16 mg/day), trihexyphenidyl (≤ 15 mg/day), or 
diphenhydramine (≤ 100 mg/day) are permitted as needed to treat extrapyramidal symptoms. 
Propranolol (≤ 120 mg/day) or amantadine (≤ 300 mg/day) are permitted as needed to treat 
akathisia. 
Concomitant use of anxiolytics, sedatives, and hypnotics is permitted with the following 
restrictions: Lorazepam is permitted up to 2 mg/day for intolerable anxiety/agitation. Lorazepam 
(≤ 2 mg/day), eszopiclone (≤ 3 mg/day), zopiclone (≤ 7.5 mg/day), zolpidem (≤ 10 mg/day), 
zolpidem CR (≤ 12.5 mg/day), and temazepam (≤ 30 mg/day) may be administered at bedtime 
for insomnia, as needed. Hypnotic agents should be administered no more than once nightly and 
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In regions that do not have the above specified medications available, similar medications at 
equivalent dosages may be permitted after consultation with and approval by the Medical 
Monitor. 
Opiates may be allowed in rare cases for a limited period of time with prior authorization from 
the Medical Monitor. 
10.4. 
Contraception Requirements 
Female subjects who participate in this study must be of: 
• Non-childbearing potential (ie, physiologically incapable of becoming pregnant), 
which includes: 
− Women who have had a hysterectomy, bilateral oophorectomy, bilateral 
salpingectomy, bilateral tubal ligation, or bilateral tubal occlusion (as determined 
by subject’s medical history) 
OR 
− Postmenopausal females, defined as at least 12 months of spontaneous 
amenorrhea and confirmed by follicle stimulating hormone (FSH) concentrations 
within postmenopausal range at Visit 1 (Screening) of the lead-in study of 
SEP-4199 CR as determined by the central laboratory  
-OR- 
• Childbearing potential with a negative urine pregnancy test at Visit 6/EOT (Day 42) 
of the lead-in study of SEP-4199 CR and satisfying one of the following 
requirements: 
− Completely abstinent from intercourse as part of the preferred and usual lifestyle 
of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-
ovulation methods) and the withdrawal method are not acceptable methods of 
contraception. Subject must have been abstinent for at least 60 days prior to 
administration of the first dose of study drug, throughout the Treatment Period 
and for a minimum of 30 days after completion or premature discontinuation from 
the study drug. 
− Use of effective methods of contraception during the Treatment Period and for 
30 days after last dose of study drug. Effective forms of contraception include: 
 Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, transdermal) 
 Progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, implantable). 
 Implanted intrauterine device; 
 Implanted intrauterine hormone-releasing system; 
 Vasectomized partner (provided that partner is the sole sexual partner). 


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 Two barrier methods used in combination (eg, condom and spermicide or 
diaphragm with spermicide). Note: a female condom and a male condom 
should not be used together due to friction between the 2 barrier methods 
reducing effectiveness of contraception. 
 Women using hormonal contraception must be supplemented with a 
barrier method (preferably male condom). 
Post-coital methods of contraception are not permitted. 
Male subjects with a female partner(s) of childbearing potential must agree to avoid fathering a 
child and either must be surgically sterile (with the appropriate post-vasectomy documentation of 
the absence of sperm in the ejaculate), completely abstinent, or use effective methods of 
contraception throughout the study and for at least 90 days after the last dose of study drug. Male 
subjects must also refrain from donation of semen/sperm throughout the study and for 90 days 
after last dose of the study drug. Female subjects are not allowed to donate eggs throughout the 
study and up to 30 days after the last dose of study drug. 
10.5. 
Guidance for Overdose 
The effects of an overdose of SEP-4199 are unknown and there is no known treatment in case of 
overdose. Standard symptom support measures should be used in the case of excessive 
pharmacological effects or overdose. 


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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. 
Duplicate Subject Check 
The Verified Clinical Trials LLC (“VCT”) Research Subject Database (“VCT Registry”) is used 
at study sites to help determine whether a subject is already participating in or has recently 
participated in another clinical trial. Subjects will be given detailed information about the 
processing of their personal data through the VCT Registry in a separate patient information and 
consent form (Verified Clinical Trials LLC Research Subject Database Declaration of Consent 
for the Processing of Personal Data) during the lead-in study of SEP-4199 CR and will be asked 
to give explicit consent by signing this separate patient information and consent form to continue 
to be monitored while participating in SEP380-303, where allowed under local laws and 
regulations. No personal data will be entered into or processed through the VCT Registry unless 
the relevant subject has given explicit consent. 
11.2. 
Demographics and Baseline Characteristics 
Demographics (date of birth, age, sex, ethnicity, race) and medical and psychiatric history 
collected in the lead-in study of SEP-4199 CR will be utilized for this study. Date of birth, age, 
and sex will be re-entered into the eCRF of this study. 
11.3. 
Effectiveness Assessments 
For all efficacy assessments, the open-label Baseline values are carried over from Visit 6/EOT 
(Day 42) assessments collected in the lead-in study of SEP-4199 CR. 
11.3.1. 
Montgomery-Asberg Depression Rating Scale (MADRS) 
The MADRS is a clinician-rated assessment of the subject’s level of depression. The MADRS 
consists of 10 items that measure Apparent Sadness, Reported Sadness, Inner Tension, Reduced 
Sleep, Reduced Appetite, Difficulty Concentrating, Lassitude, Inability to Feel, Pessimistic 
Thoughts, and Suicidal Thoughts. Each item is scored from 0 to 6, with higher scores indicating 
greater symptom severity. 
The MADRS will be administered by a trained and qualified rater. The MADRS interviews will 
be audio recorded and the recording will be reviewed by the Sponsor’s designee to monitor the 
quality of the rater interviews, where allowed by local/regional regulations. No identifying 
information should be collected with the audio recording. Further information regarding 
administration of the MADRS, including rater training and certification as well as recording of 
MADRS scores, will be provided in the Study Reference Manual. 
11.3.2. 
Clinician Global Impression-Bipolar Version-Severity of Illness (CGI-BP-S) 
The CGI-BP-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-BP-S can be completed in 1-2 minutes. The CGI-BP-S will be completed by 
a qualified rater at the site. 


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Further information regarding administration of the CGI-BP-S, including rater training and 
certification as well as recording of CGI-BP-S scores, will be provided in the Study Reference 
Manual. 
11.3.3. 
Hamilton Anxiety Rating Scale (HAM-A) 
The HAM-A is a clinician-administered scale that was developed to quantify the severity of 
anxiety symptomatology. It consists of 14 items, each defined by a series of symptoms. Each 
item is rated on a 5-point (0-4) scale, with higher scores indicating greater severity. The 
Structured Interview Guide for the HAM-A (SIGH-A) will be used for administration of the 
HAM-A. 
Further information regarding administration of the HAM-A, including rater training and 
certification as well as recording of HAM-A scores will be provided in the Study Reference 
Manual. 
11.3.4. 
Quick Inventory of Depressive Symptomatology – Self Report (QIDS-SR16) 
The QIDS-SR16 is a 16-item subject-reported depression symptom severity questionnaire. The 
scoring of the QIDS-SR16 converts responses to 16 separate items into the 9 DSM-IV symptom 
criterion domains. The total score ranges from 0-27 with higher scores indicating greater 
severity. The 9 domains are: sad mood, concentration, self-criticism, suicidal ideation, interest, 
energy/fatigue, sleep disturbance (early/middle/late insomnia or hypersomnia), decrease/increase 
in appetite/weight, and psychomotor agitation/retardation. 
Site staff will assist the subject in the initiation of the QIDS-SR16 assessment. Clinical staff will 
not participate in the administration of the QIDS-SR16 after initiation. Further information 
regarding administration of the QIDS-SR16, including recording of scores, will be provided in 
the Study Reference Manual. 
11.3.5. 
Sheehan Disability Scale (SDS) 
The SDS is a subject-reported assessment of function. The SDS is a composite of 3 items 
designed to measure the extent to which 3 major sectors in a patient’s life are impaired by 
depressive symptoms. This anchored visual analogue scale uses spatiovisual, numeric, and verbal 
descriptive anchors simultaneously to assess disability across 3 domains: work, social life or 
leisure activities, and home life or family responsibilities. The subject will rate his or her degree 
of impairment in each of these domains using an 11-point scale ranging from 0-10, with higher 
scores indicating more impairment. There are verbal descriptors for the points on the scale as 
well as numerical scores that provide more precise levels of the verbal descriptors. Scores for the 
3 items are summed into a single dimensional measure of global functional impairment that 
ranges from 0 (unimpaired) to 30 (highly impaired). 
Further information regarding administration of the SDS, including rater training and 
certification as well as recording of SDS scores, will be provided in the Study Reference Manual. 
11.3.6. 
EuroQol - 5 Dimension - 5 Level (EQ-5D-5L) 
The EQ-5D-5L is a subject self-reported, standardized instrument developed by the EuroQol 
Group as a measure of health-related quality of life that can be used in a wide range of health 


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conditions and treatments. The EQ-5D-5L consists of a descriptive system and the EuroQol 
Visual Analogue Scale (EQ-VAS). 
The descriptive system includes 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight 
problems, moderate problems, severe problems, and extreme problems. The subject is asked to 
indicate his/her health state by ticking the box next to the most appropriate statement in each of 
the 5 dimensions. This decision results in a 1-digit number that expresses the level selected for 
that dimension. The digits for the five dimensions can be combined into a 5-digit number that 
describes the subject’s health state. 
The EQ-VAS records the subject’s self-rated health on a vertical visual analogue scale, where 
the endpoints are labeled “the best health you can imagine” and “the worst health you can 
imagine”. The VAS can be used as a quantitative measure of health outcome that reflects the 
subject’s own judgment. 
11.3.7. 
Snaith-Hamilton Pleasure Scale (SHAPS) 
The SHAPS (Snaith 1995) is a subject-reported questionnaire having a 14-item scale that 
assesses 4 domains of hedonic experience: interest/pastimes, social interaction, sensory 
experience, and food/drink. Subjects are asked to respond based on their ability to experience 
pleasure in the past few days. Each of the 14 questions is in the form of the statement “I would 
enjoy_______” and asks the subject to choose between the choices: strongly disagree, disagree, 
agree, or strongly agree. 
11.4. 
Safety Assessments 
11.4.1. 
Adverse Events 
Adverse events will be collected for each subject. Subjects should be queried in a non-leading 
manner, without specific prompting (eg, “Has there been any change in your health status since 
your last visit?”). See Section 12, Safety Reporting. AEs and SAEs will be monitored throughout 
the study at all visits. 
Adverse events in the lead-in study of SEP-4199 CR that were ongoing at Visit 6/EOT (Day 42) 
will be entered into the eCRF for this study (SEP380-303). All changes in adverse events or new 
adverse events occurring during the study up to the Follow-up Visit will be recorded. 
11.4.2. 
Clinical Laboratory Tests 
Subjects are required to fast for at least 8 hours prior to sample collection for laboratory testing 
at Visit 2E, Visit 4E, Visit 6E, Visit 8E, Visit 10E, Visit 12E, and Visit 14E (EOT/ET); fasting is 
also required at Week 6 (EOT) in the lead-in study of SEP-4199 CR, which serves as baseline 
(Visit 1E) in this long-term safety study. 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 conducted centrally unless an exception is approved by the Medical Monitor. The 
site must notify the Medical Monitor as soon as possible when performing unscheduled 
laboratory tests. 


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Point of care (POC) testing will be used for the urine pregnancy test and rapid urine drug test. A 
serum pregnancy test should be submitted to the central lab for any positive urine pregnancy test, 
and a urine drug screen should be submitted to the central lab for any positive rapid urine drug 
test throughout the study. 
For detailed instructions regarding clinical laboratory procedures, sampling, and shipping 
guidelines refer to the Central Laboratory Instructions Manual. Samples will be processed at a 
central laboratory to ensure consistency. All clinical laboratories will be College of American 
Pathologists (CAP) and Clinical Laboratory Improvement Amendments (CLIA) (or equivalent) 
certified. 
11.4.3. 
Vital Signs 
Blood pressure and pulse rate measurements will be taken in a supine and standing position. 
Blood pressure and pulse rate should first be taken with the subject in the supine position after 
resting for ≥ 5 minutes. Blood pressure and pulse rate will be taken again after standing for 2 to 
4 minutes. The same arm should be used during each assessment of blood pressure and pulse rate 
throughout the study. If a subject develops symptoms consistent with orthostatic hypotension 
(light-headedness, dizziness, or changes in sensorium upon standing) at any point, his or her 
supine and standing blood pressure and pulse rate should be collected at that time in the manner 
described above. 
Respiratory rate and temperature will also be measured, and all measurements will be recorded 
in the eCRF. 
Weight will be measured in street clothes, without shoes and coat/jacket. BMI will be calculated 
in the analysis. Waist circumference will also be measured. 
Vital signs will be obtained prior to clinical laboratory collection and performance of an ECG. 
Clinically significant changes from signing the informed consent form (ICF) in vital sign 
parameters, as determined by the Investigator, will be noted as AEs in the eCRF. 
11.4.4. 
Centrally-read ECG 
All ECGs will be obtained in the supine position, after the subject has been resting supine for at 
least 10 minutes. ECGs will be 12-lead with a 10-second rhythm strip. ECGs should be obtained 
prior to drawing blood samples, with the exception of fasting blood draws. All attempts should 
be made to use the same ECG recorder for all visits within individual subjects. ECGs will be 
centrally read at a central facility, according to established quality assurance procedures for 
inter/intra reader variability. Refer to Section 20, Appendix I for additional information. ECG 
parameters to be collected include ventricular heart rate (beats/min), QT interval (msec), PR 
interval (msec), QRS interval (msec), RR interval (msec) and centrally-read overall ECG 
interpretation (Normal; Abnormal, insignificant; Abnormal, potentially significant; Abnormal, 
significant) including type of abnormality, if present. QTcF and QT interval corrected for heart 
rate using Bazett’s formula (QTcB) will also be reported. 
11.4.5. 
Neurological and Physical Examination 
Complete physical examination as well as neurological examination will be performed. The 
physical examination includes an assessment of general appearance and a review of systems 


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(dermatologic, head, eyes, ears, nose, mouth/throat/neck, thyroid, lymph nodes, respiratory, 
cardiovascular, gastrointestinal, extremities, musculoskeletal, neurologic, and psychiatric 
systems). The neurological examination includes an assessment of general appearance, mental 
status, cranial nerves, motor system, sensory system, reflexes, coordination, and gait. 
Any clinically significant changes from signing of the ICF, as determined by the Investigator, 
will be noted as AEs in the eCRF. 
11.4.6. 
Safety Scales 
11.4.6.1. Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a tool designed to systematically assess and track suicidal AEs (suicidal behavior 
and suicidal ideation) throughout the study. The strength of this suicide classification system is 
in its ability to comprehensively identify suicidal events while limiting the over-identification of 
suicidal behavior. The C-SSRS will be administered by a trained rater at the site. 
This study will utilize the “Since Last Visit” version of the C-SSRS. 
Subjects who answer “yes” to “suicidal ideation” item 4 (active suicidal ideation with some 
intent to act, without specific plan) or item 5 (active suicidal ideation with specific plan and 
intent) on any post-Baseline C-SSRS assessment must be discontinued from the study, referred 
to the Investigator for follow-up evaluation, and followed until the event resolves; in addition, an 
associated AE must be reported. 
Further information regarding administration of the C-SSRS, including rater training and 
certification as well as recording of C-SSRS scores, will be provided in the Study Reference 
Manual. 
11.4.6.2. Young Mania Rating Scale (YMRS) 
The YMRS will be administered as a safety assessment and to inform the identification of 
treatment-emergent mania or hypomania. 
The YMRS is a clinician-rated 11-item instrument used to assess the severity of mania in 
subjects with a diagnosis of bipolar disorder. The 11 items assess: Elevated Mood, Increased 
Motor Activity/Energy, Sexual Interest, Sleep, Irritability, Speech (Rate and Amount), 
Language/Thought Disorder, Content, Disruptive-Aggressive Behavior, Appearance, and Insight. 
The YMRS will be administered by a qualified rater at the site. Further information regarding 
administration of the YMRS, including rater training and qualification as well as recording of 
YMRS scores, will be provided in the Study Reference Manual. 
Treatment-emergent mania or hypomania is defined as a YMRS total score ≥ 16 at any 
2 consecutive post-Baseline visits or at the final visit, or an AE of mania or hypomania. 
11.4.6.3. Abnormal Involuntary Movement Scale (AIMS) 
The AIMS is a clinician-rated assessment of abnormal movements consisting of unobtrusive 
observation of the subject at rest (with shoes removed) and several questions for 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 
2 items related to dental status, as well as 3 global impression items assessing overall severity, 


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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. 
Further information regarding administration of the AIMS, including rater training and 
certification as well as recording of AIMS scores, will be provided in the Study Reference 
Manual. 
11.4.6.4. Barnes Akathisia Rating Scale (BARS) 
The BARS is a rating scale intended for the assessment of neuroleptic-induced akathisia. It 
consists of 4 items, including one item assessing objective restlessness, 2 items assessing 
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 uses 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, Schooler 2000). 
Further information regarding administration of the BARS, including rater training and 
certification as well as recording of BARS scores, will be provided in the Study Reference 
Manual. 
11.4.6.5. Modified Simpson-Angus Scale (SAS) 
The modified SAS is a clinician-rated assessment of neuroleptic-induced Parkinsonism 
consisting of 10 items. Items are anchor-based, rated on a 5-point scale, and address rigidity, gait 
(bradykinesia), tremor, glabellar tap, and salivation (Simpson 1970). 
Further information regarding administration of the modified SAS, including rater training and 
certification as well as recording SAS scores, will be provided in the Study Reference Manual. 
11.4.6.6. Physician’s Withdrawal Checklist (PWC) 
Potential withdrawal effects will be assessed by the clinician using the PWC after completion of 
all scheduled effectiveness and safety assessments and procedures at Visit 14E (EOT/ET) and 
Follow-up (Visit 15E). The PWC is used to evaluate symptoms of withdrawal after 
discontinuation of study medication. Symptoms are assessed as present or absent; if present, then 
intensity is assessed as mild, moderate, or severe. 
11.5. 
Pharmacokinetic Assessments 
Blood samples will be collected for population pharmacokinetics and plasma prolactin at the 
following visits: Visit 2E (Week 2/Day 14), Visit 4E (Month 2), Visit 6E (Month 4), Visit 8E 
(Month 6), Visit 10E (Month 8), Visit 12E (Month 10), Visit 14E (Month 12), and Follow-up 
(Visit 15E, 7 ± 2 days after last dose). See Section 22, Appendix III for sample collection and 
handling guidelines. 
Prior to PK blood sample collection, subjects will record the date and time of their 3 most-recent 
study drug doses; the clinical site staff will record the dates and times of the 3 doses in the eCRF 
for each of the PK collection visits during the treatment period. 


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Plasma samples will be analyzed for concentrations of aramisulpride and esamisulpride using a 
validated enantioselective liquid chromatography-tandem mass spectrometry (LC-MS/MS) 
method. Plasma samples will also be analyzed for prolactin concentrations by an enzyme-linked 
immunosorbent assay (ELISA). 
Remaining plasma samples after amisulpride PK and prolactin analysis may also be used for the 
additional bioanalytical method development and/or characterization of putative metabolites of 
amisulpride and for other exploratory measurements, if needed. 
11.6. 
Study Visits and Assessments 
To ensure subject safety and data integrity, should circumstances warrant and with Sponsor 
approval, remote site/subject visits may be conducted. 
11.6.1. 
Visit 1E: Baseline (Day -1) 
The Open-Label Baseline visit of the present study is on the same day as Visit 6/EOT (Day 42) 
in the lead-in study of SEP-4199 CR. Subjects will be evaluated at this visit to determine their 
eligibility for the study. The following study-related procedures will be performed at Visit 1E; it 
is suggested that they be performed in the order presented below, as is possible by the site: 
• Obtain informed consent, including signed informed consent for duplicate subject 
check (where local regulations allow). 
• Review inclusion and exclusion criteria. 
• Record subject demographics. 
• Review concomitant medications. Medications taken during the lead-in study of 
SEP-4199 CR that are ongoing at the start of the current extension study will be 
entered into the eCRF. 
• Record adverse events. Adverse events with onset during the lead-in study of 
SEP-4199 CR and ongoing at the start of the current extension study will be entered 
into the eCRF. 
• Dispense study drug. Instruct the subject to administer study drug as a single oral 
dose in the morning at approximately the same time each day beginning the following 
day (Day 1). 
• Schedule next visit: 
− Instruct subject to administer the morning dose prior to the clinic visit. Clinic 
visits are to begin no later than 6 hours postdose, if possible. 
− Instruct subject to record the date and time of last 3 doses prior to next visit and to 
bring back all used/unused study drug and packaging to the next visit. 
• Schedule weekly telephone check-in with subject. 
The following procedures conducted at Visit 6/EOT (Day 42) of the lead-in study of 
SEP-4199 CR do not need to be repeated for the Open-Label Baseline visit of this study: 
• Physical and neurological examinations 


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• Vital sign measurements 
• Weight 
• Waist circumference 
• 12-lead ECG 
• Blood samples for the following laboratory tests (Subjects must have fasted for at 
least 8 hours.): 
− Hematology and Serum Chemistry 
− Thyroid Panel 
− Serum Prolactin 
− HbA1c 
− Lipid Panel 
− Serum Insulin 
− High-sensitivity C-Reactive Protein (hs-CRP) 
• Blood sample for measurement of plasma concentrations of aramisulpride, 
esamisulpride, and prolactin. 
• Urine sample for rapid urine drug test, urinalysis, and urine pregnancy test (human 
chorionic gonadotropin [β-hCG], female subjects of childbearing potential) 
• MADRS 
• HAM-A 
• YMRS 
• QIDS-SR16 
• SDS 
• EQ-5D-5L 
• SHAPS 
• CGI-BP-S 
• C-SSRS 
• AIMS 
• BARS 
• SAS 


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11.6.2. 
Visit 2E (Week 2/Day 14 [± 2 days]) 
The following study-related procedures will be performed at Visit 2E; it is suggested that they be 
performed in the order presented below, as is possible by the site: 
• Administer MADRS. 
• Administer YMRS. 
• Administer CGI-BP-S. 
• Administer C-SSRS. 
• Administer AIMS. 
• Administer BARS. 
• Administer SAS. 
• Review concomitant medications. 
• Record adverse events. 
• Obtain vital signs. 
• Record weight. 
• Collect blood sample(s) for the following clinical laboratory tests (Subjects must have 
fasted for at least 8 hours.). 
− Hematology and Serum Chemistry 
− Serum Prolactin 
• Collect blood sample for measurement of plasma concentrations of aramisulpride, 
esamisulpride, and prolactin. 
• Collect urine sample for urinalysis and rapid urine drug test. 
• Perform 12-lead ECG. 
• Perform study drug accountability. 
− Collect used/unused drug and packaging. 
− Confirm with the subject the date and time of their last 3 doses of study drug and 
record in the source and eCRF. 
• Dispense study drug. 
− Instruct subject to dose once daily in the morning at approximately the same time 
each day at home. 
• Schedule next visit: 
− Instruct subject to administer the morning dose prior to the clinic visit. Clinic 
visits are to begin no later than 6 hours postdose, if possible. 


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− Instruct subject to bring back all used/unused study drug and packaging to the 
next visit. 
• Schedule weekly telephone check-in with subject. 
11.6.3. 
Visit 3E (Month 1/Day 30 [± 2 days]) 
The following study-related procedures will be performed at Visit 3E; it is suggested that they be 
performed in the order presented below, as is possible by the site: 
• Administer MADRS. 
• Administer YMRS. 
• Administer CGI-BP-S. 
• Administer C-SSRS. 
• Review concomitant medications. 
• Record adverse events. 
• Obtain vital signs. 
• Record weight. 
• Perform 12-lead ECG. 
• Collect urine sample for rapid urine drug screen and urine β-hCG (female subjects of 
childbearing potential). 
• Perform study drug accountability. 
− Collect used/unused drug and packaging. 
• Dispense study drug. 
− Instruct subject to dose once daily in the morning at approximately the same time 
each day at home. 
• Schedule next visit: 
− Instruct subject to administer the morning dose prior to the clinic visit. Clinic 
visits are to begin no later than 6 hours postdose, if possible. 
− Instruct subject to record the date and time of last 3 doses prior to next visit and to 
bring back all used/unused study drug and packaging to the next visit. 
• Schedule weekly telephone check-in with subject. 
11.6.4. 
Visit 4E (Month 2/Day 60 [± 5 days]) 
The following study-related procedures will be performed at Visit 4E; it is suggested that they be 
performed in the order presented below, as is possible by the site:: 
• Administer MADRS. 
• Administer HAM-A. 


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• Administer YMRS. 
• Administer CGI-BP-S. 
• Administer QIDS-SR16. 
• Administer SDS. 
• Administer EQ-5D-5L. 
• Administer SHAPS. 
• Administer C-SSRS. 
• Administer AIMS. 
• Administer BARS. 
• Administer SAS. 
• Review concomitant medications. 
• Record adverse events. 
• Obtain vital signs. 
• Record weight. 
• Collect blood sample(s) for the following clinical laboratory tests (Subjects must have 
fasted for at least 8 hours.). 
− Hematology and Serum Chemistry 
− Serum Prolactin 
− HbA1c 
− Lipid Panel 
− Serum Insulin 
− Thyroid Panel 
• Collect blood sample for measurement of plasma concentrations of aramisulpride, 
esamisulpride, and prolactin. 
• Collect urine sample for rapid urine drug test, urinalysis, and urine β-hCG (female 
subjects of childbearing potential). 
• Perform 12-lead ECG. 
• Perform study drug accountability. 
− Collect used/unused drug and packaging. 
− Confirm with the subject the date and time of their last 3 doses of study drug and 
record in the source and eCRF. 
• Dispense study drug. 


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− Instruct subject to dose once daily in the morning at approximately the same time 
each day at home. 
• Schedule next visit: 
− Instruct subject to administer the morning dose prior to the clinic visit. Clinic 
visits are to begin no later than 6 hours postdose, if possible. 
− Instruct subject to bring back all used/unused study drug and packaging to the 
next visit. 
• Schedule weekly telephone check-in with subject. 
11.6.5. 
Visit 5E (Month 3/Day 90 [± 5 days]) 
The following study-related procedures will be performed at Visit 5E; it is suggested that they be 
performed in the order presented below, as is possible by the site: 
• Administer MADRS. 
• Administer YMRS. 
• Administer CGI-BP-S. 
• Administer C-SSRS. 
• Review concomitant medications. 
• Record adverse events. 
• Obtain vital signs. 
• Record weight. 
• Perform 12-lead ECG. 
• Collect urine sample for rapid urine drug test and urine β-hCG (female subjects of 
childbearing potential). 
• Perform study drug accountability. 
− Collect used/unused drug and packaging. 
• Dispense study drug. 
− Instruct subject to dose once daily in the morning at approximately the same time 
each day at home. 
• Schedule next visit: 
− Instruct subject to administer the morning dose prior to the clinic visit. Clinic 
visits are to begin no later than 6 hours postdose, if possible. 
− Instruct subject to record the date and time of last 3 doses prior to next visit and to 
bring back all used/unused study drug and packaging to the next visit. 
• Schedule weekly telephone check-in with subject. 


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11.6.6. 
Visit 6E (Month 4/Day 120 [± 5 days]) 
The following study-related procedures will be performed at Visit 6E; it is suggested that they be 
performed in the order presented below, as is possible by the site: 
• Administer MADRS. 
• Administer HAM-A. 
• Administer YMRS. 
• Administer CGI-BP-S. 
• Administer QIDS-SR16. 
• Administer SDS. 
• Administer EQ-5D-5L. 
• Administer SHAPS. 
• Administer C-SSRS. 
• Administer AIMS. 
• Administer BARS. 
• Administer SAS. 
• Review concomitant medications. 
• Record adverse events. 
• Obtain vital signs. 
• Record weight. 
• Collect blood sample(s) for the following clinical laboratory tests (Subjects must have 
fasted for at least 8 hours.). 
− Hematology and Serum Chemistry 
− Serum Prolactin 
− HbA1c 
− Lipid Panel 
− Serum Insulin 
− Thyroid Panel 
• Collect blood sample for measurement of plasma concentrations of aramisulpride, 
esamisulpride, and prolactin. 
• Collect urine sample for rapid urine drug test, urinalysis, and urine β-hCG (female 
subjects of childbearing potential). 
• Perform 12-lead ECG. 
• Perform study drug accountability. 


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− Collect used/unused drug and packaging. 
− Confirm with the subject the date and time of their last 3 doses of study drug and 
record in the source and eCRF. 
• Dispense study drug. 
− Instruct subject to dose once daily in the morning at approximately the same time 
each day at home. 
• Schedule next visit: 
− Instruct subject to administer the morning dose prior to the clinic visit. Clinic 
visits are to begin no later than 6 hours postdose, if possible. 
− Instruct subject to bring back all used/unused study drug and packaging to the 
next visit. 
• Schedule weekly telephone check-in with subject. 
11.6.7. 
Visit 7E (Month 5/Day 150 [± 5 days]) 
The following study-related procedures will be performed at Visit 7E; it is suggested that they be 
performed in the order presented below, as is possible by the site: 
• Administer MADRS. 
• Administer YMRS. 
• Administer CGI-BP-S. 
• Administer C-SSRS. 
• Review concomitant medications. 
• Record adverse events. 
• Obtain vital signs. 
• Record weight. 
• Perform 12-lead ECG. 
• Collect urine sample for rapid urine drug test and urine β-hCG (female subjects of 
childbearing potential). 
• Perform study drug accountability. 
− Collect used/unused drug and packaging. 
• Dispense study drug. 
− Instruct subject to dose once daily in the morning at approximately the same time 
each day at home. 
• Schedule next visit: 
− Instruct subject to administer the morning dose prior to the clinic visit. Clinic 
visits are to begin no later than 6 hours postdose, if possible. 


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− Instruct subject to record the date and time of last 3 doses prior to next visit and to 
bring back all used/unused study drug and packaging to the next visit. 
• Schedule weekly telephone check-in with subject. 
11.6.8. 
Visit 8E (Month 6/Day 180 [± 5 days]) 
The following study-related procedures will be performed at Visit 8E; it is suggested that they be 
performed in the order presented below, as is possible by the site: 
• Administer MADRS. 
• Administer HAM-A. 
• Administer YMRS. 
• Administer CGI-BP-S. 
• Administer QIDS-SR16. 
• Administer SDS. 
• Administer EQ-5D-5L. 
• Administer SHAPS. 
• Administer C-SSRS. 
• Administer AIMS. 
• Administer BARS. 
• Administer SAS. 
• Review concomitant medications. 
• Record adverse events. 
• Perform physical examination. 
• Perform neurological examination. 
• Obtain vital signs. 
• Record weight. 
• Record waist circumference. 
• Collect blood sample(s) for the following clinical laboratory tests (Subjects must have 
fasted for at least 8 hours.). 
− Hematology and Serum Chemistry 
− Serum Prolactin 
− HbA1c 
− Lipid Panel 
− Serum Insulin 


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− hs-CRP 
− Thyroid Panel 
• Collect blood sample for measurement of plasma concentrations of aramisulpride, 
esamisulpride, and prolactin. 
• Collect urine sample for rapid urine drug test, urinalysis, and urine β-hCG (female 
subjects of childbearing potential). 
• Perform 12-lead ECG. 
• Perform study drug accountability. 
− Collect used/unused drug and packaging. 
− Confirm with the subject the date and time of their last 3 doses of study drug and 
record in the source and eCRF. 
• Dispense study drug. 
− Instruct subject to dose once daily in the morning at approximately the same time 
each day at home. 
• Schedule next visit: 
− Instruct subject to administer the morning dose prior to the clinic visit. Clinic 
visits are to begin no later than 6 hours postdose, if possible. 
− Instruct subject to bring back all used/unused study drug and packaging to the 
next visit. 
• Schedule weekly telephone check-in with subject. 
11.6.9. 
Visit 9E (Month 7/Day 210 [± 5 days]) 
The following study-related procedures will be performed at Visit 9E; it is suggested that they be 
performed in the order presented below, as is possible by the site: 
• Administer MADRS. 
• Administer YMRS. 
• Administer CGI-BP-S. 
• Administer C-SSRS. 
• Review concomitant medications. 
• Record adverse events. 
• Obtain vital signs. 
• Record weight. 
• Perform 12-lead ECG. 
• Collect urine sample for rapid urine drug test and urine β-hCG (female subjects of 
childbearing potential). 


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• Perform study drug accountability. 
− Collect used/unused drug and packaging. 
• Dispense study drug. 
− Instruct subject to dose once daily in the morning at approximately the same time 
each day at home. 
• Schedule next visit: 
− Instruct subject to administer the morning dose prior to the clinic visit. Clinic 
visits are to begin no later than 6 hours postdose, if possible. 
− Instruct subject to record the date and time of last 3 doses prior to next visit and to 
bring back all used/unused study drug and packaging to the next visit. 
• Schedule weekly telephone check-in with subject. 
11.6.10. 
Visit 10E (Month 8/Day 240 [± 5 days]) 
The following study-related procedures will be performed at Visit 10E; it is suggested that they 
be performed in the order presented below, as is possible by the site: 
• Administer MADRS. 
• Administer HAM-A. 
• Administer YMRS. 
• Administer CGI-BP-S. 
• Administer QIDS-SR16. 
• Administer SDS. 
• Administer EQ-5D-5L. 
• Administer SHAPS. 
• Administer C-SSRS. 
• Administer AIMS. 
• Administer BARS. 
• Administer SAS. 
• Review concomitant medications. 
• Record adverse events. 
• Obtain vital signs. 
• Record weight. 
• Collect blood sample(s) for the following clinical laboratory tests (Subjects must have 
fasted for at least 8 hours.). 
− Hematology and Serum Chemistry 


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− Serum Prolactin 
− HbA1c 
− Lipid Panel 
− Serum Insulin 
− Thyroid Panel 
• Collect blood sample for measurement of plasma concentrations of aramisulpride, 
esamisulpride, and prolactin. 
• Collect urine sample for rapid urine drug test, urinalysis, and urine β-hCG (female 
subjects of childbearing potential). 
• Perform 12-lead ECG. 
• Perform study drug accountability. 
− Collect used/unused drug and packaging. 
− Confirm with the subject the date and time of their last 3 doses of study drug and 
record in the source and eCRF. 
• Dispense study drug. 
− Instruct subject to dose once daily in the morning at approximately the same time 
each day at home. 
• Schedule next visit: 
− Instruct subject to administer the morning dose prior to the clinic visit. Clinic 
visits are to begin no later than 6 hours postdose, if possible. 
− Instruct subject to bring back all used/unused study drug and packaging to the 
next visit. 
• Schedule weekly telephone check-in with subject. 
11.6.11. 
Visit 11E (Month 9/Day 270 [± 5 days]) 
The following study-related procedures will be performed at Visit 11E; it is suggested that they 
be performed in the order presented below, as is possible by the site: 
• Administer MADRS. 
• Administer YMRS. 
• Administer CGI-BP-S. 
• Administer C-SSRS. 
• Review concomitant medications. 
• Record adverse events. 
• Obtain vital signs. 


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• Record weight. 
• Perform 12-lead ECG. 
• Collect urine sample for rapid urine drug test, and urine β-hCG (female subjects of 
childbearing potential). 
• Perform study drug accountability. 
− Collect used/unused drug and packaging. 
• Dispense study drug. 
− Instruct subject to dose once daily in the morning at approximately the same time 
each day at home. 
• Schedule next visit: 
− Instruct subject to administer the morning dose prior to the clinic visit. Clinic 
visits are to begin no later than 6 hours postdose, if possible. 
− Instruct subject to record the date and time of last 3 doses prior to next visit and to 
bring back all used/unused study drug and packaging to the next visit. 
• Schedule weekly telephone check-in with subject. 
11.6.12. 
Visit 12E (Month 10/Day 300 [± 5 days]) 
The following study-related procedures will be performed at Visit 12E; it is suggested that they 
be performed in the order presented below, as is possible by the site: 
• Administer MADRS. 
• Administer HAM-A. 
• Administer YMRS. 
• Administer QIDS-SR16. 
• Administer SDS. 
• Administer EQ-5D-5L. 
• Administer SHAPS. 
• Administer C-SSRS. 
• Administer AIMS. 
• Administer BARS. 
• Administer SAS. 
• Administer CGI-BP-S. 
• Review concomitant medications. 
• Record adverse events. 
• Obtain vital signs. 


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• Record weight. 
• Collect blood sample(s) for the following clinical laboratory tests (Subjects must have 
fasted for at least 8 hours.). 
− Hematology and Serum Chemistry 
− Serum Prolactin 
− HbA1c 
− Lipid Panel 
− Serum Insulin 
− Thyroid Panel 
• Collect blood sample for measurement of plasma concentrations of aramisulpride, 
esamisulpride, and prolactin. 
• Collect urine sample for rapid urine drug test, urinalysis, and urine β-hCG (female 
subjects of childbearing potential). 
• Perform 12-lead ECG. 
• Perform study drug accountability. 
− Collect used/unused drug and packaging. 
− Confirm with the subject the date and time of their last 3 doses of study drug and 
record in the source and eCRF. 
• Dispense study drug. 
− Instruct subject to dose once daily in the morning at approximately the same time 
each day at home. 
• Schedule next visit: 
− Instruct subject to administer the morning dose prior to the clinic visit. Clinic 
visits are to begin no later than 6 hours postdose, if possible. 
− Instruct subject to bring back all used/unused study drug and packaging to the 
next visit. 
• Schedule weekly telephone check-in with subject. 
11.6.13. 
Visit 13E (Month 11/Day 330 [± 5 days]) 
The following study-related procedures will be performed at Visit 13E; it is suggested that they 
be performed in the order presented below, as is possible by the site: 
• Administer MADRS. 
• Administer YMRS. 
• Administer CGI-BP-S. 
• Administer C-SSRS. 


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• Review concomitant medications. 
• Record adverse events. 
• Obtain vital signs. 
• Record weight. 
• Perform 12-lead ECG. 
• Collect urine sample for rapid urine drug test and urine β-hCG (female subjects of 
childbearing potential). 
• Perform study drug accountability. 
− Collect used/unused drug and packaging. 
• Dispense study drug. 
− Instruct subject to dose once daily in the morning at approximately the same time 
each day at home. 
• Schedule next visit: 
− Instruct subject to administer the morning dose prior to the clinic visit. Clinic 
visits are to begin no later than 6 hours postdose, if possible. 
− Instruct subject to record the date and time of last 3 doses prior to next visit and to 
bring back all used/unused study drug and packaging to the next visit. 
• Schedule weekly telephone check-in with subject. 
11.6.14. 
Visit 14E (Month 12/Day 360 [+ 5 days]; End of Treatment/Early Termination) 
The following study-related procedures will be performed at Visit 14E; it is suggested that they 
be performed in the order presented below, as is possible by the site: 
• Administer MADRS. 
• Administer HAM-A. 
• Administer YMRS. 
• Administer CGI-BP-S. 
• Administer PWC. 
• Administer QIDS-SR16. 
• Administer SDS. 
• Administer EQ-5D-5L. 
• Administer SHAPS. 
• Administer C-SSRS. 
• Administer AIMS. 
• Administer BARS. 


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• Administer SAS. 
• Review concomitant medications. 
• Record adverse events. 
• Perform physical examination. 
• Perform neurological examination. 
• Obtain vital signs. 
• Record weight. 
• Record waist circumference. 
• Collect blood sample(s) for the following clinical laboratory tests (Subjects must have 
fasted for at least 8 hours.). 
− Hematology and Serum Chemistry 
− Serum Prolactin 
− HbA1c 
− Lipid Panel 
− Serum Insulin 
− hs-CRP 
− Thyroid Panel 
• Collect blood sample for measurement of plasma concentrations of aramisulpride, 
esamisulpride, and prolactin. 
• Collect urine sample for rapid urine drug test, urinalysis, and urine β-hCG (female 
subjects of childbearing potential). 
• Perform 12-lead ECG. 
• Perform study drug accountability. 
− Collect used/unused drug and packaging. 
− Confirm with the subject the date and time of their last 3 doses of study drug and 
record in the source and eCRF. 
• Schedule Follow-up visit. 
11.6.15. 
Follow-up: Visit 15E (7 ± 2 days after last dose) 
All subjects will have a follow-up visit for safety and tolerability assessments 7 (± 2) days after 
their last dose of study drug. The following study-related procedures will be performed at 
Visit 15E; it is suggested that they be performed in the order presented below, as is possible by 
the site:  
• Administer YMRS. 


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• Administer PWC. 
• Administer C-SSRS. 
• Review concomitant medications. 
• Record adverse events. 
• Obtain vital signs. 
• Perform 12-lead ECG. 
• Collect blood sample for serum prolactin. 
• Collect blood sample for measurement of plasma concentrations of aramisulpride, 
esamisulpride, and prolactin. 
• Collect urine sample for rapid urine drug test and urine β-hCG (female subjects of 
childbearing potential). 
11.6.16. 
Telephone Contacts 
Telephone calls will be made weekly by a member of the research staff to the subject between 
scheduled study visits. The telephone calls will be used to collect AEs and concomitant 
medications, as well as to remind the subject about adherence to study drug administration and 
upcoming visits. 
11.6.17. 
Unscheduled Visit for Dose Adjustment 
11.6.17.1. Unscheduled Visit for Dose Increase 
All subjects will initiate treatment with SEP-4199 CR 200 mg/day. The dose may be increased to 
400 mg/day at Visit 2E (Week 2/Day 14) or later, based on the Investigator’s judgment. 
However, if clinically indicated, a dose increase can occur as early as Day 7 at an unscheduled 
visit. 
If a dose increase is needed between regularly scheduled visits, the subject will return to the 
clinic for an unscheduled visit. The following procedures will be conducted during this 
unscheduled visit for a dose increase: 
• Review concomitant medications. 
• Record adverse events. 
• Obtain vital signs. 
• Perform 12-lead ECG. 
• Additional safety assessments are not required but may be performed based on the 
Investigator’s judgment. 
• Perform study drug accountability. 
− Collect used/unused drug and packaging. 
• Dispense study drug. 


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11.6.17.2. Unscheduled Visit for Dose Decrease 
The dose may be decreased to 200 mg/day at any time for tolerability. If a dose decrease is 
needed between study visits, subjects will return to the clinic for an unscheduled visit. The 
following procedures will be conducted during this unscheduled visit for a dose decrease: 
• Review concomitant medications. 
• Record adverse events. 
• Safety assessments are not required but may be performed based on the Investigator’s 
judgment. 
• Perform study drug accountability. 
− Collect used/unused drug and packaging. 
• Dispense study drug. 


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12. 
SAFETY REPORTING 
12.1. 
Definitions 
12.1.1. 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
Untoward medical occurrences that occur after signing Study SEP380-303 ICF will be 
considered AEs. 
An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease occurring after the administration of a medicinal (investigational) 
product, whether or not considered related to the medicinal (investigational) product. AEs may 
include the onset of new illness and the exacerbation of pre-existing conditions. AEs will be 
collected from the signing of the ICF to the last study visit (Follow-up Visit). 
The Investigator should attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis should be documented as the AE 
and not the individual signs/symptoms. 
12.1.2. 
Serious Adverse Events 
A serious adverse event (SAE) is an AE that meets one or more of the following criteria: 
• Results in death. 
• Is life-threatening. 
• Requires hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability or incapacity. 
• Resulted in 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 an SAE. However, if the event/condition worsens during the study, it should be reported 


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as an AE (or SAE, if the event/condition results in a serious outcome such as prolongation of 
hospitalization). 
Life-threatening means that the subject was, in the view of the Investigator, at immediate risk of 
death from the event as it occurred. This definition does not include an event that had it occurred 
in a more severe form, might have caused death. 
SAE criteria information will be captured on the eCRF. 
12.1.3. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) collected during the study will include all 
hyperprolactinemia-related events, regardless of seriousness. Hyperprolactinemia-related AESI 
include, but are not limited to the following: 
• Galactorrhea/breast discharge 
• Breast disorders including gynecomastia, pain, swelling (moderate or severe events 
only) 
• Lack of or delayed menorrhea, or other menstrual disorders 
• Fractures/osteoporosis/osteopenia 
• Sexual dysfunction in females and males including erectile dysfunction/changes in 
libido 
• Any estrogen-related laboratory abnormality 
• Prolactin-producing pituitary tumor 
• Hirsutism 
Subjects should be instructed to notify the clinical site within 24 hours if they develop any of the 
signs or symptoms noted above. 
Subjects who develop any of the following AESI: amenorrhea (missed menses for a minimum of 
3 months), symptomatic gynecomastia, or galactorrhea that does not resolve within 2 weeks of 
temporary study drug interruption or that recurs with re-challenge must be discontinued from the 
study, referred to the Investigator for follow-up evaluation, and followed until the event resolves. 
Re-challenge will be at the Investigator’s discretion (see Section 13.1). 
For AESI, if the event meets seriousness criteria, the Investigator will report the event to the 
Sponsor within 24 hours of the site being made aware of the event, as outlined in Section 12.4.1. 
AESI that do not meet seriousness criteria will be reported by the Investigator to the Sponsor 
within 5 business days of site awareness and in the same manner that SAEs are reported. 
12.2. 
Objective Findings 
Clinically significant changes from signing of the ICF in objective findings (eg, clinical 
laboratory value, ECG value, vital signs, and physical or neurological examination observation), 
as determined by the Investigator, will also be recorded as AEs. 
When a clear diagnosis is available that explains the objective findings, this diagnosis will be 
recorded as the AE, and not the abnormal objective finding (eg, viral hepatitis will be recorded as 


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the AE, not transaminase elevation). If a definite diagnosis is not available, then the sign (eg, 
clinically significant elevation of transaminase levels) or symptom (eg, abdominal pain) will be 
recorded as the AE. 
Clinical laboratory test results and ECG tracings and over-read reports will be reviewed, signed, 
and dated by the Investigator.  
Any clinical laboratory value outside the normal range and any centrally over-read abnormal 
ECG finding will be flagged for the attention of the Investigator or appropriate designee at the 
study center. The Investigator or appropriate designee will indicate whether the value/finding is 
of clinical significance. Subjects with any clinically significant abnormal ECG finding at 
Visit 1E will be discontinued from the study (see Section 8.2). If a clinically significant 
laboratory or ECG abnormality is found after Visit 1E, during the study, and/or at the Follow-Up 
Visit, this should be recorded as an AE. Discontinuation due to AE with follow-up until 
resolution is mandatory for clinically significant ECG findings and hyperprolactinemia-related 
adverse events (see Section 13). Possibly drug-related or clinically relevant abnormal values of 
uncertain causality must be repeated. Additional laboratory and ECG testing during the study 
may be performed if medically indicated. 
12.3. 
Collection and Recording of Adverse Events 
All AEs must be recorded in the subject’s study records/source documents in accordance with 
the Investigator’s normal clinical practice. All AEs that occur from the signing of the informed 
consent to the subject’s last visit must be recorded on the eCRF. 
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, 
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 


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The action taken with the study treatment: 
• Drug Interrupted – Study drug stopped temporarily. 
• Drug Withdrawn – Study drug stopped permanently. 
• Dose Reduced 
• Dose Increased 
• Dose Not Changed 
• Not Applicable 
• Unknown 
The outcome of the AE: 
• Recovered/Resolved 
• Recovering/Resolving 
• Not Recovered/Not Resolved 
• Recovered/Resolved with Sequelae 
• Fatal 
• Unknown 
The causal relationship of the AE to the study treatment: Not related 
o Not related - Improbable temporal relationship and is plausibly related to other 
drugs or underlying disease. 
• Related 
o Possible - occurred in a reasonable time after study drug administration, but could 
be related to concurrent drugs or underlying disease. 
o Probable - occurred in a reasonable time after study drug administration, is 
unlikely to be attributable to concurrent drugs or underlying disease, and there is a 
plausible mechanism to implicate the study drug. 
o Definite - occurred in a reasonable time after study drug administration and 
cannot be explained by concurrent drugs or underlying disease. The adverse event 
should respond to dechallenge/rechallenge; however, this is not mandatory before 
assigning a definite causality. 
The Medical Monitor is the initial contact person for protocol related questions or discussion of 
AEs. The contact information for the Medical Monitor as well as other emergency contact 
information can be found in Table 1 of this protocol. 
12.4. 
Immediately Reportable Events 
The following medical events must be immediately reported to the Sponsor: 
• SAE 


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• Pregnancy 
Additionally, AESI (defined in Section 12.1.3) that do not meet serious criteria must be reported 
to the Sponsor within 5 business days of the site’s first awareness of the event. 
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 an SAE that occurs in a study subject 
after first administration of study drug through 30 days following the last dose of the study drug, 
this must be reported immediately to the Sponsor whether considered related or unrelated to the 
study drug. SAEs that occur from the signing of the ICF up to the last visit must be recorded on 
the eCRF, and the data recorded should agree with those on the SAE form. 
Should the Investigator become aware of an SAE greater than 30 days post last dose, the 
Investigator or an authorized delegate should report SAEs “spontaneously” to 
PPD-Pharmacovigilance (PVG) if considered at least possibly related to the study drug. 
SAEs will be followed until resolution, loss to follow-up, stabilization of condition, or the event 
is otherwise explained. 
An initial or follow-up SAE form as applicable must be completed and signed and sent via fax or 
email (see Table 1) to PPD-PVG immediately but no more than 24 hours after the Investigator or 
study center staff become aware of the event. The SAE form must be signed by the Investigator 
or appropriate designee. The Sponsor provides the SAE form used to report SAEs. 
The Sponsor or designee will promptly notify all study centers and Investigators of an SAE that 
is determined to be expedited to the Regulatory Authorities in accordance with applicable law(s) 
and regulation(s). These SAEs must be promptly reported to the Institutional Review Board 
(IRB) or Independent Ethics Committee (IEC) by the Investigator or the appropriate person at 
the study center if required per IRB/IEC guidelines. 
12.4.2. 
Pregnancy 
Pregnancies that occur from the time that informed consent is signed through 30 days following 
the last dose of the study drug will be collected and reported on the Pregnancy Event Form. 
If a subject becomes pregnant during the course of the study, she will be instructed to 
discontinue the study drug. Further, the subject will be instructed to return to the study center 
within 48 hours of the first notification of pregnancy to the study center and undergo a serum 
pregnancy test, as confirmation of pregnancy. If positive, the female pregnant subject will no 
longer receive any additional study drug. All pregnancies, whether or not the subject received 
any additional study medication, will be followed until resolution (ie, termination [voluntary or 
spontaneous] or birth). Infants may be followed for up to one year following birth. 
If a pregnancy is reported for a study subject’s partner following the subject’s first dose and up 
to 90 days following the last dose, the subject’s partner may be asked to sign a consent form to 
allow the Sponsor to follow her pregnancy. The Sponsor’s representative will provide 
instructions on how to collect pregnancy information in accordance with local requirements. 
Proper consent to collect the partner’s information will be obtained before the collection of any 
information. Infants may be followed for up to one year following birth. 


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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. 
12.5. 
Data and Safety Monitoring Board 
A Data and Safety Monitoring Board (DSMB) will review safety data at regular intervals. The 
DSMB will be independent of the Sponsor, CRO, and the Investigators and will be empowered 
to recommend stopping the study due to safety concerns, but not for efficacy or futility. The 
membership of the DSMB and its mandate will be described in a separate DSMB charter. 
 


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13. 
TERMINATION OF SUBJECT FROM 
STUDY/DISCONTINUATION OF STUDY DRUG 
13.1. 
Criteria for 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 
• Lack of efficacy (specify) 
• Lost to follow-up (specify) 
• Pregnancy 
• Withdrawal of consent (specify) 
• Non-compliance with study drug (specify) 
• Protocol deviation (specify) 
• 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. 
Discontinuation due to AE with follow-up until resolution is mandatory in the following cases: 
• Subject who, at any study visit post-Baseline, has a QTcF interval > 500 msec, or 
who has a ≥ 60 msec increase in QTcF from Baseline (machine reading or centrally 
overread report), or who experiences a life-threatening cardiac arrhythmia must be 
discontinued from the study, referred to the Investigator for follow-up evaluation, and 
followed until the event resolves; in addition, an associated AE must be reported. 
• Subject who develops an AE of amenorrhea (missed menses for a minimum of 
3 months), symptomatic gynecomastia, or galactorrhea that does not resolve within 
2 weeks of study drug interruption or that recurs with re-challenge must be 
discontinued from the study, referred to the Investigator for follow-up evaluation, and 
followed until the event resolves. 
• Subject who answers “yes” to “suicidal ideation” item 4 (active suicidal ideation with 
some intent to act, without specific plan) or item 5 (active suicidal ideation with 
specific plan and intent) on any post-Baseline C-SSRS assessment must be 
discontinued from the study, referred to the Investigator for follow-up evaluation, and 
followed until the event resolves; in addition, an associated AE must be reported. 
• Subjects who require hospitalization/prolonged hospitalization for treatment of 
COVID-19-related illness will be discontinued. Subjects with an active COVID-19 
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Monitor to obtain agreement on whether a subject with an active COVID-19 infection 
should be discontinued. 
The reason for termination of study participation and information on the epoch will be recorded 
on the appropriate eCRF. In case of death, the date of death should be captured on the eCRF. 
Subjects who prematurely terminate the study participation will not be replaced. 
Subjects who discontinue prior to Visit 14E (Month 12) will undergo procedures and 
assessments scheduled for Visit 14E (Month 12) at the time of early discontinuation 
(see Section 11.6.14). 


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14. 
STUDY TERMINATION 
The Sponsor reserves the right to discontinue the study at this study center or at multiple centers 
for safety or administrative reasons at any time while safeguarding that early termination does 
not compromise subjects’ safety or well-being. In particular, a study center that does not recruit 
at an acceptable rate may be closed. Should the study be terminated and/or the study center 
closed for whatever reason, all documentation and study 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 undergo final evaluation procedures, in 
accordance with the early termination (ET) visit described in Section 11.6.14 and safety 
Follow-up Visit described in Section 11.6.15. 


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15. 
STATISTICS 
15.1. 
Sample Size 
Assuming a completion rate of 85% in lead-in study of SEP-4199 CR and an 80% rollover rate 
of completers from that study to the current extension study, it is estimated that approximately 
355 subjects will be enrolled. 
15.2. 
Statistical Hypotheses 
Because of the nature of an open-labeled study, no statistical hypotheses are planned. 
15.3. 
Analysis Populations and Analysis Groups 
The safety population will include all subjects who receive at least one dose of study medication. 
The follow-up population includes all subjects who receive at least one dose of study medication 
and have at least 1 assessment after the last study drug administration for any evaluation. 
A total of 4 analysis groups will be formed based on a subject’s previous participation in the 
lead-in study of SEP-4199 CR (previously randomized to SEP-4199 CR 200 mg/day, previously 
randomized to SEP-4199 CR 400 mg/day, previously randomized to any SEP-4199 CR dose 
group, previously randomized to placebo). A group that combines all of these analysis groups 
will also be presented. 
15.4. 
Data Analysis 
Summary tables, wherever applicable, will be presented by analysis group. Where changes are 
reported, the reference will be to the pretreatment Baseline from the lead-in study of SEP-4199 
CR and indicated as “double-blind (DB) Baseline”. Where relevant, changes from Baseline for 
the open-label study, defined as the Week 6 assessment in the double-blind study or the last 
assessment prior to the first dose of study medication in the open-label study, will also be 
reported, and will be referred to as the open-label study Baseline or "OL Baseline". Continuous 
variables will be summarized using descriptive statistics (N, mean, standard deviation, median, 
first quartile [Q1], third quartile [Q3], range, 95% confidence interval [CI] as needed) and 
categorical variables will be reported as frequencies and percentages at DB Baseline, OL 
Baseline, each of post-OL visit, and endpoint. No statistical comparisons will be conducted and 
no inferential statistics on effectiveness and safety will be presented. 
15.4.1. 
Study Subject 
Descriptive statistics of study subjects, including analysis population, subject disposition, 
demographic and Baseline characteristics, drug exposure and compliance, medical and 
psychiatric history at DB screening, prior and concomitant medications, and important protocol 
deviations, will be presented by analysis group for the Safety population. Important protocol 
deviations (IPDs) will be identified and documented based on a review of potentially IPDs prior 
to database lock. Details of the summary approaches for subject level information will provided 
in the SAP, and no further discussion is provided hereafter. 
 


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15.4.2. 
Effectiveness Analyses 
Since this is an uncontrolled open-label extension of a lead-in study of SEP-4199 CR , no 
inferential statistics on efficacy will be presented. All effectiveness data will be summarized by 
analysis group based on the safety population. 
Descriptive statistics of observed values and changes from DB Baseline and OL Baseline will be 
summarized by study visit and analysis group for effectiveness parameters (continuous). At a 
visit in the extension study, responders relative to DB Baseline are defined as those who show a 
50% or more reduction (ie, improvement) from DB Baseline in MADRS total score. At a 
post-OL Baseline visit, responders relative to OL Baseline are defined as those who show a 50% 
or more reduction (ie, improvement) from OL Baseline. Remitters at any visit are defined as a 
subjects with a MADRS total score of ≤ 12. Frequencies and percentages of MADRS responders 
relative to both DB Baseline and OL Baseline, and frequencies and percentages of remitters will 
be summarized over time by analysis group. 
15.4.3. 
Safety Analyses 
All safety data will be summarized by analysis group based on the safety population. In addition, 
for a few selected safety assessments (ie, AEs, ECG, laboratory results, and vital signs), 
descriptive summary by analysis group will be provided based on the follow-up population, 
separately. 
15.4.3.1. Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Information on the format and version of the coding dictionary is provided in the DMP. 
A treatment-emergent adverse event (TEAE) (hereafter referred to as AE) is an adverse event 
with onset data on or after the first day of the open-label treatment period through 7 days after 
study drug discontinuation (14 days for serious adverse events). The start of the open-label 
treatment period is defined as the first dose day for subjects previously randomized to placebo 
group and the OL Baseline visit date for subjects previously randomized to SEP-4199 CR 
groups. 
The incidence of AEs, SAEs, and AEs leading to discontinuation due to AEs (or SAEs) will be 
summarized by analysis group (by presenting the number and percentage of subjects with one or 
more AEs in each category). The number and proportion of subjects with one or more AEs 
within a system organ class (SOC) and by preferred term (PT) will be presented by analysis 
group as well. The incidence of AEs (by preferred term, grouped by SOC) will also be 
summarized by severity, by the relationship to study medication, by the action taken regarding 
the study medication, as well as by the outcome. In addition, AEs will also be summarized by 
SOC, high-level term (HLT), and PT by presenting the number and percentage of subjects within 
each AE category. 
The incidence of AESI, including but not limited to hyper-prolactinemia related AEs, will be 
summarized for overall and by gender as appropriate. For selected AESI, Kaplan-Meier curves 
will be plotted by analysis group for time to the earliest onsets. AEs associated with EPS will be 
summarized by analysis group. 


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Incidence of post-treatment adverse events (defined as an AE with a start date after the date of 
last dose of study drug through the last contact/visit in the follow-up period) will be summarized 
separately for subjects in the follow-up population. 
15.4.3.2. Treatment-Emergent Mania 
Treatment-emergent mania is defined as a YMRS score of ≥ 16 on any 2 consecutive OL visits 
(ie, including OL Baseline visit for subjects previously randomized to SEP380-4199 CR group or 
excluding the visit(s) with study day ≤ Day 1 for subjects previously randomized to placebo 
group) or at the final assessment in the OL treatment period, or any treatment-emergent AE of 
mania or hypomania. If a subject has reported no AE of mania or hypomania and has no YMRS 
assessment (including OL Baseline for subjects previously randomized to SEP380-4199 CR 
group or has no post-OL Baseline YMRS assessment for subjects previously randomized to 
placebo), incidence of treatment-emergent mania will be set to missing. 
For YMRS total score, descriptive statistics will be provided for observed values and changes 
from DB Baseline and OL Baseline, respectively, by study visit and analysis group. 
15.4.3.3. Clinical Laboratory Assessments 
Descriptive statistics will be provided for observed values and changes from DB Baseline and 
OL Baseline, respectively, by study visit and analysis group for laboratory parameters measured 
on a continuous scale. Categorical results will be summarized by study visit and analysis group 
using frequency and percentage. 
Results for glucose, insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), 
and lipid tests will be presented separately by fasting status, which includes fasting only, and 
overall (fasting, non-fasting, or unknown). Serum prolactin values will be summarized by 
analysis group and gender (male, female, and overall). 
The normal reference ranges for laboratory tests will be used to determine whether the laboratory 
test value is below, within, or above the normal range. Shifts from DB Baseline and OL Baseline 
will be produced over time by analysis group to show the percentage of subjects with laboratory 
test values below, within, and above the normal range. 
Number and percentage of subjects with potentially clinically significant (PCS) laboratory value 
for select parameters will be summarized by study visit and for assessment period (treatment-
emergent) for each analysis group. Details of laboratory PCS criteria will be provided in the 
SAP. 
15.4.3.4. ECGs 
Standard 12-lead ECG parameters heart rate (HR), PR interval, RR interval, QT interval, QTcB 
and QTcF intervals, and QRS duration will be assessed. Results of each ECG parameter and their 
changes from DB Baseline and OL Baseline will be summarized by study visit and analysis 
group using descriptive statistics. 
For overall ECG assessment, shift from DB Baseline and shift from OL Baseline will be 
summarized by study visit for each analysis group. 


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The number and percentage of subjects with elevated QTc intervals (> 450 msec for males, 
> 470 msec for females, > 450 msec, > 480 msec and > 500 msec for both males or females) and 
changes from Baseline in QTc intervals ≥ 30 msec, ≥ 30 msec but < 60 msec, and ≥ 60 msec will 
be summarized by study visit and overall by analysis group. For other ECG parameters, subjects 
will be classified as normal or abnormal (details will be provided in the SAP). Number and 
percentage of subjects with PCS ECG values will be summarized by study visit and for 
assessment period (treatment-emergent) for each analysis group. Details of ECG PCS criteria 
will be provided in the SAP. 
15.4.3.5. Vital Signs 
Descriptive statistics of the following parameters will be summarized by study visit for actual 
value, change from DB Baseline, and change from OL Baseline (including percent change of 
body weight) for each analysis group. 
• Systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse rate in 
supine and standing positions;  
• Orthostatic changes in SBP, DBP, and pulse rate;  
• BMI and body weight;  
Number and percentage of subjects with weight increase of  ≥ 3%, ≥ 5%, and ≥ 7% by visit will 
be summarized by study visit for each analysis group. Shifts from DB Baseline and shifts from 
OL Baseline over time for weight status categories (Underweight/Normal, Overweight, Obese) 
will be summarized by analysis group to show the number and percentage of subjects that fall 
into categories. Number and percentage of subjects with PCS vital signs values will be 
summarized by study visit and for assessment period (treatment-emergent) for each analysis 
group. Number and percentage of subjects with orthostatic hypotension and/or orthostatic 
tachycardia will be summarized similarly. Details of vital signs PCS criteria will be provided in 
the SAP. 
15.4.3.6. Movement Disorder Measures 
Descriptive statistics for actual value, change from DB Baseline, and change from OL Baseline 
in BARS total score, BARS global clinical assessment of akathisia score, AIMS total score, and 
SAS 10-item mean score will be presented by study visit and analysis group. 
Shifts from DB Baseline and shift from OL Baseline in BARS global clinical assessment of 
Akathisia responses and AIMS global severity scores (classified as ‘worsened’, ‘unchanged’, or 
‘improved’), AIMS total score and SAS 10-item mean score (classified as ‘abnormal’, ’normal’) 
will be summarized by study visit and analysis group. Details for definition of these 
classifications will be provided in the SAP. 
15.4.3.7. Columbia-Suicide Severity Rating Scale (C-SSRS) 
The number and percentage of subjects with suicidal ideation, suicidal behavior, emergence or 
worsening of suicidal ideation or suicidal behavior will be summarized by analysis group for the 
open-label extension treatment period. 


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15.4.3.8. Physician’s Withdrawal Checklist (PWC) 
The PWC related summary will be based on the follow-up population. The PWC score will be 
summarized by presenting descriptive statistics of observed values and changes from Visit 14E 
(Month 12/EOT) by analysis group. Numbers and percentages of subjects with any new 
symptom or worsened old symptom for any PWC score or each individual symptom score will 
be provided by analysis group as well. 
15.4.4. 
Pharmacokinetic and Pharmacodynamic Analysis 
Population PK analysis methods will be used to characterize the PK/PD profiles in subjects 
treated with SEP-4199 CR. Analysis methods and results of population PK and PD analysis will 
be described in a separate document from the SAP and clinical study report. 
15.4.5. 
Interim Analysis 
No interim analysis is planned. 
15.4.6. 
Treatment of Missing Data 
Details for data handling rules of missing data will be provided in the SAP. 


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16. 
PROCEDURE FOR CLINICAL STUDY QUALITY CONTROL 
/DATA COLLECTION, MANAGEMENT, AND QUALITY 
ASSURANCE 
16.1. 
Data Collection/Electronic Data Capture (EDC) 
The results from data collected during the study (except clinical laboratory test results, ECG 
results, PK, and scales) will be recorded in the subject’s eCRF. The study centers will use an 
EDC system that is compliant with relevant US Food and Drug Administration (FDA) regulatory 
requirements per 21 code of federal regulations (CFR) Part 11 (Rave EDC). 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 eCRFs 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 is presented below, pursuant to the Guidance for Industry Computerized 
Systems Used in Clinical Investigations, May 2007. 
Table 6: 
Computerized Systems Used for Source Data 
Protocol Step  
Computerized System Type or Description 
Informed consent 
A 
Informed consent for duplicate subject check 
G 
Inclusion/Exclusion Criteria Review 
A 
Dispense Study Drug 
B 
Administer Study Drug 
A 
Study Drug Accountability 
A/B 
Demographics 
A 
Physical Examination 
A 
Neurological Examination 
A 
Prior/Concomitant Medications 
A 
Vital Sign Measurements 
A 
Weight  
A 
Waist Circumference 
A 
Adverse Event Monitoring 
A 
12-Lead Electrocardiogram (ECG) 
E 
Serum Chemistry, Hematology, and Urinalysis 
D 
Serum Prolactin 
D 
Blood sample for aramisulpride and esamisulpride PK and 
Plasma Prolactin  
F 
Hemoglobin A1c (HbA1c) 
D 
Lipid Panel 
D 
Serum Insulin  
D 
High Sensitivity C-reactive Protein (hs-CRP) 
D 


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Table 6: 
Computerized Systems Used for Source Data (Continued) 
Protocol Step  
Computerized System Type or Description 
Thyroid Panel 
D 
Urine β-hCG (Female Subjects of child-bearing potential) 
A 
Rapid Urine Drug Test 
A 
Young Mania Rating Scale (YMRS) 
C 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
C 
Abnormal Involuntary Movement Scale (AIMS) 
C 
Barnes Akathisia Rating Scale (BARS) 
C 
Modified Simpson-Angus Scale (SAS) 
C 
Physician Withdrawal Checklist (PWC) 
C 
Montgomery-Asberg Depression Rating Scale (MADRS) 
C 
Clinical Global Impression – Bipolar Version-Severity of 
Illness (CGI-BP-S) 
C 
Hamilton Anxiety Rating Scale (HAM-A) 
C 
Quick Inventory of Depressive Symptomatology – Self-
Report (QIDS-SR16) 
C 
Sheehan Disability Scale (SDS) 
C 
EuroQoL - 5 Dimensions – 5 Levels (EQ-5D-5L) 
C 
Snaith-Hamilton Pleasure Scale (SHAPS) 
C 
Statistical analysis 
SAS® software, version 9.4 or higher 
Abbreviations: ASCII = American Standard Code for Information Interchange; EDC = electronic data capture; 
eCOA = electronic clinical outcome assessments; IXRS = interactive web response system; 
LIMS = laboratory information management system; PK = pharmacokinetic(s). 
 A = EDC (Rave EDC); B = IXRS; C = eCOA; D = Central Lab; E = ECG central vendor; F = LIMS/ASCII;  
G = duplicate subject database. 
16.3. 
Study Monitoring 
This study will be monitored using a risk-based approach from initiation to completion by the 
Sponsor or its representative. Monitoring will include central review, personal visits, and 
telephone communication to assure that the investigation is conducted according to protocol and 
in order to comply with ICH GCP. On site review will be conducted to ensure source documents 
and other trial records are accurate and complete and, where applicable, consistent with eCRF 
entries. 
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 eCRF 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 


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storage areas, laboratory) and review study related records in order to evaluate the study 
compliance with the Sponsor/center standard operating procedures (SOPs), protocol, ICH GCP, 
and local regulations. The PI or appropriate designee must also agree to inspection of all study 
documents by the regulatory authorities and the 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, eCRFs, and all other administrative 
documents, eg, IRB/IEC correspondence, clinical study materials and supplies shipment 
manifests, monitoring logs, Sponsor and CRO correspondence, etc. A study specific binder will 
be provided with instructions for the maintenance of study records. 
Source document is defined as any hand-written or computer-generated document that contains 
medical information or test results that have been collected for or are in support of the protocol 
specifications, eg, clinical laboratory reports, clinic notes, drug disbursement log, subject sign-in 
sheets, subject completed questionnaires if applicable, telephone logs, ECGs, etc. All draft, 
preliminary, and pre-final iterations of a final report are also considered to be source documents, 
eg, faxed laboratory reports and hard copy laboratory reports, faxed initial results and hard copy, 
final report. 
16.6. 
Clinical Laboratory Certification and Normal Values 
A central laboratory will be used for analysis for most of the clinical laboratory tests for this 
study. The central laboratory will provide the Investigator and Sponsor/CRO with laboratory 
certification(s), and a dated copy of normal range values for the central clinical laboratory 
selected to analyze clinical specimens. If an exception is granted to use a local laboratory, the 
Investigator must supply the Sponsor/CRO with laboratory certification, lab director’s 
curriculum vitae and a current, dated copy of normal range values. 


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17. 
ETHICAL AND REGULATORY OBLIGATIONS 
17.1. 
Study Conduct 
The Investigator agrees that the study will be conducted according to the protocol, ICH 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 the Sponsor/CRO the “Investigator Approval" page. 
The Investigator must provide a copy of his or her 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 the Sponsor/CRO. 
17.2. 
Institutional Review Board/Independent Ethics Committee 
Documented approval or favorable opinion 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 with 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 the Sponsor/CRO prior to 
the start of the study. The approval or favorable opinion letter must be signed by the IRB/IEC 
chairman or designee identify the IRB/IEC name and address, identify the clinical protocol by 
title and/or protocol number, and include the date that approval or favorable opinion was granted. 
The letter must also contain a statement that the IRB/IEC complies with the requirements in 21 
CFR Part 56 for a study conducted under a US IND or ICH GCP, as applicable. 
The Investigator/CRO is responsible for obtaining from the IRB/IEC continued review of the 
clinical research or submitting periodic progress reports, in accordance with applicable 
regulations, at intervals not to exceed one year and (if applicable) as otherwise additionally 
specified by the IRB/IEC. The Sponsor must be supplied with written documentation of 
continued review of the clinical research. 


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The Investigator must promptly inform their IRB/IEC of all SAEs reported by subjects enrolled 
in the study or other safety information reported by the Sponsor/CRO in accordance with 
applicable law(s) and regulation(s). 
17.3. 
Informed Consent 
The Investigator will prepare the informed consent form and provide the form to Sponsor/CRO 
for approval prior to submission to the IRB/IEC.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 eligibility, 
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 eCRF. 
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 to uphold the subject’s 
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 to this protocol must be approved in writing by the Sponsor 
and the appropriate IRB/IEC. The Investigator will not make any changes to the conduct of the 
study or the protocol without first obtaining written approval from the Sponsor and the IRB/IEC, 
except where necessary to eliminate an apparent immediate hazard to a study subject. 
Emergency deviations or modifications may be initiated without Sponsor or IRB/IEC approval or 
favorable opinion, only in cases where the deviation or modification is necessary to eliminate or 
avoid an immediate apparent hazard to subjects. Emergency deviations or modifications must be 
reported to the Sponsor/CRO and the IRB/IEC immediately/within five business days of the 
occurrence, or in accordance with applicable regulatory requirements. 
17.6. 
Records Retention 
The Investigator/the study center must arrange for retention of study records at the study center 
for at least 15 years (or at least 25 years in the European Union [EU]) from time of completion 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-/DSP-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 
should 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. 
17.10. 
Compensation 
If subjects have any adverse event or injury directly resulting from the study medications or 
procedures, the Sponsor will appropriately compensate them in accordance with applicable 
regulatory requirements. 


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18. 
REFERENCES 
Abbas AI, Hedlund PB, Huang XP, Huang X-P, Tran TB Meltzer HY, Roth BL. Amisulpride is 
a potent 5-HT7 antagonist: relevance for antidepressant actions in vivo. Psychopharmacology 
(Berl). 2009;205:119-28. 
Barnes TRE. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672-6. 
Barnes TRE. The Barnes Akathisia Rating Scale – Revisited. J Psychopharmacology. 
2003;17(4):365-70. 
Guy W. EDCEU Assessment Manual for Psychopharmacology – Revised (DHEW Publ No 
ADM 76-338). Rockville, MD, U.S. Department of Health, Education, and Welfare, Public 
Health Service, Alcohol, Drug Abuse, and Mental Health Administration, NIMH 
Psychopharmacology Research Branch, Division of Extramural Research Programs, 1976:534-7. 
Hopkins SC, Wilkinson S, Corriveau TJ, Nishikawa H, Nakamichi K, Loebel A, et al. Discovery 
of Nonracemic Amisulpride to Maximize Benefit/Risk of 5-HT7 and D2 Receptor Antagonism 
for the Treatment of Mood Disorders. Clin Pharmacol Ther, 2021: Sep;110(3):808-815. 
Huhn M, Nikolakopoulou A, Schneier-Thomas J, Krause M, Samara M, Peter N, et. al. 
Comparative efficacy and tolerability of 32 oral antipsychotics for acute treatment of adults with 
multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet. 2019 Sep 
14;394(10202):939-951. 
Kemp DE. Managing the side effects associated with commonly used treatments for bipolar 
depression. J Affect Disord. 2014 Dec;169 Suppl 1:S34-44. 
Lecrubier Y, Boyer P, Turkanski S, Rein W, Amisulpride Study Group. Amisulpride versus 
imipramine and placebo in dysthymia and major depression. J Affect Disord. 1997;43:95-103. 
Montgomery, 2002. Dopaminergic deficit and the role of amisulpride in the treatment of mood 
disorders. International Clinical Psychopharmacology. 2002;17 (suppl 4): S9-S17. 
Munetz MR, Benjamin S. How to examine patients using the Abnormal Involuntary Movement 
Scale. Hospital and Community Psychiatry. 1988;39:1172-7. 
Schooler NR, Chengappa KNR. Adverse effects measures. In: Handbook of Psychiatric 
Measures. Washington, D.C.: American Psychiatric Association, 2000:151-68. 
Solian SMPC, 23 Mar 2021. 
Simpson GM, Angus JWS. A rating scale for extrapyramidal side effects. Acta Psychiatrica 
Scandinavia. Suppl 1970;212S:11-9. 
Snaith RP, Hamilton M, Morley S, Humayan A, Hargreaves D, Trigwell P. A scale for the 
assessment of the hedonic tone: The Snaith-Hamilton Pleasure Scale. B J Psychiatry. 
1995;167(1):99-103. 
 


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19. 
INVESTIGATOR APPROVAL 
I have read the protocol, SEP380-303, Version 2.02, “A 12-Month Open-label Extension Study 
to Evaluate the Long-term Safety, Tolerability, and Effectiveness of SEP-4199 Controlled-
Release (CR) for the Treatment of Major Depressive Episode Associated with Bipolar I Disorder 
(Bipolar I Depression)”, 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/or Sumitomo Pharma Co., 
Ltd. (SMP) and after documentation of IRB approval. 
Investigator Signature: ____________________________________________________ 
Print Investigator Name: __________________________________________________ 
Date: ___________________________________________ 


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20. 
APPENDIX I. CARDIAC SAFETY MONITORING (ECG) 
1. Requirements for Testing 
ECG equipment and supplies will be provided by the centralized cardiac safety vendor and 
should be used for all in-clinic protocol ECG assessments. 
• All 12-lead ECGs will be recorded in the same manner. 
• The study center personnel must be adequately trained in performing ECGs on the 
specific ECG equipment used in this protocol that is provided by the cardiac safety 
vendor. 
• To the extent possible, the same ECG machine and personnel should be used to 
acquire a subject’s ECGs throughout the period of their participation in the study. 
• ECGs will be recorded with at least one 10-second single-lead tracing recorded from 
Lead II. 
2. Subject Restrictions and Instructions 
• Prior to ECG acquisition, the subject will have rested 10 minutes in the supine 
position and will remain so until the ECG is obtained. 
3. Reporting 
• It is the responsibility of the Investigator to perform a safety review of the ECG data 
for changes from previous assessments and/or emergent cardiac dysfunction, and to 
determine subjects’ eligibility or continuance in the study. 
• ECGs will be reviewed, signed, and dated by the Investigator listed on the Form FDA 
1572 (MD or DO) after each ECG collection. The same Investigator should review all 
ECG reports for a given subject whenever possible. 
• For all ECGs, a report will be provided by the cardiac safety vendor to the study 
center for review and signature. 
• The ECG tracing will be kept with subject’s source documentation and / or eCRF 
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, RBC Count, WBC - Total Count, WBC Differential 
(Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils), Mean Corpuscular 
Hemoglobin (MCH), Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin 
Concentration (MCHC), and Red Cell Distribution Width (RDW) 
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), Creatinine, Creatine Phosphokinase (CPK), 
Gamma-Glutamyl Transferase (GGT), Glucose, Lactate Dehydrogenase (LDH), Magnesium 
(Mg), Phosphorus (P), Potassium (K), Protein (Total), Sodium (Na), Uric Acid 
URINALYSIS: Color, Clarity/Appearance, Specific Gravity, Bilirubin, Blood, Glucose, 
Ketones, Leukocyte esterase, Nitrites, pH, Protein, Urobilinogen, Microscopic examination 
LIPID PANEL: Total Cholesterol, Low Density Lipoprotein (LDL)-Cholesterol, High Density 
Lipoprotein (HDL)-Cholesterol, Triglycerides 
THYROID PANEL: Free T3, Free T4, Thyroid stimulating hormone (TSH) 
URINE DRUG SCREENING/RAPID URINE DRUG TEST: Amphetamines, Barbiturates, 
Benzodiazepines, Cannabinoids, Cocaine, Methamphetamines, Methadone, 
Methylenedioxymethamphetamine (MDMA), Phencyclidine (PCP), Opiates, Oxycodone, 
Tricyclic Antidepressants 
RENAL FUNCTIONING: Creatinine clearance (Calculated GFR) 
OTHER TESTS: Serum Pregnancy (β-hCG) (female subjects of childbearing potential only), 
Urine Pregnancy Test (female subjects of childbearing potential only), HbA1c, Glucose, Serum 
Insulin, hs C-reactive Protein (CRP), Serum Prolactin 
The Investigator listed on the Form FDA 1572 (MD or DO) (or Sub-Investigator MD or DO as 
described on the delegation log) will review laboratory reports and initial and date on all pages, 
or other acceptable documentation process approved by the Sponsor. Laboratory test results will 
be reviewed by the Investigator as they become available. The Investigator must determine the 
clinical significance of all out-of-range lab values (except drug screens). Possibly drug-related or 
clinically relevant abnormal values of uncertain causality must be repeated. Any abnormal values 
that persist should be followed at the discretion of the Investigator. 


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22. 
APPENDIX III. BLOOD SAMPLE COLLECTION AND 
HANDLING GUIDELINES FOR PHARMACOKINETIC AND 
PLASMA PROLACTIN ASSESSMENTS 
 
Please refer to the Laboratory Investigator Manual for all collection and shipping instructions. 
 
Blood must be collected from all subjects at the time points indicated below. 
Visit No. 
Time 
Aramisulpride and Esamisulpride PK and Plasma 
Prolactin Blood Sample Collection Times: 
1E  
Baseline (Day -1) 
Carried over from 6-week double-blind placebo-
controlled lead-in study of SEP-4199 CR 
2E 
Week 2 (± 2 days) 
Postdose* 
4E 
Month 2 (± 5 days) 
Postdose* 
6E 
Month 4 (± 5 days) 
Postdose* 
8E 
Month 6 (± 5 days) 
Postdose* 
10E 
Month 8 (± 5 days) 
Postdose* 
12E 
Month 10 (± 5 days) 
Postdose* 
14E 
Month 12 (+ 5 days) 
Postdose* 
15E 
7 ± 2 days after last 
dose 
Follow-up** 
* Sample will be collected after dosing is given on that day. Actual date and time will be recorded. 
** Actual date and time will be recorded. 
COLLECTION REQUIREMENTS: 
Collect 4 mL blood sample into a K2EDTA (ethylenediaminetetraacetic acid) treated 
Vacutainer® (or equivalent) tube at each time point. Invert gently 8 to 10 times to mix well. Keep 
the blood collection tube on wet ice prior to centrifugation, and centrifuge for 10 minutes at 
approximately x 1500 g to isolate plasma within 30 minutes of blood collection. To ensure a 
more homogenous sample, all plasma samples should first be transferred to 1 tube and mixed 
well (by repeatedly aspirating and dispensing the sample into the storage tube). Split the sample 
with approximately equal volume into 2 polypropylene tubes, and label as Set-1 and Set-2. Store 
plasma tubes at approximately -20°C or lower freezer within 1 hour until shipping to the 
bioanalytical lab. The date and time of blood collection must be recorded. 
All samples will be shipped with dry ice protection. Set-1 samples will be shipped to the 
Bioanalytical Lab for aramisulpride and esamisulpride concentration measurements and Set-2 
samples will be shipped to another lab for prolactin concentration measurement. 


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23. 
APPENDIX IV. PROHIBITED DRUGS KNOWN TO PROLONG 
THE QT INTERVAL 
Generic Name 
Trade Name 
Amiodarone 
Cordarone, Pacerone 
Azithromycin 
Zithromax 
Arsenic trioxide 
Trisenox 
Bepridil 
Vascor 
Chlorpromazine 
Thorazine 
Ciprofloxacin 
Cetraxal, Cipro XR, Ciloxan 
Cisapride 
Propulsid 
Clarithromycin 
Biaxin 
Disopyramide 
Norpace 
Dofetilide 
Tikosyn 
Dolasetron Mesylate 
Anzamet 
Domperidone 
Motilium 
Dronedarone 
Multaq 
Droperidol 
Inapsine 
Erythromycin 
E.E.S., Erythrocin 
Flecainide 
Tambocor 
Fluconazole 
Diflucan 
Gatifloxacin 
Tequin 
Halofantrine 
Halfan 
Haloperidol 
Haldol 
Ibutilide 
Corvert 
Levofloxacin 
Levaquin 
Levomethadyl 
Orlaam 
Mefloquine 
Larium 
Mesoridazine 
Serentil 
Methadone 
Dolophine, Methadose 
Moxifloxacin 
Avelox 
Ondansetron 
Zofran, Zuplenz 
Pentamidine 
NebuPent 
Pentamidine 
Pentam 
Pimozide 
Orap 
Probucol 
Lorelco 
Procainamide 
Procan, Pronestyl 
Quinidine 
Cardioquin, Quiniglute 
Sotalol 
Betapace 
Sparfloxacin 
Zagam 
Tacrolimus 
Prograf 
Thioridazine 
Mellaril 
 

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Document: 
SEP380-303 - Statistical Analysis Plan - Final – 25JAN2024.docx 
 
 
Version Number: 
Final  
 
 
Version Date: 
25JAN2024 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
SEP380-303 
A 12-MONTH OPEN-LABEL EXTENSION STUDY TO EVALUATE THE LONG-TERM 
SAFETY, TOLERABILITY, AND EFFECTIVENESS OF SEP-4199 CONTROLLED RELEASE 
(CR) FOR THE TREATMENT OF MAJOR DEPRESSIVE EPISODE ASSOCIATED WITH 
BIPOLAR I DISORDER (BIPOLAR I DEPRESSION) 
 
 
 
 
PHASE: PHASE III 
 
VERSION NUMBER AND DATE: FINAL, 25JAN2024 
 
 
 
 
 
 
 
 
 
 
 
 


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Document: 
SEP380-303 - Statistical Analysis Plan - Final – 25JAN2024.docx 
 
 
Version Number: 
Final  
 
 
Version Date: 
25JAN2024 
 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan Final (Dated 25JAN2024) for Protocol SEP380-303. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, 
authorizing that the content is acceptable for the reporting of this study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Document: 
SEP380-303 - Statistical Analysis Plan - Final – 25JAN2024.docx 
 
 
Version Number: 
Final  
 
 
Version Date: 
25JAN2024 
 
MODIFICATION HISTORY 
 
Unique 
Identifier for 
this 
Version 
Date of the 
Document Version 
Author 
Significant Changes from  
Previous Authorized Version 
1.0 
17NOV2023 
 
Not Applicable – First Version 
2.0 
01DEC2023 
 
Incorporated comments on the first draft. 
2.1 
18DEC2023 
 
Incorporated comments on the final draft. 
Final 
25JAN2024 
 
Finalization. 
 
 
 


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Document: 
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Version Number: 
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Version Date: 
25JAN2024 
 
TABLE OF CONTENTS 
2. 
INTRODUCTION ........................................................................................................................... 8 
3. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................................. 8 
3.1. 
Study Objectives ......................................................................................................................................... 8 
3.1.1. 
Primary Objective ...................................................................................................................................... 8 
3.1.2. 
Other Safety Objectives ............................................................................................................................. 8 
3.1.3. 
Effectiveness Objectives ............................................................................................................................ 8 
3.1.4. 
Pharmacokinetic/Pharmacodynamic Objectives ....................................................................................... 9 
3.2. 
Study Endpoints ......................................................................................................................................... 9 
3.2.1. 
Primary Endpoints ..................................................................................................................................... 9 
3.2.2. 
Other Safety Endpoints .............................................................................................................................. 9 
3.2.3. 
Effectiveness Endpoints ............................................................................................................................. 9 
3.2.4. 
Pharmacokinetic and Pharmacodynamic Endpoints ............................................................................... 10 
4. 
STUDY DESIGN ........................................................................................................................... 10 
4.1. 
General Description .................................................................................................................................. 10 
4.2. 
Method of Assigning Subjects to Treatment Groups................................................................................. 11 
4.3. 
Blinding .................................................................................................................................................... 11 
4.4. 
Determination of Sample Size .................................................................................................................. 11 
4.5. 
Changes in the Conduct of the Study ........................................................................................................ 12 
4.6. 
Schedule of Events ................................................................................................................................... 12 
4.7. 
Changes to Analysis from Protocol ........................................................................................................... 12 
5. 
PLANNED ANALYSES ................................................................................................................ 12 
5.1. 
Data and Safety Monitoring Board ........................................................................................................... 12 
5.2. 
Interim Analysis........................................................................................................................................ 12 
5.3. 
Final Analysis ............................................................................................................................................ 13 
6. 
ANALYSIS POPULATIONS ....................................................................................................... 13 
6.1. 
Safety Population ..................................................................................................................................... 13 
7. 
GENERAL CONSIDERATIONS ................................................................................................. 13 


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Version Date: 
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7.1. 
Reference Start Date and Study Day ......................................................................................................... 13 
7.2. 
Baseline .................................................................................................................................................... 14 
7.3. 
Derived Timepoints .................................................................................................................................. 14 
7.4. 
Retests, Unscheduled Visits, and Early Termination Data ......................................................................... 15 
7.5. 
Windowing Conventions .......................................................................................................................... 15 
7.6. 
Statistical Tests ......................................................................................................................................... 16 
7.7. 
Common Calculations ............................................................................................................................... 16 
7.8. 
Software Version ...................................................................................................................................... 16 
8. 
STATISTICAL CONSIDERATIONS ......................................................................................... 16 
8.1. 
Adjustments for Covariates and Factors to be Included in Analyses ......................................................... 16 
8.2. 
Multicenter Studies .................................................................................................................................. 16 
8.3. 
Missing Data ............................................................................................................................................. 16 
8.4. 
Multiple Comparisons/ Multiplicity .......................................................................................................... 17 
8.5. 
Examination of Subgroups ........................................................................................................................ 17 
9. 
OUTPUT PRESENTATIONS ..................................................................................................... 17 
10. 
DISPOSITION AND WITHDRAWALS ................................................................................... 17 
11. 
IMPORTANT PROTOCOL DEVIATIONS .............................................................................. 17 
12. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ...................................... 18 
12.1. 
Derivations ........................................................................................................................................... 20 
13. 
MEDICAL HISTORY ................................................................................................................... 20 
14. 
PRIOR AND CONCOMITANT MEDICATIONS ..................................................................... 20 
15. 
STUDY MEDICATION EXPOSURE ......................................................................................... 21 
15.1. 
Derivations ........................................................................................................................................... 21 
16. 
STUDY MEDICATION COMPLIANCE .................................................................................... 22 


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17. 
EFFICACY OUTCOMES .............................................................................................................. 23 
17.1. 
Derivation & Analysis of Efficacy Variables ........................................................................................... 23 
17.1.1. 
Changes from DB Baseline and from OL Baseline in MADRS total score at each scheduled visit ........... 23 
17.1.2. 
Changes from DB Baseline and from OL Baseline in CGI-BP-S score at each scheduled visit .................. 23 
17.1.3. 
MADRS response at each scheduled visit ................................................................................................ 24 
17.1.4. 
MADRS remission at each scheduled visit ............................................................................................... 24 
17.1.5. 
Changes from DB Baseline and from OL Baseline in HAM-A total score at each scheduled visit ............ 24 
17.1.6. 
Changes from DB Baseline and from OL Baseline in QIDS-SR16 total score at each scheduled visit ...... 25 
17.1.7. 
Changes from DB Baseline and from OL Baseline in SDS total score and subscale scores at each 
scheduled visit ......................................................................................................................................................... 25 
17.1.8. 
Changes from DB Baseline and from OL Baseline in EQ-5D-5L VAS and index scores at each scheduled 
visit 
26 
17.1.9. 
Changes from DB Baseline and from OL Baseline in SHAPS total score at each scheduled visit ............. 27 
17.2. 
Missing Data ......................................................................................................................................... 27 
18. 
SAFETY OUTCOMES .................................................................................................................. 27 
18.1. 
Adverse Events ..................................................................................................................................... 27 
18.1.1. 
All AEs ...................................................................................................................................................... 28 
18.1.1.1. 
Severity ............................................................................................................................................ 28 
18.1.1.2. 
Relationship to study medication .................................................................................................... 29 
18.1.2. 
AEs Leading to Discontinuation from Study ............................................................................................ 29 
18.1.3. 
Serious Adverse Events (Including Adverse Events Leading to Death) .................................................... 29 
18.1.4. 
Adverse Events of Special Interest (AESI) ................................................................................................ 29 
18.2. 
Laboratory Evaluations ......................................................................................................................... 29 
18.2.1. 
Laboratory Specific Derivations ............................................................................................................... 31 
18.2.2. 
Laboratory Reference Ranges .................................................................................................................. 31 
18.3. 
ECG Evaluations .................................................................................................................................... 31 
18.3.1. 
ECG Potentially Clinically Significant Criteria ........................................................................................... 32 
18.4. 
Vital Signs ............................................................................................................................................. 33 
18.4.1. 
Vital Signs Specific Derivations ................................................................................................................ 34 
18.4.2. 
Vital Sign Potentially Clinically Significant Criteria ................................................................................... 35 
18.5. 
Physical Examination ............................................................................................................................ 35 
18.6. 
Other Safety Assessments .................................................................................................................... 35 
18.6.1. 
Columbia Suicide Severity Rating Scale (C-SSRS) ..................................................................................... 35 
18.6.2. 
Young Mania Rating Scale (YMRS) ........................................................................................................... 37 
18.6.3. 
Abnormal Involuntary Movement Scale (AIMS) ...................................................................................... 38 
18.6.4. 
Barnes Akathisia Rating Scale (BARS) ...................................................................................................... 39 
18.6.5. 
Modified Simpson-Angus Scale (MSAS) ................................................................................................... 40 
18.6.6. 
Physician’s Withdrawal Checklist (PWC).................................................................................................. 40 
19. 
PHARMACOKINETIC ANALYSIS ............................................................................................ 40 
19.1. 
Derivation ............................................................................................................................................. 41 


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20. 
DATA NOT SUMMARIZED OR PRESENTED ....................................................................... 41 
21. 
REFERENCES ............................................................................................................................... 42 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS .............................................. 43 
Output Conventions ............................................................................................................................................ 43 
Dates & Times ...................................................................................................................................................... 44 
Spelling Format .................................................................................................................................................... 44 
Presentation of Treatment Groups ...................................................................................................................... 44 
Listings ................................................................................................................................................................. 44 
APPENDIX 2. PARTIAL DATE CONVENTIONS ............................................................................. 45 
Algorithm for Adverse Events .............................................................................................................................. 45 
Algorithm for Prior / Concomitant / Post-Treatment Medications ....................................................................... 48 
APPENDIX 3. EQ-5D-5L INDEX VALUE CALCULATION ............................................................. 50 
APPENDIX 4. INTERNATIONALLY AGREED ORDER FOR SYSTEM ORGAN CLASS ........... 51 
APPENDIX 5. ADVERSE EVENT OF SPECIAL INTEREST (AESI) .............................................. 52 
APPENDIX 6. PREDEFINED POTENTIALLY CLINICALLY SIGNIFICANT (PCS) CRITERIA 
FOR LABORATORY VALUES ............................................................................................................. 54 
APPENDIX 7. SCHEDULE OF EVENTS ............................................................................................. 57 
 
 
 


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2. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of 
efficacy and safety data for Protocol SEP380-303. It describes the data to be summarized and 
analyzed, including specifics of the statistical analyses to be performed.  
This statistical analysis plan (SAP) is based on protocol version 2.0, dated 07SEP2021. 
The Data and Safety Monitoring Board (DSMB) analysis plan will be described in a separate document. 
An Important Protocol Deviation (IPD) Review Plan and a Pre-lock Data Review (PLDR) Plan will be 
written to describe the process and the outputs to be delivered during the IPD/PLDR meetings. 
3. STUDY OBJECTIVES AND ENDPOINTS 
3.1. STUDY OBJECTIVES 
The objective of Study SEP380-303 is to evaluate the long-term safety, tolerability, and effectiveness of 
SEP-4199 CR at a flexible daily dose of 200 mg/day or 400 mg/day in subjects who previously 
completed the 6 weeks lead-in Study SEP380-301 of SEP-4199 CR for the treatment of major 
depressive episode associated with bipolar I disorder (bipolar I depression). 
3.1.1. 
PRIMARY OBJECTIVE 
The primary objective of the current study is to evaluate the long-term safety and tolerability of 
treatment with SEP-4199 CR 200-400 mg/day, as reflected in rates of adverse events (AEs), 
discontinuations due to an AE, serious AEs (SAEs), and adverse events of special interest (AESI).  
3.1.2. 
OTHER SAFETY OBJECTIVES 
Long-term safety and tolerability of flexible-dose SEP-4199 CR treatment will be evaluated as follows: 
   • Measurements including 12-lead electrocardiogram (ECG), clinical laboratory values, vital signs, body 
weight, and metabolic parameters  
  • Prolactin levels 
  • Manic symptoms using the Young Mania Rating Scale (YMRS) 
  • Suicidality using the Columbia-Suicide Severity Rating Scale (C-SSRS) 
  • Movement disorders using the Barnes Akathisia Rating Scale (BARS), Abnormal Involuntary 
Movement Scale (AIMS), and modified Simpson-Angus Scale (SAS) 
  • Potential for withdrawal symptoms after discontinuation, using the Physician’s Withdrawal Checklist 
(PWC). 
3.1.3. 
EFFECTIVENESS OBJECTIVES 
Long-term effectiveness of flexible-dose SEP-4199 CR treatment will be evaluated as follows:  
  • Severity of depression symptoms as measured by the Montgomery-Asberg Depression Rating Scale 
(MADRS)  
  • Overall bipolar depression severity assessed using the Clinical Global Impression-Bipolar Version-
Severity of Illness (CGI-BP-S) Depression scale 


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  • Anxiety symptoms severity assessed using the clinician-administered Hamilton Anxiety Rating Scale 
(HAM-A) 
  • Severity of subject-reported depression symptoms as measured by the Quick Inventory of Depressive 
Symptomatology, Self-Report (QIDS-SR16) 
  • Functional impairment, as measured by the Sheehan Disability Scale (SDS) 
  • Quality of life, as measured by the EuroQol - 5 Dimension - 5 Level (EQ-5D-5L) 
  • Anhedonia symptoms, as measured by the Snaith-Hamilton Pleasure Scale (SHAPS). 
3.1.4. 
PHARMACOKINETIC/PHARMACODYNAMIC OBJECTIVES 
  • Perform population pharmacokinetic (Pop-PK) analysis using plasma SEP-4199 concentrations. 
  • Explore the relationship between MADRS score and plasma SEP-4199 exposure using population 
PK/pharmacodynamics (PD) methods. 
  • Explore the relationship between safety outcomes and plasma SEP-4199 exposure. 
3.2. STUDY ENDPOINTS 
3.2.1. 
PRIMARY ENDPOINTS 
  •  The incidence of overall AEs, discontinuation due to AEs, and SAEs 
3.2.2. 
OTHER SAFETY ENDPOINTS 
  • The incidence of AESI including but not limited to hyperprolactinemia-related AEs 
  • Clinical laboratory evaluations (serum chemistry, hematology, thyroid panel, urinalysis) 
  • Clinical evaluation (vital signs including orthostatic effects, and 12-lead ECG measurements) 
  • Changes in prolactin values 
  • Changes in metabolic parameters (insulin, glucose, hemoglobin A1c (HbA1c), lipid panel) 
  • Change and percent change in body weight 
  • Change in body mass index (BMI) 
  • Incidence of treatment-emergent mania, defined as a YMRS total score ≥ 16 at post-Baseline visit 
(scheduled or unscheduled), or an adverse event of hypomania or mania  
  • Changes from Baseline in movement disorders scales: AIMS, BARS, and modified SAS 
  • Frequency and severity of suicidal ideation and suicidal behavior using the C-SSRS 
• Change from Week 52/EOT (end of treatment) visit to the safety follow-up visit on the PWC 
3.2.3. 
EFFECTIVENESS ENDPOINTS 
  • Changes in MADRS total score  
  • Changes in CGI-BP-S depression score  
  • The proportion of subjects with treatment response, defined as ≥ 50% reduction from Baseline in 
MADRS total score  
  • The proportion of subjects meeting criteria for remission, defined as MADRS total score ≤ 12 
  • Changes in HAM-A total score  


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  • Changes in QIDS-SR16 total score  
  • Changes in SDS total and subscale scores (work/school, family, and social function)  
  • The proportion of subjects meeting criteria for functional remission, defined as having a score ≤ 2 on 
each of the SDS subscale scores (work/school, family, and social function) 
  • Changes in the EQ-5D-5L Visual Analog Scale (VAS) and Index scores  
  • Changes in the SHAPS total score  
3.2.4. 
PHARMACOKINETIC AND PHARMACODYNAMIC ENDPOINTS 
• Plasma concentrations of aramisulpride and esamisulpride  
• Plasma concentrations of prolactin 
4. STUDY DESIGN 
4.1. GENERAL DESCRIPTION 
SEP380-303 is a 12-month open-label safety extension study to evaluate the long-term safety, tolerability, 
and effectiveness of SEP-4199 CR 200-400 mg/day in the treatment of subjects with bipolar I depression 
who previously completed a lead-in study of SEP-4199 CR. 
The study will consist of a 12-month open-label flexible-dose treatment period, and a safety follow-up 
period, as shown in the following figure. There are 15 scheduled visits, including a Baseline visit, 13 
visits during the open-label treatment period, and 1 safety follow-up visit 7 (± 2) days after the last dose 
of study drug. If necessary, subjects may return to the clinic at any time for an unscheduled visit (see 
Figure 1). 
Subjects who meet the entry criteria will transition immediately at the End of Treatment (EOT) visit from 
Study SEP380-301. The EOT visit from studies SEP380-301 will generally serve as the Baseline visit 
for the present study. Informed consent will be obtained from all subjects before any study procedures 
are performed for the present study. 
A study schematic is presented in Figure 1. 
 
 


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Figure 1: Study schematic – All Subjects 
 
 
Note: All subjects are to take SEP-4199 CR 200 mg beginning on Day 1, the day following Baseline (Visit 1E). There 
is an extra visit for Japan (Visit1EJ) on Day 1 (evaluates ECG). 
Abbreviations: BL = Baseline; CR = controlled release; EOT = end of treatment. V = visit; E = extension; W = Week; 
M = Month 
 
4.2. METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS 
There is an open-label study and no randomization planned in this study. All subjects will receive 
flexible dosing with SEP-4199 CR 200 mg/day or 400 mg/day during the 52 weeks of treatment. 
4.3. BLINDING 
This is an open-label study. All subjects will receive flexible dosing with SEP-4199 CR 200 mg/day or 
400 mg/day. 
4.4. DETERMINATION OF SAMPLE SIZE 
All subjects who complete the 6-week double-blind treatment period in Study SEP380-301 are eligible 
to enrol in the current study. Assuming a completion rate of 85% in the SEP-4199 CR Study SEP380-
301 and 80% rollover rate of completers from that study to the current extension study, it is estimated 
that approximately 355 subjects will be enrolled in this study. Due to early termination of the Study 
SEP380-301, there are 64 subjects were enrolled in this study. 


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4.5. CHANGES IN THE CONDUCT OF THE STUDY 
The first subject was enrolled on ddmmm2022 under protocol Version 1.00 (dated 20MAY2021). 
Additional protocol versions and amendments are listed below. 
• 
Protocol version 2.00 (7SEP2021); Amendment 1.00 (7SEP2021). 
4.6. SCHEDULE OF EVENTS 
Schedule of events can be found in Section 1, Table 2 of the Clinical Study Protocol (CSP). This table 
is also included in APPENDIX 7 of the SAP. 
4.7. CHANGES TO ANALYSIS FROM PROTOCOL 
Because of the small sample size due to study early termination, the following main changes will be made for this 
study: 
1. Only 2 treatment groups will be formed based on a subject’s previous participation in the lead-in study of 
SEP-4199 CR (SEP-SEP: previously randomized to any SEP-4199 CR dose group and PBO-SEP: 
previously randomized to placebo).  
2. No subgroup summaries will be performed. 
3. No summaries using Follow-up population will be performed. 
4. Except for PWC, follow-up period summaries will not be performed, PWC will be summarized by Safety 
population. 
5. AE will not be summarized by high-level term (HLT). 
6. No Kaplan-Meier curves will be plotted for time to discontinuation and time to the earliest onsets of the 
selected AESI. The Kaplan-Meier estimation will also not be performed. 
7. To be consistent with AIMS and BARS, MSAS will be summarized by total score. 
5. PLANNED ANALYSES 
The following analyses will be performed for this study: 
• 
Analyses for independent DSMB meetings 
• 
Final Analysis  
5.1. DATA AND SAFETY MONITORING BOARD  
A DSMB SAP and charter, describing the methodology, meeting schedule, and presentation of results 
as well as access to results will be maintained by another Contract Research Organization (CRO) and 
SMPA as separate documents. All DSMB analyses will be performed independently by the CRO 
approximately three times a year. 
5.2. INTERIM ANALYSIS 
There is no interim analysis of efficacy data planned for this study. 


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5.3. FINAL ANALYSIS 
All final, planned analyses specified in this SAP will be performed inhouse by SMPA following this SAP, 
after database lock.  
Some minor modifications may be necessary to the planned design of tables, figures, and listings to 
accommodate data collected during the actual study conduct.  
6. ANALYSIS POPULATIONS 
Agreement and authorization of enrolled subjects included/excluded from the analysis population listed 
below will be conducted prior to database lock.  
Enrolled subjects in SEP380-303 will include all subjects who signed the informed consent form (ICF) of 
study 380-303. 
6.1. SAFETY POPULATION 
The Safety Population will consist of all subjects who are enrolled and have received at least one dose 
of study drug during the 52-week open-label extension treatment period. The Safety Population will be 
used for the long-term safety, tolerability, and efficacy analyses. Subjects will be analyzed according to 
the following 3 treatment groups: 
• 
PBO-SEP: Subjects whose actual treatment group is Placebo in study SEP380-301 and received 
SEP-4199 CR in study SEP380-303. 
• 
SEP-SEP: Subjects whose actual treatment group is either SEP-4199 CR 200 mg/day or SEP-4199 CR 
400 mg/day in study SEP380-301 and received SEP-4199 CR in study SEP380-303. 
• 
ALL EXT: all subjects received SEP-4199 CR in study SEP380-303.  
7. GENERAL 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 OLE study medication of study 
SEP380-303 (Day 1 is the Study Day of the first dose of OLE study medication of study SEP380-303).  
• 
If the date of assessment or event is prior to the reference start date, then:  
Study Day = (date of assessment or event - reference start date). 
• 
If the date of assessment or event is on or after the reference start date, then:  
Study Day = (date of assessment or event - reference start date) + 1. 
In the situation where the assessment or event date is partial or missing, Study Day and any 


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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, double-blind (DB) Baseline is defined as the last non-missing measurement 
taken prior to the first dose of study medication of study SEP380-301, including unscheduled 
assessments. DB Baseline values are essentially the “Baseline” values of study SEP380-301 and will 
be directly obtained from the SEP380-301 ADaM datasets. 
Open-label (OL) Baseline is defined as the last non-missing measurement taken prior to the first dose 
of OLE study medication of study SEP380-303, including unscheduled assessments. These values will 
be derived in SEP380-303 ADaM datasets using data collected in studies SEP380-301 and SEP380-
303. 
Whenever available, the time information should be accounted for in the derivation of OL 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 OLE study medication coincide, that measurement will be considered the 
OL Baseline. 
7.3. DERIVED TIMEPOINTS 
The last non-missing post-OL Baseline (i.e., post first OLE dose) measurement collected up to and 
including the Visit 14E (EOT/ET) measurement and within 7 days post the last OLE dose will be carried 
forward and defined as the last observation carried forward (LOCF) endpoint. Both scheduled and 
unscheduled assessments as well as the early termination assessments that are collected during this 
period will contribute to the derivation of the LOCF endpoint. However, scheduled and unscheduled 
measurements taken after the Visit 14E (EOT/ET) measurement or beyond 7 days post the last OLE 
dose will not be used in the derivation.  
The study visits will be mapped to analysis visits for table summaries (Table 1). 
Table 1: Mapping of study visits to analysis visits. 
Study Visit 
Analysis Visit Number 
Analysis Visit 
NA* 
0 
DB Baseline 
Visit 1E 
1 
OL Baseline 
Visit 1EJ# 
1.1 
OL Day 1 
Visit 2E 
2 
OL Week 2 
Visit 3E 
3 
OL Month 1 
Visit 4E 
4 
OL Month 2 
Visit 5E 
5 
OL Month 3 
Visit 6E 
6 
OL Month 4 
Visit 7E 
7 
OL Month 5 
Visit 8E 
8 
OL Month 6 
Visit 9E 
9 
OL Month 7 


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Visit 10E 
10 
OL Month 8 
Visit 11E 
11 
OL Month 9 
Visit 12E 
12 
OL Month 10 
Visit 13E 
13 
OL Month 11 
Visit 14E (if representing true 
EOT visit). For ET visit 
mapping see Section 7.4 
14 
OL Month 12 
Visit 15E 
15 
Follow-up  
* Several assessments from that visit are collected in SEP380-301 study. #An extra visit for Japan (Visit 
1EJ) on Day 1 that evaluates ECG. 
Original study visit collected on the case report forms (CRFs) will be displayed in the listings. 
7.4. RETESTS, UNSCHEDULED VISITS, AND EARLY TERMINATION DATA 
In general, for by-visit summaries, data recorded at the planned visits where assessment is intended to 
be given and collected within 7 days post the last OLE dose will be presented, as well as the derived 
DB and OL Baseline values and the LOCF value. 
Unscheduled measurements will not be included in by-visit summaries as a separate time point. 
However: 
• 
Unscheduled measurements collected prior to the first dose of study medication in SEP380-301 
contributed to the derivation of the DB Baseline value.  
• 
Unscheduled measurements collected in SEP380-301 or SEP380-303 prior to the first dose of OLE 
study medication in SEP380-303 will contribute to the derivation of the OL Baseline value. 
• 
Unscheduled measurements collected post-OL Baseline up to and including 7 days post the last OLE 
dose in SEP380-303 will contribute to the derivation of the LOCF value, the potential clinically 
significant (PCS) value, and the best/worst case value where required (e.g., shift table).  
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. 
As per protocol, study Visit 14E can be a Week 52/End of Treatment (EOT) visit or an Early 
Termination (ET) visit. If a subject terminates early, his/her measurements taken at the ET visit and 
within 7 days post the last OLE dose will be mapped to the next planned visit (after the last scheduled 
visit the subject attended) during which that assessment was expected to be performed as specified by 
the Schedule of Assessments table in the protocol. This applies to both efficacy and safety data. ET 
measurements taken beyond 7 days post the last OLE dose will not be mapped. 
Listings will include scheduled, unscheduled, retest, and early discontinuation data without regard to the 
7-day window, with original dates and visits displayed. 
7.5. WINDOWING CONVENTIONS  
No visit windowing will be performed during the analysis for this study. Data will be analyzed according 


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to the schedule outlined in the CSP. However, with the exception of SAE and PWC, any data collected 
beyond 7 days post the last OLE dose will be excluded from the efficacy and safety analyses unless 
otherwise specified; these data will be presented in data listings only. 
7.6. STATISTICAL TESTS 
No statistical inference will be made for this open-label extension study. 
7.7. COMMON CALCULATIONS 
Below derivation will be applied separately for both DB Baseline and OL Baseline as appropriate. 
For quantitative measurements, change from Baseline will be calculated as: 
• 
Assessment Value at Visit X - Baseline Value 
For quantitative measurements, percentage change from Baseline will be calculated as: 
• 
(Test Value at Visit X - Baseline Value) × 100 / Baseline Value 
7.8. SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.4 or higher.  
8. STATISTICAL CONSIDERATIONS 
8.1. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED IN 
ANALYSES 
No statistical comparison will be conducted, so no adjustments for covariates and factors are to be 
considered. 
8.2. MULTICENTER STUDIES 
This study will be conducted by multiple investigators at multiple centers in the US and non-US 
countries, including Bulgaria, Romania, and Japan. 
Center pooling will not be implemented in the analyses for this open-label extension study. 
8.3. MISSING DATA 
Individual missing items in any rating scale will not be imputed in any analysis. When calculating a total 
score, subscale score, or any summary scores based on more than one item, if one or more items are 
missing at a visit, then the associated summary score will be set to missing. For additional details, see 
the individual scale description sections. 


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• 
Handling of missing efficacy data, if any, is described in Section 17.2. 
• 
Handling of missing safety data, if any, is described in Sections 18.1.1 and 18.6. 
• 
See APPENDIX 2 for details of handling incomplete/missing dates. 
8.4. MULTIPLE COMPARISONS/ MULTIPLICITY 
No statistical comparison will be conducted, so no multiplicity adjustment will be performed. 
8.5. EXAMINATION OF SUBGROUPS 
Because the small sample size, no subgroup analysis will be conducted for this study. 
9. 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 separately. 
10. DISPOSITION AND WITHDRAWALS 
Unless otherwise specified, the disposition summary tables will include the following columns: 
PBO-SEP, SEP-SEP, and ALL EXT (all rollovers from SEP380-301). 
All subjects who were enrolled in study SEP380-303 will be accounted for in this study. 
Subject disposition will be presented by the actual treatment group. The number and percentage of 
subjects who enrolled in study SEP380-303, received at least one dose of OLE study medication, 
enrolled but did not receive OLE study medication, and completed or discontinued from the OLE 
treatment period (including reasons for discontinuation) will be presented. 
Discontinuation by visit will be summarized for the enrolled subjects by the actual treatment group.  
The number and percentage of enrolled subjects will also be summarized by region, country, and site, 
by the actual treatment group. 
11. IMPORTANT PROTOCOL DEVIATIONS 
Important protocol deviations (IPDs) will be identified and documented for all subjects based on reviews 
of data listings and the protocol deviations log; the data will be presented separately.  
Unless otherwise specified, the IPD summary tables will include the following columns: PBO-SEP, 
SEP-SEP (S200-SEP and S400-SEP combined), and ALL EXT (all rollovers from SEP380-301). 
The IPD categories may include, but may not be limited to: 
• 
Did not satisfy inclusion and/or exclusion criteria for study SEP380-303. 
• 
Received prohibited medication in study SEP380-303. 


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IPDs will be identified for all subjects enrolled in study SEP380-303 and presented in a data listing. The 
number and percentage of subjects within each IPD category will be summarized by the actual 
treatment for the Safety Population. 
12. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Unless otherwise specified, the demographic and Baseline characteristics summary table will include 
the following columns: PBO-SEP, SEP-SEP, and ALL EXT (all rollovers from SEP380-301). 
Demographic data and other Baseline characteristics will be presented for the Safety Population by the 
actual treatment group. 
The following demographic and other Baseline characteristics will be reported for this study. According 
to protocol, year of birth, age, and sex collected in the core studies are re-entered into the eCRF of 
SEP380-303. For statistical analysis, date of birth, age, sex, race, and ethnicity will be retrieved from 
the ADaM datasets of studies SEP380-301. Unless otherwise specified, the categories below apply to 
all subjects: 
• 
Age (years) - calculated relative to date of informed consent in SEP380-301, as a continuous variable  
• 
Age (years) categories: 
o 
< 55 years 
o 
≥ 55 
• 
Sex: 
o 
Female 
o 
Male  
• 
Race:  
o 
American Indian or Alaska Native  
o 
Asian  
o 
Black or African American  
o 
Native Hawaiian or Other Pacific Islander  
o 
White  
o 
Other 
• 
Ethnicity: 
o 
Hispanic or Latino 
o 
Not Hispanic or Latino 
• 
Country: 
o 
United States 
o 
Bulgaria 
o 
Japan 
o 
Romania 
• 
Geographic region: 
o 
USA 
o 
Europe  
o 
Japan 


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• 
DB Baseline Height (cm), as a continuous variable 
• 
DB Baseline and OL Baseline Weight (kg), as a continuous variable  
• 
DB Baseline and OL Baseline BMI (kg/m²), as a continuous variable 
• 
DB Baseline and OL Baseline BMI (kg/m²) category: 
o 
Underweight: <18.5 kg/m² 
o 
Normal: ≥18.5 to <25.0 kg/m² 
o 
Overweight: ≥25.0 to <30.0 kg/m² 
o 
Obese: ≥30.0 kg/m² 
• 
DB Baseline and OL Baseline MADRS Total Score, as a continuous variable  
• 
DB Baseline and OL Baseline CGI-BP-S Score, as a continuous variable 
The following psychiatric history data will be summarized for Safety Population by the actual treatment 
in a separate table. All values were collected or derived in the SEP380-301 study: 
• 
Time since initial onset of bipolar I disorder (years) - calculated relative to date of informed consent 
in SEP380-301 
• 
Age at initial onset of bipolar I disorder (years)  
• 
Time since onset of current episode of major depression associated with bipolar I disorder 
symptoms (months) - calculated relative to date of informed consent in SEP380-301 
• 
Bipolar I diagnosis subtype: 
o 
Bipolar I disorder without rapid cycling 
o 
Bipolar I disorder with rapid cycling 
• 
Number of prior hospitalizations for treatment of bipolar I disorder: 
o 
0 
o 
1 
o 
2 
o 
3 
o 
4 or more 
• 
Any other current psychiatric disorders: 
o 
Yes 
o 
No 
Diagnosis and DSM-5 code for any other current psychiatric disorders will be summarized in a separate table for 
Safety Population. These other current psychiatric disorders will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) central coding dictionary, Version 22.0, and presented by System Organ Class 
(SOC) and Preferred Term (PT). 


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12.1. DERIVATIONS 
• 
BMI expressed in kg/m2:  
Weight (kg)/ [height (cm)/100]2 
All other derivations are detailed in SEP380-301 Statistical Analysis Plan, and all derivations are done 
in SEP380-301 ADaM datasets. 
13. MEDICAL HISTORY 
Unless otherwise specified, the medical and surgical history summary tables will include the following 
columns: PBO-SEP, SEP-SEP, and ALL EXT (all rollovers from SEP380-301). 
Medical and surgical history information, including both past and concomitant medical conditions and 
major surgical history, as collected on the “Medical History” CRF form of study SEP380-301, will be 
coded using MedDRA, Version 22.0, and presented by SOC and PT for the Safety Population by the 
actual treatment. Data will be sorted by SOC based on the internationally agreed order (see 
APPENDIX 4) and by PT in decreasing frequency in the “ALL EXT” column. 
14. PRIOR AND CONCOMITANT MEDICATIONS 
Unless otherwise specified, the concomitant medications summary tables will include the following 
columns: PBO-SEP, SEP-SEP, and ALL EXT (all rollovers from SEP380-301). 
Medications will be coded to Anatomical Therapeutic Chemical (ATC) Levels and Preferred Names 
according to World Health Organization Drug (WHODRUG) dictionary, Version SEP2021.  
Whenever available, the time information should be accounted for in the derivation of prior, 
concomitant, and post-treatment medications. See APPENDIX 2 for the handling of partial dates for 
medications.  
• 
Prior medications are medications which started prior to the first dose of OLE study medication. 
• 
Concomitant medications are medications which started at the same time of or after the first dose 
of OLE study medication and at the same time of or before the last dose of OLE study medication; 
or started prior to and ended at the same time of or after the first dose of OLE study medication; or 
started at the same time of or prior to the last dose of OLE study medication and marked as 
ongoing. 
• 
Post-treatment medications are medications which stopped after the last dose of OLE study 
medication or ongoing. 
Concomitant medication use will be summarized by ATC Level 3 and Preferred Name for the Safety 
Population by the actual treatment. If ATC Level 3 is missing, then ATC Level 2 will be used.  
Medications will be sorted by ATC Level 3 alphabetically and by Preferred Name in decreasing 
frequency in the “ALL EXT” column. 
Prior, concomitant, and post-treatment medications will be provided in data listings. 


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15. STUDY MEDICATION EXPOSURE 
Unless otherwise specified, the study medication exposure summary tables will include the following 
columns: PBO-SEP, SEP-SEP, and ALL EXT (all rollovers from SEP380-301). 
Exposure to OLE study medication data will be summarized for the Safety Population by the actual 
treatment group. 
The date/time of first dose of OLE study drug and the date/time of last dose of OLE study drug will be 
respectively derived as the earliest (“Date Dosing Started” & “Time Dosing Started”) pair and the latest 
(“Date Dosing Ended” & “Time Dosing Ended”) pair as collected on the “Study Drug Administration / 
Drug Accountability” CRF form. The start and end dates/times from blister cards with the number of 
tablets dispensed equal to the (number of tablets returned + number of tablets reported lost) are 
excluded from the derivation. 
Duration of exposure (in days) will be summarized both as a continuous variable for the OLE treatment 
period and categorically:  
• 
Number and percentage of subjects with OLE study drug exposure ≥ 1, ≥ 14, ≥ 30, ≥ 60, ≥ 90, ≥ 120, 
≥ 150, ≥ 180, ≥ 210, ≥ 240, ≥ 270, ≥ 300, ≥ 330, and ≥ 360 days; 
• 
Number and percentage of subjects with OLE study drug exposure for 1 - 13, 14 - 29, 30 - 59, 
60 - 89, 90 - 119, 120 - 149, 150 - 179, 180 – 209, 210 – 239, 240 – 269, 270 -299, 300 – 329, 
330 – 359, and ≥ 360 days. 
Total person-years of exposure to OLE study medication will be calculated for each actual treatment 
sequence and overall for all subjects in the Safety Population. 
Mean daily dose and modal daily dose will be calculated for the entire OLE treatment period and 
summarized. 
The number of days that a subject received the CR 200 mg/day dose level, and the CR 400 mg/day 
dose level during the OLE treatment period will be summarized for the Safety Population both as a 
continuous variable and categorically: 
• 
Number and percentage of subjects with exposure to a particular dose level for 1 - 13, 14 - 29, 
30 - 59, 60 - 89, 90 - 119, 120 - 149, 150 - 179, 180 - 209, 210 – 239, 240 – 269, 270 - 299, 300 – 329, 
330 – 359, and ≥ 360 days. 
Duration of exposure since SEP380-301 first dose (in days) will be summarized as a continuous 
variable for the Safety Population by the actual treatment group. 
15.1. DERIVATIONS 
Per protocol, Study drug will be provided in one-week blister cards (7 days + 2 extra days) containing 
9 or 18 tablets of SEP-4199 CR 200 mg tablets. The 200 mg blister cards will contain 9 tablets; 
subjects will be instructed to take a column of one tablet per day, according to dosing instructions. 
The 400 mg blister cards will contain 18 tablets; subjects will be instructed to take a column of two 
tablets each day, according to dosing instructions. Each subject will be dispensed two or four 9-day (7 
days + 2 extra days) blister cards per scheduled visit, depending on the timing of the next scheduled 
visit. 
• 
Duration of exposure (days) = date of last dose of OLE study drug – date of first dose of OLE study 
drug + 1. Interruptions in exposure (i.e., missed doses) and dose changes (if any) are not considered 
in the calculation of overall exposure. 


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• 
Duration of exposure since SEP380-301 first dose (days) = date of last dose of OLE study drug – date 
of first dose of study drug in SEP380-301 + 1. This calculation is only performed for the subjects 
whose actual treatment group is SEP-4199 CR 200, or 400 mg/day in SEP380-301. Interruptions in 
exposure (i.e., missed doses) and dose changes (if any) are not considered in this calculation. 
• 
The number of days that a subject received a specific dose level (the CR 200 mg/day or CR 400 
mg/day) of study medication during the OL treatment period is calculated as the cumulative days 
the subject is expected to take the specific dose level during the OL treatment period. 
• 
Total person-years of exposure is the sum of all durations of exposure in days / 365.25. 
• 
Mean daily dose (mg/day) 
∑Dose per tablet for Visit 𝑗𝑗× (# Tablets Dispensed for Visit 𝑗𝑗−# Tablets Returned for Visit 𝑗𝑗−# Tablets Lost for Visit 𝑗𝑗)
Duration of Exposure
 
If the number of tablets dispensed, returned, and/or lost as collected on the “Study Drug Administration 
/ Drug Accountability” CRF form is missing for one or more visits, the mean daily dose will be calculated 
based on visits with complete drug accountability data available. That is, the numerator of the formula 
above will only include visits with the number of tablets dispensed, returned, and lost available, and the 
denominator should be adjusted to exclude dosing periods covered by visits excluded from the 
calculation (i.e., Duration of Exposure – dosing periods [sum of (EXENDTC – EXSTDTC+1)] covered 
by visits with missing or incomplete accountability data). If the dose level of a visit is unknown, that visit 
should be excluded from the calculation as well in both the numerator and the denominator. 
• 
Modal daily dose will be determined as the daily dose that is taken for the most time (in terms of 
number of days) among all doses taken. If there are ties, the latest modal dose is used for summary. 
A subject’s modal daily dose may fall in one of the categories below: 
o 
CR 200 mg/day 
o 
CR 400 mg/day 
16. STUDY MEDICATION COMPLIANCE 
Unless otherwise specified, the study medication compliance tables will include the following columns: 
PBO-SEP, SEP-SEP, and ALL EXT (all rollovers from SEP380-301). 
Compliance to OLE study medication will be presented for the Safety Population, by the actual 
treatment group.  
Percent compliance will be calculated overall for the OLE treatment period. Non-compliance is defined 
as less than 75% or more than 125% non-missing compliance for the OLE treatment period. Subjects 
with missing compliance will not be classified as non-compliant. Compliance will be summarized both 
as a continuous variable and categorically (i.e., number and percentage of subjects with compliance 
< 75%, 75% - 125%, > 125%, and missing). 
16.1. DERIVATIONS 
• 
Overall Compliance (%) to study medication in percentage will be calculated as follows: 
∑(# Tablets Dispensed for Visit 𝑗𝑗−# Tablets Returned for Visit 𝑗𝑗−# Tablets Lost for Visit 𝑗𝑗)
# Tablets should be taken per day × Duration of Exposure
× 100% 


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If the number of tablets dispensed, returned, and/or lost as collected on the “Study Drug Administration / 
Drug Accountability” CRF form is missing for one or more visits, the overall compliance will be calculated 
based on visits with complete drug accountability data available. That is, the numerator of the formula 
above will only include visits with the number of tablets dispensed, returned, and lost available, and the 
denominator should be adjusted to exclude dosing periods covered by visits excluded from the calculation 
(i.e., change “Duration of Exposure” to be Duration of Exposure – dosing periods [sum of (EXENDTC – 
EXSTDTC+1)] covered by visits with missing or incomplete accountability data). In addition, among all the 
visits included in the overall compliance calculation of a subject, the first visit must have dosing start date 
(EXSTDTC) available and the last visit must have dosing end date (EXENDTC) available. 
17. EFFICACY OUTCOMES 
Unless otherwise specified, the efficacy summary tables will include the following columns: PBO-SEP, 
SEP-SEP, and ALL EXT (all rollovers from SEP380-301). 
All analyses of the efficacy variables will be based on the Safety Population by the actual treatment 
group. 
17.1. DERIVATION & ANALYSIS OF EFFICACY VARIABLES 
17.1.1. 
CHANGES FROM DB BASELINE AND FROM OL BASELINE IN MADRS TOTAL SCORE AT EACH 
SCHEDULED VISIT 
The MADRS (Montgomery-Asberg Depression Rating Scale) 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. Total score will be equal to the sum of the 10 items 
(range between 0 and 60). 
MADRS is assessed at Week 2 and monthly and at these study visits: from Visit 1E (coinciding with 
Visit 6 of SEP380-301) to Visit 14E. 
The DB Baseline and OL Baseline MADRS total score will be derived as described in Section 7.2. The 
change from DB Baseline and OL Baseline in MADRS total score will be derived as described in 
Section 17.1.1. 
The observed values of MADRS total score at both the DB Baseline and the OL Baseline, and at each 
scheduled OLE study visit (starting from Visit 1E) and LOCF, will be summarized descriptively.  
Changes from DB Baseline in MADRS total score will be summarized for each scheduled OLE study 
visit (starting from Visit 1E) and LOCF. Changes from OL Baseline will be summarized for each 
scheduled post-OL Baseline extension study visit (starting from Visit 2E) and LOCF. The line plots of 
the mean (SD) of change from DB baseline as well as change from OL baseline will be created. 
17.1.2. 
CHANGES FROM DB BASELINE AND FROM OL BASELINE IN CGI-BP-S SCORE AT EACH SCHEDULED 
VISIT 
The CGI-BP-S (Clinical Global Impression-Bipolar Version-Severity) 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-BP-S depression score takes one of the following values: 1 (normal, not at all 


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ill), 2 (borderline mentally ill), 3 (mildly ill), 4 (moderately ill), 5 (markedly ill), 6 (severely ill), 7 (among 
the most extremely ill patients). 
CGI-BP-S is assessed at week 2 and monthly and at these study visits: from Visit 1E (coinciding with 
Visit 6 of SEP380-301), to Visit 14E. 
The DB Baseline and OL Baseline CGI-BP-S depression score will be derived as described in 
Section 7.2. The change from DB Baseline and OL Baseline in CGI-BP-S depression score will be 
derived as described in Section 17.1.2. 
The observed values of CGI-BP-S depression score at both the DB Baseline and the OL Baseline, and 
at each scheduled OLE study visit (starting from Visit 1E) and LOCF, will be summarized descriptively.  
Changes from DB Baseline in CGI-BP-S depression score will be summarized for each scheduled OLE 
study visit (starting from Visit 1E) and LOCF. Changes from OL Baseline will be summarized for each 
scheduled post-OL Baseline extension study visit (starting from Visit 2E) and LOCF. The line plots of 
the mean (SD) of change from DB baseline as well as change from OL baseline will be created. 
17.1.3. 
MADRS RESPONSE AT EACH SCHEDULED VISIT 
MADRS response is defined as a 50% or greater improvement (i.e., decrease) in MADRS total score 
from DB Baseline.  
The percent change in MADRS total score from DB Baseline will be calculated by: 
MADRS total score at a visit or the LOCF endpoint - MADRS total score at DB Baseline
MADRS total score at DB Baseline 
× 100% 
For each subject, the responder indicator will be set to Y if the percent change is negative and the 
magnitude is equal to or greater than 50%. The indicator will be set to N if the percentage is negative 
but the magnitude is less than 50% or if the percentage is non-negative. The indicator will be set to 
missing if the percentage is missing. 
MADRS response will be derived for all scheduled OLE study visits and LOCF. 
The number and percentage of subjects who achieve a MADRS response will be summarized 
descriptively for each scheduled OLE study visit (starting from Visit 1E) and LOCF. 
17.1.4. 
MADRS REMISSION AT EACH SCHEDULED VISIT 
MADRS remission is defined as MADRS total score ≤ 12. 
For each subject, the remitter indicator will be set to Y if the MADRS total score is less than or equal to 
12. The indicator will be set to N if the MADRS total score is more than 12. The indicator will be set to 
missing if the MADRS total score is missing. 
MADRS remission will be derived for all scheduled OLE study visits and LOCF. 
The number and percentage of subjects who achieve a MADRS remission will be summarized 
descriptively for each scheduled OLE study visit (starting from Visit 1E) and LOCF. 
17.1.5. 
CHANGES FROM DB BASELINE AND FROM OL BASELINE IN HAM-A TOTAL SCORE AT EACH SCHEDULED 
VISIT 
The Hamilton Anxiety Rating Scale (HAM-A) is a clinician-administered scale that was developed to 
quantify the severity of anxiety symptomatology. It consists of 14 items, each defined by a series of 
symptoms. Each item is rated on a 5-point (0-4) scale, with higher scores indicating greater severity. 


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HAM-A total score will be equal to the sum of the 14 items and ranges between 0 and 56. 
HAM-A is assessed at these study visits: Visit 1E (coinciding with Visit 9 of SEP380-301), Visit 4E, 
Visit 6E, Visit 8E, Visit 10E, Visit 12E, and Visit 14E. 
The DB Baseline and OL Baseline HAM-A total score will be derived as described in Section 7.2. The 
change from DB Baseline and OL Baseline in HAM-A total score will be derived as described in 
Section 17.1.5. 
The observed values of HAM-A total score at both the DB Baseline and the OL Baseline, and at each 
scheduled OLE study visit (starting from Visit 1E) and LOCF, will be summarized descriptively. 
Changes from DB Baseline in HAM-A total score will be summarized for each scheduled OLE study 
visit (starting from Visit 1E) and LOCF. Changes from OL Baseline will be summarized for each 
scheduled post-OL Baseline extension study visit (starting from Visit 4E) and LOCF. 
17.1.6. 
CHANGES FROM DB BASELINE AND FROM OL BASELINE IN QIDS-SR16 TOTAL SCORE AT EACH 
SCHEDULED VISIT 
The Quick Inventory of Depressive Symptomatology – Self Report (QIDS-SR16) is a 16-item subject-
reported depression symptom severity questionnaire. Each item is rated 0 to 3. The scoring of the 
QIDS-SR16 converts responses to 16 separate items into the 9 DSM-IV symptom criterion domains. 
The 9 domains are: sad mood (Item 5), concentration (Item 10), self-criticism (Item 11), suicidal ideation 
(Item 12), interest (Item 13), energy/fatigue (Item 14), sleep disturbance (early/middle/late insomnia or 
hypersomnia) (Items 1 to 4), decrease/increase in appetite/weight (Items 6 to 9), and psychomotor 
agitation/retardation (Items 15 and 16). For symptom domains that consist of more than one item, the 
highest score among the items relevant to the given domain is taken. The total score will be equal to 
the sum of the 9 domains and ranges from 0-27 with higher scores indicating greater severity. 
QIDS-SR16 is assessed at these study visits: Visit 1E (coinciding with Visit 9 of SEP380-301), Visit 4E, 
Visit 6E, Visit 8E, Visit 10E, Visit 12E, and Visit 14E. 
The DB Baseline and OL Baseline QIDS-SR16 total score will be derived as described in Section 7.2. 
The change from DB Baseline and OL Baseline in QIDS-SR16 total score will be derived as described 
in Section 17.1.6. 
The observed values of QIDS-SR total score at both the DB Baseline and the OL Baseline, and at each 
scheduled OLE study visit (starting from Visit 1E) and LOCF, will be summarized descriptively.  
Changes from DB Baseline in QIDS-SR total score will be summarized for each scheduled OLE study 
visit (starting from Visit 1E) and LOCF. Changes from OL Baseline will be summarized for each 
scheduled post-OL Baseline extension study visit (starting from Visit 4E) and LOCF. 
17.1.7. 
CHANGES FROM DB BASELINE AND FROM OL BASELINE IN SDS TOTAL SCORE AND SUBSCALE SCORES 
AT EACH SCHEDULED VISIT 
The Sheehan Disability Scale (SDS) is a subject-reported assessment of function. The SDS is a 
composite of 3 items designed to measure the extent to which 3 major sectors in a patient’s life are 
impaired by depressive symptoms. This anchored visual analogue scale uses spatiovisual, numeric, 
and verbal descriptive anchors simultaneously to assess disability across 3 domains: work, social life or 
leisure activities, and home life or family responsibilities. The subject will rate his or her degree of 
impairment in each of these domains using an 11-point scale ranging from 0-10, with higher scores 
indicating more impairment. There are verbal descriptors for the points on the scale as well as 
numerical scores that provide more precise levels of the verbal descriptors. Scores for the 3 items are 
summed into a single dimensional measure of global functional impairment that ranges from 0 
(unimpaired) to 30 (highly impaired). 


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SDS is assessed at these study visits: Visit 1E (coinciding with Visit 9 of SEP380-301), Visit 4E, 
Visit 6E, Visit 8E, Visit 10E, Visit 12E, and Visit 14E. 
The DB Baseline and OL Baseline SDS total score will be derived as described in Section 7.2. The 
change from DB Baseline and OL Baseline in SDS total score will be derived as described in 
Section 17.1.7. 
The observed values of SDS total score at both the DB Baseline and the OL Baseline, and at each 
scheduled OLE study visit (starting from Visit 1E) and LOCF, will be summarized descriptively.  
Changes from DB Baseline in SDS total score will be summarized for each scheduled OLE study visit 
(starting from Visit 1E) and LOCF. Changes from OL Baseline will be summarized for each scheduled 
post-OL Baseline extension study visit (starting from Visit 4E) and LOCF. 
17.1.8. 
CHANGES FROM DB BASELINE AND FROM OL BASELINE IN EQ-5D-5L VAS AND INDEX SCORES AT 
EACH SCHEDULED VISIT 
The EuroQol-5 Dimensions – 5 Levels (EQ-5D-5L) is a standardized instrument developed by the 
EuroQol Group as a measure of health-related quality of life that can be used in a wide range of health 
conditions and treatments. The EQ-5D-5L consists of two parts: a) the EQ-5D-5L descriptive system, 
and b) the EQ VAS. 
The EQ-5D-5L descriptive system comprises five dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 5 levels: level 1 (no problems), level 2 
(slight problems), level 3 (moderate problems), level 4 (severe problems), and level 5 (extreme 
problems/unable to do). The patient is asked to indicate his/her health state by ticking the box next to 
the most appropriate statement in each of the five dimensions. This decision results in a 1-digit number 
that expresses the level selected for that dimension (i.e., the index score). 
The index scores for the five dimensions can be combined into a 5-digit code that describes the 
patient’s health state. An index value (a weighted scoring of the 5 dimension scores with a possible 
range from less than 0 [where 0 is the value of a health state equivalent to dead; negative values 
representing values as worse than dead] to 1 [the value of full health]) will be assigned to each 
observed health state using the US standard value set as defined in APPENDIX 3. 
The EQ VAS records the patient’s self-rated health on a vertical visual analogue scale from 0 to 100, 
where the endpoints are labelled ‘The best health you can imagine’ and ‘The worst health you can 
imagine’. The VAS can be used as a quantitative measure of health outcome that reflect the patient’s 
own judgment. 
EQ-5D-5L is assessed at these study visits: Visit 1E (coinciding with Visit 9 of SEP380-301), Visit 4E, 
Visit 6E, Visit 8E, Visit 10E, Visit 12E, and Visit 14E. 
The DB Baseline and OL Baseline EQ-5D-5L VAS and Index scores will be derived as described in 
Section 7.2. The change from DB Baseline and OL Baseline in EQ-5D-5L VAS and Index scores will be 
derived as described in Section 17.1.8. 
The observed values of EQ-5D-5L VAS and Index scores at both the DB Baseline and the OL Baseline, 
and at each scheduled OLE study visit (starting from Visit 1E) and LOCF, will be summarized 
descriptively. 
Changes from DB Baseline in EQ-5D-5L VAS and Index scores will be summarized for each scheduled 
OLE study visit (starting from Visit 1E) and LOCF. Changes from OL Baseline will be summarized for 
each scheduled post-OL Baseline extension study visit (starting from Visit 4E) and LOCF. 


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17.1.9. 
CHANGES FROM DB BASELINE AND FROM OL BASELINE IN SHAPS TOTAL SCORE AT EACH SCHEDULED 
VISIT 
The Snaith-Hamilton Pleasure Scale (SHAPS) is a subject-reported questionnaire having a 14-item 
scale that assesses 4 domains of hedonic experience: interest/pastimes, social interaction, sensory 
experience, and food/drink. Each of the items has a set of four response categories: strongly disagree, 
disagree, agree, or strongly agree, with either of the Disagree responses receiving a score of 1 and 
either of the Agree responses receiving a score of 0. Thus, the SHAPS total score is scored as the sum 
of the 14 items and ranges from 0 to 14. A higher SHAPS total score indicated higher levels of present 
state of anhedonia. 
SHAPS is assessed at these study visits: Visit 1E (coinciding with Visit 9 of SEP380-301), Visit 4E, 
Visit 6E, Visit 8E, Visit 10E, Visit 12E, and Visit 14E. 
The DB Baseline and OL Baseline SHAPS total score will be derived as described in Section 7.2. The 
change from DB Baseline and OL Baseline in SHAPS total score will be derived as described in 
Section 17.1.9. 
The observed values of SHAPS total score at both the DB Baseline and the OL Baseline, and at each 
scheduled OLE study visit (starting from Visit 1E) and LOCF, will be summarized descriptively.  
Changes from DB Baseline in SHAPS total score will be summarized for each scheduled OLE study 
visit (starting from Visit 1E) and LOCF. Changes from OL Baseline will be summarized for each 
scheduled post-OL Baseline extension study visit (starting from Visit 4E) and LOCF. 
17.2. MISSING DATA 
Any individual missing item in any scale will not be imputed. 
For derived scores that depend on more than one individual item (e.g., MADRS total score, EQ-5D-5L 
index score), if one or more items are missing at a visit, the derived score will be set to missing. The 
corresponding change from DB Baseline or OL Baseline value at a given time point will be set to 
missing if the DB Baseline or OL Baseline derived score is missing or if the derived score at that time 
point is missing. 
For MADRS response compared to DB Baseline, any subject with a missing MADRS total score at DB 
Baseline or at any scheduled OLE study visit (starting from Visit 1E) or LOCF will have their MADRS 
response set to missing for that time point. 
18. SAFETY OUTCOMES 
Unless otherwise specified, the safety summary tables will include the following columns: PBO-SEP, 
SEP-SEP, and ALL EXT (all rollovers from SEP380-301). 
All analyses of the safety outcomes will be based on the Safety Population, by the actual treatment 
groups.  
18.1. ADVERSE EVENTS 
Adverse Events (AEs) and pre-treatment events will be coded using MedDRA central coding dictionary, 
Version 22.0. 
The concept of “pre-treatment events” only applies to study SEP380-301. Pre-treatment events are 
untoward medical occurrences that started prior to the first dose of study medication in SEP380-301. 


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Adverse events of study SEP380-301 are untoward medical occurrences that started at the same time 
of or after the first dose of study medication in SEP380-301, but before the first dose of OLE study 
medication in SEP380-303. These events will be recorded in the SEP380-301 databases. 
Adverse events (AEs) of the SEP380-303 extension study are untoward medical occurrences that 
started at the same time of or after the first dose of the OLE study drug. These events will be recorded 
in the SEP380-303 database.  
AEs (and pre-treatment events) that started in study SEP380-301 and are ongoing at the time of 
subject rollover will be re-entered into the SEP380-303 database and continue to be followed. These 
events will not be included in any AE summary table of SEP380-303. They will only be listed in a 
separate data listing. 
Whenever available, the time information should be accounted for to determine if a record in the 
SEP380-303 AE database belongs to study SEP380-301 or SEP380-303. In the case where time is not 
available, untoward medical occurrences that started prior to the day of the first OLE dose will be 
considered to belong to study SEP380-301; those that started after the day of the first OLE dose will be 
considered to belong to study SEP380-303. Events that started on the same day of the first OLE dose 
will be assigned to study SEP380-301 or SEP380-303 depending on whether this AE record also exists 
in the SEP380-301 database (based on a comparison of subject ID, verbatim term, AE start date (and 
time if available), severity, and seriousness. 
See APPENDIX 2 for handling of partial dates for AEs. 
Overall summary of the incidence of all AEs, study medication-related AEs, severe AEs, serious AEs, 
AEs leading to discontinuation from study, AEs leading to death, and AEs of special interest (AESI) will 
be provided by the actual treatment groups.  
Listings will be provided for all AEs, study medication-related AEs, severe AEs, serious AEs, AEs 
leading to discontinuation from the study, AEs leading to death, and AEs of special interest (AESI). A 
listing of SEP380-301 events (pre-treatment events and AEs) present in the SEP380-303 database will 
also be presented. When complete event start date and complete event end date are available, 
duration of AEs from SEP380-301/303 and pre-treatment events from SEP380-301 will be calculated 
as: event end date – event start date + 1. Duration will be presented in data listings. 
For all summaries, each subject will be counted only once within each category (e.g., an AE type, a 
severity level, a relationship category, a SOC, and a PT). If not otherwise specified, all summaries will 
present the number and percentage of subjects as well as the number of events. For summaries by 
SOC and PT, AEs will be sorted by SOC based on the internationally agreed order (see APPENDIX 4) 
and then by PT in decreasing frequency in the “ALL EXT” column. For summaries by SOC, and PT, 
AEs will be sorted by SOC based on the internationally agreed order and then by PT in decreasing 
frequency in the “ALL EXT” column.  
18.1.1. 
ALL AES  
All AEs will be summarized by PT, as well as by SOC and PT.  
In addition, summary tables (by SOC and PT) will be generated for those AEs starting after the last 
dose of OLE study drug and those AEs starting more than 1 day after the last dose of OLE study drug. 
The summary by SOC and PT will be broken down further by maximum severity and by strongest 
relationship to study medication. These summaries are described in the sections below. 
18.1.1.1. 
Severity 
Severity is classed as mild/ moderate/ severe (increasing severity). AEs with a missing severity will be 
classified as severe. 
If a subject reported an AE more than once within the same SOC/ PT with different severity levels, the 


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subject will be assigned to a severity level for that SOC/ PT based on the worst case severity (i.e., 
maximum severity). Event counts will not be included in this summary. 
In a separate table, severe AEs will be summarized by SOC and PT. 
18.1.1.2. 
Relationship to study medication 
Relationship to study medication, as indicated by the Investigator, is classed as “not related”/ “possible”/ 
“probable”/ “definite” (increasing strength of relationship). A “related” AE is defined as an AE with a 
relationship to study medication as “possible”, “probable” or “definite”. AEs with a missing relationship to 
study medication will be regarded as related to the study medication. For this summary, AEs will be 
presented in 2 categories, related and not related. 
If a subject reported an AE more than once within the same SOC/ PT in different relationship 
categories, the subject will be assigned to a category for that SOC/ PT based on the worst case 
relationship (i.e., strongest relationship). Event counts will not be included in this summary. 
18.1.2. 
AES LEADING TO DISCONTINUATION FROM STUDY 
AEs leading to discontinuation from the study are those AEs with “Caused Study Discontinuation” = 
“Yes” on the “Adverse Events” CRF form for subjects with reason for discontinuation as AE on the 
Study Disposition CRF page or AE action taken = ”Drug Withdrawn”. 
AEs leading to discontinuation from the study will be summarized by SOC and PT. A listing of AEs 
leading to discontinuation from the study treatment period will be presented. 
 
18.1.3. 
SERIOUS ADVERSE EVENTS (INCLUDING ADVERSE EVENTS LEADING TO DEATH) 
SAEs are those AEs recorded as ”Serious” on the “Adverse Events” CRF form. AEs leading to death 
are those AEs with “Outcome” = ”Fatal” on the “Adverse Events” CRF form. 
SAEs (including AEs leading to death) will be summarized by SOC and PT. A listing of SAEs (including 
deaths) will be presented. 
18.1.4. 
ADVERSE EVENTS OF SPECIAL INTEREST (AESI)  
A list of preferred terms that are to be combined for assessment of adverse events of special interest 
(AESI), eg, hyperprolactinemia-related AEs, details of definition are provided in Appendix 5. 
AEs potentially associated with the study medication SEP-4199 CR:  
• Extrapyramidal symptoms (EPS): SMQ Extrapyramidal symptoms and 4 sub-classes (broad),  
• QT prolongation: SMQ Torsade de Pointes/QT prolongation (narrow, broad), 
AESI will be summarized by AESI category and preferred term for overall subjects. 
18.2. LABORATORY EVALUATIONS 
Results from the central laboratory to be reported for this study include Hematology, Chemistry 
(including lipid panel and thyroid panel), Urinalysis, Urine drug screening, Serum pregnancy (β-HcG) (in 


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female subjects only), and Urine pregnancy (in female subjects only). 
Serum and urine pregnancy results in female subjects and any unexpected lab parameters not 
specified in protocol Section 21 (APPENDIX II. CLINICAL LABORATORY TESTS) will only be listed. 
Laboratory parameters prespecified in protocol Section 21 under the categories of “HEMATOLOGY”, 
“BLOOD CHEMISTRIES” (plus HOMA-IR), “URINALYSIS”, and “URINE DRUG SCREENING will be 
summarized in tables as well as presented in listings. 
Listing presentations will use both standard international (SI) Units and conventional units. Table 
summaries will also be provided using both SI units and conventional 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 they will be presented as recorded, i.e., as “< X” or “> X” in the listings.  
The following summaries will be provided: 
• 
For quantitative measurements in hematology, chemistry, and urinalysis: By-visit summary of 
observed values at DB Baseline, OL Baseline, each scheduled OLE study visit (starting from Visit 2E), 
and LOCF; by-visit summary of change from DB Baseline at each scheduled OLE study visit (starting 
from Visit 1E) and LOCF; by-visit summary of change from OL Baseline at each scheduled post-OL 
Baseline extension study visit (starting from Visit 2E) and LOCF.  
Serum prolactin results will be summarized overall and separately by sex. Glucose, insulin, HOMA-IR, and 
lipid panel results (total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides) will be summarized 
by fasting status: fasting only and overall (fasting, non-fasting, or fasting status unknown combined).  
Change from DB Baseline for glucose, insulin, HOMA-IR, and lipid panel results will only be calculated if the 
fasting status at a given OLE study visit is matching the fasting status at DB Baseline. Change from OL 
Baseline will only be calculated if the fasting status at a given post-OL Baseline extension study visit is 
matching the fasting status at OL Baseline.  
• 
For qualitative measurements in urinalysis (as applicable) and for urine drug screening results: By-
visit summary of the number and percentage of subjects in each outcome category at DB Baseline, 
OL Baseline, each scheduled OLE study visit (starting from Visit 2E), and LOCF. Urine drug screening 
results will be reported as “Positive”/ “Negative”. 
• 
Shift in laboratory results (chemistry, hematology, urinalysis) from DB Baseline to each scheduled 
OLE study visit (starting from Visit 1E) and LOCF, and shift from OL Baseline to each scheduled post-
OL Baseline extension study visit (starting from Visit 2E) and LOCF, according to the reference range 
criteria.  
The existing reference range indicators provided by the central laboratory will be mapped as needed to 
categories of “Normal” (within the reference range) / “Abnormal” (outside the reference range) for 
urinalysis non-pH results, and to categories of “Low” (below the reference range) / “Normal” (within the 
reference range) / “High” (above the reference range) for chemistry and hematology results as well as 
urinalysis pH results. 
• 
Number and percentage of subjects with at least one potentially clinically significant (PCS) 
laboratory value (see APPENDIX 6) post-OL Baseline. The period of evaluation includes both the OLE 
treatment period and the OLE follow-up period up to and including 7 days post the last OLE dose, 
including unscheduled visits. Subjects will be counted in a particular PCS category if they met that 
PCS criteria at least once during the period of evaluation, regardless of their DB or OL Baseline 
value.  


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All laboratory data will be provided in data listings, with the values outside the reference ranges flagged. 
In addition, separate listings will be provided to present the laboratory data that met the PCS criteria. 
18.2.1. 
LABORATORY SPECIFIC DERIVATIONS 
• 
Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) will be calculated for each visit: 
HOMA IR = Glucose (mg/dL) × Insulin (mU/L) / 405 
The following conversion factors will be used if needed:  
Glucose (mg/dL) = Glucose (mmol/L) × 18.015588; 
Insulin (mU/L) = Insulin (pmol/L) × (1/6). 
18.2.2. 
LABORATORY REFERENCE RANGES 
Laboratory reference range indicators will be provided by the laboratory vendor and 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 laboratory parameters with categorical outcomes 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”. 
18.3. ECG EVALUATIONS 
Data from the centrally over-read ECG (Electrocardiogram) results will be included in the reporting of 
this study.  
The following ECG parameters will be reported for this study: 
• 
PR Interval (msec) 
• 
RR Interval (msec) 
• 
QRS Duration (msec) 
• 
QRS Axis (deg) 
• 
QT Interval (msec) 
• 
QTcF Interval (msec) (Fridericia’s Correction of QT interval) 
• 
QTcB Interval (msec) (Bazett’s Correction of QT interval) 


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• 
Heart Rate (bpm) 
• 
Overall assessment of ECG as determined by the central over-read: 
o 
Normal 
o 
Abnormal, Insignificant 
o 
Abnormal, Potentially Significant  
o 
Abnormal, Significant  
o 
Exclusion Alert (only given for the Screening visit of core study). In table summaries, the 
category of “Exclusion Alert” will be combined into the category of “Abnormal, Significant”. 
o 
Not Evaluable 
• 
ECG findings 
ECG findings will only be listed. Other ECG data will be summarized in tables as well as presented in 
listings. 
The following summaries will be provided: 
• 
For quantitative measurements: By-visit summary of observed values at DB Baseline, OL Baseline, 
each scheduled OLE study visit (starting from Visit 2E, Visit 1EJ for Japan subjects), and LOCF; by-
visit summary of change from DB Baseline at each scheduled OLE study visit (starting from Visit 1E) 
and LOCF; by-visit summary of change from OL Baseline at each scheduled post-OL Baseline 
extension study visit (starting from Visit 2E,  Visit 1EJ for Japan subjects) and LOCF. 
• 
For ECG overall assessment results as determined by the central over-read (“Normal”, “Abnormal, 
not Clinically Significant (NCS)”, “Abnormal, Clinically Significant (CS)”, “Not Evaluable”): By-visit 
summary of number and percentage of subjects in each category at DB Baseline, OL Baseline, each 
scheduled OLE study visit (starting from Visit 2E, Visit 1EJ for Japan subjects), and LOCF.  
• 
Shift in ECG overall assessment as determined by the central over-read from DB Baseline to each 
scheduled OLE study visit (starting from Visit 1E) and LOCF, and shift from OL Baseline to each post-
OL Baseline extension study visit (starting from Visit 2E, Visit 1EJ for Japan subjects) and LOCF. 
• 
Number and percentage of subjects who met each of the QTc interval prolongation criteria (see 
Section 18.3.1) considering both DB Baseline and OL Baseline. The period of evaluation includes 
both the OLE treatment period and the OLE follow-up period up to and including 7 days post the 
last OLE dose, including unscheduled visits. 
• 
Number and percentage of subjects with at least one PCS ECG value (see Table 3 in Section 18.3.1) 
post-OL Baseline. The period of evaluation includes both the OLE treatment period and the OLE 
follow-up period up to and including 7 days post the last OLE dose, including unscheduled visits. 
Subjects will be counted in a particular PCS category if they met that PCS criteria at least once 
during the period of evaluation, regardless of their OL or DB Baseline value.  
All ECG parameters, overall assessment as determined by the central over-read, and findings will be 
provided in a data listing. In addition, separate listings will be generated to present the QTc interval data 
of subjects who met at least one QTc prolongation criterion and the ECG data that met the PCS criteria. 
18.3.1. 
ECG POTENTIALLY CLINICALLY SIGNIFICANT CRITERIA 
QTc interval prolongation in adult subjects will be identified in accordance with the following predefined 
Potentially clinically significant criteria (same criteria apply to both QTcF and QTcB): 


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• 
> 450 msec for males \ > 470 msec for females at any post-OL Baseline time point (including 
unscheduled visits) not present at DB Baseline  
• 
> 450 msec for males \ > 470 msec for females at any post-OL Baseline time point (including 
unscheduled visits) not present at OL Baseline 
• 
> 480 msec at any post-OL Baseline time point (including unscheduled visits) not present at DB 
Baseline  
• 
> 480 msec at any post-OL Baseline time point (including unscheduled visits) not present at OL 
Baseline 
• 
> 500 msec at any post-OL Baseline time point (including unscheduled visits) not present at DB 
Baseline  
• 
> 500 msec at any post-OL Baseline time point (including unscheduled visits) not present at OL 
Baseline 
• 
≥ 30 msec increase from DB Baseline for at least one post-OL Baseline measurement (including 
unscheduled visits) and < 60 msec increase from DB Baseline for all post-OL Baseline measurements 
(including unscheduled visits) 
• 
≥ 30 msec increase from OL Baseline for at least one post-OL Baseline measurement (including 
unscheduled visits) and < 60 msec increase from OL Baseline for all post-OL Baseline measurements 
(including unscheduled visits) 
• 
≥ 60 msec increase from DB Baseline for at least one post-OL Baseline measurement (including 
unscheduled visits) 
• 
≥ 60 msec increase from OL Baseline for at least one post-OL Baseline measurement (including 
unscheduled visits) 
Except for the potentially clinically significant QTc criteria as described above, the PCS ECG 
measurements will be identified in accordance with the following predefined PCS criteria: 
Table 3: Predefined ECG PCS criteria. 
ECG Parameter 
PCS Low 
PCS High 
Heart Rate (beats/min) 
< 50 
> 100 
PR Interval (msec) 
-- 
> 210 
QRS Interval (msec) 
-- 
> 120 
18.4. VITAL SIGNS 
The following vital sign measurements will be reported for this study: 
• 
Supine and Standing Systolic Blood Pressure (mmHg) 
• 
Supine and Standing Diastolic Blood Pressure (mmHg) 


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• 
Supine and Standing Pulse Rate (bpm) 
• 
Respiratory Rate (breaths/min) 
• 
Temperature (⁰C) 
• 
Weight (kg) 
• 
BMI (kg/m2) 
• 
Waist Circumference (cm) 
Height will be summarized as part of the Baseline characteristics only. 
The following summaries will be provided: 
• 
By-visit summary of observed values at DB Baseline, OL Baseline, each scheduled OLE study visit 
(starting from Visit 2E), and LOCF; by-visit summary of change from DB Baseline at each scheduled 
OLE study visit (starting from Visit 1E) and LOCF; by-visit summary of change from OL Baseline at 
each scheduled post-OL Baseline extension study visit (starting from Visit 2E) and LOCF.  
• 
Number and percentage of subjects with at least one PCS vital sign value (see Section 18.4.2) post-
OL Baseline. The period of evaluation includes both the OLE treatment period and the OLE follow-
up period up to and including 7 days post the last OLE dose, including unscheduled visits. Subjects 
will be counted in a particular PCS category if they met that PCS criteria at least once during the 
period of evaluation, regardless of their DB Baseline or OL Baseline value. 
• 
Number and percentage of subjects with orthostatic hypotension and/or orthostatic tachycardia 
(see Section 18.4.1). The data will be summarized for DB Baseline, OL Baseline, overall post-OL 
Baseline extension period (which covers both the OLE treatment period and the OLE follow-up 
period up to and including 7 days post the last OLE dose, including unscheduled visits), each 
scheduled OLE study visit (starting from Visit 2E), and LOCF. 
• 
By-visit summary of BMI category (see Section 12) at DB Baseline, OL Baseline, each scheduled OLE 
study visit (starting from Visit 2E), and LOCF. 
All vital signs data will be provided in a data listing. In addition, a separate listing will be generated to 
present the vital signs data that met the PCS criteria. All occurrences of orthostatic hypotension and 
orthostatic tachycardia will also be presented in a listing. 
18.4.1. 
VITAL SIGNS SPECIFIC DERIVATIONS  
• 
BMI expressed in kg/m2 = Weight (kg)/ [height (cm)/100]2. 
The height collected at Visit 1 in SEP380-301 will be used to derive BMI where needed throughout the study. 
• 
Orthostatic hypotension is defined as a decrease of ≥ 20 mmHg in systolic blood pressure or ≥ 10 
mmHg in diastolic blood pressure after a subject has been standing for at least 2 to 4 minutes, 
compared to the systolic blood pressure and diastolic blood pressure measured in the supine 
position, respectively. 


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• 
Orthostatic tachycardia is defined as a heart rate increase of ≥ 20 bpm after a subject has been 
standing for at least 2 to 4 minutes compared to the heart rate measured in the supine position, 
and a heart rate of > 100 bpm after the subject has been standing for at least 2 to 4 minutes. 
18.4.2. 
VITAL SIGN POTENTIALLY CLINICALLY SIGNIFICANT CRITERIA 
Potentially clinically significant vital sign measurements will be identified in accordance with the 
following predefined PCS criteria, considering both DB Baseline and OL Baseline: 
Table 4: Predefined vital sign PCS criteria 
Vital Sign Parameter 
PCS Low 
PCS High 
Systolic Blood Pressure (Supine, 
Standing) (mmHg) 
Value ≤ 90 and ≥ 20 decrease 
from DB/OL Baseline 
Value ≥ 180 and ≥ 20 increase 
from DB/OL Baseline 
Diastolic Blood Pressure (Supine, 
Standing) (mmHg) 
Value ≤ 50 and ≥ 15 decrease 
from DB/OL Baseline 
Value ≥ 105 and ≥ 15 increase 
from DB/OL Baseline 
Pulse Rate (Supine, Standing) 
(beats/min) 
Value ≤ 50 and ≥ 15 decrease 
from DB/OL Baseline 
Value ≥ 120 and ≥ 15 increase 
from DB/OL Baseline 
Respiration Rate (breaths/min) 
Value ≤10 and ≥ 50% decrease 
from DB/OL Baseline 
Value ≥ 25 and ≥ 50% increase 
from DB/OL Baseline 
Weight (kg) 
≥ 7% decrease from DB/OL 
Baseline 
≥ 7% increase from DB/OL 
Baseline 
Temperature (°C) 
NA 
Value ≥ 38.3°C and ≥ 0.8°C 
increase from DB/OL Baseline 
18.5. PHYSICAL EXAMINATION 
As all physical and neurological findings will be recorded as AEs, no specific analysis of physical and 
neurological examination will be performed. 
18.6. OTHER SAFETY ASSESSMENTS 
18.6.1. 
COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS) 
The C-SSRS is a tool designed to systematically assess and track suicidal behavior and suicidal 
ideation throughout the study. The strength of this suicide classification system is in its ability to 
comprehensively identify suicidal events while limiting the over-identification of suicidal behavior. The 
C-SSRS Baseline/Screening Version is used at the screening visit of studies SEP380-301. The 
C-SSRS Since Last Visit Version is used from Visit 2 and onward in studies SEP380-301, and at all 
visits in extension study SEP380-303. 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 two main sections: Suicidal Ideation and Suicidal Behavior. 
The following outcomes are C-SSRS categories and have binary responses (yes/no). The categories 
are re-ordered from the scale to facilitate the definitions of the C-SSRS endpoints, and to provide clarity 


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in the presentation of the results. 
• 
Suicidal ideation is measured by 5 categories, representing 5 subtypes of suicidal ideation with 
increasing severity: 
o 
Category 1: Wish to be Dead 
o 
Category 2: Non-specific Active Suicidal Thoughts 
o 
Category 3: Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
o 
Category 4: Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
o 
Category 5: Active Suicidal Ideation with Specific Plan and Intent 
• 
Suicidal behavior is measured by 5 categories, representing 5 subtypes of suicidal behavior: 
o 
Category 6: Preparatory Acts or Behavior 
o 
Category 7: Aborted Attempt 
o 
Category 8: Interrupted Attempt 
o 
Category 9: Actual Attempt (non-fatal) 
o 
Category 10: Completed Suicide 
The 10 categories above are mutually exclusive. Subjects will be counted in the most severity category 
for which they have an event. 
Self-injurious behavior without suicidal intent is a non-suicide-related C-SSRS outcome, and also has a 
binary response (yes/no). 
For the purpose of C-SSRS analysis, “DB Baseline”, “OL Baseline”, and the overall “post-OL Baseline 
Extension” periods are defined as follows. 
Time point 
Study Visit 
C-SSRS Version 
Derivation 
Rule 
DB Baseline 
Visit 1 of study SEP380-
301  
Baseline/Screening – Past 1 
Month for Suicidal Ideation / 
Past 6 Months for Suicidal 
Behavior 
Most severe 
outcome 
Visit 2* of study SEP380-
301 
Since Last Visit 
OL Baseline 
Week 6/Visit 6** of study 
SEP380-301 
Since Last Visit 
As collected 
for that visit 
Post-OL 
Baseline 
Extension 
Period 
All post-OL Baseline 
extension study visits up to 
and including 7 days post 
the last OLE dose, 
including unscheduled 
visits 
Since Last Visit 
Most severe 
outcome 
* Note: The Visit 2 C-SSRS assessment must be administered prior to the first dose of SEP380-301 
study medication in order to be used in the C-SSRS DB Baseline derivation. 
**Note: The Visit 6 C-SSRS assessment must be administered prior to the first dose of SEP380-303 
extension study medication in order to be used as the C-SSRS OL Baseline. In the rare event where 
the Visit 6 assessment is administered after the first dose of SEP380-303 extension study medication, 
take the assessment from the previous visit as the OL Baseline. 
The following C-SSRS composite endpoints will be derived for each time point of interest (i.e., DB 
Baseline, OL Baseline, overall post-OL Baseline extension period, and each OLE study visit) as follows: 


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• 
Any suicidal ideation: A “yes” answer to any one of the 5 suicidal ideation questions on C-SSRS 
(Categories 1-5). 
• 
Any suicidal behavior: A “yes” answer to any one of the 5 suicidal behavior questions on the C-SSRS 
(Categories 6-10). 
• 
Any suicidality: A “yes” answer to any one of the 10 suicidal ideation and behavior questions on the 
C-SSRS (Categories 1-10). 
For each subject, the suicidal ideation score at each time point of interest (i.e., DB Baseline, OL 
Baseline, overall post-OL Baseline extension period, each OLE study visit, and LOCF) is defined as the 
maximum suicidal ideation category (1-5) present for the time point of interest. If no ideation is present 
a score of 0 is assigned. 
The number and percentage of subjects with any suicidality, any suicidal ideation and subtypes of 
ideation, any suicidal behavior and subtype of behavior, and any non-suicidal self-injurious behavior will 
be presented for: 
• 
DB Baseline (as defined above) 
• 
OL Baseline (as defined above) 
• 
Overall post-OL Baseline extension period (as defined above) 
• 
Each scheduled OLE study visit (starting from Visit 2E) 
Shift in suicidal ideation score from DB Baseline to the overall post-OL Baseline extension period, each 
scheduled OLE study visit (starting from Visit 1E), and LOCF, and shift from OL Baseline to each 
scheduled post-OL Baseline extension study visit (starting from Visit 2E), and LOCF, will be presented. 
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-point scale from 0 = ‘Behavior not likely to result in injury’ to 2 = ‘Behavior 
likely to result in death despite available medical care’. 
Responses to each C-SSRS question will be listed. The ideation intensity total score and the actual 
lethality and potential lethality of actual attempts will only be presented in data listings. 
18.6.2. 
YOUNG MANIA RATING SCALE (YMRS) 
The YMRS will be administered as a safety assessment and to inform the identification of treatment-
emergent mania or hypomania. 
The YMRS is a clinician-rated 11-item instrument used to assess the severity of mania in subjects with 
a diagnosis of bipolar disorder. The 11 items assess: Elevated Mood, Increased Motor Activity/Energy, 
Sexual Interest, Sleep, Irritability, Speech (Rate and Amount), Language/Thought Disorder, Content, 
Disruptive-Aggressive Behavior, Appearance, and Insight. The YMRS total score is the sum of the 11 
individual items and ranges from 0 to 60. A higher score is associated with a greater severity of mania. 


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If one or more items are missing at a visit, the total score will be set to missing.  
YMRS is assessed at Week 2 and monthly and at these study visits: from Visit 1E (coinciding with Visit 
6 of SEP380-301) to Visit 15E. 
Treatment-emergent mania or hypomania is defined as a YMRS total score ≥ 16 at any 2 consecutive 
post-OL Baseline visits or at the final visit, or an AE of mania or hypomania during the post-OL Baseline 
extension period (including both the OLE treatment period and the OLE follow-up period up to and 
including 7 days post the last OLE dose). 
The DB Baseline and OL Baseline YMRS total score will be derived as described in Section 7.2. The 
change from DB Baseline and OL Baseline in YMRS total score will be derived as described in 
Section 7.7. 
The observed values of YMRS total score at both the DB Baseline and the OL Baseline, and at each 
scheduled OLE study visit (starting from Visit 2E) and LOCF, will be summarized descriptively.  
Changes from DB Baseline in YMRS total score will be summarized for each scheduled OLE study visit 
(starting from Visit 1E) and LOCF. Changes from OL Baseline will be summarized for each scheduled 
post-OL Baseline extension study visit (starting from Visit 2E) and LOCF.  
Frequency and percentage of subjects experiencing treatment-emergent mania at any time during the 
study will be presented by treatment group. 
18.6.3. 
ABNORMAL INVOLUNTARY MOVEMENT SCALE (AIMS) 
The AIMS is a clinician-rated assessment of abnormal movements consisting of unobtrusive 
observation of the subject at rest (with shoes removed) and several questions or instructions directed 
toward the subject. It contains seven items related to: facial, lip, jaw, and tongue movements (items 
1 - 4), upper and lower extremity movements (items 5 - 6), and trunk movements (item 7). Three other 
items assess the subject at a global level (items 8 - 10), and two items assess dental status (items 
11 - 12).  
AIMS is assessed at these study visits: Visit 1E (coinciding with Visit 9 of SEP380-301), Visit 2E, 
Visit 4E, Visit 6E, Visit 8E, Visit 10E, Visit 12E, and Visit 14E. 
The (non-global) AIMS total score is the sum of items 1 through 7. (Items 8 through 12 are not used in 
AIMS total score calculation.) The possible range for AIMS total score is 0 to 28. Higher values of the 
AIMS total score indicate increased severity in abnormal movement. If one or more of the 7 items 
contributing to AIMS total score calculation are missing at a visit, the total score will be set to missing 
for that visit.  
AIMS total score at each visit is classified as ‘abnormal’ if: either at least two items (out of items 1 - 7) 
have a response of ‘Mild’ or higher (i.e., item score ≥ 2); or at least one item (out of items 1 - 7) has a 
response of ‘Moderate’ or higher (i.e., item score ≥ 3). Otherwise, the non-missing AIMS total scores is 
classified as ‘normal’. 
Item 8 of AIMS represents the global severity score. Post-Baseline AIMS global severity scores will be 
classified as ‘worsened’, ‘unchanged’, or ‘improved’, relative to a subject’s Baseline response to item 8. 
A higher score than that of the Baseline would be classified as ‘worsened’. Conversely, a lower score 
would be classified as ‘improved’. If the score is equal to that of Baseline, the score will be classified as 
‘unchanged’. Relative to DB Baseline, the classification will be made for each OLE study visit. Relative 
to OL Baseline, the classification will be made for each post-OL Baseline extension study visit. 
The DB Baseline and OL Baseline AIMS total score and global severity score will be derived as 
described in Section 7.2. The change from DB Baseline and OL Baseline in AIMS total score and global 
severity score will be derived as described in Section 7.7. 
The observed values of AIMS total score and global severity score at both the DB Baseline and the OL 
Baseline, and at each scheduled OLE study visit (starting from Visit 2E) and LOCF, will be summarized 


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descriptively.  
Changes from DB Baseline in AIMS total score and global severity score will be summarized for each 
scheduled OLE study visit (starting from Visit 1E) and LOCF. Changes from OL Baseline will be 
summarized for each scheduled post-OL Baseline extension study visit (starting from Visit 2E) and 
LOCF. 
Shift in AIMS total score category (Normal/Abnormal) from DB Baseline to each scheduled OLE study 
visit (starting from Visit 1E), LOCF, and the overall post-OL Baseline extension period (including both 
the OLE treatment period and the OLE follow-up period up to and including 7 days post the last OLE 
dose) will be summarized descriptively. Similarly, shift from OL Baseline in AIMS total score category to 
each scheduled post-OL Baseline extension study visit (starting from Visit 2E), LOCF, and the overall 
post-OL Baseline extension period will be summarized descriptively. 
Frequency distribution of the AIMS global severity item will be summarized descriptively for DB 
Baseline, OL Baseline, each scheduled OLE study visit (starting from Visit 2E), and LOCF. 
Changes in AIMS global severity score relative to DB Baseline (Worsened/Unchanged/Improved) will 
be summarized descriptively for each scheduled OLE study visit (starting from Visit 1E) and LOCF; 
changes relative to OL Baseline will be summarized descriptively for each scheduled post-OL Baseline 
extension study visit (starting from Visit 2E) and LOCF. 
18.6.4. 
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 (item 1), two items targeting subjective 
restlessness (awareness and related distress; items 2 - 3), and one global clinical assessment of 
akathisia item (item 4). The objective and subjective items are anchored and utilize a 4-point scale. The 
global assessment item has a 6-point scale (from absence of akathisia through severe akathisia). 
BARS is assessed at these study visits: Visit 1E (coinciding with Visit 9 of SEP380-301), Visit 2E, 
Visit 4E, Visit 6E, Visit 8E, Visit 10E, Visit 12E, and Visit 14E. 
The BARS total score is the sum of items 1 through 3 and ranges from 0 to 9. Higher values of the 
BARS total score indicate higher severity of akathisia. If one or more of items 1 to 3 are missing at a 
visit, the BARS total score will be set to missing for that visit. 
The post-Baseline BARS Global Clinical Assessment of Akathisia responses will be classified as 
‘worsened’, ‘unchanged’, or ‘improved’, relative to a subject’s Baseline response to this item. A higher 
score than that of the Baseline would be classified as ‘worsened’. Conversely, a lower score would be 
classified as ‘improved’. If the score is equal to that of Baseline, the score will be classified as 
‘unchanged’. Relative to DB Baseline, the classification will be made for each OLE study visit. Relative 
to OL Baseline, the classification will be made for each post-OL Baseline extension study visit. 
The DB Baseline and OL Baseline BARS total score and BARS item scores will be derived as 
described in Section 7.2. The change from DB Baseline and OL Baseline in BARS total score and 
BARS item scores will be derived as described in Section 7.7. 
The observed values of BARS total score at both the DB Baseline and the OL Baseline, and at each 
scheduled OLE study visit (starting from Visit 2E) and LOCF, will be summarized descriptively.  
Changes from DB Baseline in BARS total score will be summarized for each scheduled OLE study visit 
(starting from Visit 1E) and LOCF. Changes from OL Baseline will be summarized for each scheduled 
post-OL Baseline extension study visit (starting from Visit 2E) and LOCF. 
Changes in BARS global clinical assessment score relative to DB Baseline 
(Worsened/Unchanged/Improved) will be summarized descriptively for each scheduled OLE study visit 
(starting from Visit 1E) and LOCF; changes relative to OL Baseline will be summarized descriptively for 
each scheduled post-OL Baseline extension study visit (starting from Visit 2E) and LOCF. 


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18.6.5. 
MODIFIED SIMPSON-ANGUS SCALE (MSAS) 
The MSAS is a clinician-rated assessment of neuroleptic-induced Parkinsonism consisting of 10 items. 
Items are anchor-based, rated on a 5-point scale (ranging between 0 and 4), and address rigidity, gait 
(bradykinesia), tremor, akathisia, shoulder shaking, glabellar tap, and salivation.  
MSAS total score is defined as the sum of all 10 items and ranges between 0 and 40. Lower values of 
the MSAS total score indicate milder symptoms. If one or more of the MSAS items are missing at a 
visit, the MSAS total score will be set to missing for that visit.  
The MSAS total score at each visit will be classified as ‘abnormal’ if it exceeds 3 (Rush, et al., 2000). 
Otherwise, the non-missing MSAS total score will be classified as ‘normal’. 
MSAS is assessed at these study visits: Visit 1E (coinciding with Visit 9 of SEP380-301), Visit 2E, 
Visit 4E, Visit 6E, Visit 8E, Visit 10E, Visit 12E, and Visit 14E. 
The DB Baseline and OL Baseline MSAS total score will be derived as described in Section 7.2. The 
change from DB Baseline and OL Baseline in MSAS total score will be derived as described in 
Section 7.7. 
The observed values of MSAS total score at both the DB Baseline and the OL Baseline, and at each 
scheduled OLE study visit (starting from Visit 1E) and LOCF, will be summarized descriptively. 
Changes from DB Baseline in MSAS total score will be summarized for each scheduled OLE study visit 
(starting from Visit 1E) and LOCF. Changes from OL Baseline will be summarized for each scheduled 
post-OL Baseline extension study visit (starting from Visit 2E) and LOCF. 
Shift in MSAS total score category (Normal/Abnormal) from DB Baseline to each scheduled OLE study 
visit (starting from Visit 1E), LOCF, and the overall post-OL Baseline extension period (including both 
the OLE treatment period and the OLE follow-up period up to and including 7 days post the last OLE 
dose) will be summarized descriptively. Similarly, shift from OL Baseline in MSAS total score category 
to each scheduled post-OL Baseline extension study visit (starting from Visit 2E), LOCF, and the overall 
post-OL Baseline extension period will be summarized descriptively. 
18.6.6. 
PHYSICIAN’S WITHDRAWAL CHECKLIST (PWC) 
Potential withdrawal effects will be assessed by the clinician using the PWC after completion of all 
scheduled effectiveness and safety assessments and procedures at Visit 14E (EOT/ET) and Follow-up 
(Visit 15E).  
The PWC scale includes 20 symptoms and each symptom is assessed on a 4 point scale using the 
following: 0=Not Present, 1=Mild, 2=Moderate and 3=Severe. The score for each question is summed 
to compute a total score ranging from 0 to 60. If the response to any question is missing, then the total 
score will be missing.  
The PWC total score will be summarized using descriptive statistics by visit and treatment group. 
The frequency distribution of the PWC will be tabulated at Visit 14E and Follow-up. 
19. PHARMACOKINETIC ANALYSIS 
All PK analysis will be performed using Safety population. 
Blood sample for plasma concentrations of R-amisulpride, S-amisulpride, total amisulpride, and/or 
plasma prolactin measurement will be collected at: Visit 1E (coinciding with Visit 9 of SEP380-301), 
Visit 2E, Visit 4E, Visit 6E, Visit 8E, Visit 10E, Visit 12E, Visit 14E, and Visit 15E/Follow-up. Any plasma 
concentration or summary statistics below the lower limit of quantification (LLOQ) will be represented by 
“BLQ” (below the limit of quantification) in tables and listings. Amisulpride plasma concentration will not 


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be presented for the placebo group. 
R-amisulpride, S-amisulpride, total amisulpride, and plasma prolactin concentrations at each scheduled 
sample collection time point (including ET and Follow-up, see Section 7.4 for mapping of the ET visit) 
will be summarized descriptively (n, mean, median, minimum, maximum, coefficient of variation [CV] 
and if appropriate, geometric mean and geometric CV [GCV]). In addition, if there is at least 
1 concentration < LLOQ within a treatment group at a time point, it will be set to ½ LLOQ for summary 
statistics calculations.  Number and percentage of concentrations that are below the LLOQ will be 
provided for each visit. All PK summaries will be presented.  
Population PK analysis methods will be used to characterize the PK/PD profiles in subjects treated with 
SEP-4199 CR. Analysis methods and results of population PK and PD analysis will be described in a 
separate document from the SAP and clinical study report. 
19.1. DERIVATION 
LLOQ is 0.0500 ng/mL for R-amisulpride and S-amisulpride and LLOQ is 1.56 ng/mL for plasma 
prolactin. 
Below derivations apply after concentrations lower then LLOQ are set to ½ LLOQ. 
• 
Coefficient of variation 
100*Standard Deviation/Mean 
• 
Geometric Mean 
Exponential (mean of loge transformed data) 
• 
Geometric CV 
Square Root (Exponential (Variance (loge transformed data)-1))*100 
 
20. DATA NOT SUMMARIZED OR PRESENTED 
The variables and/or domains not summarized or presented are: 
• 
Subject initials. 
 


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21. REFERENCES 
 
Buysse, D., Reynolds, C., Monk, T., Berman, S., & Kupfer, D. (1989). The Pittsburgh Sleep Quality Index (PSQI): A new 
instrument for psychiatric research and practice. Psychiatry Research, 28(2), 193-213. 
Hopkins, S., Ogirala, A., Loebel, A., & Koblan, K. (2018). Transformed PANSS factors intended to reduce 
pseudospecificity among symptom domains and enhance understanding of symptom change in 
antipsychotic-treated patients with schizophrenia. Schizophrenia Bull, 44(3), 593-602. 
Hopkins, S., Ogirala, A., Loebel, A., & Koblan, K. (2020). Characterization of specific and distinct patient types in 
clinical trials of acute schizophrenia using an uncorrelated PANSS score matrix transform (UPSM). Psychiatry 
Research. 
Keefe, R., Philip, H., Terry, G., James, G., Trina, W., Courntey, K., & Kirsten, H. (2008). Norms and standardization of 
the Brief Assessment of Cognition in Schizophrenia (BACS). Schizophrenia Reaseach, 108-115. 
Marder, S., Davis, J., & Chouinard, G. (1997). The effects of risperidone on the five dimensions of schizophrenia. J 
Clin Psychiatry, 58, 538–546. 
Rush, A., Pincus, H., First, M., Blacker, D., Endicott, J., Keith, S., . . . Zarin, D. (2000). Handbook of Psychiatric Measures. 
American Psychiatric Association. 
 
 
 
 


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APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
OUTPUT CONVENTIONS 
Where applicable, the Appendix_compilation_working_update_2022Final.pdf document – provided by 
SMPA – will be followed. 
In addition, the following output conventions are to be followed: 
• 
General presentation: 
o 
The left-hand column should start in column 1. No centering of the output should occur. 
o 
Rounding should be done with the SAS function ROUND. 
o 
Numbers in tables should be rounded, not truncated. 
o 
Alphanumeric output should be left aligned. 
o 
Numbers should be decimal point aligned. 
o 
Whole numbers should be right aligned. 
o 
Text values should be left aligned. 
o 
The first letter of a text entry should be capitalized. 
• 
Univariate Statistics: If the raw data has N decimal places, then the summary statistics should have 
the following decimal places: 
o 
Minimum and maximum: N 
o 
Mean, median, Q1, and Q3: N + 1 
o 
SD: N + 2 
• 
Frequencies and percentages (n and %): 
o 
Percent values should be reported inside parentheses, with one space between the count 
(n) and the left parenthesis of the percentage. Parentheses should be justified to accept a 
maximum of 100.0 as a value and padded with blank space if the percent is less than 100.0. 
o 
Percentages will be reported to one decimal place, except cases where percent < 100.0% 
but > 99.9% will be presented as ‘> 99.9%’ (e.g., 99.99% is presented as > 99.9%); and cases 
where percent < 0.1% will be presented as ‘< 0.1%’ (e.g., 0.08% is presented as < 0.1%). 
Rounding will be applied after the < 0.1% and >99.9% rule. 
o 
Where counts are zero, no percentage should appear in the output. 
• 
Confidence Intervals: 
o 
Confidence intervals and estimates are presented to one place more than the raw data, 
and standard errors to two places more than the raw data. 
o 
Confidence intervals should be justified so that parentheses displayed on consecutive lines 
of a table “line up”. 
o 
Boundary values of confidence intervals should be separated by a comma. 
o 
Boundary values should be padded as necessary to accept negative values and to allow 
alignment of the decimal place. 
• 
Ratios should be reported to one more decimal place than the raw data. 
• 
Spacing must be a minimum of 1 blank space between columns (preferably 2). 
• 
Missing values: 
o 
A “0” should be used to indicate a zero frequency. 


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o 
A blank will be used to indicate missing data in an end-of-text table or subject listing. 
• 
Figures: 
o 
Figures should be provided in RTF files using the SAS Output Delivery System (ODS), as 
Computer Graphics Metafile (CGM) formatted graphical output generated by SAS. 
o 
The image should be clear and of high quality when viewed in the Word document, and 
when printed. 
o 
In general, boxes around the figures should be used. 
• 
Footers should be defined as follows: 
o 
A continuous line of underscores (‘_’) will follow the body of the table or listing prior to any 
footnotes at the bottom of the page. 
o 
Table footnotes should appear directly after the body of the table. 
o 
If text wraps across more than one line (for a note), the first letter for all lines of text after 
the first one will be indented to align beneath the first letter of the text in the first line. 
DATES & TIMES 
Depending on data available, dates and times will take the form yyyy-mm-ddThh:mm:ss. 
SPELLING FORMAT 
English US.  
PRESENTATION OF TREATMENT GROUPS 
For outputs, treatment sequences will be represented as follows and in that order: 
Treatment Sequence 
For Tables (Column 
Order)  
For Graphs (Order) 
Placebo - SEP-4199 CR 
PBO-SEP (1) 
PBO-SEP (2) 
SEP-4199 CR 200 mg/day - SEP-4199 CR 
SEP-SEP (2) 
SEP-SEP (3) 
SEP-4199 CR 400 mg/day - SEP-4199 CR 
SEP-SEP (2) 
SEP-SEP (3) 
 
ALL-EXT (3) 
ALL EXT (1) 
LISTINGS 
All listings will be ordered by the following (unless otherwise indicated in the template): 
• 
Subject ID.  
• 
Visit (where applicable) 
• 
Original date/time (where applicable). 
 


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APPENDIX 2. PARTIAL DATE CONVENTIONS 
The actual dates as collected on the CRF will be presented in the listings. Imputed dates will NOT be 
presented in the listings unless otherwise specified. 
ALGORITHM FOR ADVERSE EVENTS 
The algorithm below applies to all SEP380-301/303 AEs and SEP380-301 pre-treatment event records 
collected in the SEP380-303 clinical database. 
 
Step 1) For events that exist in the SEP380-301 databases and have a missing or partial start date, 
retrieve imputed event start dates from the respective ADaM dataset. 
Events in the SEP380-303 database which also exist in the SEP380-301 databases will be identified 
based on a comparison of subject ID, PT, AE start date (and time if available), severity, and 
seriousness. 
 
Step 2) For events that do not exist in the SEP380-301 databases yet the known part of the event start 
and/or end dates show that the event unambiguously started before first OLE dose in SEP380-303, 
impute missing or partial event start and/or end dates (if not ongoing) using the algorithm below.  
If an event has some missing components in both the start and end dates, first impute the end date. 
AE end date imputation 
• 
If year and month (YYYY-MM) of AE end date are known, then impute the missing day to be the 
earlier of (last day of the month; date of SEP380-301 last contact). 
• 
If only year (YYYY) of AE end date is known, then impute the missing month and day to be the earlier 
of (31st December; date of SEP380-301 last contact). 
• 
If AE end date is completely missing and AE is not ongoing, then impute AE end date to be date of 
SEP380-301 last contact. 
AE start date imputation 
• 
If year and month (YYYY-MM) of AE start date are known and YYYY-MM = year and month of 
SEP380-301 study med start date, then impute AE start date to be the earlier of (SEP380-301 study 
med start date; full or imputed AE end date [if non-missing]). 
• 
If year and month (YYYY-MM) of AE start date are known and YYYY-MM ≠ year and month of 
SEP380-301 study med start date, then impute AE start date to be YYYY-MM-01. 
• 
If only year (YYYY) of AE start date is known and YYYY = year of SEP380-301 study med start date, 
then impute AE start date to be the earlier of (SEP380-301 study med start date; full or imputed AE 
end date [if non-missing]). 
• 
If only year (YYYY) of AE start date is known and YYYY ≠ year of SEP380-301 study med start date, 
then impute AE start date to be YYYY-01-01. 
• 
If AE start date is completely missing, then impute AE start date to be the earlier of (SEP380-301 
study med start date; full or imputed AE end date [if non-missing]). 
 


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Step 3) For the remaining events in SEP380-303 database, impute missing or partial event start and/or 
end dates (if not ongoing) using the algorithm below. 
If an event has some missing components in both the start and end dates, first impute the end date. 
AE end date imputation 
• 
If year and month (YYYY-MM) of AE end date are known, then impute the missing day to be the 
earlier of (last day of the month; date of SEP380-303 last contact). 
• 
If only year (YYYY) of AE end date is known, then impute the missing month and day to be the earlier 
of (31st December; date of SEP380-303 last contact). 
• 
If AE end date is completely missing and AE is not ongoing, then impute AE end date to be date of 
SEP380-303 last contact. 
AE start date imputation 
• 
If year and month (YYYY-MM) of AE start date are known and YYYY-MM = year and month of OLE 
study med start date, then impute AE start date to be the earlier of (OLE study med start date; full or 
imputed AE end date [if non-missing]). 
• 
If year and month (YYYY-MM) of AE start date are known and YYYY-MM ≠ year and month of OLE 
study med start date, then impute AE start date to be YYYY-MM-01. 
• 
If only year (YYYY) of AE start date is known and YYYY = year of OLE study med start date, then 
impute AE start date to be the earlier of (OLE study med start date; full or imputed AE end date [if 
non-missing]). 
• 
If only year (YYYY) of AE start date is known and YYYY ≠ year of OLE study med start date, then 
impute AE start date to be YYYY-01-01. 
• 
If AE start date is completely missing, then impute AE start date to be the earlier of (OLE study med 
start date; full or imputed AE end date [if non-missing]). 
 
Step 4) Using the full or imputed event dates, assign events into SEP380-301 pre-treatment event, 
SEP380-301 AE, or SEP380-303 AE as described below. 
 
If both event start date/time and SEP380-303 OLE study med start date/time are available: 
• 
If event start date/time < SEP380-303 OLE study med start date/time, then SEP380-301 
pre-treatment event or SEP380-301 AE*. 
• 
If event start date/time ≥ SEP380-303 OLE study med start date/time, then SEP380-303 AE. 
 
If (event start date is avaialble and time is not avaialble) and/or (SEP380-303 OLE study med start date 
is avaialble and time is not avaialble): 
• 
If event start date < SEP380-303 OLE study med start date, then SEP380-301 pre-treatment event or 
SEP380-301 AE*. 
• 
If event start date > SEP380-303 OLE study med start date, then SEP380-303 AE. 
• 
If event start date = SEP380-303 OLE study med start date and the event record exists in 
SEP380-301 database§, then SEP380-301 pre-treatment event or SEP380-301 AE*. 
• 
If event start date = SEP380-303 OLE study med start date and the event record does not exist in 
SEP380-301 database§, then SEP380-303 AE. 


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*The distinction between SEP380-301 pre-treatment event and SEP380-301 AE should be performed 
as specified in the SEP380-301 SAP. 
§Based on a comparison of subject ID, PT, AE start date (and time if available), severity, and 
seriousness. 
 
 
 


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ALGORITHM FOR PRIOR / CONCOMITANT / POST-TREATMENT MEDICATIONS 
In case of partial or missing medication start and/or stop dates, impute the partial or missing dates 
using the algorithm below.  
If a medication has some missing components in both the start and stop dates, first impute the stop 
date. 
Impute stop date as latest possible date 
• 
If only day unknown, impute to the earlier of (last day of the month; date of SEP380-303 last contact). 
• 
If month and day unknown, impute to the earlier of (31st December; date of SEP380-303 last contact). 
• 
If stop date is completely unknown and medication is not ongoing, impute to date of SEP380-303 last 
contact. 
Impute start date as earliest possible date 
CRF questions: ‘Started prior to first dose?’ = Yes; ‘Started after last dose of study medication?’ = No. 
• 
If only day unknown, impute to the first day of the month. 
• 
If month and day unknown, impute to the 1st January. 
• 
If start date is completely unknown, impute to the earlier of (date of informed consent*; full or imputed 
medication stop date [if not missing]). 
 
CRF questions: ‘Started prior to first dose?’ = No; ‘Started after last dose of study medication?’ = Yes. 
• 
If only day unknown, impute to the later of (first day of the month; SEP380-303 OLE study med end 
date + 1). 
• 
If month and day unknown, impute to the later of (1st January; SEP380-303 OLE study med end date 
+ 1). 
• 
If start date is completely unknown, impute to SEP380-303 OLE study med end date + 1. 
 
CRF questions: ‘Started prior to first dose?’ = No; ‘Started after last dose of study medication?’ = No. 
• 
If only day unknown, impute to the later of (first day of the month; SEP380-303 OLE study med start 
date). 
• 
If month and day unknown, impute to the later of (1st January; SEP380-303 OLE study med start 
date). 
• 
If start date is completely unknown, impute to SEP380-303 OLE study med start date. 
Then assign a medication into prior, concomitant, or post-treatment 
The concept of “date” below should also include time information whenever time is available for both 
comparators. 
• 
If medication stop date < SEP380-303 OLE study med start date, assign as prior. 
• 
If (SEP380-303 OLE study med start date ≤ medication stop date ≤ SEP380-303 OLE study med 
end date ) and  
1. 
medication start date < SEP380-303 OLE study med start date, assign as prior and 
concomitant. 


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2. 
SEP380-303 OLE study med start date ≤ medication start date ≤ SEP380-303 OLE study 
med end date, assign as concomitant. 
• 
If (medication start date > SEP380-303 OLE study med end date on ongoing) and 
1. 
medication start date < SEP380-303 OLE study med start date, assign as prior, 
concomitant, and post-treatment. 
2. 
SEP380-303 OLE study med start date ≤ medication start date ≤ SEP380-303 OLE study 
med end date, assign as concomitant and post-treatment. 
3. 
medication start date > SEP380-303 OLE study med end date, assign as post-treatment. 
 
 


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APPENDIX 3. 
EQ-5D-5L INDEX VALUE CALCULATION  
EQ-5D-5L health states, defined by the EQ-5D-5L descriptive system, may be converted into a single 
index value using an appropriate EQ-5D-5L value set. If a standard EQ-5D-5L value set is not available, 
but an EQ-5D-3L value set is available, a “crosswalk” value set can be used to derive the index value. 
For multiregional trials, EuroQol recommends applying a single standard value set (or crosswalk value 
set) to all study sites. For this study, the US EQ-5D-5L standard value set will be used for all countries. 
Please refer the following EuroQol website for EQ-5D-5L value sets and further information. 
https://euroqol.org/publications/key-euroqol-references/value-sets/ 
 
 
 


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APPENDIX 4. 
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 
 
 
 












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APPENDIX 7. 
SCHEDULE OF EVENTS 
 
 
 


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12-Month Open-Label Treatment Period 
Study Visit Numbera 
V1E 
V2E 
V3E 
V4E 
V5E 
V6E 
V7E 
V8E 
V9E 
Study Week or Month 
Baseline
b 
Week 2 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 
Month 7 
Study Day 
-1 
14 (± 2) 
30 (± 2) 
60 (± 5) 
90 (± 5) 
120 (± 5) 150 (± 5) 180 (± 5) 210 (± 5) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
Dispense Study Drug  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Accountability 
 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
Physical Examination 
Core 
 
 
 
 
 
 
X 
 
Neurological Examination 
Core 
 
 
 
 
 
 
X 
 
Prior/Concomitant 
Medicationsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Schedule Next Visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Schedule Telephone Check-
in With Subjectd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SAFETY ASSESSMENTS 
 
 
 
 
 
 
 
 
 
Vital Sign Measurements 
Core 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
Core 
X 
X 
X 
X 
X 
X 
X 
X 
Waist Circumference 
Core 
 
 
 
 
 
 
X 
 
Adverse Eventse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGf 
Core 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistryg 
Core 
X 
 
X 
 
X 
 
X 
 
Hematology 
Core 
X 
 
X 
 
X 
 
X 
 
Urinalysis 
Core 
X 
 
X 
 
X 
 
X 
 
Serum Prolactinh 
Core 
X 
 
X 
 
X 
 
X 
 
Blood Sampling for Plasma 
PK and Plasma Prolactini 
Core 
X 
 
X 
 
X 
 
X 
 


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12-Month Open-Label Treatment Period 
Study Visit Numbera 
V1E 
V2E 
V3E 
V4E 
V5E 
V6E 
V7E 
V8E 
V9E 
Study Week or Month 
Baseline
b 
Week 2 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 
Month 7 
Study Day 
-1 
14 (± 2) 
30 (± 2) 
60 (± 5) 
90 (± 5) 
120 (± 5) 150 (± 5) 180 (± 5) 210 (± 5) 
Hemoglobin A1c (HbA1c) 
Core 
 
 
X 
 
X 
 
X 
 
Lipid Panelg 
Core 
 
 
X 
 
X 
 
X 
 
Serum Insuling 
Core 
 
 
X 
 
X 
 
X 
 
High-sensitivity C-Reactive 
Protein (hs-CRP) 
Core 
 
 
 
 
 
 
X 
 
Thyroid Panel 
Core 
 
 
X 
 
X 
 
X 
 
Urine Pregnancy Test 
(females of childbearing 
potential)j 
Core 
 
X 
X 
X 
X 
X 
X 
X 
Rapid Urine Drug Test 
Core 
X 
X 
X 
X 
X 
X 
X 
X 
Young Mania Rating Scale 
(YMRS) 
Core 
X 
X 
X 
X 
X 
X 
X 
X 
Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
Core 
X 
X 
X 
X 
X 
X 
X 
X 
Abnormal Involuntary 
Movement Scale (AIMS) 
Core 
X 
 
X 
 
X 
 
X 
 
Barnes Akathisia Scale 
(BARS) 
Core 
X 
 
X 
 
X 
 
X 
 
Modified Simpson-Angus 
Scale (SAS) 
Core 
X 
 
X 
 
X 
 
X 
 
Physician’s Withdrawal 
Checklist (PWC) 
 
 
 
 
 
 
 
 
 


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12-Month Open-Label Treatment Period 
Study Visit Numbera 
V1E 
V2E 
V3E 
V4E 
V5E 
V6E 
V7E 
V8E 
V9E 
Study Week or Month 
Baseline
b 
Week 2 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 
Month 7 
Study Day  
-1 
14 (± 2) 
30 (± 2) 
60 (± 5) 
90 (± 5) 
120 (± 5) 150 (± 5) 180 (± 5) 210 (± 5) 
EFFECTIVENESS 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
Montgomery-Asberg 
Depression 
Rating 
Scale 
(MADRS) 
Core 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Global Impression-
Bipolar Version-Severity of 
Illness (CGI-BP-S)  
Core 
X 
X 
X 
X 
X 
X 
X 
X 
Hamilton 
Anxiety 
Rating 
Scale (HAM-A) 
Core 
 
 
X 
 
X 
 
X 
 
Quick 
Inventory 
of 
Depressive Symptomatology, 
Self-Report (QIDS-SR16) 
Core 
 
 
X 
 
X 
 
X 
 
Sheehan 
Disability 
Scale 
(SDS) 
Core 
 
 
X 
 
X 
 
X 
 
EuroQoL - 5 Dimension - 
5 Level (EQ-5D-5L) 
Core 
 
 
X 
 
X 
 
X 
 
Snaith-Hamilton 
Pleasure 
Scale (SHAPS) 
Core 
 
 
X 
 
X 
 
X 
 
 
 


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12-Month Open-Label Treatment Period 
Follow-Up 
Study Visit Numbera 
V10E 
V11E 
V12E 
V13E 
V14E (EOT/ET) 
V15Em 
Study Week or Month 
Month 8 
Month 9 
Month 10 
Month 11 
Month 12k,l 
(Week 52) 
7 (± 2) days 
after last dose 
Study Day 
240 (± 5) 
270 (± 5) 
300 (± 5) 
330 (± 5) 
360 (+ 5) 
Informed Consent 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
 
 
 
 
 
Dispense Study Drug  
X 
X 
X 
X 
 
 
Study Drug Accountability 
X 
X 
X 
X 
X 
 
Physical Examination 
 
 
 
 
X 
 
Neurological Examination 
 
 
 
 
X 
 
Prior/Concomitant Medications 
X 
X 
X 
X 
X 
X 
Schedule Next Visit 
X 
X 
X 
X 
X 
 
Schedule Telephone Check-in With Subjectd 
X 
X 
X 
X 
 
 
SAFETY ASSESSMENTS 
 
 
 
 
 
 
Vital Sign Measurements 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
 
Waist Circumference 
 
 
 
 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
X 
X 
X 
X 
X 
Serum Chemistryg 
X 
 
X 
 
X 
 
Hematology 
X 
 
X 
 
X 
 
Urinalysis 
X 
 
X 
 
X 
 
Serum Prolactinh 
X 
 
X 
 
X 
X 
Blood Sampling for Plasma PK and Plasma 
Prolactinh,i 
X 
 
X 
 
X 
X 
Hemoglobin A1c (HbA1c) 
X 
 
X 
 
X 
 
Lipid Panelg 
X 
 
X 
 
X 
 
Serum Insuling 
X 
 
X 
 
X 
 
High-sensitivity 
C-Reactive 
Protein 
(hs-CRP) 
 
 
 
 
X 
 


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12-Month Open-Label Treatment Period 
Follow-Up 
Study Visit Numbera 
V10E 
V11E 
V12E 
V13E 
V14E (EOT/ET) 
V15Em 
Study Week or Month 
Month 8 
Month 9 
Month 10 
Month 11 
Month 12k,l 
(Week 52) 
7 (± 2) days 
after last dose 
Study Day 
240 (± 5) 
270 (± 5) 
300 (± 5) 
330 (± 5) 
360 (+ 5) 
Urine 
Pregnancy 
Test 
(females 
of 
childbearing potential)j 
X 
X 
X 
X 
X 
X 
Rapid Urine Drug Test 
X 
X 
X 
X 
X 
X 
Young Mania Rating Scale (YMRS) 
X 
X 
X 
X 
X 
X 
Columbia-Suicide Severity Rating Scale 
(C-SSRS) 
X 
X 
X 
X 
X 
X 
Abnormal Involuntary Movement Scale 
(AIMS) 
X 
 
X 
 
X 
 
Barnes Akathisia Scale (BARS) 
X 
 
X 
 
X 
 
Modified Simpson-Angus Scale (SAS) 
X 
 
X 
 
X 
 
Physician’s Withdrawal Checklist (PWC) 
 
 
 
 
X 
X 
EFFECTIVENESS ASSESSMENTS 
 
 
 
 
 
 
Montgomery-Asberg 
Depression 
Rating 
Scale (MADRS) 
X 
X 
X 
X 
X 
 
Clinical Global Impression-Bipolar Version-
Severity of Illness (CGI-BP-S) 
X 
X 
X 
X 
X 
 
Hamilton Anxiety Rating Scale (HAM-A) 
X 
 
X 
 
X 
 
Quick 
Inventory 
of 
Depressive 
Symptomatology, Self-Report (QIDS-SR16) 
X 
 
X 
 
X 
 
Sheehan Disability Scale (SDS) 
X 
 
X 
 
X 
 
EuroQoL - 5 Dimension - 5 Level (EQ-5D-
5L) 
X 
 
X 
 
X 
 
Snaith-Hamilton Pleasure Scale (SHAPS) 
X 
 
X 
 
X 
 
Abbreviations: BL = Baseline; eCRF = electronic case report form; E = extension; ECG = electrocardiogram; EOT = End of Treatment; ET = Early 
Termination; PK = pharmacokinetic 
Note: To ensure subject safety and data integrity, should circumstances warrant and with Sponsor approval, remote site/subject visits may be conducted. 
There is an extra visit for Japan (Visit 1EJ) on Day 1 that evaluates ECG. 


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a Visit windows are as follows: ± 2 days for Visits 2E (Week 2/Day 14) and 3E (Month 1), ± 5 days for monthly visits between Visit 4E (Month 2) and 
Visit 13E (Month 11), + 5 days for Visit 14E (Month 12), and ± 2 days for the Follow-up Visit (Visit 15E). 
b Visit 6/ End of Treatment (EOT) (Day 42) of the lead-in study of SEP-4199 CR serves as the Baseline visit (Day -1) for the present study. “Core” 
indicates assessments that were conducted at Visit 6/EOT (Day 42) in the lead-in study of SEP-4199 CR and do not need to be repeated for this study. 
c Medications taken during the lead-in study of SEP-4199 CR that are ongoing at the start of the current extension study will be entered into the eCRF. 
d Between study visits, subjects will be contacted weekly by telephone. 
e Adverse events with onset during the lead-in study of SEP-4199 CR and ongoing at the start of the current extension study will be entered into the eCRF. 
f ECG machine measurements are to be considered for subject eligibility at Baseline. 
g Subjects are required to fast for at least 8 hours prior to sample collection for laboratory testing. 
h Prolactin values at open-label Baseline visit (including any repeat testing) will be masked. Prolactin values after the first dose of study drug in the 
extension study will not be masked. 
i Blood sample for SEP-4199 population pharmacokinetic analysis for R- and S-enantiomers and/or plasma prolactin measurement will be collected at 
Visit 2E (Week 2/Day 14), Visit 4E (Month 2), Visit 6E (Month 4), Visit 8E (Month 6), Visit 10E (Month 8), V12E (Month 10), Visit 14E (Month 12), 
and Follow-up (Visit 15E, 7  ± 2 days after last dose), with a record of the time of last 3 administered doses on the CRF for PK sampling visits during 
the treatment period. The blood sample will be collected at time of clinical safety laboratory test sample collection. Plasma concentrations of 
aramisulpride and esamisulpride and plasma prolactin levels will be measured. Remaining plasma from samples may also be used for the additional 
bioanalytical method development and/or characterization of putative metabolites of amisulpride and for other exploratory measurements, if needed. 
j Any positive urine β-Human chorionic gonadotropin (hCG) test should be confirmed by a serum β-hCG test. 
k Visit 14E (Month 12) is the End of Treatment/Early Termination visit. Subjects who discontinue the study prior to Visit 14E will have all Visit 14E 
procedures performed at the time of discontinuation. 
l For subjects completing the 12-month treatment period, a visit window of + 5 days is strongly preferred. 
m Follow-up visit to be scheduled 7 (± 2) days after last dose of study drug.