Clinical trial NCT05169710
Conditions: Depressive Episodes, Bipolar I Depression
Keywords: Depression, Depressive episode, Bipolar, Bipolar 1, Bipolar 1 depression
Sponsor: Sumitomo Pharma America, Inc.
Start date: 2021-12-21; Completion date: 2023-10-18
Enrollment: 83 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A clinical trial to study the efficacy and safety of an investigational drug in people with major depressive episodes associated with with Bipolar I disorder (bipolar I depression) Participants in the study will either receive the drug being studied or a placebo. The study will be conducted in approximately 90 sites in North America, Europe, Latin America and Japan. It will be have both male and female participants ages 18-65. Participation in the study will be approximately 10 weeks.

Detailed description:
This study is a randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the efficacy, safety, and tolerability of treatment with SEP-4199 CR at fixed doses of 200 mg/day or 400 mg/day compared with placebo for the treatment of major depressive episode associated with bipolar I disorder (bipolar I depression). The study is projected to randomize approximately 522 subjects inNorth America, Japan, Europe and Latin America, to SEP-4199 CR 200 mg/day, SEP-4199 CR 400 mg/day, and placebo treatment groups in a 1:1:1 ratio

Arms: arm 1: SEP-4199 CR 200 mg/day arm 2: SEP-4199 CR 400 mg/day arm 3: Placebo
Interventions: intervention 1: SEP-4199 CR 200 mg intervention 2: SEP-4199 CR 400 mg intervention 3: Placebo
Intervention descriptions: intervention 1: SEP-4199 CR 200 mg Tablet (supplied in one 200mg tablet and one placebo tablet) intervention 2: SEP-4199 CR 400 mg tablet (supplied in two 200mg tablets) intervention 3: Placebo tablet (supplied in two tablets)

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 Multi-region, Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study Evaluating 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 
Phase of Development: 3 
Study Objectives:  
The objective of Study SEP380-301 is to evaluate the efficacy, safety, and tolerability of SEP-4199 
CR formulation given as monotherapy at fixed doses of 200 mg/day and 400 mg/day compared with 
placebo in the treatment of subjects with major depressive episode associated with bipolar I disorder 
(bipolar I depression). 
Primary Efficacy: 
Evaluate the efficacy of SEP-4199 CR in the reduction of depression symptoms, as measured using 
the Montgomery-Asberg Depression Rating Scale (MADRS). 
Secondary Efficacy: 
Evaluate the efficacy of SEP-4199 CR in global improvement of bipolar depression severity, as 
measured using the Clinical Global Impression-Bipolar Version-Severity of Illness, Depression scale 
(CGI-BP-S depression). 
Additional Efficacy: 
• 
Assess the proportion of subjects with treatment response, defined as ≥ 50% reduction in 
MADRS total score. 
• 
Assess the proportion of subjects with depression symptom remission, defined as a MADRS 
total score ≤ 12. 
• 
Assess the effect of treatment on the core symptoms of depression, as measured using the 
MADRS-6 subscale, defined as summation of items 1, 2, 3, 7, 8, and 9. 
• 
Assess the effect of treatment in the reduction of anxiety symptoms, as measured using the 
Hamilton Anxiety Rating Scale (HAM-A). 
• 
Assess the effect of treatment on subject self-rated depression symptom severity, as measured 
by the Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR16). 
• 
Assess the effect of treatment on functional impairment, as measured by the Sheehan 
Disability Scale (SDS). 
• 
Assess the effect of treatment on quality of life, as measured by the 
EuroQol - 5 Dimension - 5 Level (EQ-5D-5L). 
• 
Assess the effect of treatment on anhedonia, as measured by the Snaith-Hamilton Pleasure 
Scale (SHAPS). 


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Safety: 
• 
Determine the incidence of adverse events (AEs), discontinuation due to AEs, serious AEs 
(SAEs), and adverse events of special interest (AESI). 
• 
Evaluate safety and tolerability using physical examinations, 12-lead electrocardiogram 
(ECG), vital signs, clinical laboratory tests, prolactin levels, metabolic parameters, body 
weight, and body mass index (BMI). 
• 
Monitor for akathisia and extrapyramidal symptoms (EPS) using the Abnormal Involuntary 
Movement Scale (AIMS), Barnes Akathisia Scale (BARS), and Modified Simpson-Angus 
Scale (SAS). 
• 
Monitor for treatment-emergent mania or hypomania, defined as a Young Mania Rating Scale 
(YMRS) score of ≥ 16 on any 2 consecutive visits or at the final assessment, or an AE of 
mania or hypomania. 
• 
Monitor for suicidality using the Columbia-Suicide Severity Rating Scale (C-SSRS). 
• 
Evaluate potential withdrawal symptoms using the Physician’s Withdrawal Checklist (PWC). 
Pharmacokinetics and Pharmacodynamics: 
• 
Evaluate the therapeutic plasma concentration range of SEP-4199 CR taken as 200 mg/day 
and 400 mg/day for treatment of major depressive episode associated with bipolar I disorder. 
• 
Perform population pharmacokinetic (Pop-PK) analysis using plasma concentrations of 
SEP-4199 CR 200 mg/day and 400 mg/day. 
• 
Evaluate the relationship between SEP-4199 PK and plasma prolactin levels for 
SEP-4199 CR 200 mg/day and 400 mg/day. 
• 
Explore the exposure-response relationship of SEP-4199 CR 200 mg/day and 400 mg/day and 
symptoms as measured by MADRS using population pharmacokinetic 
(PK)/pharmacodynamics (PD) methods. 
Study Design: SEP380-301 is a randomized, double-blind, placebo-controlled, parallel-group study 
designed to evaluate the efficacy, safety, and tolerability of treatment with SEP-4199 CR at fixed 
doses of 200 mg/day or 400 mg/day compared with placebo for the treatment of major depressive 
episode associated with bipolar I disorder (bipolar I depression). The study is projected to randomize 
approximately 522 subjects in North America, Latin America, Japan, and Europe to SEP-4199 CR 
200 mg/day, SEP-4199 CR 400 mg/day, and placebo treatment groups in a 1:1:1 ratio, resulting in 
approximately 174 subjects/group. 
The study will consist of a Screening Period (up to 21 days), a 6-week double-blind Treatment Period 
(42 days), and a Follow-up Period (7 [± 2] days after the last study drug dose), as shown in the Study 
Schematic. If necessary, subjects may return to the clinic at any time for an unscheduled visit. 
Subjects who complete the Treatment Period are eligible to enroll directly into a long-term open-label 
safety extension study (SEP380-303) of SEP-4199 CR. Those subjects who prematurely discontinue 
or who complete the Treatment Period and choose not to enroll in the long-term open-label safety 
extension study will have a follow-up safety visit 7 (± 2) days after their last dose of double-blind 
study drug. 
 


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Study Schematic 
 
 
 
Abbreviations: CR = controlled release; EOT = end of treatment; ET = early termination; V = visit; Wk = week 
Note: Subjects who do not enroll in the long-term open-label safety extension study will have Visit 7. 
 
Screening Period (Visit 1, Day -22 to -2) 
Subjects will be evaluated at the Screening Visit (Visit 1) to determine their eligibility to enroll in the 
study. This visit should be scheduled as an early morning appointment, if possible, due to the 
recommendation that subjects fast prior to blood sample collection for clinical laboratory tests. 
Subjects should be advised to obtain and bring medical records as well as any current medications that 
they are taking. A highly reliable informant (who has had close contact with the subject and is 
approved by the Sponsor Eligibility Committee) should be identified to provide collateral information 
on the subject’s psychiatric and treatment history. 
Informed consent will be obtained from each subject before any study procedures are performed for 
this study. Medical, psychiatric, family (eg, biological mother, father, siblings, children) psychiatric 
and medical, and medication histories will be obtained. Medical history should include information 
about prior coronavirus disease 2019 (COVID-19) vaccination, infection, and illness, if any.  
Information supporting a diagnosis of Bipolar I disorder with at least one prior manic episode or 
manic episode with mixed features must be obtained from additional sources to confirm the Screening 
evaluation. 
The subject’s eligibility assessments will be reviewed by the Sponsor Eligibility Committee, which 
consists of the contract research organization’s (CRO) medical team along with the Sponsor and 
sponsor designees based on protocol-specified inclusion and exclusion criteria (see Section 26, 
Appendix VII for details). The Sponsor will participate in the eligibility review process with the CRO 
to ascertain the subject’s eligibility. In the event the Sponsor Eligibility Committee and Investigator 
do not agree on a subject’s eligibility, then the subject will not be approved to proceed to the Baseline 
Visit (Visit 2). 
Subjects will discontinue and wash out prior or concomitant medications, as applicable, prior to 
Baseline. Psychotropic medications (eg, antipsychotic agents, antidepressants, and mood stabilizers) 
are to be discontinued as tolerated and clinically appropriate at least 3 days or 5 half-lives (whichever 
is longer) prior to Baseline. 
Hospitalization during the Screening Period will not be allowed, except 


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• 
where required by local regulations, or 
• 
when determined to be clinically indicated based on the subject’s psychiatric history and 
current psychiatric symptoms. 
Medical justification must be provided to the Medical Monitor and the Medical Monitor must 
approve the request for hospitalization. In such cases, a maximum of 7 days’ hospitalization during 
washout of prior medications in the Screening Period and a maximum of 7 days’ hospitalization 
during Week 1 of study medication dosing will be allowed. If an extension is required, medical 
justification must be provided to the Medical Monitor, and the Medical Monitor, following Sponsor 
review, must approve the request to extend the duration of hospitalization. 
To determine subject eligibility, abnormal Screening clinical laboratory tests may only be repeated 
after discussion with the Medical Monitor. 
To determine subject eligibility, the Screening ECG may be repeated in the event of technical 
difficulty or error associated with the first ECG or if clinically indicated. Subjects should rest supine 
for at least 10 minutes prior to all ECGs. 
All Screening assessments should be completed in sufficient time for Site and CRO/Sponsor to 
receive and review results prior to the Baseline Visit (Visit 2). If necessary, to ensure receipt and 
review of all Screening information, an extension of the Screening Period by up to 7 days may be 
allowed, with prior approval from the Medical Monitor. 
Subjects who meet all inclusion criteria and no exclusion criteria after full evaluation of Screening 
data may proceed to the Baseline Visit (Visit 2) after receiving approval from the Sponsor Eligibility 
Committee. 
Baseline Visit (Visit 2, Day -1) 
Subjects who meet eligibility criteria during the Screening Period will return to the study site on 
Day -1 for confirmation of Screening evaluations as well as completion of pre-dose assessments. 
Subjects who continue to meet all inclusion criteria and no exclusion criteria at Baseline will be 
randomized and dispensed study drug at Day -1. 
Double-blind Treatment Period (Visits 3-6, Days 1 to 42) 
Subjects will self-administer the study drug on an outpatient basis once daily with or without food 
beginning on the morning of Day 1 (the day after the Baseline Visit [Visit 2]) and continue for 
6 weeks. Subjects will be instructed to administer study drug as a single oral dose at approximately 
the same time each morning. Subsequent clinic visits should be scheduled to begin no later than 
6 hours post-dose, if possible. The last dose of study drug will be self-administered by the subject at 
home on the morning of Visit 6 (Day 42). 
During the Treatment Period, subjects will have clinic visits as follows: Visit 3 (Day 7), Visit 4 
(Day 14), and Visit 5 (Day 28). Telephone calls to ascertain AEs and concomitant medications will be 
scheduled on Days 21 and 35. In order to facilitate scheduling of clinic visits and telephone calls, a 
window of ± 2 days will be allowed for each clinic visit and telephone call. 
End of Treatment (EOT)/Early Termination (ET) (Visit 6, Day 42 [± 2 days]) 
Subjects will have a clinic visit at Visit 6 (Day 42) for efficacy and safety assessments. Subjects who 
complete the 6-week double-blind Treatment Period will be considered study completers, and may be 
eligible to enroll directly into a long-term open-label safety extension study of SEP-4199 CR 
(SEP380-303). 
Subjects who prematurely discontinue the study will undergo an Early Termination (ET) Visit at the 
time of discontinuation. The ET Visit will include all efficacy and safety assessments scheduled for 
Visit 6 (Day 42). Prematurely discontinued subjects will not be eligible for the long-term open-label 
safety extension study. 


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Follow-up Period (Visit 7, 7 [± 2] days after last dose) 
All subjects who received at least one dose of study drug and who do not enroll in the subsequent 
open-label safety extension study will have a Follow-up Visit for safety and tolerability assessments 
7 (± 2) days after their last dose of double-blind study drug. Assessment of potential withdrawal 
effects will also be made during the Follow-up Period. During the Follow-up Period, completed 
subjects who do not continue into an open-label safety extension study will not be allowed to initiate 
treatment with a psychotropic medication until after completion of the Follow-up Visit. In the event 
that the severity of major depressive episode (MDE) symptoms at the Week 6 EOT/ET visit is judged 
to present a safety risk to complying with this requirement, the subject should be discontinued from 
the study and managed as clinically appropriate by the Investigator. 
Diagnostic and Symptom Severity Scales to Inform Subject Eligibility 
The Lifetime Illness Characteristics Questionnaire will be administered as an initial Screening 
assessment at Visit 1, prior to other Screening assessments. Subject responses are used to calculate a 
Bipolarity Index Score. A score ≥ 50 is associated with a high likelihood of a diagnosis of bipolar 
disorder. 
Diagnosis of bipolar I disorder, current episode depressed, will be based on the Structured Clinical 
Interview for DSM-5-Clinical Trials version (SCID-5-CT). Moderate-to-severe depression symptoms 
will be established with a score ≥ 22 on both the MADRS and Montgomery-Asberg Depression 
Rating Scale, self-rating version (MADRS-S), and with a CGI-BP-S depression score ≥ 4. Absence of 
mania will be established with a YMRS score ≤ 12. 
Details of these diagnostic and symptom severity scales are provided in Section 11.3. 
Efficacy Assessments 
Efficacy assessments include the clinician-rated MADRS, CGI-BP-S, and HAM-A; and subject 
self-reported measures of depression (QIDS-SR16), functional impairment (SDS), quality of life 
(EQ-5D-5L), and anhedonia (SHAPS). Details of these efficacy assessments are provided in 
Section 11.4 and in Table 2 (Schedule of Assessments). 
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, BMI, and 
waist circumference will also be recorded. Adverse events of special interest (AESI), including but 
not limited to hyperprolactinemia-related AEs, will be evaluated. Movement disorders will be 
assessed by AIMS, BARS, and modified SAS; and AEs associated with EPS will be summarized. 
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 
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 11.5 and in Table 2 (Schedule of Assessments). 
Pharmacokinetic Assessments 
Blood samples will be collected for pop-PK at Baseline (Visit 2), Visit 4 (Day 14), Visit 6 (Day 42), 
and Visit 7 (Follow-up). These samples, together with a sample collected at Screening (Visit 1), will 
also be measured for plasma prolactin levels. 
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 electronic 
case report form (eCRF) (Visit 4 [Day 14] and Visit 6 [Day 42] only). 


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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. 
An enzyme-linked immunosorbent assay (ELISA) will be used for determination of plasma prolactin 
concentrations. 
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): 522 (174/group) 
Main Diagnosis and Criteria for Subject Inclusion:  
Primary Inclusion Criteria (not all inclusive): 
1. Subject provides written informed consent and is willing and able to comply with the protocol in 
the opinion of the Investigator. 
2. Subject or legally acceptable representative must possess an educational level and degree of 
understanding of English or the local language that enables them to communicate suitably with 
the Investigator and the study coordinator. 
3. Subject is 18 to 65 years of age, inclusive, at the time of informed consent. 
4. Subject meets DSM-5 criteria, based on the SCID-5-CT, for bipolar I disorder, current episode 
depressed with or without rapid cycling disease course (≥ 4 episodes of mood disturbance but 
< 8 episodes in the previous 12 months) with or without psychotic features. 
5. Subject has a lifetime history of at least 1 manic episode or manic episode with mixed features 
corroborated by at least one of the following: medical records, documented correspondence with a 
treating psychiatrist or mental healthcare provider/staff, or information from a reliable informant 
who is familiar with the subject’s psychiatric history. The adequacy of the information will be 
assessed by the Sponsor Eligibility Committee. 
6. Attempts should be made to obtain supporting information regarding the subject’s current 
major depressive episode from additional sources. This may include relevant medical 
records and/or documented correspondence with a treating psychiatrist or mental 
healthcare provider/staff if the subject has been evaluated during the current MDD 
episode, or information from a reliable informant who is familiar with the subject’s recent 
psychiatric history.  
7. Subject’s current major depressive episode is ≥ 4 weeks and less than 12 months in duration at 
Screening. 
8. Subject has a MADRS-S total score ≥ 22 at Screening. 
9. Subject has a MADRS total score ≥ 22 at both Screening and Baseline. 
10. Subject has a CGI-BP-S depression score ≥ 4 at both Screening and Baseline. 
11. Subject has a YMRS total score ≤ 12 at both Screening and Baseline. 
12. Subjects meets an additional inclusion criterion at Baseline that will remain blinded to clinical site 
Investigators and staff. 
Primary Exclusion Criteria (not all inclusive): 
1. Subject currently has any DSM-5 defined psychiatric diagnosis other than bipolar I disorder that 
was the primary focus of treatment or is currently being treated with concomitant medication. 
2. Subject has a lifetime history of, or symptoms consistent with, schizophrenia, schizoaffective 
disorder, or a major psychiatric diagnosis other than bipolar I disorder that is judged to pose risk 
to the study scientific objectives based on the judgement of the Investigator or the Sponsor 


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Eligibility Committee. A lifetime history of anxiety disorders, attention-deficit/hyperactivity 
disorder (ADHD), and post-traumatic stress disorder (PTSD) are not exclusionary if the disorder 
does not meet Exclusion Criterion 1. (Note: Subjects with a previous diagnosis of major 
depressive disorder or bipolar II disorder that was subsequently changed to bipolar I disorder are 
allowed.) 
3. Subject has a history within the past 12 months prior to Screening of substance use disorder.  
4. Subject has confirmed or suspected borderline personality disorder. 
5. Subject demonstrates a decrease (improvement) of ≥ 25% in MADRS total score from Screening 
to Baseline. 
6. Subject is considered by the Investigator to be at imminent risk of suicide or injury to self or 
others, or has a score ≥ 4 on MADRS item 10 (suicidal ideation) 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 the Screening 
Visit (in the past 3 months [90 days]) or at Baseline. 
7. Subject has received any psychotropic medication or herbal supplement within 3 days or 
5 half-lives (whichever is longer) prior to Baseline or anticipates the need for psychotropic 
medications or herbal supplements during participation in this study, with the exception of the 
medications specified in Protocol Section 10.3. The following treatments have additional 
restrictions as specified below: 
a. Monoamine oxidase inhibitors (MAOIs) must be discontinued at least 28 days prior to 
Baseline. 
b. Fluoxetine, and olanzapine/fluoxetine combination must be discontinued at least 28 days prior 
to Baseline. 
c. Clozapine used at 200 mg/day or less for insomnia, agitation, or anxiety must be discontinued 
at least 28 days prior to Baseline. Subjects with a history of treatment with clozapine for any 
reason at doses greater than 200 mg/day or at doses less than or equal to 200 mg/day for a 
usage other than insomnia, agitation, or anxiety are excluded from study participation. 
d. Depot neuroleptics must have been discontinued at least one treatment cycle or at least 
30 days (whichever is longer) prior to Baseline. 
e. Subjects with a history of treatment with ketamine, esketamine, arketamine, or psychedelic 
therapies (eg, psilocybin, methylenedioxymethamphetamine [MDMA]) for MDD or any 
psychedelic treatment. 
f.  Electroconvulsive therapy (ECT) or repetitive transcranial magnetic stimulation (rTMS) 
within 90 days prior to Baseline. 
g. Subjects with a history of treatment with vagus nerve stimulation (VNS) or deep brain 
stimulation (DBS) are excluded from study participation. 
8. Subject initiated a new psychotherapeutic intervention (eg, psychotherapy) focused on treatment 
of bipolar I depression within the past 12 weeks prior to Screening. (Note: Subjects who have 
participated in ongoing psychotherapy treatment for at least 12 weeks prior to Screening will be 
permitted to continue this treatment during the study.) 
9. Subject has a history of non-response to an adequate (6-week) trial of 3 or more antidepressants 
(with or without mood stabilizers) during the current major depressive episode. 
10. Subject was hospitalized during the Screening Period without explicit approval by the Medical 
Monitor. (Note: Hospitalization during the Screening Period will not be allowed, except where 
required by local regulations, or when determined to be clinically indicated based on the subject’s 
psychiatric history and current psychiatric symptoms. Medical justification must be provided to 
the Medical Monitor and the Medical Monitor must approve the request for hospitalization.) 


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11. Subject has any clinically significant unstable medical condition or any clinically significant 
chronic disease that would pose a risk to the subject or that might confound the results of the 
study. (Note: Active medical conditions that are minor or well-controlled are not exclusionary if 
they do not affect risk to subject or study results. In cases in which the impact of the condition 
upon risk to subject or study results is unclear, the Medical Monitor should be consulted.) 
a. Hematological (including deep vein thrombosis) or bleeding disorder, renal, metabolic, 
endocrine, pulmonary, gastrointestinal, urological, cardiovascular (including unstable 
hypertension), hepatic, neurologic, or allergic disease that is clinically significant or unstable 
(except for seasonal allergies at time of dosing). (Note: Any subject with a known 
cardiovascular disease or condition, including hypertension, [even if under control and 
considered stable] must be discussed with the Medical Monitor before being randomized in 
the study.) 
b. Chronic organic disease of the CNS such as tumors, inflammation, active (or history of) 
seizure disorder, vascular disorder, Parkinson’s disease, Alzheimer’s disease or other forms of 
dementia, myasthenia gravis, or other degenerative processes. Subject has history of 
intellectual disability or persistent neurological symptoms attributable to serious head injury. 
(Note: Past history of febrile seizure is not exclusionary.) 
c. Evidence of acute hepatitis, clinically significant chronic hepatitis, or evidence of clinically 
significant impaired hepatic function through clinical and laboratory evaluation. Subjects who 
test positive for hepatitis C antibody at Screening and have a positive or indeterminate 
confirmatory test for hepatitis C are excluded. Subjects who test positive for hepatitis B 
surface antigen at Screening are excluded. 
d. History of any cardiovascular disorder/condition known to increase the possibility of QT 
prolongation, history of additional risk factors for torsade de pointes (eg, heart failure, 
hypokalemia, family history of Long QT Syndrome or Brugada Syndrome) or cardiac 
conduction disorders, or requires treatment with an antiarrhythmic medication. 
e. History of neuroleptic malignant syndrome (NMS). 
f. History of malignancy < 5 years prior to the Screening Visit, except for adequately treated 
basal cell carcinoma or squamous cell skin cancer or in situ cervical cancer. Subjects with 
lifetime history of pituitary tumors, including pituitary adenoma, of any duration are 
excluded. 
g. History of a condition (including history of malabsorption) or previous gastrointestinal 
surgery (eg, cholecystectomy, vagotomy, bowel resection) that could interfere with drug 
absorption, distribution, metabolism, excretion, gastrointestinal motility, or pH. 
h. Known history of human immunodeficiency virus (HIV) seropositivity. 
i. 
Type 1 diabetes or insulin-dependent type 2 diabetes. 
12. Subject with a supine systolic blood pressure (SBP) ≥ 150 millimeters of mercury (mmHg) and/or 
supine diastolic blood pressure (DBP) ≥ 95 at Screening or Baseline. A repeat blood pressure 
measurement is allowed once during the Screening Period and once at Baseline. The repeat 
measurements can be used to determine eligibility. The repeat blood pressure measurement at 
Screening can be conducted on a different day within the Screening Period, if needed. 
13. Subject has a BMI ≥ 40 or < 18 kg/m2 at Screening. 
A complete listing of study entry criteria is provided in Section 8. 


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Investigational Product, Dosage and Mode of Administration:  
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 group, each dose of study drug will consist of 1 x 200 mg 
tablet and 1 x matching placebo tablet. 
• 
For the SEP-4199 CR 400 mg/day group, each dose of study drug will consist of 2 x 200 mg 
tablets. 
• 
For the placebo group, each dose of study drug will consist of 2 x matching placebo 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:  
Double-blind treatment will be self-administered by the subject once daily for 6 weeks.  
Reference Therapy, Dosage and Mode of Administration:  
Placebo will be supplied as tablets matching the active treatment. 
Placebo 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. 
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 eCRF. 
Treatment with all prior psychotropic medications (eg, antipsychotic agents, antidepressants, and 
mood stabilizers) and herbal supplements must be discontinued as tolerated and clinically appropriate 
at least 3 days or 5 half-lives (whichever is longer) prior to Baseline. Subjects treated with MAOIs, 
fluoxetine, or olanzapine/fluoxetine combination must discontinue these medications at least 28 days 
prior to randomization. Clozapine used at 200 mg/day or less for insomnia, agitation, or anxiety must 
be discontinued at least 28 days prior to Baseline. Subjects with a history of treatment with clozapine 
for any reason at doses greater than 200 mg/day or at doses less than or equal to 200 mg/day for a 
usage other than insomnia, agitation, or anxiety are excluded from study participation. Depot 
neuroleptics must have been discontinued at least 30 days or one treatment cycle (whichever is 
longer) prior to Baseline. Subjects who, in the opinion of the Investigator, cannot safely discontinue 
prior psychotropic medications, are not eligible for the study and will be screen failed. 
Non-psychotropic medications used to treat mild, chronic medical conditions may be used during 
Screening and after Baseline if the dose and regimen have been stable (± 25%) for at least 30 days 
prior to Screening. Medications for short-term (no more than 10 days) treatment of a medical 
condition are allowed provided that the medications do not prolong the QTc interval. Section 24, 
Appendix V provides a representative, but not exhaustive, list of medications that prolong the QT 
interval and are not allowed during the study.  
Medications used to treat movement disorders should be tapered and discontinued prior to Baseline 
but may be reinstituted 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 during Screening and for 
Weeks 1-3 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 


Protocol SEP380-301, Version 3.00 
 
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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 for any reason, and the use of dietary supplements or other 
complementary or alternative medications for treating depression during the trial is not permitted. 
Further details are provided in Section 10.3. 
Study Endpoints:  
Primary Efficacy Endpoint: 
• 
Change from Baseline to Week 6 in MADRS total score 
Secondary Efficacy Endpoints: 
• 
Change from Baseline to Week 6 in CGI-BP-S depression score 
Additional Efficacy Endpoints:  
• 
Change from Baseline in MADRS total score at Weeks 1, 2, and 4 
• 
Change from Baseline in CGI-BP-S depression score at Weeks 1, 2, and 4 
• 
The proportion of subjects with treatment response, defined as ≥ 50% reduction from Baseline in 
MADRS total score, at Week 6 
• 
The proportion of subjects meeting criteria for remission, defined as MADRS total score ≤ 12, at 
Week 6 
• 
Change from Baseline to Week 6 in the MADRS-6 core symptoms subscale 
• 
Change from Baseline in HAM-A total score at Weeks 1, 2, 4, and 6 
• 
Change from Baseline to Week 6 in the QIDS-SR16 score 
• 
Change from Baseline to Week 6 in the SDS total score 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) at Week 6 
• 
Change from Baseline to Week 6 in the EQ-5D-5L Index score and VAS score 
• 
Change from Baseline to Week 6 in the SHAPS total score 
Safety Endpoints:  
• 
The incidence of overall AEs, discontinuation due to AEs, and SAEs 
• 
The incidence of hyperprolactinemia-related AESI by sex and overall 
• 
Clinical laboratory evaluations (serum chemistry, hematology, thyroid panel, and urinalysis) 
• 
Clinical evaluations (vital signs including orthostatic effects, and 12-lead ECGs) 
• 
Change and percent change from Baseline to Week 6 in body weight (kg) 
• 
Change from Baseline to Week 6 in BMI (kg/m2) 
• 
Changes from Baseline in metabolic parameters, including glucose, hemoglobin A1c (HbA1c), 
insulin, Homeostatic Model Assessment for Insulin (HOMA-IR), total cholesterol, high density 
lipoprotein (HDL), low density lipoprotein (LDL), and triglycerides at Week 6. 
• 
Incidence of treatment-emergent mania, defined as a YMRS total score ≥ 16 at two consecutive 
visits or at final visit, or an AE of hypomania or mania 
• 
Mean changes from Baseline and the proportion of subjects with worsening on the movement 
disorders scales: AIMS, BARS, and modified SAS at Week 6 


Protocol SEP380-301, Version 3.00 
 
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• 
Frequency and severity of suicidal ideation and suicidal behavior as assessed by the C-SSRS 
• 
Occurrence of potential symptoms of withdrawal from SEP-4199 CR measured by change from 
Week 6 in the PWC total score at the safety Follow-up Visit 
Pharmacokinetic and Pharmacodynamic Endpoints:  
• 
Plasma concentrations of aramisulpride and esamisulpride 
• 
Plasma concentrations of prolactin.  
Statistical Methods: 
The primary analysis population for the efficacy analysis will be the Intent-to-Treat (ITT) population. 
The ITT population will include all randomized subjects who receive at least one dose of study 
medication and have at least one post-Baseline assessment in any efficacy variable. 
Unless otherwise specified, the safety data analysis will be based on the Safety population. The Safety 
population will include all randomized subjects who receive at least one dose of study medication. 
Estimand of Primary Interest 
Population of 
Interest 
Adults who meet inclusion/exclusion criteria (major depressive episode 
associated with bipolar I disorder and have moderate-to-severe symptoms of 
depression as demonstrated by a MADRS total score ≥ 22 and CGI-BP-S 
depression score ≥ 4 at Screening and Baseline) and are in the ITT 
population. 
Outcome Measure/ 
Endpoint 
Change from Baseline in MADRS total score at Week 6 
Treatment 
Condition of 
Interest 
A hypothetical strategy is used to address intercurrent event, assuming that 
the value of the variable to reflect the clinical question of interest is the value 
which the variable would have taken in the hypothetical scenario defined. 
Intercurrent Event 
Regardless of adherence to treatment (ie, discontinuation of assigned 
treatment) 
Population Level 
Summary Measure 
Treatment difference between SEP-4199 CR dose groups and placebo for 
mean change from Baseline in MADRS total score by using the mixed model 
for repeated measures (MMRM) per the randomized treatment based on the 
ITT population. 
Primary Efficacy Endpoint Analyses 
The primary efficacy analyses of the primary efficacy endpoint (the change from Baseline in MADRS 
total score at Week 6) will be performed using a likelihood-based MMRM model based on the ITT 
population. The response (dependent) variable is the change from Baseline in the MADRS total score 
assessed at Weeks 1, 2, 4, and 6. Specifically, the MMRM model includes fixed effects terms for 
treatment, visit (as a categorical variable), pooled country, Baseline MADRS total score, and 
treatment-by-visit interaction. Restricted maximum likelihood estimation method will be applied 
using an unstructured covariance model. The Kenward Roger approximation will be used to estimate 
denominator degrees of freedom. The least squares (LS) mean treatment differences (each SEP-4199 
CR dose minus placebo) of change from Baseline at Week 6, 2-sided 95% confidence intervals (CI), 
and the associated p-values will be calculated based on this model. 
The model assumptions underlying the primary analysis will be assessed. Specifically, the normality 
and homoscedasticity assumptions underlying the primary MMRM model will be assessed 
graphically. Conditional studentized and scaled residuals will be plotted against the predicted values, 
respectively, and Q-Q (quantile-quantile) plots of these residuals versus the expected quantiles of the 
standard normal distribution will be presented to provide a graphical view of similarity and difference 


Protocol SEP380-301, Version 3.00 
 
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in the two distributions. If the unstructured covariance model fails to converge, a more parsimonious 
model is likely necessary, but not necessarily correct. in this case, an MMRM based on structures 
more general than unstructured one, ie, separate unstructured matrices by treatment, will be checked. 
If there is evidence of deviations from the model assumption(s), the degree and nature of such 
deviation(s) will be explored to better understand the potential impact on interpretation of the primary 
efficacy analysis. 
The primary efficacy analysis will be repeated for the Per Protocol (PP) population to examine the 
impact of protocol violation and deviations in a way that is less biased and to obtain a more 
interpretable result. 
The primary efficacy endpoint will also be analyzed using an analysis of covariance (ANCOVA) 
model using the last observation carried forward (LOCF) approach, as a supportive analysis. The 
model will include terms for treatment, pooled country, and Baseline MADRS total score as 
covariates. 
To address early dropouts under the assumption of missing not at random (MNAR), a pattern-mixture 
model using a placebo-based multiple imputation method and a pattern mixture model using multiple 
imputations with penalties (ie, deflating the individually estimated treatment effect size by known 
factors) will be performed as sensitivity analyses to explore the robustness of the MMRM results for 
the primary analysis. In case of a deviation from the assumptions required for the primary analysis, to 
confirm the robustness of the primary analysis result, additional sensitivity analysis per permutation 
test will be performed: fit a large number of datasets based on a same MMRM for the primary 
analysis with randomly assigning pseudo-treatment group designations. 
To support global regulatory decision-making, the consistency of treatment effects across regions (ie, 
North America, Latin America, Europe, Japan) will be assessed. Treatment effects and measures of 
their uncertainty for individual region, and treatment-by-region interaction will be evaluated for the 
primary efficacy endpoint. An MMRM model that includes fixed effects terms for treatment, visit (as 
a categorical variable), region, Baseline MADRS total score, treatment*visit interaction, 
treatment*region interaction, and treatment*visit*region interaction, will be performed using an 
unstructured covariance matrix. If p-value for treatment-by-region interaction at Week 6 is significant 
at level of 0.10, the nature of this significant interaction (quantitative vs qualitative) will be further 
evaluated using the Gail and Simon test (Gail 1985) and other interaction tests such as the Pan-Wolfe 
test (Pan 1997). Shrinkage analyses for treatment effect of regions, which are based on weighted 
averages of the overall effect estimate and the estimate using data from individual regions, will be 
performed. Shrinkage analyses for treatment effect of countries may be performed, as appropriate. 
Secondary Efficacy Endpoint Analyses 
The secondary efficacy endpoint (change from Baseline in CGI-BP-S depression score at Week 6) 
will be analyzed with an MMRM model similar to the one used in the primary efficacy analysis 
(adjusted with the corresponding Baseline). The LS mean treatment differences (each SEP-4199 CR 
dose minus placebo) of change from Baseline at Week 6, their 2-sided 95% CIs, and the associated 
p-values will be calculated based on the model. Additional supportive and sensitivity analyses to the 
ones performed for the primary efficacy endpoint will be conducted for the secondary efficacy 
endpoint to address early dropouts or potential deviations from the model assumption(s). 
Multiplicity Adjustment 
The hypotheses associated with the primary and secondary variables for efficacy claim are grouped 
into 2 hierarchical families: Families 1 and 2, respectively. The enhanced mixture truncated 
Hochberg-based gatekeeping procedure with the logical relationships among the hypotheses (ie, 
𝐻𝐻21 will be tested only if 𝐻𝐻11 is rejected; 𝐻𝐻22 will be tested only if 𝐻𝐻12 is rejected) will be applied to 
control the family-wise Type 1 error rate of 5% (two-sided) for the hypotheses in Families 1 and 2. 
The truncation parameter in Family 1, which is used to determine α propagation rule, is chosen as 0.5. 
The details for how to generate corresponding adjusted p-value for individual hypothesis based on 


Protocol SEP380-301, Version 3.00 
 
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above multiplicity adjustment approach will be provided in the statistical analysis plan (SAP), and the 
rationale of choosing a truncation parameter is provided in Section 15.4.3.4. 
 
 
Additional Efficacy Endpoint Analyses 
MADRS-6 core symptoms subscale score and HAM-A total score will be analyzed with an MMRM 
model similar to the one used in the primary efficacy analysis adjusted with the corresponding 
Baseline. QIDS-SR16 total score, SDS total score and subscale scores, EQ-5D-5L related scores, and 
SHAPS total score will be analyzed with an ANCOVA model similar to the one used in the 
supportive ANCOVA analysis for the primary efficacy endpoint adjusted with the corresponding 
Baseline as covariate. 
Categorical efficacy endpoints (ie, proportion of the responders and proportion of the remitters at 
Week 6) will be analyzed using a logistic regression model with treatment, region, and Baseline 
MADRS total score as covariates using a LOCF approach. Proportion of subjects meeting functional 
remission criteria per the SDS subscales (defined as SDS total score ≤ 6 and SDS subscale scores ≤ 2) 
will be analyzed using a similar logistic regression model with corresponding Baseline as covariate. 
Safety Analyses: 
A treatment-emergent adverse event (hereafter referred to as AE) is defined as an AE with a start date 
on or after the date of first dose through 7 days after study drug discontinuation (14 days for serious 
adverse events) for subjects who complete or discontinue this study but do not enter into the extension 
study, or through the last study day of the double-blind treatment period for subjects continuing into 
the extension study. 
The number and percentage of subjects with AEs, discontinuation due to AEs, and SAEs will be 
summarized by treatment group. The incidence of AEs of special interest, including but not limited to 
hyperprolactinaemia-related AEs, will be summarized by treatment group for overall and by gender as 
appropriate. Incidence of post-treatment AEs (defined as an AE with a start date after the date of last 


Protocol SEP380-301, Version 3.00 
 
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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. 
Descriptive statistics (mean, median, etc) will be provided by visit and treatment group for observed 
values or changes from Baseline for safety variables (continuous). Categorical results (eg, urinalysis 
tests) will be summarized by study visit and treatment group using frequency and percentage. In 
addition, the change from Baseline at endpoint for selected laboratory parameters (eg, HbA1c, insulin, 
HOMA-IR, glucose, lipids parameters, prolactin) will be evaluated using a nonparametric rank 
ANCOVA analysis. For comparison versus placebo, stratified by region, the change from Baseline at 
endpoint and Baseline value will be ranked. A linear regression will be conducted by region, on the 
change from Baseline ranks and Baseline value rank as independent variable to produce regression 
residuals. Using the values of the residuals as scores, Mantel-Haenszel row mean score tests will be 
produced for each SEP-4199 CR dose group versus placebo after stratification by region. 
An MMRM analysis will be performed to compare SEP-4199 CR dose groups with placebo for 
change from Baseline in YMRS score. The MMRM model includes fixed effects terms for treatment, 
visit (as a categorical variable), region, corresponding Baseline score, and treatment-by-visit 
interaction. An ANCOVA model using the LOCF approach will be conducted for change and percent 
change from Baseline in body weight (kg), changes from Baseline in BMI (kg/m2), BARS total score, 
AIMS total score, and SAS 10-item mean score. The ANCOVA model will include terms for 
treatment, region, and corresponding Baseline value as covariate. 
Treatment-emergent mania is defined as a YMRS score of ≥ 16 on any 2 consecutive post-Baseline 
visits or at the final assessment, or an AE of mania or hypomania. If a subject has no reported AE of 
mania or hypomania and has no post-Baseline assessment of YMRS, incidence of treatment-emergent 
mania will be set to missing. SEP-4199 CR will be compared to placebo in incidence of treatment-
emergent mania in a logistic regression model including factors of treatment, region, and Baseline 
YMRS total score as covariate. 
For the 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 treatment 
group for overall post-Baseline treatment period. 
The PWC score will be summarized by presenting descriptive statistics of observed values and 
changes from Week 6 (EOT/ET) by treatment group for the follow-up period. 
Sample Size: The sample size is estimated based on the primary efficacy endpoint, the change from 
Baseline in MADRS total score at Week 6. Based on the Phase 2 Study SEP380-201 results for both 
planned and post-hoc analyses of the primary endpoint, a common standard deviation (SD) of 10 and 
mean improvement of 3.5 (which resulted in an effect size 0.35) over placebo are assumed for both 
SEP-4199 CR 200 mg/day and 400 mg/day dose groups. With a randomization ratio of 1:1:1 for 
placebo, SEP-4199 CR 200 mg/day and 400 mg/day, a sample size of 165 subjects per treatment 
group will provide at least 80% conjunctive power to reject both null hypotheses of no difference 
between SEP-4199 CR doses and placebo and at least 85% power to reject each individual null 
hypothesis after multiplicity adjustment for two comparisons of the primary endpoint using the 
enhanced mixture truncated Hochberg gatekeeping procedure (truncation parameter 0.5, 2-sided 
Type I error of 0.05). An upward adjustment of approximately 5% is assumed to compensate for 
subjects who are randomized but have no post-Baseline efficacy assessment. Thus, a total sample of 
approximately 174 subjects per group (522 subjects in total) will be randomized. The sample size 
calculation is based Monte Carlo computer simulations. 
 


Protocol SEP380-301, Version 3.00 
 
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Table 2: Schedule of Assessments 
 
Visit 1 
Visit 2a 
Visit 3 
Visit 4 
TC1b 
Visit 5 
TC2b 
Visit 6c 
Visit 7d 
Screening 
Washoute 
Baseline 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
EOT/ET 
Follow-up 
Day 
-22 to -2 
Day -1 
Day 7 
(± 2) 
Day 14 
(± 2) 
Day 21 
(± 2) 
Day 28 
(± 2) 
Day 35 
(± 2) 
Day 42 
(± 2) 
7 (± 2) 
days after 
last dose 
Obtain informed consent 
X 
 
 
 
 
 
 
 
 
Obtain informed consent for 
duplicate subject check (where 
local regulations allow) 
X 
 
 
 
 
 
 
 
 
Obtain informed consent for 
optional pharmacogenomic 
sampling, if applicable 
 
X 
 
 
 
 
 
 
 
Lifetime Illness Characteristics 
Questionnairef 
X 
 
 
 
 
 
 
 
 
Montgomery-Asberg Depression 
Rating Scale, Self-rating version 
(MADRS-S)f 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
Duplicate Subject Check 
X 
 
 
 
 
 
 
 
 
Pre-Baseline Eligibility Reviewg 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Psychiatric Historyh 
X 
 
 
 
 
 
 
 
 
Family Psychiatric and Medical 
History 
X 
 
 
 
 
 
 
 
 
Structured Clinical Interview for 
DSM-5-Clinical Trial Version 
(SCID-5-CT)i 
X 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
 
 
 
X 
X 


Protocol SEP380-301, Version 3.00 
 
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Table 2: 
Schedule of Assessments (Continued) 
 
Visit 1 
Visit 2a 
Visit 3 
Visit 4 
TC1b 
Visit 5 
TC2b 
Visit 6c 
Visit 7d 
Screening 
Washoute 
Baseline 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
EOT/ET 
Follow-up 
Day 
-22 to -2 
Day -1 
Day 7 
(± 2) 
Day 14 
(± 2) 
Day 21 
(± 2) 
Day 28 
(± 2) 
Day 35 
(± 2) 
Day 42 
(± 2) 
7 (± 2) 
days after 
last dose 
Neurological Examination 
X 
X 
 
 
 
 
 
X 
X 
Prior/Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subject Eligibility Checkj  
 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Dispense Study Drug  
 
X 
X 
X 
 
X 
 
 
 
Study Drug Accountabilityk 
 
 
X 
X 
 
X 
 
X 
 
Schedule Next Visitl 
X 
X 
X 
X 
 
X 
 
X 
 
EFFICACY ASSESSMENTS 
 
 
 
 
 
 
 
 
 
Montgomery-Asberg Depression 
Rating Scale (MADRS)m 
X 
X 
X 
X 
 
X 
 
X 
 
Hamilton Anxiety Rating Scale 
(HAM-A)n 
 
X 
X 
X 
 
X 
 
X 
 
Quick Inventory of Depressive 
Symptomatology-Self-Report 
(QIDS-SR16) 
 
X 
 
 
 
 
 
X 
 
Sheehan Disability Scale (SDS) 
 
X 
 
 
 
 
 
X 
 
EuroQol - 5 Dimension - 5 Level 
(EQ-5D-5L) 
 
X 
 
 
 
 
 
X 
 
Snaith-Hamilton Pleasure Scale 
(SHAPS) 
 
X 
 
 
 
 
 
X 
 
Clinical Global Impression-
Bipolar Version-Severity of 
Illness (CGI-BP-S)o 
X 
X 
X 
X 
 
X 
 
X 
 


Protocol SEP380-301, Version 3.00 
 
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Table 2: 
Schedule of Assessments (Continued) 
 
Visit 1 
Visit 2a 
Visit 3 
Visit 4 
TC1b 
Visit 5 
TC2b 
Visit 6c 
Visit 7d 
Screening 
Washoute 
Baseline 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
EOT/ET 
Follow-up 
Day 
-22 to -2 
Day -1 
Day 7 
(± 2) 
Day 14 
(± 2) 
Day 21 
(± 2) 
Day 28 
(± 2) 
Day 35 
(± 2) 
Day 42 
(± 2) 
7 (± 2) 
days after 
last dose 
SAFETY ASSESSMENTS 
 
 
 
 
 
 
 
 
 
Vital Sign Measurementsp 
X 
X 
X 
X 
 
X 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
Weight and Body Mass Indexq 
X 
X 
 
 
 
 
 
X 
X 
Waist Circumference 
 
X 
 
 
 
 
 
X 
 
Pretreatment Event/ 
Adverse Events Monitoringr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
X 
X 
X 
 
X 
 
X 
X 
Serum Chemistrys 
X 
X 
 
X 
 
 
 
X 
X 
Hematology 
X 
X 
 
X 
 
 
 
X 
X 
Urinalysis 
X 
X 
 
X 
 
 
 
X 
X 
Serum Prolactint 
X 
X 
 
X 
 
 
 
X 
X 
Hemoglobin A1c (HbA1c) 
X 
X 
 
 
 
 
 
X 
 
Lipid Panel s 
X 
X 
 
 
 
 
 
X 
 
Serum Insulins 
X 
X 
 
 
 
 
 
X 
 
High Sensitivity C-Reactive 
Protein (hs-CRP) 
X 
X 
 
 
 
 
 
X 
 
Hepatitis B/C Panel 
X 
 
 
 
 
 
 
 
 
Thyroid Panel  
X 
X 
 
 
 
 
 
X 
 
Serum Follicle Stimulating 
Hormone (postmenopausal 
women or if menopause is 
suspected) 
X 
 
 
 
 
 
 
 
 


Protocol SEP380-301, Version 3.00 
SEP-4199 CR 
Confidential and Proprietary 
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06 Dec 2022 
Table 2: 
Schedule of Assessments (Continued) 
Visit 1 
Visit 2a 
Visit 3 
Visit 4 
TC1b 
Visit 5 
TC2b 
Visit 6c 
Visit 7d 
Screening 
Washoute 
Baseline 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
EOT/ET 
Follow-up 
Day 
-22 to -2 
Day -1 
Day 7 
(± 2) 
Day 14 
(± 2) 
Day 21 
(± 2) 
Day 28 
(± 2) 
Day 35 
(± 2) 
Day 42 
(± 2) 
7 (± 2) 
days after 
last dose 
Serum Pregnancy Test (females 
of childbearing potential)u 
X 
Urine Pregnancy Test (females 
of childbearing potential)u,v 
X 
X 
X 
X 
Urine Drug Screenv 
X 
Rapid Urine Drug Testv 
X 
X 
X 
X 
Young Mania Rating Scale 
(YMRS)w 
X 
X 
X 
X 
X 
X 
X 
Physician’s Withdrawal 
Checklist (PWC)x 
X 
X 
Columbia-Suicide Severity 
Rating Scale (C-SSRS)y 
X 
X 
X 
X 
X 
X 
X 
Abnormal Involuntary 
Movement Scale (AIMS) 
X 
X 
Barnes Akathisia Scale (BARS) 
X 
X 
Modified Simpson-Angus Scale 
(SAS) 
X 
X 
Blood Sampling for Plasma PK 
and Plasma Prolactint,z 
X 
X 
X 
X 
X 
Optional Blood Sampling for 
Pharmacogenomic Testingaa 
X 
Abbreviations: BMI = body mass index; eCRF = electronic case report form; DSM-5 = The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; EOT = End of 
Treatment; ET = Early Termination; hCG = human chorionic gonadotropin; PK = pharmacokinetics; TC = telephone call. 
Note: To ensure subject safety and data integrity, should circumstances warrant and with Sponsor approval, remote site/subject visits may be conducted. 
a Visit 2 is defined as the Baseline Visit. Study drug will be dispensed at Visit 2/Day -1, and subjects will be instructed to take their first dose of study drug the following morning 
(Day 1). 


Protocol SEP380-301, Version 3.00 
 
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b A telephone call at Day 21 and Day 35 to ascertain adverse events and concomitant medications since last visit. 
c Visit 6 is the End of Treatment/Early Termination visit. Subjects who discontinue the study prior to Visit 6 will have all Visit 6 procedures performed at the time of 
discontinuation. 
d Subjects who discontinue early from the study or complete the study and do not enter the extension study (SEP380-303) will have a safety Follow-up Visit (7 [± 2] days after 
their last dose of study drug). 
e Screening assessments may occur over multiple days. Hospitalization during the Screening Period will not be allowed, except where required by local regulations or when 
determined to be clinically indicated based on the subject’s psychiatric history and current psychiatric symptoms. Medical justification must be provided to the Medical Monitor 
and the Medical Monitor must approve the request for hospitalization. In such cases, a maximum of 7 days’ hospitalization during washout of prior medications in the Screening 
Period will be allowed. An extension of the Screening Period by up to 7 days may be allowed, with prior approval from the Medical Monitor. 
f Following Informed Consent, the Lifetime Illness Characteristics Questionnaire and the MADRS-S will be completed by the subject prior to other assessments at Screening. 
Subject must have a MADRS-S total score ≥ 22 at Screening. 
g For the pre-Baseline review by the Sponsor Eligibility Committee, sites will be required to submit specific Screening information for CRO and Sponsor review, prior to 
proceeding to Baseline. Details are provided in Section 26, Appendix VII. 
h Includes a psychiatric history form that will include variables related to duration of illness, treatment response (eg, prior medications used to treat bipolar disorder) and other 
similar variables. 
i The SCID-5-CT will be used to support the DSM-5 diagnosis and must be administered by a qualified rater at the site. 
j Subject eligibility check in IXRS is to be performed prior to randomization, but after all scales are completed, to confirm Blinded Inclusion Criterion 12 is met.  
k Clinical site staff will record the date and time of the 3 doses prior to the study visit in the source (all visits) and eCRF (Visit 4 [Day 14] and Visit 6 [Day 42] only), based on 
subject self-report. 
l Instruct subject to record dosing date and time of the last 3 doses prior to the study visit on the blister pack wallet or other format and bring back all used/unused study drug and 
packaging to next visit. 
m Subjects must have a MADRS total score ≥ 22 at Screening (Visit 1) and Baseline (Visit 2). Subjects who demonstrate a decrease (improvement) of ≥ 25% in MADRS total 
score from Screening (Visit 1) to Baseline (Visit 2) must be screen failed. 
n The Structured Interview Guide for the HAM-A (SIGH-A) will be used for administration of the HAM-A. 
o Subjects must have a CGI-BP-S depression score ≥ 4 at Screening (Visit 1) and Baseline (Visit 2). 
p 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. Respiratory rate and temperature will also be measured. 
q BMI will be calculated by clinical site staff at Screening (Visit 1) and recorded in the eCRF. At Baseline (Visits 2), Visit 6/EOT/ET (Day 42), and Visit 7 (Follow-up), BMI does 
not need to be calculated by the clinical site staff as it will be calculated in the analysis. 
r Events occurring prior to first dose of study drug are programmatically identified as pretreatment events. Events occurring after first dose of study drug are programmatically 
identified as adverse events. 
s Subjects are required to fast for at least 8 hours prior to sample collection for laboratory testing at Baseline (Visit 2) and Visit 6/EOT/ET (Day 42). Fasting for 8 hours prior to 
Screening (Visit 1) is also recommended to avoid potential retests. 
t Prolactin levels (serum and plasma) will be masked for any assessment collected after the first study drug dose. Prolactin levels prior to the first study drug dose will be 
unmasked. 
u For females of childbearing potential, any positive urine ß-hCG test should be confirmed by serum β-hCG. 
v 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. 
w To be eligible for enrollment, subjects must have a YMRS total score ≤ 12 at Screening (Visit 1) and Baseline (Visit 2). 
x The PWC will be completed for early termination subjects and subjects who complete the study and do not rollover into Study SEP380-303; it will not be completed for subjects 
who rollover into Study SEP380-303. 
y At the Screening visit (Visit 1), the “Baseline/Screening” version will be completed; for all subsequent visits, the “Since Last Visit” version of the C-SSRS will be administered. 


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z Blood sample for SEP-4199 population pharmacokinetic analysis for R- and S-enantiomers and/or plasma prolactin measurement will be collected at Screening (Visit 1), Baseline 
(Visit 2), Visit 4 (Day 14), Visit 6/EOT/ET (Day 42), and Visit 7/Follow-up (7 ± 2 days after last dose), with a record of the time of last 3 administered doses on the eCRF at 
Visit 4 (Day 14) and Visit 6/EOT/ET (Day 42). 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. 
aa Blood sampling for pharmacogenomic testing will be requested but is not required for participation in the study. 
 


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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 ...............24 
TABLE OF CONTENTS ...............................................................................................................24 
LIST OF TABLES .........................................................................................................................29 
LIST OF FIGURES .......................................................................................................................29 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................30 
4. 
INTRODUCTION ......................................................................................................35 
4.1. 
Background .................................................................................................................35 
4.2. 
Study Conduct Rationale ............................................................................................36 
4.3. 
Risk-Benefit Assessment ............................................................................................36 
5. 
STUDY OBJECTIVES ..............................................................................................37 
5.1. 
Primary Efficacy Objective ........................................................................................37 
5.2. 
Secondary Efficacy Objective ....................................................................................37 
5.3. 
Additional Efficacy Objectives ...................................................................................37 
5.4. 
Safety Objectives ........................................................................................................37 
5.5. 
Pharmacokinetic and Pharmacodynamic Objectives ..................................................38 
6. 
STUDY ENDPOINTS ................................................................................................39 
6.1. 
Primary Efficacy Endpoint .........................................................................................39 
6.2. 
Secondary Efficacy Endpoints ....................................................................................39 
6.3. 
Additional Efficacy Endpoints ...................................................................................39 
6.4. 
Safety Endpoints .........................................................................................................39 
6.5. 
Pharmacokinetic and Pharmacodynamic Endpoints ...................................................40 
7. 
INVESTIGATIONAL PLAN .....................................................................................41 
7.1. 
Overall Study Design ..................................................................................................41 
7.2. 
Treatment Assignment and Blinding ..........................................................................44 
7.2.1. 
Treatment Assignment ................................................................................................44 
7.2.2. 
Blinding ......................................................................................................................44 


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7.2.3. 
Emergency Unblinding Procedures ............................................................................45 
7.3. 
Rationale .....................................................................................................................45 
7.3.1. 
Rationale for the Study Design ...................................................................................45 
7.3.2. 
Rationale for the Dosages ...........................................................................................45 
7.3.3. 
Rationale for the Study Population .............................................................................47 
7.3.4. 
Rationale for the Endpoints ........................................................................................47 
7.4. 
Prevention of Missing Data ........................................................................................47 
8. 
SELECTION OF SUBJECTS ....................................................................................48 
8.1. 
Subject Inclusion Criteria ...........................................................................................48 
8.2. 
Subject Exclusion Criteria ..........................................................................................49 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................54 
9.1. 
Description of Study Drug ..........................................................................................54 
9.2. 
Study Drug Packaging and Labeling ..........................................................................54 
9.2.1. 
Package Description ...................................................................................................54 
9.2.2. 
Labeling Description ..................................................................................................54 
9.3. 
Study Drug Storage .....................................................................................................55 
9.4. 
Dispensing of Study Drug ..........................................................................................55 
9.5. 
Study Drug Accountability .........................................................................................55 
9.6. 
Study Drug Handling and Disposal ............................................................................56 
10. 
TREATMENT OF SUBJECTS ..................................................................................57 
10.1. 
Study Medication ........................................................................................................57 
10.2. 
Treatment Compliance ................................................................................................57 
10.3. 
Concomitant Medications and Therapies ...................................................................57 
10.3.1. 
Prior Medications ........................................................................................................58 
10.3.2. 
Concomitant Non-psychotropic Medications .............................................................58 
10.3.3. 
Concomitant Psychotropic Medications .....................................................................58 
10.3.4. 
Prohibited Medications ...............................................................................................59 
10.4. 
Contraception Requirements ......................................................................................59 
10.5. 
Guidance for Overdose ...............................................................................................61 
11. 
STUDY ASSESSMENTS ..........................................................................................62 
11.1. 
Duplicate Subject Check .............................................................................................62 
11.2. 
Demographics and Baseline Characteristics ...............................................................62 
11.3. 
Diagnostic and Symptom Severity Scales to Inform Subject Eligibility ....................62 


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11.3.1. 
Lifetime Illness Characteristics Questionnaire ...........................................................62 
11.3.2. 
SCID-5-CT .................................................................................................................63 
11.3.3. 
Montgomery-Asberg Depression Rating Scale (MADRS) ........................................63 
11.3.4. 
Montgomery-Asberg Depression Rating Scale, Self-rating Version 
(MADRS-S) ................................................................................................................63 
11.3.5. 
Clinician Global Impression-Bipolar Version-Severity of Illness (CGI-BP-S) .........64 
11.3.6. 
Young Mania Rating Scale (YMRS) ..........................................................................64 
11.4. 
Efficacy Assessments .................................................................................................64 
11.4.1. 
Montgomery-Asberg Depression Rating Scale (MADRS) ........................................64 
11.4.2. 
Clinician Global Impression-Bipolar Version-Severity of Illness (CGI-BP-S) .........64 
11.4.3. 
Hamilton Anxiety Rating Scale (HAM-A) .................................................................64 
11.4.4. 
Quick Inventory of Depressive Symptomatology – Self Report (QIDS-SR16) .........65 
11.4.5. 
Sheehan Disability Scale (SDS) .................................................................................65 
11.4.6. 
EuroQol - 5 Dimension - 5 Level (EQ-5D-5L) ..........................................................65 
11.4.7. 
Snaith-Hamilton Pleasure Scale (SHAPS) .................................................................66 
11.5. 
Safety Assessments .....................................................................................................66 
11.5.1. 
Adverse Events ...........................................................................................................66 
11.5.2. 
Clinical Laboratory Tests ...........................................................................................66 
11.5.3. 
Vital Signs ..................................................................................................................67 
11.5.4. 
Centrally-read ECG ....................................................................................................67 
11.5.5. 
Neurological and Physical Examination .....................................................................67 
11.5.6. 
Safety Scales ...............................................................................................................68 
11.5.6.1. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................68 
11.5.6.2. 
Young Mania Rating Scale (YMRS) ..........................................................................68 
11.5.6.3. 
Abnormal Involuntary Movement Scale (AIMS) .......................................................68 
11.5.6.4. 
Barnes Akathisia Rating Scale (BARS) .....................................................................69 
11.5.6.5. 
Modified Simpson-Angus Scale (SAS) ......................................................................69 
11.5.6.6. 
Physician’s Withdrawal Checklist (PWC) ..................................................................69 
11.6. 
Pharmacokinetic Assessments ....................................................................................69 
11.7. 
Pharmacogenomic Testing (Optional) ........................................................................70 
11.8. 
Study Visits and Assessments ....................................................................................70 
11.8.1. 
Screening: Visit 1 (Day -22 to -2) ..............................................................................70 
11.8.2. 
Baseline and Treatment Period: Day -1 to Day 42 .....................................................72 


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11.8.2.1. 
Visit 2: Baseline (Day -1) ...........................................................................................72 
11.8.2.2. 
Visit 3 (Day 7 ± 2) ......................................................................................................74 
11.8.2.3. 
Visits 4 (Day 14 ± 2) ..................................................................................................75 
11.8.2.4. 
Telephone Contact (Day 21 ± 2) ................................................................................76 
11.8.2.5. 
Visit 5 (Day 28 ± 2) ....................................................................................................76 
11.8.2.6. 
Telephone Contact: (Day 35 ± 2) ...............................................................................77 
11.8.3. 
Visit 6: End of Treatment/Early Termination (Day 42 ± 2) .......................................77 
11.8.4. 
Follow-up: Visit 7 (7 ± 2 days after last dose) ...........................................................78 
12. 
SAFETY REPORTING ..............................................................................................80 
12.1. 
Definitions ..................................................................................................................80 
12.1.1. 
Adverse Events ...........................................................................................................80 
12.1.2. 
Serious Adverse Events ..............................................................................................80 
12.1.3. 
Adverse Events of Special Interest .............................................................................81 
12.2. 
Objective Findings ......................................................................................................82 
12.3. 
Collection and Recording of Adverse Events .............................................................82 
12.4. 
Immediately Reportable Events ..................................................................................84 
12.4.1. 
Serious Adverse Event/Serious Pretreatment Event ...................................................84 
12.4.2. 
Pregnancy ...................................................................................................................84 
12.5. 
Data and Safety Monitoring Board .............................................................................85 
13. 
TERMINATION OF SUBJECT FROM STUDY/DISCONTINUATION OF 
STUDY DRUG ...........................................................................................................86 
13.1. 
Criteria for Subject Termination .................................................................................86 
14. 
STUDY TERMINATION ..........................................................................................88 
15. 
STATISTICS ..............................................................................................................89 
15.1. 
Sample Size ................................................................................................................89 
15.2. 
Statistical Hypotheses .................................................................................................89 
15.3. 
Analysis Populations ..................................................................................................89 
15.4. 
Data Analysis ..............................................................................................................90 
15.4.1. 
Study Subject ..............................................................................................................90 
15.4.2. 
Per Protocol Criteria ...................................................................................................91 
15.4.3. 
Efficacy Analyses .......................................................................................................91 
15.4.3.1. 
Primary Efficacy Endpoint Analysis ..........................................................................92 
15.4.3.2. 
Secondary Efficacy Endpoint Analysis ......................................................................94 


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15.4.3.3. 
Additional Efficacy Endpoint Analyses .....................................................................94 
15.4.3.4. 
Adjustment for Multiplicity ........................................................................................94 
15.4.3.5. 
Efficacy Subgroup Analysis .......................................................................................96 
15.4.4. 
Safety Analyses ..........................................................................................................96 
15.4.4.1. 
Adverse Events ...........................................................................................................96 
15.4.4.2. 
Treatment-Emergent Mania and YMRS .....................................................................97 
15.4.4.3. 
Clinical Laboratory Assessments ...............................................................................97 
15.4.4.4. 
ECGs ...........................................................................................................................97 
15.4.4.5. 
Vital Signs ..................................................................................................................98 
15.4.4.6. 
Movement Disorder Measures ....................................................................................98 
15.4.4.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................98 
15.4.4.8. 
Physician’s Withdrawal Checklist (PWC) ..................................................................99 
15.4.5. 
Pharmacokinetic Analysis ..........................................................................................99 
15.4.6. 
Interim Analysis ..........................................................................................................99 
15.4.7. 
Treatment of Missing Data .........................................................................................99 
16. 
PROCEDURE FOR CLINICAL STUDY QUALITY CONTROL /DATA 
COLLECTION, MANAGEMENT, AND QUALITY ASSURANCE ....................100 
16.1. 
Data Collection/Electronic Data Capture (EDC) ......................................................100 
16.2. 
Computerized Systems Used for Source Data ..........................................................100 
16.3. 
Study Monitoring ......................................................................................................102 
16.4. 
Audits ........................................................................................................................102 
16.5. 
Study Documentation ...............................................................................................102 
16.6. 
Clinical Laboratory Certification and Normal Values ..............................................103 
17. 
ETHICAL AND REGULATORY OBLIGATIONS................................................104 
17.1. 
Study Conduct ..........................................................................................................104 
17.2. 
Institutional Review Board/Independent Ethics Committee ....................................104 
17.3. 
Informed Consent .....................................................................................................105 
17.4. 
Subject Privacy .........................................................................................................105 
17.5. 
Protocol Amendments and Emergency Deviations ..................................................106 
17.6. 
Records Retention .....................................................................................................106 
17.7. 
Inspection of Records ...............................................................................................106 
17.8. 
Financial Disclosure .................................................................................................106 
17.9. 
Publication Policy .....................................................................................................107 


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17.10. 
Compensation ...........................................................................................................107 
18. 
REFERENCES .........................................................................................................108 
19. 
INVESTIGATOR APPROVAL ...............................................................................110 
20. 
APPENDIX I. CARDIAC SAFETY MONITORING (ECG) ..................................111 
21. 
APPENDIX II. CLINICAL LABORATORY TESTS .............................................112 
22. 
APPENDIX III. BLOOD SAMPLE COLLECTION AND HANDLING 
GUIDELINES FOR PHARMACOKINETIC AND PLASMA PROLACTIN 
ASSESSMENTS.......................................................................................................113 
23. 
APPENDIX IV. PHARMACOGENOMICS SAMPLE COLLECTON AND 
HANDLING GUIDELINE .......................................................................................114 
24. 
APPENDIX V. PROHIBITED DRUGS KNOWN TO PROLONG THE QT 
INTERVAL ..............................................................................................................115 
25. 
APPENDIX VI. MINIMUM MADRS TOTAL SCORE CRITERIA AT 
BASELINE ...............................................................................................................116 
26. 
APPENDIX VII. PRE-BASELINE ELIGIBILITY REVIEW .................................117 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Schedule of Assessments ............................................................................................18 
Table 3: 
List of Abbreviations ..................................................................................................30 
Table 4: 
Definition of Key Study Terms ..................................................................................34 
Table 5: 
Investigational Product ...............................................................................................54 
Table 6: 
Computerized Systems Used for Source Data ..........................................................100 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................41 
Figure 2: 
Hierarchy of Hypothesis Testing for Primary and Secondary Efficacy 
Endpoints ....................................................................................................................95 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The abbreviations and the definition of key study terms used in the clinical study protocol are 
shown in Table 3 and Table 4. 
 
Table 3: List of Abbreviations 
Abbreviation 
Full Form 
AE 
Adverse event 
AESI 
Adverse events of special interest 
AIMS 
Abnormal Involuntary Movement Scale 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
BARS 
Barnes Akathisia Rating Scale 
BDRM 
Blinded data review meeting 
BLQ 
Below the limit of quantification 
BMI 
Body mass index  
bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CGI-BP-S 
Clinical Global Impression – Bipolar Version-Severity of Illness 
CI 
Confidence interval 
COVID-19 
Coronavirus disease 2019 
Cr 
Creatinine 
CR 
Controlled release 
CRO 
Contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV 
Coefficient of variation 
DBP 
Diastolic blood pressure 
DBS 
Deep brain stimulation 
DMP 
Data Management Plan 
DSMB 
Data and Safety Monitoring Board 
DSM-5 
The Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition 
ECG 
Electrocardiogram 


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Table 3: 
List of Abbreviations (Continued) 
Abbreviation 
Full Form 
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 
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 
HDL 
High density lipoprotein 
HIV 
Human immunodeficiency virus 
HLT 
High-level term 
HR 
Heart rate 
hs 
High sensitivity 
ICF 
Informed consent form 
ICH 
International Council on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug  
IR 
Immediate release 
IRB 
Institutional Review Board 
ITT 
Intention-to-treat 
IXRS 
Interactive Web Response System 
JP 
Japan 
LDL 
Low density lipoprotein 
LLN 
Lower limit of normal 
LOCF 
Last observation carried forward 


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Table 3: 
List of Abbreviations (Continued) 
Abbreviation 
Full Form 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MADRS-S 
Montgomery-Asberg Depression Rating Scale, Self-rating Version 
MDE 
Major depressive episode 
MedDRA 
Medical Dictionary for Regulatory Activities 
MAOI 
Monoamine oxidase inhibitor 
mmHg 
Millimeters of mercury 
MMRM 
Mixed model for repeated measures 
MNAR 
Missing not at random 
msec 
Millisecond 
N 
Number of subjects 
NMS 
Neuroleptic malignant syndrome 
PCS 
Potentially clinically significant 
PD 
Pharmacodynamics 
PET 
Positron emission tomography  
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
POC 
Point of care 
Pop-PK 
Population pharmacokinetics 
PP 
Per Protocol 
PR 
Time between P wave and QRS in electrocardiography 
PRN 
As needed 
PT 
Preferred term 
PVG 
Pharmacovigilance 
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 


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Table 3: 
List of Abbreviations (Continued) 
Abbreviation 
Full Form 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RR 
RR interval 
rTMS 
Repetitive transcranial magnetic stimulation  
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Simpson-Angus Scale 
SBP 
Systolic blood pressure 
SCID-5-CT 
Structured Clinical Interview for DSM-5-Clinical Trial Version 
SD 
Standard deviation 
SDS 
Sheehan Disability Scale 
SHAPS 
Snaith-Hamilton Pleasure Scale 
SIGH-A 
Structured Interview Guide for the HAM-A  
SOC 
System organ class 
SOP 
Standard Operating Procedure 
SUSARs 
Suspected unexpected serious adverse reactions 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
V 
Visit 
VCT 
Verified Clinical Trials LLC 
VNS 
Vagus nerve stimulation 
WHO-DD 
World Health Organization drug dictionary 
Wk 
Week 
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. 
Screened Subject 
Any subject who signed the study specific informed consent and 
completed at least one study related procedure. 
Screen Failures 
Any subject who signed the study specific informed consent but either 
failed to meet study requirements during Screening or met study 
requirements at Screening but was not randomized. 
Study Drug (or Study 
medication) 
Term to cover investigational drug and placebo. 
Treatment Period 
The period of the study in which the study drug is administered. 
Randomized Subject 
Any subject who was randomized into the treatment period of the study 
and was assigned a randomization number. 
Enrolled Subject 
Any subject who was successfully screened and enrolled into the 
Screening period of the study. 
Completed Subject 
Any subject who participated throughout the duration of the treatment 
period, up to and including Visit 6. 
Early Termination 
Subject 
Any subject who was successfully screened and randomized into the 
treatment period of the study but did not complete the treatment period 
of the study. 
End of Treatment 
The day that the subject receives the protocol-defined last dose of the 
study drug. 


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4. 
INTRODUCTION 
4.1. 
Background 
Bipolar spectrum illness (Bipolar I, Bipolar II, Bipolar Disorder NOS) is estimated to affect 
4.4% of the population (Merikangas 2007). Bipolar disorder causes more marked functional 
impairment (Shippee 2011) and has greater impact on quality of life than unipolar depression 
(Gutierrez-Rojaz 2008). Patients with bipolar depression spend considerably more time in 
depressive than in manic states over the course of their illnesses (Judd 2002, Judd 2003), and 
depressive symptoms therefore contribute more to impaired functioning, caregiver/family 
burden, and economic costs than do manic/mixed symptoms (Miller 2014). 
The treatment of bipolar depression is challenging, due to the complexity of clinical 
presentations, which may include mixed symptoms with depression predominating. Greater 
depressive illness burden has been associated with increased utilization of complex 
polypharmacy (Goldberg 2009), and also with greater medical comorbidity in patients with 
bipolar depression (Magalhaes 2012). Although the pharmacologic treatment of bipolar 
depression continues to be dominated by three 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). In 
addition, treatment of bipolar depression with antidepressants remains controversial due to 
concerns regarding limited efficacy (Ghaemi 2010), and risk of switching patients into mania, 
hypomania, or rapid cycling (APA 2002). 
The clinical efficacy of racemic amisulpride on depressive symptoms in mood disorders 
(Montgomery 2002) has been demonstrated at dose levels associated with relatively low 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. 


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4.2. 
Study Conduct Rationale 
Sunovion is developing SEP-4199 for the treatment of major depressive episode associated with 
bipolar I disorder (bipolar I depression). The objective of the current study SEP380-301 is to 
evaluate the efficacy, safety, and tolerability of SEP-4199 controlled release (CR) formulation at 
doses of 200 mg/day and 400 mg/day compared with placebo in the treatment of subjects with 
bipolar I depression. 
4.3. 
Risk-Benefit Assessment 
The clinical efficacy of amisulpride on depressive symptoms in mood disorders 
(Montgomery 2002) has been demonstrated at dose levels associated with relatively low 
D2 receptor occupancy. 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. 
A previous Phase 2 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. Results from this study demonstrated proof-of-concept for SEP-4199 at 
both fixed doses of 200 mg/day and 400 mg/day in the treatment of bipolar I depression and 
warrant further development of SEP-4199 at these doses. 
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, SEP-4199 CR will be administered in the current study. 


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5. 
STUDY OBJECTIVES 
The objective of Study SEP380-301 is to evaluate the efficacy, safety, and tolerability of 
SEP-4199 CR given as monotherapy at fixed doses of 200 mg/day and 400 mg/day compared 
with placebo in the treatment of subjects with major depressive episode associated with bipolar I 
disorder (bipolar I depression). 
5.1. 
Primary Efficacy Objective 
Evaluate the efficacy of SEP-4199 CR in the reduction of depression symptoms, as measured 
using the Montgomery-Asberg Depression Rating Scale (MADRS). 
5.2. 
Secondary Efficacy Objective 
Evaluate the efficacy of SEP-4199 CR in global improvement of bipolar depression severity, as 
measured using the Clinical Global Impression-Bipolar Version-Severity of Illness, Depression 
scale (CGI-BP-S depression). 
5.3. 
Additional Efficacy Objectives 
• Assess the proportion of subjects with treatment response, defined as ≥ 50% 
reduction in MADRS total score. 
• Assess the proportion of subjects with depression symptom remission, defined as a 
MADRS total score ≤ 12. 
• Assess the effect of treatment on the core symptoms of depression, as measured using 
the MADRS-6 subscale, defined as summation of items 1, 2, 3, 7, 8, and 9. 
• Assess the effect of treatment in the reduction of anxiety symptoms, as measured 
using the Hamilton Anxiety Rating Scale (HAM-A). 
• Assess the effect of treatment on subject self-rated depression symptom severity, as 
measured by the Quick Inventory of Depressive Symptomatology - Self Report 
(QIDS-SR16). 
• Assess the effect of treatment on functional impairment, as measured by the Sheehan 
Disability Scale (SDS). 
• Assess the effect of treatment on quality of life, as measured by the 
EuroQol-5 Dimension-5 Level (EQ-5D-5L). 
• Assess the effect of treatment on anhedonia, as measured by the Snaith-Hamilton 
Pleasure Scale (SHAPS). 
5.4. 
Safety Objectives 
• Determine the incidence of adverse events (AEs), discontinuation due to AEs, serious 
AEs (SAEs), and adverse events of special interest (AESI). 
• Evaluate safety and tolerability using physical examinations, 12-lead 
electrocardiograms (ECG), vital signs, clinical laboratory tests, prolactin levels, 
metabolic parameters, body weight, and body mass index (BMI). 


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• Monitor for akathisia and extrapyramidal symptoms (EPS) using the Abnormal 
Involuntary Movement Scale (AIMS), Barnes Akathisia Scale (BARS), and Modified 
Simpson-Angus Scale (SAS). 
• Monitor for treatment-emergent mania or hypomania, defined as a Young Mania 
Rating Scale (YMRS) score of ≥ 16 on any 2 consecutive visits or at the final 
assessment, or an AE of mania or hypomania. 
• Monitor for suicidality using the Columbia-Suicide Severity Rating Scale (C-SSRS). 
• Evaluate potential withdrawal symptoms using the Physician’s Withdrawal Checklist 
(PWC). 
5.5. 
Pharmacokinetic and Pharmacodynamic Objectives 
• Evaluate the therapeutic plasma concentration range of SEP-4199 CR taken as 
200 mg/day and 400 mg/day for treatment of major depressive episode associated 
with bipolar I disorder. 
• Perform population pharmacokinetic (Pop-PK) analysis using plasma concentrations 
of SEP-4199 CR 200 mg/day and 400 mg/day. 
• Evaluate the relationship between SEP-4199 PK and plasma prolactin levels for 
SEP-4199 CR 200 mg/day and 400 mg/day. 
• Explore the exposure-response relationship of SEP-4199 CR 200 mg/day and 
400 mg/day and symptoms as measured by MADRS using population 
pharmacokinetic (PK)/ pharmacodynamic (PD) methods. 


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6. 
STUDY ENDPOINTS 
6.1. 
Primary Efficacy Endpoint 
• Change from Baseline to Week 6 in MADRS total score 
6.2. 
Secondary Efficacy Endpoints 
• Change from Baseline to Week 6 in CGI-BP-S depression score 
6.3. 
Additional Efficacy Endpoints 
• Change from Baseline in MADRS total score at Weeks 1, 2, and 4 
• Change from Baseline in CGI-BP-S depression score at Weeks 1, 2, and 4 
• The proportion of subjects with treatment response, defined as ≥ 50% reduction from 
Baseline in MADRS total score, at Week 6 
• The proportion of subjects meeting criteria for remission, defined as MADRS total 
score ≤ 12, at Week 6 
• Change from Baseline to Week 6 in the MADRS-6 core symptoms subscale 
• Change from Baseline in HAM-A total score at Weeks 1, 2, 4, and 6 
• Change from Baseline to Week 6 in the QIDS-SR16 total score 
• Change from Baseline to Week 6 in the SDS total score 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) at Week 6 
• Change from Baseline to Week 6 in the EQ-5D-5L Index score and VAS score 
• Change from Baseline to Week 6 in the SHAPS total score 
6.4. 
Safety Endpoints 
• The incidence of overall AEs, discontinuation due to AEs, and SAEs 
• The incidence of hyperprolactinemia-related AESI by sex and overall 
• Clinical laboratory evaluations (serum chemistry, hematology, thyroid panel, and 
urinalysis) 
• Clinical evaluations (vital signs including orthostatic effects, and 12-lead ECGs) 
• Change and percent change from Baseline to Week 6 in body weight (kg) 
• Change from Baseline to Week 6 in BMI (kg/m2) 
• Changes from Baseline in metabolic parameters, including glucose, hemoglobin A1c 
(HbA1c), insulin, Homeostatic Model Assessment for Insulin (HOMA-IR), total 


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cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), and 
triglycerides at Week 6 
• Incidence of treatment-emergent mania, defined as a YMRS total score ≥ 16 at two 
consecutive visits or at final visit, or an AE of hypomania or mania 
• Mean changes from Baseline and the proportion of subjects with worsening on the 
movement disorders scales: AIMS, BARS, and modified SAS at Week 6 
• Frequency and severity of suicidal ideation and suicidal behavior as assessed by the 
C-SSRS 
• Occurrence of potential symptoms of withdrawal from SEP-4199 CR measured by 
change from Week 6 in the PWC total score at the safety Follow-up Visit 
6.5. 
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 
SEP380-301 is a randomized, double-blind, placebo-controlled, parallel-group study designed to 
evaluate the efficacy, safety, and tolerability of treatment with SEP-4199 CR at fixed doses of 
200 mg/day or 400 mg/day compared with placebo for the treatment of major depressive episode 
associated with bipolar I disorder (bipolar I depression). The study is projected to randomize 
approximately 522 subjects in North America, Latin America, Japan, and Europe to SEP-4199 
CR 200 mg/day, SEP-4199 CR 400 mg/day, and placebo treatment groups in a 1:1:1 ratio, 
resulting in approximately 174 subjects/group. 
The study will consist of a Screening Period (up to 21 days), a 6-week double-blind Treatment 
Period (42 days), and a Follow-up Period (7 [± 2] days after the last study drug dose), as shown 
in the following figure. If necessary, subjects may return to the clinic at any time for an 
unscheduled visit. Subjects who complete the Treatment Period are eligible to enroll directly into 
a long-term open-label safety extension study (SEP380-303) of SEP-4199 CR. Those subjects 
who prematurely discontinue or who complete the Treatment Period and choose not to enroll in 
the long-term open-label safety extension study will have a follow-up safety Visit 7 (± 2) days 
after their last dose of double-blind study drug. 
Figure 1: 
Study Schematic 
 
 
Abbreviations: CR = controlled release; EOT = end of treatment; V = visit; Wk = week 
Note: Subjects who do not enroll in long-term open-label safety extension study will have Visit 7. 
 
Screening Period (Visit 1, Day -22 to -2) 
Subjects will be evaluated at the Screening Visit (Visit 1) to determine their eligibility to enroll 
in the study. This visit should be scheduled as an early morning appointment, if possible, due to 
the recommendation that subjects fast prior to blood sample collection for clinical laboratory 
tests. Subjects should be advised to obtain and bring medical records as well as any current 
medications that they are taking. A highly reliable informant (who has had close contact with the 


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subject and is approved by the Sponsor Eligibility Committee) should be identified to provide 
collateral information on the subject’s psychiatric and treatment history. 
Informed consent will be obtained from each subject before any study procedures are performed 
for this study. Medical, psychiatric, family (eg, biological mother, father, siblings, children) 
psychiatric and medical, and medication histories will be obtained. Medical history should 
include information about prior coronavirus disease 2019 (COVID-19) vaccination, infection, 
and illness, if any. Information supporting a diagnosis of Bipolar I disorder with at least one prior 
manic episode or manic episode with mixed features must be obtained from additional sources to 
confirm the Screening evaluation. 
The subject’s eligibility assessments will be reviewed by the Sponsor Eligibility Committee, 
which consists of the contract research organization’s (CRO) medical team along with the 
Sponsor and sponsor designees based on protocol-specified inclusion and exclusion criteria (see 
Section 26, Appendix VII for details). The Sponsor will participate in the eligibility review 
process with the CRO to ascertain the subject’s eligibility. In the event the Sponsor Eligibility 
Committee and Investigator do not agree on a subject’s eligibility, then the subject will not be 
approved to proceed to the Baseline Visit (Visit 2). 
Subjects will discontinue and wash out prior or concomitant medications, as applicable, prior to 
Baseline. Psychotropic medications (eg, antipsychotic agents, antidepressants, and mood 
stabilizers) are to be discontinued as tolerated and clinically appropriate at least 3 days or 
5 half-lives (whichever is longer) prior to Baseline. 
Hospitalization during the Screening Period will not be allowed, except  
• where required by local regulations, or 
• when determined to be clinically indicated based on the subject’s psychiatric history 
and current psychiatric symptoms. 
Medical justification must be provided to the Medical Monitor and the Medical Monitor must 
approve the request for hospitalization. In such cases, a maximum of 7 days’ hospitalization 
during washout of prior medications in the Screening Period and a maximum of 7 days’ 
hospitalization during Week 1 of study medication dosing will be allowed. If an extension is 
required, medical justification must be provided to the Medical Monitor and the Medical 
Monitor, following Sponsor review, must approve the request to extend the duration of 
hospitalization. 
To determine subject eligibility, abnormal Screening clinical laboratory tests may only be 
repeated after discussion with the Medical Monitor. 
To determine subject eligibility, the Screening ECG may be repeated in the event of technical 
difficulty or error associated with the first ECG or if clinically indicated. Subjects should rest 
supine for at least 10 minutes prior to all ECGs. 
All Screening assessments should be completed in sufficient time for Site and CRO/Sponsor to 
receive and review results prior to the Baseline Visit (Visit 2). If necessary, to ensure receipt and 
review of all Screening information, an extension of the Screening Period by up to 7 days may be 
allowed, with prior approval from the Medical Monitor. 


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Subjects who meet all inclusion criteria and no exclusion criteria after full evaluation of 
Screening data may proceed to the Baseline Visit (Visit 2) after receiving approval from the 
Sponsor Eligibility Committee. 
Baseline Visit (Visit 2, Day -1) 
Subjects who meet eligibility criteria during the Screening Period will return to the study site on 
Day -1 for confirmation of Screening evaluations as well as completion of pre-dose assessments. 
Subjects who continue to meet all inclusion criteria and no exclusion criteria at Baseline will be 
randomized and dispensed study drug at Day -1. 
Double-blind Treatment Period (Visits 3-6, Days 1 to 42) 
Subjects will self-administer the study drug on an outpatient basis once daily with or without 
food beginning on the morning of Day 1 (the day after the Baseline Visit [Visit 2]) and continue 
for 6 weeks. Subjects will be instructed to administer study drug as a single oral dose at 
approximately the same time each morning. Subsequent clinic visits should be scheduled to 
begin no later than 6 hours post-dose, if possible. The last dose of study drug will be self-
administered by the subject at home on the morning of Visit 6 (Day 42). 
During the Treatment Period, subjects will have clinic visits as follows: Visit 3 (Day 7), Visit 4 
(Day 14), and Visit 5 (Day 28). Telephone calls to ascertain AEs and concomitant medications 
will be scheduled on Days 21 and 35. In order to facilitate scheduling of clinic visits and 
telephone calls, a window of ± 2 days will be allowed for each clinic visit and telephone call. 
End of Treatment (EOT)/Early Termination (ET) (Visit 6, Day 42 [± 2 days]) 
Subjects will have a clinic visit at Visit 6 (Day 42) for efficacy and safety assessments. Subjects 
who complete the 6-week double-blind Treatment Period will be considered study completers, 
and may be eligible to enroll directly into a long-term open-label safety extension study of 
SEP-4199 CR (SEP380-303). 
Subjects who prematurely discontinue the study will undergo an Early Termination (ET) visit at 
the time of discontinuation. The ET Visit will include all efficacy and safety assessments 
scheduled for Visit 6 (Day 42). Prematurely discontinued subjects will not be eligible for the 
long-term open-label safety extension study. 
Follow-up Period (Visit 7, 7 [± 2] days after last dose) 
All subjects who received at least one dose of study drug and who do not enroll in the subsequent 
open-label safety extension study will have a Follow-up Visit for safety and tolerability 
assessments 7 (± 2) days after their last dose of double-blind study drug. Assessment of potential 
withdrawal effects will also be made during the Follow-up Period. During the Follow-up Period, 
completed subjects who do not continue into an open-label safety extension study will not be 
allowed to initiate treatment with a psychotropic medication until after completion of the 
Follow-up Visit. In the event that the severity of major depressive episode (MDE) symptoms at 
the Week 6 EOT/ET visit is judged to present a safety risk to complying with this requirement, 
the subject should be discontinued from the study and managed as clinically appropriate by the 
Investigator. 


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7.2. 
Treatment Assignment and Blinding 
7.2.1. 
Treatment Assignment 
Subjects who successfully meet eligibility criteria will be randomly assigned to receive 
SEP-4199 CR 200 mg/day, SEP-4199 CR 400 mg/day, or matching placebo in a double-blind 
fashion in a 1:1:1 ratio. The randomization will be balanced using permuted blocks with 
stratification factor of countries. The stratification process will be handled in an Interactive Web 
Response Systems (IXRS). 
At the Baseline Visit (Visit 2), the treatment code, which is linked to the randomization schedule, 
will be assigned by the IXRS designated by the Sponsor. A unique subject number will be 
assigned by the IXRS when a subject enters the Screening Period. Each subject will be given one 
subject number comprised of 9 digits. Each subject number will specify the study (3 digits), site 
(3 digits), and subject (3 digits) (eg, 301001001 would denote: Study 301, Site 001, and 
Subject 001). If a subject does not meet study entry criteria, his or her subject number cannot be 
reassigned to another subject. 
Subjects may be screened up to a maximum of 3 times, if judged appropriate by the Investigator 
and approved by the Medical Monitor. Each time the subject is rescreened, they will be 
reconsented and receive a new subject number, which cannot be reassigned to another subject. 
Subjects who do not pass Inclusion Criterion#12 (ie, subject meets an additional inclusion 
criterion at Baseline that will remain blinded to clinical site Investigators and staff) may not be 
re-screened. 
7.2.2. 
Blinding 
Subjects, Investigators, clinical site staff, persons performing the assessments, clinical operations 
personnel (including the Sponsor’s bioanalytical manager), data analysts, personnel at central 
laboratories (including imaging), and the Sponsor will remain blinded to randomization scheme 
until blinding is formally broken for all subjects. For this to occur, all subjects must have 
completed the study and the study database must be locked. 
Randomization data are kept strictly confidential until the time of unblinding, and will not be 
accessible by anyone else involved in the study with the following exceptions: bioanalytical 
laboratory personnel involved in the analysis of PK samples, Data and Safety Monitoring Board 
(DSMB) members involved in regular review of safety data, external statistical staff involved in 
preparing materials for DSMB reviews, and the Sponsor’s clinical trials materials management. 
Prolactin levels will be masked in regular lab data transfer for any assessment collected after the 
first study drug dose and until database is locked and treatment is unblinded (that is to say, 
prolactin assessed prior to the first study drug dose will be unmasked and available for study 
personnel during the study). 
The identity of the treatments will be concealed by the use of study drugs that are all identical in 
packaging, labeling, schedule of administration, and appearance. 
Plasma concentrations of aramisulpride, esamisulpride, and total amisulpride will not be 
disclosed before unblinding. In any case that concentration data transfer to the Sponsor becomes 
necessary prior to the database lock, then the concentration data can only be shared with the 
Sponsor’s bioanalytical project manager with dummy subject IDs. 


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7.2.3. 
Emergency Unblinding Procedures 
In the case of a medical emergency, where knowledge of study drug by the Investigator or an 
authorized delegate is essential for immediate medical management, a 24-hour code-break 
service will be available via the IXRS. The date and reason for unblinding are to be documented 
in the source documents. Any subject for whom the treatment assignment was unblinded is to be 
discontinued from further study participation. The subject should return for a final study 
assessment as described in Section 11.8.4. The identity and responsibility of those individuals at 
the study site who gain access to the unblinded treatment assignment must be documented. It is 
mandatory that all personnel who are involved in the unblinding, and who have access to the 
unblinded treatment assignment, maintain the confidentiality of the information and do not 
divulge the treatment assignment. 
7.3. 
Rationale 
7.3.1. 
Rationale for the Study Design 
Sunovion is developing SEP-4199 for the treatment of major depressive episode associated with 
bipolar I disorder (bipolar I depression). The objective of the current study SEP380-301 is to 
evaluate the efficacy, safety, and tolerability of SEP-4199 CR at doses of 200 mg/day and 
400 mg/day compared with placebo in the treatment of subjects with bipolar I depression. 
A previous Phase 2 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. Results from this study demonstrated proof-of-concept for SEP-4199 IR at both fixed 
doses of 200 mg/day and 400 mg/day in the treatment of bipolar I depression and warrant further 
development of the SEP-4199 compound at these doses. 
A novel CR formulation of SEP-4199 has been developed. SEP-4199 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, SEP-4199 CR will be administered in the current study. 
7.3.2. 
Rationale for the Dosages 
The hypothesized therapeutic dose range of SEP-4199 is 200 mg/day to 400 mg/day based on 
results from pharmacology studies in human volunteers and a completed Phase 2 clinical study 
of SEP-4199 IR (Study SEP380-201) in 337 subjects with bipolar I depression. This dose range 
will be confirmed in the current fixed-dose study of SEP-4199 CR. 
Fixed doses of 200 mg/day and 400 mg/day were previously selected for clinical evaluation 
based on a demonstrated pharmacodynamic effect of 5HT7 receptor antagonism, and moderate 
dopamine D2 receptor occupancy within this dose range. The unique pharmacology of SEP-4199 
at doses of 200 mg/day to 400 mg/day is hypothesized to be optimal for the treatment of bipolar I 
depression while minimizing the extrapyramidal symptoms associated with high levels of D2 
receptor antagonism. 


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In a previously completed Phase 2 study (SEP380-201) in 337 subjects from the US, Europe, and 
Japan with bipolar I depression, SEP-4199 administered as the IR formulation at fixed doses of 
200 mg/day and 400 mg/day demonstrated proof of concept in the treatment of bipolar I 
depression. On the prespecified primary analysis of change from Baseline to Week 6 on MADRS 
total score in a cohort of US and European subjects (N = 289), SEP-4199 IR 200 mg/day and 
400 mg/day doses resulted in similar numerical improvements compared to placebo but just 
missed significance (adjusted p = 0.054 for both treatment groups) due to higher-than-anticipated 
placebo response and variability. For the full global intention-to-treat (ITT) population including 
US, European, and Japanese subjects (N = 337), both doses of SEP-4199 demonstrated 
significantly greater change from Baseline to Week 6 in MADRS total score compared to 
placebo (post-hoc adjusted p = 0.025 for both treatment groups using the same multiplicity 
adjustment approach). Results based on the full global ITT population strengthened the evidence 
in favor of efficacy at both SEP-4199 IR doses. 
Efficacy results for the 200 mg/day and 400 mg/day doses were generally highly similar on all 
primary, key secondary, and additional secondary endpoints. However, in the primary analysis 
cohort of US and European subjects, the odds vs. placebo of achieving remission (defined as 
MADRS ≤ 12 at Week 6), while not significant for the 200 mg/day group, were significantly 
greater for the 400 mg/day group (p = 0.024). This result suggests that some subjects may have 
derived greater benefit from the higher dose and warrants further evaluation of both 200 mg/day 
and 400 mg/day doses. 
SEP-4199 IR at fixed doses of 200 mg/day and 400 mg/day was well tolerated in the Phase 2 
SEP380-201 study. For the full global safety population, rates of discontinuation due to an AE 
were similar in the 200 mg/day (8.8%) and 400 mg/day (7.0%) SEP-4199 IR treatment groups, 
and higher than in the placebo group (1.8%). The only AE with incidence reflecting a dose-
response relationship was ECG QTc prolonged, which was reported for 9 subjects in the 
400 mg/day treatment group and 0 subjects in the 200 mg/day and placebo groups; however, 
none of the subjects in the 400 mg/day group also reported an AE in the Cardiac Disorders 
Medical Dictionary for Regulatory Activities (MedDRA) system organ class (SOC). As Study 
SEP380-105 demonstrated that the lower Cmax of the CR formulation was associated with 
substantially lower QTc prolongation than the IR formulation, an improved therapeutic index 
with regard to cardiac safety is expected in the current study. 
The incidence of mania or hypomania was higher in the SEP-4199 IR 200 mg/day group (4.4%) 
than in the 400 mg/day group (0.9%). This finding suggests the possibility that the 400 mg/day 
dose may provide additional benefit in mood stabilization by virtue of its greater D2 receptor 
antagonism. 
Most other AEs occurred at comparable rates in the two SEP-4199 IR groups. Marked prolactin 
elevation (≥ 5x upper limit of normal [ULN]) was observed in 79% of female subjects who 
received SEP-4199 IR in this study. A total of 10 (4.4%) subjects reported hyperprolactinemia-
related AEs, of which the most common was galactorrhea, reported in 3 (2.7%) subjects in the 
200 mg/day group and 4 (3.5%) subjects in the 400 mg/day group. Racemic amisulpride is 
known to increase prolactin levels; therefore, the prolactin elevation observed with SEP-4199 IR 
treatment in the completed study was expected. The data demonstrate that a relatively small 
proportion of subjects with increased prolactin levels is likely to experience any AEs. 


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Taken together, these results demonstrated proof of concept for the efficacy of SEP-4199 IR at 
doses of 200 mg/day and 400 mg/day for the treatment of bipolar I depression. They further 
show that SEP-4199 IR treatment was well tolerated at these doses; and SEP-4199 CR is 
hypothesized to be therapeutically equivalent to SEP-4199 IR based on the SEP380-105 study 
but with an improved therapeutic index due to improved cardiac safety, suggesting a positive 
benefit/risk that supports further clinical development of SEP-4199 CR in this dose range for the 
treatment for bipolar I depression. 
7.3.3. 
Rationale for the Study Population 
The subject population includes males and females ranging from 18 to 65 years of age, and in 
concert with standard practice guidelines, will be required to have a diagnosis of bipolar I 
disorder, whose most recent episode is depressed with or without rapid cycling disease course 
(≥ 4 episodes of mood disturbance but < 8 episodes in the previous 12 months) with or without 
psychotic features (diagnosed by DSM-5 criteria, and confirmed by the SCID-5-CT). The current 
episode of major depression associated with bipolar I disorder will be confirmed by the 
Investigator and noted in the source records. 
7.3.4. 
Rationale for the Endpoints 
The efficacy assessments and their timing are considered appropriate to assess the efficacy 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 on these 
parameters. The standard safety assessments and their timing are appropriate to assess the safety 
of SEP-4199 in adults with bipolar I depression. 
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 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. 
Refer to Section 15.4.7 for statistical considerations related to missing data. 


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8. 
SELECTION OF SUBJECTS 
Attempts should be made to obtain relevant medical and pharmacy records for subjects during 
screening. This is strongly encouraged to confirm past diagnoses and treatment history. 
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 or legally acceptable representative must possess an educational level and degree 
of understanding of English or the local language that enables them to communicate 
suitably with the Investigator and the study coordinator. 
3. Subject is 18 to 65 years of age, inclusive, at the time of informed consent. 
4. Subject meets DSM-5 criteria, based on the SCID-5-CT, for bipolar I disorder, current 
episode depressed with or without rapid cycling disease course (≥ 4 episodes of mood 
disturbance but < 8 episodes in the previous 12 months) with or without psychotic 
features. 
5. Subject has a lifetime history of at least 1 manic episode or manic episode with mixed 
features corroborated by at least one of the following: medical records, documented 
correspondence with a treating psychiatrist or mental healthcare provider/staff, or 
information from a reliable informant who is familiar with the subject’s psychiatric 
history. The adequacy of the information will be assessed by the Sponsor Eligibility 
Committee. 
6. Attempts should be made to obtain supporting information regarding the subject’s current 
major depressive episode from additional sources. This may include relevant medical 
records, or documented correspondence with a treating psychiatrist or mental healthcare 
provider/staff if the subject has been evaluated during the current MDD episode, or 
information from a reliable informant who is familiar with the subject’s recent psychiatric 
history.  
7. Subject’s current major depressive episode is ≥ 4 weeks and less than 12 months in 
duration at Screening. 
8. Subject has a MADRS-S total score ≥ 22 at Screening. 
9. Subject has a MADRS total score ≥ 22 at both Screening and Baseline. 
10. Subject has a CGI-BP-S depression score ≥ 4 at both Screening and Baseline. 
11. Subject has a YMRS total score ≤ 12 at both Screening and Baseline. 
12. Subject meets an additional inclusion criterion at Baseline that will remain blinded to 
clinical site Investigators and staff. 
13. 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 


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drug has been taken. In the Investigator’s judgment, the subject will adhere to this 
requirement. Contraception requirements are detailed in Section 10.4. 
14. Female subjects of childbearing potential must have a negative serum ß-hCG test at 
Screening and a negative urine pregnancy test at Baseline. 
15. Male subjects agree to avoid fathering a child and to use effective methods of birth 
control throughout the study and for at least 90 days after the last study drug 
administration. Contraception requirements are detailed in Section 10.4. 
16. Subject is in good physical health, based on medical history, physical examination, 
neurological examination, vital signs, ECGs, and results of clinical laboratory tests 
(hematology, chemistry, and urinalysis). 
17. Subjects with type 2 diabetes are eligible for study inclusion only if all following 
conditions are met:  
• Subject’s random (non-fasting) blood glucose is < 200 mg/dL (11.1 mmol/L) or 
fasting blood glucose < 126 mg/dL (7.0 mmol/L) at Screening. 
• Subject’s HbA1c is ≤ 7.0% at Screening. 
• If a subject is currently being treated with oral hypoglycemics, the dose has been 
stable for at least 30 days prior to Screening. (Such medication may subsequently be 
adjusted or discontinued during the study, as clinically indicated.) 
• Subject has not required hospitalization for diabetes or related complications in the 
12 months prior to Screening. 
• Subject’s type 2 diabetes was not newly diagnosed at Screening. 
18. Subject who requires concomitant medication treatment with the following agents may be 
included if they have been on stable doses for the specified times below, and if the 
subject’s medical condition is deemed clinically stable following consultation with the 
Medical Monitor. 
• Oral hypoglycemics must be stable for at least 30 days prior to Screening. 
• Thyroid hormone replacement must be stable for at least 90 days prior to Screening. 
• Anti-hypertensive agents must be stable for at least 30 days prior to Screening. 
19. Subject is approved by the Sponsor Eligibility Committee to proceed to the Baseline Visit 
following review of all required information collected at Screening. See Section 26, 
Appendix VII for details. 
8.2. 
Subject Exclusion Criteria 
The subjects who meet any of the following criteria will be excluded from the study: 
1. Subject currently has any DSM-5 defined psychiatric diagnosis other than bipolar I 
disorder that was the primary focus of treatment or that is currently being treated with 
concomitant medication. 


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2. Subject has a lifetime history of or symptoms consistent with schizophrenia, 
schizoaffective disorder, or a major psychiatric diagnosis other than bipolar I disorder 
that is judged to pose risk to the study scientific objectives based on the judgement of the 
Investigator or the Sponsor Eligibility Committee. A lifetime history of anxiety disorders, 
attention-deficit/hyperactivity disorder (ADHD), and post-traumatic stress disorder 
(PTSD) are not exclusionary if the disorder does not meet Exclusion Criterion #1.(Note: 
Subjects with a previous diagnosis of major depressive disorder or bipolar II disorder that 
was subsequently changed to bipolar I disorder are allowed.) 
3. Subject has a history within the past 12 months prior to Screening of substance use 
disorder. 
4. Subject has confirmed or suspected borderline personality disorder. 
5. Subject demonstrates a decrease (improvement) of ≥ 25% in MADRS total score from 
Screening to Baseline. 
6. Subject is considered by the Investigator to be at imminent risk of suicide or injury to self 
or others, or has a score ≥ 4 on MADRS item 10 (suicidal ideation), 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 the Screening Visit (in the past 3 months [90 days]) or at Baseline. 
7. Subject has received any psychotropic medication or herbal supplement within 3 days or 
5 half-lives (whichever is longer) prior to Baseline or anticipates the need for 
psychotropic medications or herbal supplements during participation in this study, with 
the exception of the medications specified in Section 10.3. The following treatments have 
additional restrictions as specified below: 
a. Monoamine oxidase inhibitors (MAOIs) must be discontinued at least 28 days prior 
to Baseline. 
b. Fluoxetine, and olanzapine/fluoxetine combination must be discontinued at least 
28 days prior to Baseline. 
c. Clozapine used at 200 mg/day or less for insomnia, agitation, or anxiety must be 
discontinued at least 28 days prior to Baseline. Subjects with a history of treatment 
with clozapine for any reason at doses greater than 200 mg/day or at doses less than 
or equal to 200 mg/day for a usage other than insomnia, agitation, or anxiety are 
excluded from study participation. 
d. Depot neuroleptics must have been discontinued at least one treatment cycle or at 
least 30 days (whichever is longer) prior to Baseline. 
e. Subjects with a history of treatment with ketamine, esketamine, arketamine, or 
psychedelic therapies (eg, psilocybin, methylenedioxymethamphetamine [MDMA]) 
for major depressive disorder (MDD) or any psychedelic treatment. 
f.  Electroconvulsive therapy (ECT) or repetitive transcranial magnetic stimulation 
(rTMS) within 90 days prior to Baseline. 
g. Subjects with a history of treatment with vagus nerve stimulation (VNS) or deep 
brain stimulation (DBS) are excluded from study participation. 


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8. Subject initiated a new psychotherapeutic intervention (eg, psychotherapy) focused on 
treatment of bipolar I depression within the past 12 weeks prior to Screening. (Note: 
Subjects who have participated in ongoing psychotherapy treatment for at least 12 weeks 
prior to Screening will be permitted to continue this treatment during the study.) 
9. Subject has a history of non-response to an adequate (6-week) trial of 3 or more 
antidepressants (with or without mood stabilizers) during the current major depressive 
episode. 
10. Subject was hospitalized during the Screening Period without explicit approval by 
Medical Monitor. (Note:  Hospitalization during the Screening Period will not be 
allowed, except where required by local regulation or when determined to be clinically 
indicated based on the subject’s psychiatric history and current psychiatric symptoms. 
Medical justification must be provided to the Medical Monitor and the Medical Monitor 
must approve the request for hospitalization.) 
11. Subject has any clinically significant unstable medical condition or any clinically 
significant chronic disease that would pose a risk to the subject or that might confound 
the results of the study. (Note: Active medical conditions that are minor or well-
controlled are not exclusionary if they do not affect risk to subject or study results. In 
cases in which the impact of the condition upon risk to subject or study results is unclear, 
the Medical Monitor should be consulted.) 
a. Hematological (including deep vein thrombosis) or bleeding disorder, renal, 
metabolic, endocrine, pulmonary, gastrointestinal, urological, cardiovascular 
(including unstable hypertension), hepatic, neurologic, or allergic disease that is 
clinically significant or unstable (except for seasonal allergies at time of dosing). 
(Note: Any subject with a known cardiovascular disease or condition, including 
hypertension, [even if under control and considered stable] must be discussed with 
the Medical Monitor before being randomized in the study.) 
b. Chronic organic disease of the CNS such as tumors, inflammation, active (or history 
of) seizure disorder, vascular disorder, Parkinson’s disease, Alzheimer’s disease or 
other forms of dementia, myasthenia gravis, or other degenerative processes. Subject 
has history of intellectual disability or persistent neurological symptoms attributable 
to serious head injury. (Note: Past history of febrile seizure is not exclusionary.) 
c. Evidence of acute hepatitis, clinically significant chronic hepatitis, or evidence of 
clinically significant impaired hepatic function through clinical and laboratory 
evaluation. Subjects who test positive for hepatitis C antibody at Screening and have 
a positive or indeterminate confirmatory test for hepatitis C are excluded. Subjects 
who test positive for hepatitis B surface antigen at Screening are excluded. 
d. History of any cardiovascular disorder/condition known to increase the possibility of 
QT prolongation, history of additional risk factors for torsade de pointes (eg, heart 
failure, hypokalemia, family history of Long QT Syndrome or Brugada Syndrome) or 
cardiac conduction disorders, or requires treatment with an antiarrhythmic 
medication. 
e. History of neuroleptic malignant syndrome (NMS). 
f. History of malignancy < 5 years prior to the Screening Visit, except for adequately 
treated basal cell carcinoma or squamous cell skin cancer or in situ cervical cancer. 


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Subjects with lifetime history of pituitary tumors, including pituitary adenomas, of 
any duration are excluded. 
g. History of a condition (including history of malabsorption) or previous 
gastrointestinal surgery (eg, cholecystectomy, vagotomy, bowel resection) that could 
interfere with drug absorption, distribution, metabolism, excretion, gastrointestinal 
motility, or pH. 
h. Known history of human immunodeficiency virus (HIV) seropositivity. 
i. Type 1 diabetes or insulin-dependent type 2 diabetes. 
12. Subject with a supine systolic blood pressure (SBP) ≥ 150 mmHg and/or supine diastolic 
blood pressure (DBP) ≥ 95 at Screening or Baseline. A repeat blood pressure 
measurement is allowed once during the Screening Period and once at Baseline. The 
repeat measurements can be used to determine eligibility. The repeat blood pressure 
measurement at Screening can be conducted on a different day within the Screening 
Period, if needed. 
13. Subject has a body BMI ≥ 40 or < 18 kg/m2 at Screening. 
14. Subject has a clinically significant abnormal 12-lead ECG at Screening (based on central 
cardiologist review) or Baseline (based on machine reading), including: 
• QT interval corrected for heart rate using Fridericia’s formula (QTcF) 
> 450 milliseconds (msec) (males) or > 470 msec (females) 
• QRS > 110 msec 
• PR > 220 msec 
• Second- or third-degree atrioventricular block 
• Any rhythm other than sinus rhythm, that is interpreted by the Investigator to be 
clinically significant 
• Heart rate (HR) < 50 beats per minute (bpm) 
• HR > 100 bpm 
15. Subject requires treatment with a drug that is associated with an increase in QTc interval 
(see Section 24, Appendix V for a list of medications, not all inclusive). 
16. Subject has a first degree family history of QTc prolongation or unexplainable sudden 
death at < 50 years of age. 
17. Subject has any laboratory test result at Screening that indicates a clinically significant 
medical condition. These include but are not limited to the following test results. Clinical 
significance of other abnormalities will be based on Investigator judgment in consultation 
with the Medical Monitor. 
• Thyroid stimulating hormone (TSH) ≤ 0.5x lower limit of normal (LLN) or ≥ 1.25x 
ULN (regardless of whether T3 and T4 are within the normal reference range) 
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3x ULN 
• Creatinine clearance ≤ 60 ml/min 


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• Serum blood urea nitrogen (BUN) or serum creatinine (Cr) value ≥ 1.5x ULN 
• Fasting blood glucose ≥ 126 mg/dL (7.0 mmol/L). (Note: Subjects with fasting blood 
glucose from 100-125 mg/dL [5.6-6.9 mmol/L] may enter the study based on the 
approval of the Medical Monitor. Subjects who are found to have been non-fasting at 
Screening may be allowed if their random [non-fasting] blood glucose is 
< 200 mg/dL [11.1 mmol/L]. Subjects with random [non-fasting] blood glucose at 
Screening ≥ 200 mg/dL [11.1 mmol/L] must be retested in a fasted state.) 
• HbA1c > 7.0% 
18. Subject has a prolactin concentration > 100 ng/mL at Screening. 
19. Subject exhibits evidence of severe tardive dyskinesia, severe dystonia, or any other 
severe movement disorder, as judged by the Investigator. 
20. Subject tests positive for drugs of abuse at Screening. In the event a subject tests positive 
for cannabinoids (tetrahydrocannabinol), the Investigator will evaluate the subject’s 
ability to abstain from cannabis during the study. This information will be discussed with 
the Medical Monitor for study enrollment consideration. However, a positive test urine 
drug screen may not result in exclusion of subjects if the Investigator determines that the 
positive test is a result of prescription medicine(s), and the medication can be safely 
washed out prior to Baseline and confirmed by a repeat urine drug screen. 
21. Subject tests positive for any drug of abuse or cannabis on rapid urine drug test at 
Baseline. 
22. Subject has a history of allergic reaction or suspected sensitivity to amisulpride, any other 
substance that is contained in the study drug formulation, or to more than two distinct 
chemical classes of drug (eg, sulfas and penicillins). 
23. Subject who is lactating or plans to get pregnant during the study. 
24. Subject has received any investigational drug product within 90 days prior to signing 
informed consent or has participated in more than 3 studies in psychiatric indications of 
investigational drug products within their lifetime. 
25. Subject previously randomized in a SEP-4199 clinical study. 
26. Subject is in the opinion of the Investigator, Medical Monitor and/or Sponsor, unsuitable 
in any other way to participate in this study. 


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9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
9.1. 
Description of Study Drug 
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 group, each dose of study drug will consist of 
1 x 200 mg tablet and 1 x matching placebo tablet. 
• For the SEP-4199 CR 400 mg/day group, each dose of study drug will consist of 
2 x 200 mg tablets. 
• For the placebo group, each dose of study drug will consist of 2 x matching placebo 
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 
Matching Placebo 
Dosage form 
Tablets 
Tablets 
Unit dose 
Tablet 
Tablet 
Route of administration 
Oral 
Oral 
Physical description 
Pale orange round film-coated 
unmarked tablets 
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 
Placebo also contains microcrystalline cellulose. Placebo does not contain 
partially hydrolyzed pregelatinized starch and partially hydrolyzed 
polyvinyl alcohol.  
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 
18 tablets of SEP-4199 CR 200 mg or Placebo tablets. Each blister card will be arranged in nine 
columns and two rows. 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 


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• 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 
• 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 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 one to two 9-day (7 days + 2 extra days) blister cards per scheduled visit, 
depending on the timing of the next scheduled visit (see Table 2). IXRS drug dispensing 
guidelines should be followed for dispensing study drug to subjects. A specific user manual will 
be provided. 
The first study drug dose will be taken on Day 1. Subjects will take a column of two tablets 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 


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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. 
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/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 and placebo 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 6 
(Day 42). 
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 
Prior psychotropic and non-psychotropic medications taken during the 60 days prior to Screening 
will be recorded on the electronic case report form (eCRF) at the Screening Visit (Visit 1). 
If the duration of the current major depressive episode is > 60 days, then all psychotropic 
medications taken since the onset of the current major depressive episode will be recorded on the 
eCRF. 
Every effort should be made to collect medical and/or pharmacy records for psychotropic and 
non-psychotropic medications recorded on the eCRF. However, if medical records cannot be 
obtained, prior medications are to be reported based on subject and highly reliable informant 
report. 
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 eCRF. Medication name, dose, frequency, route, start date, stop date, and 
indication 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). 
Initiation of new psychotherapeutic interventions (eg, a new course of psychotherapy) will not be 
permitted during the study. Subjects who have participated in ongoing psychotherapy treatment 


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for at least 12 weeks prior to Screening will be permitted to continue this treatment during the 
study. 
During the Follow-up Period, completed subjects who do not continue into an open-label safety 
extension study will not be allowed to initiate treatment with a psychotropic medication until 
after completion of the Follow-up Visit. 
10.3.1. 
Prior Medications 
Treatment with all prior psychotropic medications (eg, antipsychotic agents, antidepressants, and 
mood stabilizers) and herbal supplements must be discontinued as tolerated and clinically 
appropriate at least 3 days or 5 half-lives (whichever is longer) prior to Baseline. Subjects treated 
with MAOIs, fluoxetine, or olanzapine/fluoxetine combination must discontinue these 
medications at least 28 days prior to Baseline. Clozapine used at 200 mg/day or less for 
insomnia, agitation, or anxiety must be discontinued at least 28 days prior to Baseline. Subjects 
with a history of treatment with clozapine for any reason at doses greater than 200 mg/day or at 
doses less than or equal to 200 mg/day for a usage other than insomnia, agitation, or anxiety are 
excluded from study participation. Depot neuroleptics must be discontinued at least 30 days or 
one treatment cycle (whichever is longer) prior to Baseline. Subjects who, in the opinion of the 
Investigator, cannot safely discontinue prior psychotropic medications, are not eligible for the 
study and will be screen failed. 
10.3.2. 
Concomitant Non-psychotropic Medications 
Medications for short-term (no more than 10 days) treatment of a medical condition are allowed 
provided that the medications do not prolong the QTc interval. Section 24, Appendix V provides 
a representative, but not exhaustive, list of medications that prolong the QT interval and are not 
allowed during the study. Non-psychotropic medications used to treat mild, chronic medical 
conditions may be used during Screening and after Baseline if the dose and regimen have been 
stable (± 25%) for at least 30 days prior to Screening. The concomitant medication dose may 
change as needed after Screening. β-adrenergic antagonists used to treat stable hypertension may 
be continued. In addition, use of non-prescription pain medications (eg, aspirin, 
acetaminophen/paracetamol, ibuprofen) is 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 used to treat movement disorders should be tapered and discontinued 3 days or 
5 half-lives (whichever is longer) prior to Baseline but may be reinstituted 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 during Screening and for 
Weeks 1-3 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), 


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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. 
10.3.4. 
Prohibited Medications 
Treatment with all prior psychotropic medications (eg, antipsychotic agents, antidepressants, and 
mood stabilizers) must be discontinued as tolerated and clinically appropriate at least 3 days or 
5 half-lives (whichever is longer) prior to Baseline. Subjects treated with MAOIs, fluoxetine, or 
olanzapine/fluoxetine combination must discontinue these medications at least 28 days prior to 
Baseline. Clozapine used at 200 mg/day or less for insomnia, agitation, or anxiety must be 
discontinued at least 28 days prior to Baseline. Subjects with a history of treatment with 
clozapine for any reason at doses greater than 200 mg/day or at doses less than or equal to 
200 mg/day for a usage other than insomnia, agitation, or anxiety are excluded from study 
participation. Depot neuroleptics must have been discontinued at least 30 days or one treatment 
cycle (whichever is longer) prior to Baseline. 
Treatment with sedative hypnotics (for insomnia) is permitted during the Screening Period, but 
should be tapered as clinically appropriate to ensure the subject meets and can comply with the 
protocol-specified dosing limitations applicable to these agents following Baseline (see 
Section 10.3.3). 
Medications that prolong the QTc interval are prohibited during the study. For a list of these 
medications, please see Section 24, Appendix V. 
The use of herbal supplements for any reason is prohibited during trial participation and must be 
discontinued at least 3 days or 5 half-lives (whichever is longer) prior to Baseline. The use of 
dietary supplements (eg, omega fatty acids) or other complementary or alternative medications 
for treating depression during the trial is not permitted. 
With the exception of benztropine, biperiden, trihexyphenidyl, diphenhydramine, propranolol, 
and amantadine (or their equivalent as agreed by the Medical Monitor) as specified in 
Section 10.3.3, medications used to treat movement disorders (including levodopa) are 
prohibited. 
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 
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OR 
− Postmenopausal females, defined as at least 12 months of spontaneous 
amenorrhea and confirmed by follicle stimulating hormone (FSH) concentrations 
within postmenopausal range as determined by the central laboratory 
-OR- 
• Childbearing potential with a negative serum pregnancy test at Screening and 
satisfying one of the following requirements: 
− Completely abstinent from intercourse as part of the preferred and usual lifestyle 
of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-
ovulation methods) and the withdrawal method are not acceptable methods of 
contraception. Subject must have been abstinent for at least 60 days prior to 
administration of the first dose of study drug, throughout the Treatment Period 
and for a minimum of 30 days after completion or premature discontinuation from 
the study drug. 
− Use of 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. 
 Vasectomised partner (provided that partner is the sole sexual partner) 
 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 for 30 days after last dose of the study drug. 


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10.5. 
Guidance for Overdose 
The effects of an overdose of SEP-4199 CR 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) and will be asked to give explicit consent by signing this 
separate patient information and consent form. Where allowed under local laws and regulations, 
such consent from subjects is a precondition for being able to participate in this clinical study. 
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, medical history, psychiatric history, and prior and concomitant medication use 
will be collected.  
Demographics collected at Screening will include sex, race, ethnicity, date of birth, weight, and 
height, as allowed per region. 
Clinical site staff will calculate and record BMI at Screening. BMI for all other visits will be 
calculated in the analyses. 
Waist circumference will be measured in inches or centimeters and recorded in the eCRF. 
For medical history, only relevant/significant medical history and recurrence of any condition 
will be collected. 
11.3. 
Diagnostic and Symptom Severity Scales to Inform Subject 
Eligibility 
11.3.1. 
Lifetime Illness Characteristics Questionnaire 
The Lifetime Illness Characteristics Questionnaire will be administered at Screening, prior to 
other Screening assessments. The Lifetime Illness Characteristics Questionnaire is a subject-
reported computerized assessment that establishes disease-related life history across 
5 dimensions: hypomania or mania, age of onset of first mood symptoms, illness course and 
other features generally only visible over time, response to medications (antidepressants and 
mood stabilizers), and family history of mood and substance use disorders. Subject responses are 
used to calculate a Bipolarity Index Score. A score ≥ 50 is associated with a high likelihood of a 
diagnosis of bipolar disorder (Aitken 2015). 


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11.3.2. 
SCID-5-CT 
The Structured Clinical Interview for DSM-5 (SCID-5) is the most widely used structured 
diagnostic instrument for assessing DSM-5 disorders. The SCID-5 is organized into diagnostic 
modules, and it assesses mood disorders, psychotic disorders, substance use disorders, anxiety 
disorders, obsessive–compulsive and related disorders, eating disorders, somatic symptom 
disorders, some sleep disorders (ie, insomnia and hypersomnolence disorders), “externalizing 
disorders” (ie, intermittent explosive disorder, gambling disorder, and adult attention deficit 
hyperactivity disorder), and trauma- and stressor-related disorders. The SCID-5 for clinical trials 
(SCID-5-CT; First 2015) will be utilized to confirm the diagnosis of bipolar I depression for this 
study. 
The SCID-5-CT will be administered by a qualified rater at the site. The SCID-5-CT 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 SCID-5-CT to determine study eligibility will be provided in the Study 
Reference Manual. 
11.3.3. 
Montgomery-Asberg Depression Rating Scale (MADRS) 
The MADRS will be administered at Screening and Baseline to determine subject eligibility. 
Subjects will be required to have moderate-to-severe depression symptoms, as demonstrated by a 
MADRS total score ≥ 22 at both Screening and Baseline. In addition, subjects having a decrease 
(improvement) of ≥ 25% in MADRS total score from Screening to Baseline will be excluded 
from study participation. 
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. 
11.3.4. 
Montgomery-Asberg Depression Rating Scale, Self-rating Version (MADRS-S) 
The MADRS-S is a computerized version of the MADRS assessment (Fantino 2009) that the 
subject will complete at the Screening Visit prior to the clinician-administered MADRS 
interview. The self-rating version of the MADRS has been validated against the clinician-
administered MADRS (Mundt 2006). A MADRS-S score ≥ 22 will be required at Screening for 
subject eligibility. The MADRS-S will additionally be used to ascertain the reliability of site 
clinician-administered MADRS assessment at Screening. 


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11.3.5. 
Clinician Global Impression-Bipolar Version-Severity of Illness (CGI-BP-S) 
The CGI-BP-S will be administered at Screening and Baseline to determine subject eligibility. A 
CGI-BP-S depression score ≥ 4 (moderate) will be required at Screening and Baseline. 
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. 
Further information regarding administration of the CGI-BP-S, including rater training and 
certification as well as recording CGI-BP-S scores will be provided in the Study Reference 
Manual. 
11.3.6. 
Young Mania Rating Scale (YMRS) 
The YMRS will be administered at Screening and Baseline to determine subject eligibility. 
Subjects must have a YMRS total score ≤ 12 at both the Screening and Baseline Visits. 
The YMRS is an 11-item instrument used to assess the severity of mania in patients with a 
diagnosis of bipolar disorder. The 11 items are: Elevated Mood, Increased Motor Activity 
Energy, Sexual Interest, Sleep, Irritability, Speech (Rate and Amount), Language-Thought 
Disorder, Content, Disruptive-Aggressive Behaviour, Appearance, and Insight. The YMRS is 
a clinician-rated assessment. 
The YMRS will be administered by a qualified rater at the site. Further information regarding 
administration of the YMRS, including rater training and certification as well as recording of 
YMRS scores to determine study eligibility, will be provided in the Study Reference Manual. 
11.4. 
Efficacy Assessments 
11.4.1. 
Montgomery-Asberg Depression Rating Scale (MADRS) 
In addition to administration of the MADRS at Screening and Baseline to determine subject 
eligibility, the MADRS will be administered at post-Baseline study visits during the Treatment 
Period (Visits 3, 4, 5, and 6 at Days 7, 14, 28, and 42, respectively) as an efficacy assessment. 
See Section 11.3.3 for a description of the MADRS instrument. 
11.4.2. 
Clinician Global Impression-Bipolar Version-Severity of Illness (CGI-BP-S) 
In addition to Screening and Baseline, the CGI-BP-S will be administered at post-Baseline study 
visits during the Treatment Period (Visits 3, 4, 5, and 6 at Days 7, 14, 28, and 42, respectively) as 
an efficacy assessment. See Section 11.3.5 for a description of the CGI-BP-S instrument. 
11.4.3. 
Hamilton Anxiety Rating Scale (HAM-A) 
The HAM-A is a clinician-administered scale that will be administered at Baseline, and at post-
Baseline study visits during the Treatment Period (Visits 3, 4, 5, and 6 at Days 7, 14, 28, and 42, 
respectively). 
The HAM-A is a rating scale 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) 


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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. 
11.4.4. 
Quick Inventory of Depressive Symptomatology – Self Report (QIDS-SR16) 
The QIDS-SR16 is a 16-item subject-reported depression symptom severity questionnaire that 
will be completed at Baseline and Visit 6 (Day 42). 
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. 
11.4.5. 
Sheehan Disability Scale (SDS) 
The SDS is a subject-reported assessment of function that will be completed at Baseline and 
Visit 6 (Day 42). 
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. 
11.4.6. 
EuroQol - 5 Dimension - 5 Level (EQ-5D-5L) 
The EQ-5D-5L is a quality of life assessment that the subject will complete at Baseline and 
Visit 6 (Day 42). 
The 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 a descriptive system and the EuroQol Visual Analogue Scale 
(EQ-VAS). 


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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 5 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. 
11.4.7. 
Snaith-Hamilton Pleasure Scale (SHAPS) 
The SHAPS (Snaith 1995) is a subject-reported questionnaire that will be administered at 
Baseline and Visit 6 (Day 42). 
The SHAPS is a 14-item scale that assesses 4 domains of hedonic experience: interests/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. 
11.5. 
Safety Assessments 
11.5.1. 
Adverse Events 
Adverse events will be collected for each subject. Subjects should be queried in a non-leading 
manner, without specific prompting (eg, “Has there been any change in your health status since 
your last visit?”). See Section 12, Safety Reporting. 
AEs and SAEs will be monitored throughout the study at all visits. 
11.5.2. 
Clinical Laboratory Tests 
Subjects are required to fast for at least 8 hours prior to sample collection for laboratory testing 
at Baseline (Visit 2) and Visit 6/EOT/ET (Day 42). 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.  
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 
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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. 
To determine subject eligibility, abnormal Screening clinical laboratory tests may only be 
repeated after discussion with the Medical Monitor. 
11.5.3. 
Vital Signs 
Blood pressure and pulse rate measurements will be taken in a supine and standing position. 
Blood pressure and pulse rate should first be taken with the subject in the supine position after 
resting for ≥ 5 minutes. Blood pressure and pulse rate will be taken again after standing for 2 to 
4 minutes. The same arm should be used during each assessment of blood pressure and pulse rate 
throughout the study. If a subject develops symptoms consistent with orthostatic hypotension 
(light-headedness, dizziness, or changes in sensorium upon standing) at any point, his or her 
supine and standing blood pressure and pulse rate should be collected at that time in the manner 
described above. 
Respiratory rate and temperature will also be measured, and all measurements will be recorded 
in the eCRF. 
Weight will be measured in street clothes, without shoes and coat/jacket. BMI will be calculated 
by site staff using the equation BMI = weight [kg]/height [m]² at Screening (Visit 1). 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 Screening in vital sign parameters, as determined by the 
Investigator, will be noted as AEs in the eCRF. 
11.5.4. 
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. 
To determine subject eligibility, the Screening ECG may be repeated in the event of technical 
difficulty or error associated with the first ECG or if clinically indicated. Subject should rest 
supine for at least 10 minutes prior to all ECGs. 
11.5.5. 
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 
(dermatologic, head, eyes, ears, nose, mouth/throat/neck, thyroid, lymph nodes, respiratory, 
cardiovascular, gastrointestinal, extremities, musculoskeletal, neurologic, and psychiatric 


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systems). The neurological examination includes an assessment of general appearance, mental 
status, cranial nerves, motor system, sensory system, reflexes, coordination, and gait. 
All physical examination and neurological examination findings at Screening will be captured in 
the medical history in the eCRF. Any clinically significant changes from Screening, as 
determined by the Investigator, will be noted as AEs in the eCRF. 
11.5.6. 
Safety Scales 
11.5.6.1. 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 2 versions of the C-SSRS. At the Screening Visit, the Baseline/Screening 
version will be completed; for all subsequent visits, the “Since Last Visit” version of the C-SSRS 
will be administered. 
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 the C-SSRS assessment at the Screening Visit (in the past 3 months [90 days]) or 
Baseline are not eligible and must be referred to the Investigator for follow-up evaluation. 
If a subject answers “yes” to “suicidal ideation” item 4 (active suicidal ideation with some intent 
to act, without specific plan) or item 5 (active suicidal ideation with specific plan and intent) on 
any post-Baseline C-SSRS assessment, the subject 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. 
11.5.6.2. Young Mania Rating Scale (YMRS) 
In addition to administration of the YMRS at Screening and Baseline to determine subject 
eligibility, the YMRS will be administered post-Baseline as a safety assessment and to inform 
the identification of treatment-emergent mania or hypomania. See Section 11.3.6 for a 
description of the YMRS instrument. 
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. 
11.5.6.3. Abnormal Involuntary Movement Scale (AIMS) 
The AIMS will be administered at Baseline and Visit 6 (Day 42). 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, incapacitation, and the 


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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. 
11.5.6.4. Barnes Akathisia Rating Scale (BARS) 
The BARS will be administered at Baseline and Visit 6 (Day 42). 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 
(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. 
11.5.6.5. Modified Simpson-Angus Scale (SAS) 
The modified SAS will be administered at Baseline and Visit 6 (Day 42). 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 of SAS scores, will be provided in the Study Reference Manual. 
11.5.6.6. Physician’s Withdrawal Checklist (PWC) 
Potential withdrawal effects will be assessed by the clinician using the PWC after completion of 
all scheduled efficacy and safety assessments and procedures at Visit 6 (Day 42) and Visit 7 
(Follow-up). 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. 
11.6. 
Pharmacokinetic Assessments 
Plasma samples will be collected for population pharmacokinetics (Pop-PK) at Baseline 
(Visit 2), Visit 4 (Day 14), Visit 6 (Day 42), and Visit 7 (Follow-up). These samples, together 
with a sample collected at Screening, will also be measured for plasma prolactin levels (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 
at Visit 4 (Day 14) and Visit 6 (Day 42) only. 


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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. An enzyme-linked immunosorbent assay (ELISA) will be used for determination of 
plasma prolactin concentrations. 
Remaining plasma samples after amisulpride PK and prolactin analysis may also be used for the 
additional characterization and/or bioanalytical method development of putative metabolites of 
amisulpride and for other exploratory measurements, if needed. 
11.7. 
Pharmacogenomic Testing (Optional) 
Subjects will be asked if they are willing to provide a blood sample at Baseline for 
pharmacogenomic testing. This is optional and requires a separate Informed Consent. 
If a subject has consented to have a deoxyribonucleic acid (DNA) sample taken for potential 
need of genetic analysis (and is eligible for randomization), a blood sample (approximately 
4 mL) for potential pharmacogenetic (PGx) analysis will be taken at Baseline prior to dosing on 
Day 1. Details on collection and shipment will be provided in the Laboratory Investigator 
Manual. Following shipment, DNA will be extracted and stored safely until further decision on 
whether an actual genomics testing will be performed is made by the Sponsor. If yes, the timing 
of the analysis may be following completion of this study and as such will be reported 
separately. The PGx laboratory will remain blinded to the identity of the subject but will have 
access to information relating to demographics (ethnic origin and gender). See Section 23, 
Appendix IV for details, including instructions of PGx sample handling. Samples should not be 
collected if the subject has not consented to PGx sampling. 
11.8. 
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. 
11.8.1. 
Screening: Visit 1 (Day -22 to -2) 
Subjects will be evaluated at the Screening Visit to determine their eligibility to enroll in the 
study. This visit should be scheduled as an early morning appointment due to subject 
recommendation to fast for blood sample collection for clinical laboratory tests. 
Hospitalization during the Screening Period will not be allowed, except  
• where required by local regulations, or  
• when determined to be clinically indicated based on the subject’s psychiatric history 
and current psychiatric symptoms. 
Medical justification must be provided to the Medical Monitor and the Medical Monitor must 
approve the request for hospitalization. In such cases, a maximum of 7 days’ hospitalization 
during washout of prior medications in the Screening Period will be allowed. If an extension is 
required, medical justification must be provided to the Medical Monitor and the Medical 
Monitor, following Sponsor review, must approve the request to extend the duration of 
hospitalization. 


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To determine subject eligibility, abnormal Screening clinical laboratory tests may only be 
repeated after discussion with the Medical Monitor. 
To determine subject eligibility, the Screening ECG may be repeated in the event of technical 
difficulty or error associated with the first ECG or if clinically indicated. 
The following study-related procedures will be performed at Visit 1; it is suggested that they be 
performed in the order presented below, as is possible by the site: 
• Obtain signed informed consent from the subject before conducting any other visit 
procedures, including signed informed consent for duplicate subject check (where 
local regulations allow). 
• Obtain signed consent for optional pharmacogenomic sampling (if applicable). 
• Administer Lifetime Illness Characteristics Questionnaire. 
• Administer MADRS-S. To be eligible for enrollment, subjects must have a 
MADRS-S total score ≥ 22 (see Section 25, Appendix VI). 
• Administer MADRS. To be eligible for enrollment, subjects must have a MADRS 
total score ≥ 22 (see Section 25, Appendix VI). 
• Administer SCID-5-CT. 
• Administer YMRS. To be eligible for enrollment, subjects must have a YMRS total 
score ≤ 12. 
• Administer CGI-BP-S. 
• Administer C-SSRS (Baseline/Screening version). 
• Review inclusion and exclusion criteria. 
• Perform duplicate enrollment check (a separate informed consent is required). 
(see Section 11.1) 
• Record demographics. 
• Record medical history. 
• Record psychiatric history. Note: the psychiatric history includes a psychiatric history 
form that will include variables related to duration of illness, treatment response (eg, 
prior medications used to treat bipolar disorder) and other similar variables. 
• Record family (eg, biological mother, father, siblings, children) psychiatric and 
medical history. 
• Record prior and concomitant medications. 
• Record adverse events (Note: events occurring prior to first dose of study of study 
drug will be identified programmatically as pretreatment events.) 
• Perform physical examination. 
• Perform neurological examination. 


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• Record height and weight. 
• Calculate and record BMI. 
• Obtain vital signs, including orthostatic changes in blood pressure and heart rate. 
• Collect blood sample(s) for the following clinical laboratory tests (If possible, 
subjects should fast for at least 8 hours to avoid potential for retest.): 
− Hematology and Serum Chemistry  
− Thyroid Panel  
− Serum Follicle Stimulating Hormone (Female Subjects) 
− Serum β-hCG (Female Subjects of childbearing potential) 
− Serum prolactin 
− HbA1c 
− Lipid Panel 
− Serum Insulin 
− high sensitivity (hs) C-reactive Protein 
• Collect blood sample for Hepatitis B/C testing. 
• Collect blood sample for measurement of plasma concentrations of aramisulpride, 
esamisulpride, and prolactin. 
• Collect urine sample for urine drug screen and urinalysis. 
• Perform 12-lead ECG. 
• Schedule next visit. 
• Approval from the Sponsor Eligibility Committee to proceed to the Baseline Visit is 
required (Inclusion Criterion 19) (See Section 26, Appendix VII). 
11.8.2. 
Baseline and Treatment Period: Day -1 to Day 42 
11.8.2.1. Visit 2: Baseline (Day -1) 
Hospitalization at Baseline will not be allowed, except  
• where required by local regulations, or  
• when determined to be clinically indicated based on the subject’s psychiatric history 
and current psychiatric symptoms. 
Medical justification must be provided to the Medical Monitor and the Medical Monitor must 
approve the request for hospitalization. In such cases, a maximum of 7 days’ hospitalization 
during Week 1 of study medication dosing will be allowed. If an extension is required, medical 
justification must be provided to the Medical Monitor and the Medical Monitor, following 
Sponsor review, must approve the request to extend the duration of hospitalization. 


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The following study-related procedures will be performed at Baseline; it is suggested that they be 
performed in the order presented below, as is possible by the site: 
• Obtained signed consent for optional pharmacogenomic sampling, where applicable 
(if not done at Screening). 
• Review inclusion and exclusion criteria. 
• Record prior and concomitant medications. 
• Record adverse events. (Note: events occurring prior to first dose of study of study 
drug will be identified programmatically as pretreatment events.) 
• Administer MADRS: To be eligible for enrollment, subjects must have a MADRS 
total score ≥ 22. Subjects who have a decrease (improvement) of ≥ 25% in MADRS 
total score from Screening to Baseline, or who have a MADRS total score < 22 at 
Baseline will not be eligible for enrollment (see Section 25, Appendix VI). 
• Administer HAM-A using the SIGH-A. 
• Administer YMRS. To be eligible for enrollment, subjects must have a YMRS total 
score ≤ 12. 
• Administer QIDS-SR16. 
• Administer SDS. 
• Administer EQ-5D-5L. 
• Administer SHAPS. 
• Administer CGI-BP-S. 
• Administer C-SSRS (Since Last Visit version). 
• Administer AIMS. 
• Administer BARS. 
• Administer Modified SAS. 
• Subject Eligibility Check via IXRS 
• Perform physical examination. 
• Perform neurological examination. 
• Record weight. 
• Record waist circumference. 
• Obtain vital signs, including orthostatic changes in blood pressure and heart rate. 
• Collect blood sample(s) for the following clinical laboratory tests (Subjects must have 
fasted for at least 8 hours.): 
− Hematology and Serum Chemistry 
− Thyroid Panel 


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− Serum prolactin 
− HbA1c 
− Lipid Panel 
− Serum Insulin 
− hs C-Reactive Protein 
• Collect blood sample for measurement of plasma concentrations of aramisulpride, 
esamisulpride, and prolactin. 
• Collect blood sample for pharmacogenomic testing (subjects signing a separate 
informed consent). 
• Collect urine sample for rapid urine drug test, urinalysis, and urine β-hCG (female 
subjects of childbearing potential). 
• Perform 12-lead ECG. 
• Randomize subject. 
• Dispense study drug. 
− Instruct subject to administer a single oral dose of study medication 
approximately the same time each day at home beginning the following morning 
(Day 1). 
• Schedule next visit: 
− Instruct subject to take the morning dose prior to the next clinic visit. Clinic visits 
are to begin no later than 6 hours postdose, if possible. 
− Instruct subject to record date and time of the last 3 doses prior to next visit and 
bring back all used/unused study drug and packaging to the next visit. 
11.8.2.2. Visit 3 (Day 7 ± 2) 
The following study-related procedures will be performed at Visit 3; it is suggested that they be 
performed in the order presented below, as is possible by the site: 
• Administer MADRS. 
• Administer HAM-A using the SIGH-A. 
• Administer YMRS. 
• Administer CGI-BP-S. 
• Administer C-SSRS (Since Last Visit version). 
• Record prior and concomitant medications. 
• Record adverse events. 
• Obtain vital signs, including orthostatic changes in blood pressure and heart rate. 
• Perform 12-lead ECG. 


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• Perform study drug accountability. 
− Collect used/unused study drug and packaging. 
− Confirm with the subject the date and time of their last 3 doses of study drug and 
record in the source. 
• 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 take 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 date and time of the last 3 doses prior to next visit and to 
bring back all used/unused study drug and packaging to the next visit. 
11.8.2.3. Visits 4 (Day 14 ± 2) 
The following study-related procedures will be performed at Visit 4; it is suggested that they be 
performed in the order presented below, as is possible by the site: 
• Administer MADRS. 
• Administer HAM-A using the SIGH-A. 
• Administer YMRS. 
• Administer CGI-BP-S. 
• Administer C-SSRS (Since Last Visit version). 
• Record prior and concomitant medications. 
• Record adverse events. 
• Obtain vital signs, including orthostatic changes in blood pressure and heart rate. 
• Perform 12-lead ECG. 
• Collect blood sample(s) for the following clinical laboratory tests: 
− Hematology and Serum Chemistry 
− Serum prolactin 
• 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 study drug accountability. 
− Collect used/unused study drug and packaging. 


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− 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 record date and time of the last 3 doses prior to next visit and to 
bring back all used/unused study drug and packaging to next visit. 
11.8.2.4. Telephone Contact (Day 21 ± 2) 
The clinical site will contact subjects by telephone on Day 21 (± 2) to assess adverse events and 
concomitant medications. The clinical site will remind the subject of their next scheduled visit 
and to continue once daily dosing with study drug and remind subject to administer the morning 
dose prior to the next clinic visit. 
11.8.2.5. Visit 5 (Day 28 ± 2) 
The following study-related procedures will be performed at Visit 5; it is suggested that they be 
performed in the order presented below, as is possible by the site: 
• Administer MADRS. 
• Administer HAM-A using the SIGH-A. 
• Administer YMRS. 
• Administer CGI-BP-S. 
• Administer C-SSRS (since last visit version). 
• Record prior and concomitant medications. 
• Record adverse events. 
• Obtain vital signs, including orthostatic changes in blood pressure and heart rate. 
• Perform 12-lead ECG. 
• Perform study drug accountability. 
− Collect used/unused study drug and packaging. 
− Confirm with the subject the date and time of their last 3 doses of study drug and 
record in the source. 
• Dispense study drug. 
− Instruct subject to dose once daily in the morning at approximately the same time 
each day at home. 


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• 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 date and time of the last 3 doses prior to next visit and to 
bring back all used/unused study drug and packaging to the next visit. 
11.8.2.6. Telephone Contact: (Day 35 ± 2) 
The clinical site will contact subjects by telephone on Day 35 (± 2) to assess adverse events and 
concomitant medications. The clinical site will remind the subject of their next scheduled visit 
and to continue once daily dosing with study drug and remind subject to administer the morning 
dose prior to the next clinic visit. 
11.8.3. 
Visit 6: End of Treatment/Early Termination (Day 42 ± 2) 
The following study-related procedures will be performed at Visit 6; it is suggested that they be 
performed in the order presented below, as is possible by the site: 
• Administer MADRS. 
• Administer HAM-A using the SIGH-A. 
• Administer YMRS. 
• Administer PWC. 
• Administer QIDS-SR16. 
• Administer SDS. 
• Administer EQ-5D-5L. 
• Administer SHAPS. 
• Administer CGI-BP-S. 
• Administer C-SSRS (Since Last Visit version). 
• Administer AIMS. 
• Administer BARS. 
• Administer Modified SAS. 
• Perform physical examination. 
• Perform neurological examination. 
• Record weight. 
• Record waist circumference. 
• Record prior and concomitant medications. 
• Record adverse events. 
• Obtain vital signs, including orthostatic changes in blood pressure and heart rate. 


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• Collect blood sample(s) for the following clinical laboratory tests (Subjects must have 
fasted for at least 8 hours.): 
− Hematology and Serum Chemistry 
− Thyroid Panel 
− Serum prolactin 
− HbA1c 
− Lipid Panel 
− Serum Insulin 
− hs C-reactive Protein 
• 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 study 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. 
At this visit, subjects who have participated throughout the duration of the Treatment Period, up 
to and including Visit 6 (Day 42) will have the option to enroll and continue treatment in an 
open-label safety extension study (SEP380-303). Subjects who provide consent to participate in 
the extension study and meet the study entry criteria will not need to return for further visits in 
this study. 
A Follow-up Visit will be scheduled for subjects who do not enter the extension study. 
11.8.4. 
Follow-up: Visit 7 (7 ± 2 days after last dose) 
All subjects who discontinue early or do not enroll in the open-label safety extension study 
(Study SEP380-303) will have a safety Follow-up Visit 7 ± 2 days after their last dose of study 
drug. The following study-related procedures will be performed at Visit 7; it is suggested that 
they be performed in the order presented below, as is possible by the site: 
• Administer YMRS. 
• Administer PWC. 
• Administer C-SSRS (Since Last Visit version). 
• Record prior and concomitant medications. 
• Record adverse events. 
• Perform physical examination. 


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• Perform neurological examination. 
• Record weight. 
• Obtain vital signs, including orthostatic changes in blood pressure and heart rate. 
• Perform 12-lead ECG. 
• Collect blood sample(s) for the following clinical laboratory tests: 
− Hematology and Serum Chemistry 
− Serum prolactin 
• 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). 
 


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12. 
SAFETY REPORTING 
12.1. 
Definitions 
12.1.1. 
Adverse Events 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related. 
Untoward medical occurrences that occur between the time of signing the informed consent form 
(ICF) and drug administration are pretreatment events. Those that occur after administration of 
study drug are considered AEs. Pretreatment hospitalizations that occur in accordance with local 
clinical practice during the Screening Period (for wash-out from prior or concomitant 
medications) will not be considered SAEs and do not need to be reported as such. Any untoward 
event that may occur during the hospitalization must be recorded as a pretreatment event. If 
hospitalization is prolonged by an untoward event, the event must be reported as an SAE. 
An AE can, therefore, be any unfavorable and unintended sign (including an abnormal or 
clinically significant 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. 
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. 


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During the study, if a subject has a hospitalization or procedure (eg, elective surgery) that was 
scheduled before the study entry, ie, before informed consent for an event/condition that 
occurred before the study, the hospitalization is considered a therapeutic intervention and not the 
result of a SAE. However, if the event/condition worsens during the study, it should be reported 
as an AE (or SAE, if the event/condition results in a serious outcome such as prolongation of 
hospitalization). 
Life-threatening means that the subject was, in the view of the Investigator, at immediate risk of 
death from the event as it occurred. This definition does not include an event that had it occurred 
in a more severe form, might have caused death. 
SAE criteria information will be captured on the 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. 
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. 
Adverse events of special interest 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. 
A subject who develops an AE of amenorrhea, gynecomastia, or galactorrhea must be 
discontinued from the study, referred to the Investigator for follow-up evaluation, and followed 
until the event resolves (see Section 13.1). 


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12.2. 
Objective Findings 
Clinically significant abnormal objective findings (eg, clinical laboratory value, ECG value, vital 
signs, and physical or neurological examination observation) occurring after the Screening Visit 
will also be recorded as AEs. 
When a clear diagnosis is available that explains the objective findings, this diagnosis will be 
recorded as the AE, and not the abnormal objective finding (eg, viral hepatitis will be recorded as 
the AE, not transaminase elevation). If a definite diagnosis is not available, then 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. If the result of any test (or repeat test, if done) from the samples taken 
during Screening is indicated as clinically significant and is not covered by the inclusion criteria 
in Section 8.1, the subject will not be allowed into the study. Additional testing during the study 
may be done if medically indicated. If a clinically significant abnormality is found in any clinical 
laboratory test, ECG value, vital sign measurement, or physical or neurological examination 
observation after dosing, during the study, and/or at the Follow-Up Visit, this should be recorded 
as an AE and the subject will be followed until the test(s) has (have) normalized or stabilized. 
12.3. 
Collection and Recording of Adverse Events 
All pretreatment events and AEs must be recorded in the subject’s study records/source 
documents in accordance with the Investigator’s normal clinical practice. Pretreatment events 
and AEs and SAEs that occur from the signing of informed consent to the subject’s last study 
visit must be recorded on the eCRF. Determination of whether an event is a pretreatment event, 
or an adverse event will be made programmatically by the Sponsor or designee, not by the site. 
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. 


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• Severe - Symptoms cause considerable discomfort. Substantial influence on subject’s 
daily activities. May be unable to continue the study, and other treatment may be 
necessary. 
The frequency of AE: 
• Once – an isolated episode. 
• Intermittent – occurs on two or more separate occasions. 
• Continuous – does not abate from date of onset to date of resolution. 
The action taken with the study treatment: 
• Drug Interrupted – Study drug stopped temporarily. 
• Drug Withdrawn – Study drug stopped permanently. 
• Dose 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 
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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/serious pretreatment event  
• 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/Serious Pretreatment 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. Serious pretreatment 
events must be reported on the SAE form and recorded on the CRF, in the same manner as 
SAEs. 
Should the Investigator become aware of an SAE greater than 30 days post last dose, the 
Investigator or an authorized delegate should report SAEs “spontaneously” to 
PPD-Pharmacovigilance (PVG) if considered at least possibly related to the study drug. 
SAEs will be followed until resolution, loss to follow-up, stabilization of condition, or the event 
is otherwise explained. 
An initial or follow-up SAE form as applicable must be completed and signed and sent via fax or 
email (see Table 1) to PPD-PVG immediately but no more than 24 hours after the Investigator or 
study center staff become aware of the event. The SAE form must be signed by the Investigator 
or appropriate designee. The Sponsor provides the SAE form used to report SAEs. 
The Sponsor or designee will promptly notify all study centers and Investigators of a SAE that is 
determined to be expedited to the Regulatory Authorities in accordance with applicable law(s) 
and regulation(s). These SAEs must be promptly reported to the Institutional Review Board 
(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 and undergo a serum pregnancy test, as 


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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. 
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 
DSMB may review blinded, unblinded, or partially unblinded data, but the Sponsor (with the 
exception of the relevant members of the pharmacovigilance team responsible for reporting 
Suspected Unexpected Serious Adverse Reactions [SUSARs]), the CRO, and the Investigators 
will remain blinded until the official unblinding of the database. The membership of the DSMB 
and its mandate will be described in a separate DSMB charter. 
 


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13. 
TERMINATION OF SUBJECT FROM 
STUDY/DISCONTINUATION OF STUDY DRUG 
13.1. 
Criteria for Subject Termination 
Subjects may 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, gynecomastia, or galactorrhea 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 even 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 
infection should be discussed on a case-by-case basis with the IQVIA Medical 
Monitor to obtain agreement on whether a subject with active COVID-19 infection 
should be discontinued. 


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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 6 (Day 42) will undergo procedures and assessments 
scheduled for Visit 6 (Day 42) at the time of early discontinuation (see Section 11.8.3). 


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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 11.8.3 and safety 
Follow-up Visit described in Section 11.8.4. 


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15. 
STATISTICS 
15.1. 
Sample Size 
The sample size is estimated based on the primary efficacy endpoint, the change from Baseline 
in MADRS total score at Week 6. Based on the Phase 2 Study SEP380-201 results for both 
planned and post-hoc analyses of the primary endpoint, assuming a common standard deviation 
(SD) of 10 and a mean improvement of 3.5 (effect size 0.35) and 3.5 (effect size 0.35) over 
placebo for SEP-4199 200 mg and 400 mg dose groups, respectively, with a randomization ratio 
of 1:1:1 for placebo, SEP-4199 200 mg and 400 mg, a sample size of 165 subjects per treatment 
group will provide at least 80% conjunctive power to reject both null hypotheses of no difference 
between SEP-4199 doses and placebo and at least 85% power to reject each individual null 
hypothesis after multiplicity adjustment for two comparisons of the primary endpoint using the 
enhanced mixture truncated Hochberg gatekeeping procedure (Kordzakhia 2018) with truncation 
parameter 0.5 and 2-sided Type I error of 0.05. An upward adjustment of approximately 5% is 
assumed to compensate for subjects who are randomized but have no post-Baseline efficacy 
assessment. Thus, a total sample of approximately 174 subjects per group (522 subjects in total) 
will be randomized. The sample size calculation is based Monte Carlo computer simulations. 
15.2. 
Statistical Hypotheses 
The hypotheses associated with the primary and secondary efficacy endpoints will be tested 
using a testing procedure described in Section 15.4.3.4. 
Primary Hypotheses 
In adults with moderate-to-severe symptoms of depression, after 6 weeks of treatment,  
• SEP-4199 CR 200 mg/day leads to greater reductions from Baseline in MADRS total 
score at Week 6 relative to placebo 
• SEP-4199 CR 400 mg/day leads to greater reductions from Baseline in MADRS total 
score at Week 6 relative to placebo 
Secondary Hypotheses 
In adults with moderate-to-severe symptoms of depression, after 6 weeks of treatment, 
• SEP-4199 CR 200 mg/day leads to greater reductions from Baseline in CGI-BP-S 
depression score at Week 6 relative to placebo 
• SEP-4199 CR 400 mg/day leads to greater reduction from Baseline in CGI-BP-S 
depression score at Week 6 relative to placebo 
15.3. 
Analysis Populations 
Intention-to-Treat Population: The intention-to-treat (ITT) population will consist of subjects 
who are randomized who received at least one dose of study medication and have at least one 
post-Baseline assessment in any efficacy variable. The ITT population is the primary population 
for efficacy analyses, ie, unless otherwise specified, all efficacy analyses will be based on the 
ITT population. Subjects in the ITT population will be analyzed based on the treatment to which 
they are randomized. 


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Per Protocol Population: The Per Protocol (PP) population will consist of all ITT subjects who 
have no major protocol deviations that may affect the interpretation of the primary efficacy 
endpoint defined in Section 15.4.2. Subjects in the Per Protocol population will be analyzed 
according to their randomized treatment group. 
Primary analysis of the primary and the secondary efficacy endpoints will also be performed 
using the Per Protocol population. 
Safety Population: The safety population will consist of all subjects who randomized and 
receive at least one dose of study medication. Subjects will be analyzed according to modal dose 
(the predominant treatment, used interchangeably) received. The modal dose or predominant 
treatment is defined as the treatment to which the subject is exposed for the greatest duration 
during the treatment period. This will generally be the same as the randomized treatment group, 
unless the subject takes incorrect study medication during their entire participation in the study. 
Follow-up Population: The follow-up population includes all randomized subjects who receive 
at least one dose of study medication, and either discontinue the study drug during the treatment 
period before the Week 6 visit or complete the 6-week treatment period but do not enter the 
extension study (Study SEP380-303), and have at least one assessment after the double-blind 
Treatment Period for any safety evaluation. The follow-up population will be mainly used to 
summarize a few selected safety assessments (ie, AE, ECG, Lab, Vital Signs, PWC score) which 
have a follow-up assessment. 
Pharmacokinetic (PK) Population: The PK population includes all subjects who are 
randomized, receive at least 1 dose of study drug, and have any post-Baseline PK concentrations 
of SEP-4199. PK samples collected from placebo subjects will not be analyzed. 
The PK analysis will be based on the PK population. 
Population PK (Pop-PK) analysis methods will be used to characterize the PK/PD profiles in 
subjects treated with SEP-4199. These methods will be described in a separate document and 
will not be included in the SAP. 
15.4. 
Data Analysis 
All statistical inference analyses will be performed with 2-sided tests at a significance level of 
0.05, and 2-sided 95% confidence intervals (CI) will be calculated whenever appropriate. All 
data will be summarized by treatment group and visit as appropriate. All subject data will be 
presented in data listings by subject. 
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, prior and concomitant medication, and the important protocol deviations, will 
be presented by treatment group, and overall for both the ITT and the Safety population. Details 
of the summary approaches for subject level information will be provided in the SAP and no 
further discussion is provided hereafter in this document. 


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15.4.2. 
Per Protocol Criteria 
Protocol violator criteria used to define the Per Protocol population may include, but will not be 
limited to the following: 
• Subject received incorrect study treatment or was not dosed in double-blind treatment 
period. 
• Subject does not have a Baseline efficacy measurement or at least one post-Baseline 
efficacy measurement for primary efficacy variable. 
• Subject was unblinded during the double-blind treatment period. 
• Subject does not have 14 days or more of drug exposure. 
• Subject had < 75% or > 125% non-missing medication compliance or missing 
medication compliance unless the overall drug compliance per the worst-case 
imputation is ≥ 75% and ≤ 125%. 
• Subject violated inclusion/exclusion criteria which have any potential impact on 
efficacy results (confirmed by medical review). 
• Subject took a prohibited medication or more than one day of a prohibited dose of an 
allowed medication or received prohibited psychotherapy during the double-blind 
treatment period that would impact the primary efficacy analysis (confirmed by 
medical review). 
• If subject tests positive for substance abuse at post-Baseline during the double-blind 
treatment period, without a verified prescription for use of a drug that potentially 
could have caused the positive test result (confirmed by medical review). 
A complete list of subjects who meet at least one of above protocol deviations criteria, will be 
identified through a blinded data review meeting (BDRM) prior to database lock. Subjects in the 
ITT population regarded as protocol deviators per above criteria will not be included in the PP 
population. 
15.4.3. 
Efficacy Analyses 
The primary analysis population for the efficacy analysis will be ITT population. Assessment of 
the primary and secondary efficacy endpoints on the PP population will be conducted as 
supportive analyses. 
Multiplicity adjustment to control the global familywise Type I error rate for testing SEP-4199 
CR 200 mg versus placebo and SEP-4199 CR 400 mg versus placebo across the primary and 
secondary efficacy endpoints at the 5% level is described in Section 15.4.3.4. 
Whenever mixed model for repeated measures (MMRM) or analysis of covariance (ANCOVA) 
analyses are conducted, LS mean of treatment difference, associated 95% confidence interval 
(CI), and p-value (nominal) will be generated per corresponding statistical model. For each 
efficacy variable, effect sizes for within-group and between-group at each post-Baseline visit 
will be provided. 
For total and subscale scale scores of all efficacy variables (continuous), and for individual item 
scores of selected efficacy variables (MADRS, HAM-A, YMRS, etc.), summary statistics (N, 


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mean, standard deviation, median, first quartile [Q1], third quartile [Q3], and range) will be 
presented at each assessment time point for the actual values and the changes from Baseline, and 
95% CIs of the changes from Baseline will also be presented by treatment. 
15.4.3.1. Primary Efficacy Endpoint Analysis 
The estimand of primary interest is described below:  
Population of 
Interest 
Adults who meet inclusion/exclusion criteria (major depressive episode 
associated with bipolar I disorder and have moderate-to-severe symptoms of 
depression as demonstrated by a MADRS total score ≥ 22 and CGI-BP-S 
depression score ≥ 4 at Screening and Baseline) and be in the ITT population. 
Outcome Measure/ 
Endpoint 
Change from Baseline in MADRS total score at Week 6. 
Treatment 
Condition of 
Interest 
A hypothetical strategy is used to address intercurrent event, assuming that the 
value of the variable to reflect the clinical question of interest is the value 
which the variable would have taken in the hypothetical scenario defined. 
Intercurrent Event 
Regardless of adherence to treatment (ie, discontinuation of assigned 
treatment) 
Population-Level 
Summary Measure 
Treatment difference between SEP-4199 CR dose groups and placebo for 
mean change from Baseline in MADRS total score by using the mixed model 
for repeated measures (MMRM) per the randomized treatment based on the 
ITT population. 
 
The primary efficacy analyses of the primary efficacy endpoint (the change from Baseline in 
MADRS total score at Week 6) will be performed using a likelihood-based MMRM model based 
on the ITT population. The response (dependent) variable is the change from Baseline in the 
MADRS total score assessed at Weeks 1, 2, 4, and 6. Specifically, the MMRM model includes 
fixed effects terms for treatment, visit (as a categorical variable), pooled country, Baseline 
MADRS total score, and treatment-by-visit interaction. Restricted maximum likelihood 
estimation method will be applied using an unstructured covariance model. The Kenward Roger 
approximation will be used to estimate denominator degrees of freedom. The least squares (LS) 
mean treatment differences (each SEP-4199 CR dose minus placebo) of change from Baseline at 
Week 6, 2-sided 95% confidence intervals (CI), and the associated p-values will be calculated 
based on this model. 
Multiplicity adjustment to control the global familywise Type I error rate at 5% is described in 
Section 15.4.3.4. 
The model assumptions underlying the primary analysis will be assessed. Specifically, the 
normality and homoscedasticity assumptions underlying the primary MMRM model will be 
assessed graphically. Conditional studentized and scaled residuals will be plotted against the 
predicted values, respectively, and Q-Q (quantile-quantile) plots of these residuals versus the 
expected quantiles of the standard normal distribution will be presented to provide a graphical 
view of similarity and difference in the two distributions. If the unstructured covariance model 
fails to converge, a more parsimonious model is likely necessary, but not necessarily correct. In 


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this case, MMRM based on structures more general than unstructured one, ie, separate 
unstructured matrices by treatment, will be checked. For rare chance, if such model fails again, a 
more parsimonious model (eg, spatial exponential covariance pattern) may be assessed as 
necessary. If there is evidence of deviations from the model assumption(s), the degree and nature 
of such deviation(s) will be explored to better understand the potential impact on interpretation 
of the primary efficacy analysis. 
15.4.3.1.1. Sensitivity Analyses 
To address early dropouts under the assumption of missing not at random (MNAR), a 
pattern-mixture model using a placebo-based multiple imputation method and a pattern mixture 
model using multiple imputations with penalties (ie, deflating the individually estimated 
treatment effect size by known factors) will be performed as sensitivity analyses to explore the 
robustness of the MMRM results for the primary analysis. In case of a deviation from the 
assumptions required for the primary analysis, to confirm the robustness of the primary analysis 
result, additional sensitivity analysis per permutation test will be performed: fit a large number of 
datasets based on a same MMRM for the primary analysis with randomly assigning pseudo-
treatment group designations. 
15.4.3.1.2. Supportive Analyses 
The primary efficacy endpoint will also be analyzed using an ANCOVA model using the LOCF 
approach, as a supportive analysis. The model will include terms for treatment, pooled country, 
and Baseline MADRS total score as covariates. 
The primary efficacy analysis will be repeated for the PP population to examine the impact of 
protocol violation and deviations in a way that is less biased and to obtain a more interpretable 
result. 
15.4.3.1.3. Additional Analyses for Regional Effect 
To support global regulatory decision-making, the consistency of treatment effects across regions 
(ie, North America, Latin America, Europe, Japan) will be assessed. Treatment effects and 
measures of their uncertainty for individual region, and treatment-by-region interaction will be 
evaluated for the primary efficacy endpoint. An MMRM model that includes fixed effects terms 
for treatment, visit (as a categorical variable), region, Baseline MADRS total score, 
treatment*visit interaction, treatment*region interaction, and treatment*visit*region interaction, 
will be performed using an unstructured covariance matrix. If p-value for treatment-by-region 
interaction at Week 6 is significant at level of 0.10, the nature of this significant interaction 
(quantitative vs qualitative) will be further evaluated using the Gail and Simon test (Gail 1985) 
and other interaction tests such as the Pan-Wolfe test (Pan 1997). The Gail and Simon test tends 
to perform better when there are several subgroups with effects which are positive and several 
also with effects which are negative while the Pan and Wolfe tends to perform better if the 
effects in most of the subgroups are in one direction and there are only one or very few 
subgroups for which the effect is in the opposite direction. Shrinkage analyses for treatment 
effect of regions, which are based on weighted averages of the overall effect estimate and the 
estimate using data from individual regions, will be performed. Shrinkage analyses for treatment 
effect of countries may be performed, as appropriate. 


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15.4.3.2. Secondary Efficacy Endpoint Analysis 
The secondary efficacy endpoint (change from Baseline in CGI-BP-S depression score at 
Week 6) will be analyzed with an MMRM model similar to the one used in the primary efficacy 
analysis (adjusted with the corresponding Baseline). The LS mean treatment differences (each 
SEP-4199 CR dose minus placebo) of change from Baseline at Week 6, their 2-sided 95% CIs, 
and the associated p-values will be calculated based on the model. Additional supportive and 
sensitivity analyses similar to the ones performed for the primary efficacy endpoint will be 
conducted for the secondary efficacy endpoint to address early dropouts or potential deviations 
from the model assumption(s). 
Multiplicity adjustment to control the global familywise Type I error rate at 5% is described in 
Section 15.4.3.4. 
15.4.3.3. Additional Efficacy Endpoint Analyses 
MADRS-6 core symptoms subscale score and HAM-A total score will be analyzed with an 
MMRM model similar to the one used in the primary efficacy analysis adjusted with the 
corresponding Baseline. QIDS-SR16 total score, SDS total score and subscale scores, EQ-5D-5L 
related scores, and SHAPS total score will be analyzed with an ANCOVA model similar to the 
one used in the supportive ANCOVA analysis for the primary efficacy endpoint adjusted with 
the corresponding Baseline as covariate. 
Categorical efficacy endpoints (ie, proportion of responders and proportion of remitters at 
Week 6) will be analyzed using a logistic regression model with treatment, region, and Baseline 
MADRS total score as covariates using a LOCF approach. Proportion of subjects meeting 
functional remission criteria per the SDS subscales (defined as SDS total score ≤ 6 and SDS 
subscale scores ≤ 2) will be analyzed using a similar logistic regression model with 
corresponding Baseline as covariate. 
15.4.3.4. Adjustment for Multiplicity 
The hypotheses associated with the primary and secondary variables for efficacy claim are 
grouped into 2 hierarchical families: Families 1 and 2, respectively. The enhanced mixture 
truncated Hochberg-based gatekeeping procedure with the logical relationships among the 
hypotheses (ie, 𝐻𝐻21 will be tested only if 𝐻𝐻11 is rejected; 𝐻𝐻22 will be tested only if 𝐻𝐻12 is 
rejected) will be applied to control the family-wise Type 1 error rate of 5% (two-sided) for the 
hypotheses in Families 1 and 2. The truncation parameter in Family 1, which is used to 
determine α propagation rule, is chosen as 0.5. The details for how to generate corresponding 
adjusted p-value for individual hypothesis based on above multiplicity adjustment approach will 
be provided in the SAP. 


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Figure 2: 
Hierarchy of Hypothesis Testing for Primary and Secondary Efficacy 
Endpoints 
 
 
Choice of Truncation Parameter γ per Power Simulation for Sample Size Calculation 
Assessment of the procedure’s power facilitates the selection of the truncation parameter γ. The 
truncation parameter γ determines the balance of power between Families 1 and 2. Due to the 
testing logical restriction, power of 𝐻𝐻21 will be less than that of 𝐻𝐻11 and power of 𝐻𝐻22 will be 
less than that of 𝐻𝐻12. Various types of power of the truncated Hochberg-based gatekeeping 
procedure can be evaluated via simulations. Power simulations were performed using the 
parameter settings below and other scenarios were also performed to further evaluate the 
robustness of power profile when deviation from the initial assumption of effect size occurs. 
 
Correlation 
ρ 
 
Simulation 
Case 
Effect Size 
MADRS Total Score 
CGI-BP-S Depression Score 
Low Dose 
High Dose 
Low Dose 
High Dose 
0.7 
Case 1 
0.35 
0.35 
0.35 
0.35 
Case 2 
0.35 
0.35 
0.33 
0.33 
Simulation parameters for power: N=165/Arm, 100,000 simulations. 
Details of the simulation results, including both conjunctive power (rejecting both hypotheses 
within a family) and disjunctive power (rejecting at least one null hypothesis within a family) for 
Family 1 and Family 2 will be provided in the SAP. The key simulation results are summarized 
here: under the parameter settings, both conjunctive and disjunctive powers for Family 1 are very 
stable regardless of choice of the truncation parameter; on the contrary, disjunctive power for 
Family 2 showed a clear variation pending on selection of the truncation parameter. It is 
important to point out that the Hochberg-based truncated gatekeeping procedure does not make 
any assumption about the correlation among the two endpoints. 


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15.4.3.5. Efficacy Subgroup Analysis 
The primary efficacy variable (change from Baseline in MADRS total score at Week 6) and 
secondary efficacy variable (change from Baseline in CGI-BP-S depression score at Week 6) 
will be examined to explore the consistency of the treatment effect across certain subgroups at 
Week 6. Subgroups, including but not limited to gender, race, region, and country (pooled), will 
be detailed in the SAP. For each subgroup except region and country, a subgroup analysis will be 
conducted on an MMRM model similar to the one used in the corresponding primary efficacy 
analysis with 3 additional terms: subgroup, treatment-by-subgroup interaction, and 3-way 
interaction of treatment*subgroup*visit. For country, a subgroup analysis will be conducted on 
an MMRM model similar to the one used in the corresponding primary efficacy analysis with 2 
additional terms: treatment-by-subgroup interaction, and 3-way interaction of 
treatment*subgroup*visit. For region, a similar MMRM subgroup analysis as for ‘country’ will 
be performed by replacing ‘country’ by ‘region’. Based on the above analysis models, LS mean 
treatment differences (each SEP-4199 CR dose group vs. placebo) at Week 6, corresponding 
2-sided 95% CIs for each subgroup level, and p-value of treatment-by-subgroup interaction at 
Week 6 will be generated. Summary statistics by treatment group within each subgroup level 
will be provided as well. 
15.4.4. 
Safety Analyses 
Unless otherwise specified, the safety data analysis will be based on the Safety population. For a 
few selected safety assessments (AE, ECG, Lab, Vital Signs), additional summaries will be 
provided per the follow-up population as well, as appropriate. 
15.4.4.1. Adverse Events 
All AEs will be coded using MedDRA. Information on the format and version of coding 
dictionary is provided in the DMP. A treatment-emergent adverse event ( hereafter referred to as 
AE) is defined as an untoward medical event with a start date on or after the date of the first dose 
of study drug through 7 days after study drug discontinuation (14 days for SAEs) for subjects 
who complete or discontinue this study but do not enter into the extension study), or through the 
last study day of the double-blind treatment period for subjects continuing into the extension 
study. 
The overall incidence (ie, number and percentage of subjects with one or more AEs in each 
category) of AEs, discontinuation due to AEs, and SAEs will be summarized by treatment group. 
The AEs also will be summarized by system organ class (SOC) and preferred term (PT) by 
presenting the number and percentage of subjects with each AE category. The incidence of AEs 
(by PT, grouped by SOC, and presented by treatment group) also will 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 be also 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 hyperprolactinemia-related AEs, will be 
summarized by treatment group for overall and by gender as appropriate. AEs associated with 
EPS will be summarized by treatment 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 
by SOC and PT separately for subjects in the Follow-up population. 
15.4.4.2. Treatment-Emergent Mania and YMRS 
Treatment-emergent mania is defined as a YMRS score ≥ 16 on any 2 consecutive post-Baseline 
visits or at the final assessment, or an AE of mania or hypomania. If a subject has no reported 
AE of mania or hypomania and has no post-Baseline assessment of YMRS, incidence of 
treatment-emergent mania will be set to missing. SEP-4199 CR will be compared to placebo in 
incidence of treatment-emergent mania in a logistic regression model including factors of 
treatment, region, and Baseline YMRS total score covariate. 
The change from Baseline in YMRS total score will also be analyzed using the MMRM method 
described above for the primary efficacy variable and appropriate Baseline as a covariate. 
15.4.4.3. Clinical Laboratory Assessments 
Descriptive statistics (mean, median, etc) will be provided by visit and treatment group for 
observed values or changes from Baseline for safety variables (continuous). Categorical results 
(eg, urinalysis tests) will be summarized by study visit and treatment group using frequency and 
percentage. Results for glucose, insulin, HOMA-IR, and lipid tests will be presented separately 
by fasting status, which includes fasting only, and overall (fasting, non-fasting, or unknown). 
Prolactin values will be summarized by treatment group and gender (male, female, and overall). 
In addition, the change from Baseline at endpoint for selected laboratory parameters (eg, HbA1c, 
insulin, HOMA-IR, glucose, lipids parameters, prolactin) will be evaluated using a 
nonparametric rank ANCOVA analysis. For comparison versus placebo, stratified by region, the 
change from Baseline at endpoint and Baseline value will be ranked. A linear regression will be 
conducted by region, on the change from Baseline ranks and Baseline value rank as independent 
variable to produce regression residuals. Using the values of the residuals as scores, Mantel-
Haenszel row mean score tests will be produced for each SEP-4199 CR dose group versus 
placebo after stratification by region. 
Laboratory data will be summarized by presenting descriptive statistics of shift tables. Number 
and percentage of subjects with potentially clinically significant (PCS) post-Baseline laboratory 
value for selected parameters will be summarized by treatment, and by study visit and for 
assessment period (the SAP will provide details of laboratory PCS criteria). 
15.4.4.4. ECGs 
Standard 12-lead ECG parameters HR, PR interval, RR interval, QT interval, Bazett’s corrected 
QT (QTcB) and Fridericia’s corrected QT (QTcF) intervals, and QRS duration will be assessed. 
Results of each ECG parameter and their changes from Baseline will be summarized by visit 
using descriptive statistics. 
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 and < 60 msec, and ≥ 60 msec will 
be summarized by treatment group. Number and percentage of subjects with PCS post-baseline 


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ECG values will be summarized by treatment, by study visit, and for assessment period (the SAP 
will provide details of ECG PCS criteria). 
15.4.4.5. Vital Signs 
Descriptive statistics (mean, median etc.) of the following parameters will be summarized by 
study visit for actual value as well as change from Baseline (including percent change of body 
weight) for each treatment 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 treatment group. 
An ANCOVA model using the LOCF approach will be conducted for changes from Baseline at 
Week 6 in change and percent change from Baseline in body weight (kg), and change from 
Baseline in BMI (kg/m2). The ANCOVA model will include terms for treatment, region, and 
corresponding Baseline value as covariate. 
Number and percentage of subjects with PCS post-Baseline vital sign values will be summarized 
by treatment, by study visit, and for assessment period. Number and percentage of subjects with 
orthostatic hypotension and/or orthostatic tachycardia will be summarized similarly (the SAP 
will provide details of vital signs PCS Criteria). 
15.4.4.6. Movement Disorder Measures 
An ANCOVA model using the LOCF approach will be conducted for changes from Baseline at 
Week 6 in BARS total score, AIMS total score, and SAS 10-item mean score. The ANCOVA 
model will include terms for treatment, region, and corresponding Baseline value as covariate. 
LS means for each treatment group, the LS mean of treatment difference (SEP-4199 CR group 
minus placebo) and the associated two-sided 95% CI will be presented at Week 6. Summary 
statistics for the observed and change from 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 as well. 
Shifts from 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 
treatment group, respectively. Details for definition of these classifications will be provided in 
the SAP. 
15.4.4.7. 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 treatment group for 
the overall post-Baseline treatment period. 


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15.4.4.8. Physician’s Withdrawal Checklist (PWC) 
The PWC score will be summarized by presenting descriptive statistics of observed values and 
changes from Week 6 (Day 42) by treatment group for the follow-up period. Numbers and 
percentages of subjects with any new symptom or worsened old symptom for any PWC score or 
each individual symptom score will be also provided. 
15.4.5. 
Pharmacokinetic Analysis 
All PK analysis (except of plasma prolactin concentration) will be performed using the PK 
population. The plasma prolactin concentration will be summarized based on the Safety 
population in order to display summary statistics for placebo plasma prolactin data. 
Any plasma concentration summary statistics below the limit of quantification will be 
represented by “BLQ”. Concentrations at each scheduled sample collection time point will be 
summarized descriptively (n, mean, SD, median, range, coefficient of variation [CV%], 
geometric mean, and geometric CV%). 
Population PK (Pop-PK) analysis methods will be used to characterize the PK/PD profiles in 
subjects treated with SEP-4199 CR. Methods and results of Pop-PK analysis will be described in 
a separate document from the SAP and clinical study report. 
15.4.6. 
Interim Analysis 
No interim analysis is planned. 
15.4.7. 
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 Screening and data collected during the study (except clinical laboratory test 
results, ECG results, Pop-PK, pharmacogenomic testing, and scales) will be recorded in the 
subject’s eCRF. The study centers will use an EDC system that is compliant with relevant FDA 
regulatory requirements per 21 Code of Federal Regulations (CFR) Part 11 (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 
Informed consent for optional pharmacogenomic sampling 
A 
Lifetime Illness Characteristics Questionnaire 
C 
Montgomery-Asberg Depression Rating Scale, Self-rating 
Version (MADRS-S) 
C 
Inclusion/Exclusion Criteria Review 
A 
Demographics 
A 
Medical History 
A 
Psychiatric History 
A 
Family Psychiatric and Medical History 
A 
Structured Clinical Interview for DSM 5 Clinical Trial 
Version (SCID-5-CT) 
C 
Physical Examination 
A 
Neurological Examination 
A 
Prior/Concomitant Medications 
A 
Subject Eligibility Check 
B 
Randomization 
B 


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Table 6: 
Computerized Systems Used for Source Data (Continued) 
Protocol Step  
Computerized System Type or Description 
Study Drug Accountability 
A/B 
Dispense Study Drug 
B 
Administer Study Drug 
A 
Montgomery-Asberg Depression Rating Scale (MADRS) 
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 Dimension – 5 Level (EQ-5D-5L) 
C 
Snaith-Hamilton Pleasure Scale (SHAPS) 
C 
Clinical Global Impression – Bipolar Version-Severity of 
Illness (CGI-BP-S) 
C 
Vital Signs 
A 
Height 
A 
Weight (Including Body Mass Index) 
A 
Waist Circumference 
A 
Pretreatment and Adverse Event Monitoring 
A 
12-Lead Electrocardiogram (ECG) 
E 
Hematology, Serum Chemistry, and Urinalysis 
D 
Serum Prolactin 
D 
Hemoglobin A1c (HbA1c) 
D 
Lipid Panel 
D 
Serum Insulin  
D 
High Sensitivity C-reactive Protein 
D 
Hepatitis B/C 
D 
Thyroid Panel 
D 
Serum Follicle Stimulating Hormone (Female Subjects) 
D 
Serum β-hCG (Female Subjects of child-bearing potential) 
D 
Urine β-hCG (Female Subjects of child-bearing potential) 
A 
Urine Drug Screen 
D 
Rapid Urine Drug Test 
A 
Young Mania Rating Scale (YMRS) 
C 
Physician’s Withdrawal Checklist (PWC) 
C 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
C 
Abnormal Involuntary Movement Scale (AIMS) 
C 
Barnes Akathisia Rating Scale (BARS) 
C 


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Table 6: 
Computerized Systems Used for Source Data (Continued) 
Protocol Step  
Computerized System Type or Description 
Modified Simpson-Angus Scale (SAS) 
C 
Blood sample for aramisulpride and esamisulpride PK and 
Plasma Prolactin 
F 
Optional Blood Sampling for Pharmacogenomic Testing 
F 
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 International Council on Harmonization (ICH) Good Clinical Practice 
(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 
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. 


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Source document is defined as any handwritten or computer-generated document that contains 
medical information or test results that have been collected for or are in support of the protocol 
specifications, eg, clinical laboratory reports, clinic notes, drug disbursement log, subject sign-in 
sheets, subject completed questionnaires if applicable, telephone logs, ECGs, etc. All draft, 
preliminary, and pre-final iterations of a final report are also considered to be source documents, 
eg, faxed laboratory reports and hard copy laboratory reports, faxed initial results and hard copy, 
final report. 
16.6. 
Clinical Laboratory Certification and Normal Values 
A central laboratory will be used for analysis 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 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 and 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 IRBIEC 
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, ICF 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 Investigational New Drug (IND) or ICH GCP, as 
applicable. 
The Investigator/CRO is responsible for obtaining from the IRB/IEC continued review of the 
clinical research or submitting periodic progress reports, in accordance with applicable 
regulations, at intervals not to exceed one year and (if applicable) as otherwise additionally 


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specified by the IRB/IEC. The Sponsor must be supplied with written documentation of 
continued review of the clinical research. 
The Investigator must promptly inform their IRB/IEC of all SAEs reported by subjects enrolled 
in the study or other safety information reported 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. 


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If any cases are identified where the subject’s confidentiality has been breached, this must be 
rectified immediately. All subject identifiable information should be removed, and the Sponsor 
notified. 
17.5. 
Protocol Amendments and Emergency Deviations 
All revisions and/or amendments to this protocol must be approved in writing by the Sponsor 
and the appropriate IRB/IEC. The Investigator will not make any changes to the conduct of the 
study or the protocol without first obtaining written approval from the Sponsor and the IRB/IEC, 
except where necessary to eliminate an apparent immediate hazard to a study subject. 
Emergency deviations or modifications may be initiated without Sponsor or IRB/IEC approval or 
favorable opinion, only in cases where the deviation or modification is necessary to eliminate or 
avoid an immediate apparent hazard to subjects. Emergency deviations or modifications must be 
reported to the Sponsor/CRO and the IRB/IEC immediately/within five business days of the 
occurrence, or in accordance with applicable regulatory requirements. 
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 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 the 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. 


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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 
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 AE 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. 
Aitkin CB, Weisler RH, Sachs GS. The Bipolarity index: a clinician-rated measure of diagnostic 
confidence. Journal of Affective Disorders. 2015;177(59-64). 
American Psychiatric Association (APA) Practice guideline for the treatment of patient with 
bipolar disorder (revision). Am J Psychiatry. 2002;159(4) suppl:1-50. 
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. 
Fantino B, Moore N. The self-reported Montgomery-Asberg Depression Rating Scale is a useful 
evaluative tool in Major Depressive Disorder. BMC Psychiatry. 2009; 9(26):1-6. 
First MB, Williams JBW, Karg RS, Spitzer RL: Structured Clinical Interview for DSM-5—
Clinical Trials Version (SCID-5-CT); Arlington, VA, American Psychiatric Association, 2015. 
Gail MH, Simon R. Tests for Qualitative Interactions between Treatment Effects and Patient 
Subsets. Biometrics. 1985; 41:361-372. 
Ghaemi SN, Ostacher MM, El-Mallakh RS, Borrelli D, Baldassano CF, Kelly ME, et. al. 
Antidepressant discontinuation in bipolar depression: A Systematic Treatment Enhancement 
Program for Bipolar Disorder (STEP-BD) randomized clinical trial of long-term effectiveness 
and safety. J Clin Psychiatry. 2010;71(4):372-80. 
Goldberg JF, Brooks JO 3rd, Kurita K, Hoblyn JC, Ghaemi SN, Perlis RH, et. al. Depressive 
illness burden associated with complex polypharmacy in patients with bipolar disorder; findings 
from the STEP-BD. J Clin Psychiatry. 2009:70(2):155-62. 
Gutierrez-Rojas L, Gurpegui M., Ayuso-Mateos JL, Gutierrez-Ariza JA, Ruiz-Veguilla M, 
Jurado D. Quality of life in bipolar disorder patients: a comparison with a general population 
sample. Bipolar Disord. 2008:10(5):625-34. 
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. 
Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA, et al. The long term 
natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 
2002;59:530-7. 


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Judd LL, Akiskal HS, Schettler PJ, Coryell W, Endicott J, Maser J, et al. A prospective 
investigation of the natural history of the long-term weekly symptomatic status of bipolar II 
disorder. Arch Gen Psychiatry. 2003;60:261-9. 
Kemp DE. Managing the side effects associated with commonly used treatments for bipolar 
depression. J Affect Disord. 2014 Dec;169 Suppl 1:S34-44. 
Kordzakhia G, Brechenmacher T, Ishida E, Dmitrienko A, Zheng WW, Li DF. An enhanced 
mixture method for constructing gatekeeping procedures in clinical trials. Journal of 
Biopharmaceutical Statistics. 2018;28(1):113-128. 
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. 
Magalhaes PV, Kapczinski F, Nierenberg AA, Dackersbach T, Weisinger D, Dodd S, et al. 
Illness burden and medical comorbidity in the Systematic Treatment Enhancement Program for 
Bipolar Disorder. Acta Psychiatr Scand. 2012;125(4):303-8. 
Merikangas KR, Akiskal HS, Angst J, Greenberg MA, Hirschfeld RM, Petukhova M, et al. 
Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity 
Survey replication. Archives of General Psychiatry. 2007;64:543-52. 
Miller S, Dell’Osso B, Ketter TA. The prevalence and burden of bipolar depression. J Affect 
Disord. 2014 Dec;169 Suppl 1:S3-S11. 
Montgomery, 2002. Dopaminergic deficit and the role of amisulpride in the treatment of mood 
disorders. International Clinical Psychopharmacology. 2002;17 (suppl 4): S9-S17. 
Mundt JC, Katzelnick DJ, Kennedy SH, Eisfeld BS, Bouffard BB, Greist JH. Validation of an 
IVRS version of the MADRS. J Psychiatr Res. 2006 Apr; 40(3):242-6. 
Munetz MR, Benjamin S. How to examine patients using the Abnormal Involuntary Movement 
Scale. Hospital and Community Psychiatry. 1988;39:1172-7. 
Pan G, Wolfe DA. Test for qualitative interaction of clinical significance. Statistics in Medicine. 
1997; 16(14):1645-1652. 
Schooler NR, Chengappa KNR. Adverse effects measures. In: Handbook of Psychiatric 
Measures. Washington, D.C.: American Psychiatric Association, 2000:151-68. 
Shippee ND, Shah ND, Williams MD, Moriarty JP, Frye MA, Ziegenfuss JY. Differences in 
demographic composition and in work, social, and functional limitations among the populations 
with unipolar depression and bipolar disorder: results from a nationally representative sample. 
Health Qual Life Outcomes. 2011;9:90. 
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, SEP380-301, Version 3.00, “A Multi-region, Multicenter, Randomized, 
Double-Blind, Placebo-Controlled, Parallel-Group Study Evaluating 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), Alkaline Phosphatase (ALP), 
Albumin, 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, LDL-Cholesterol, 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  
SEROLOGY PANEL: Hepatitis B Ag and Hepatitis C Ab 
RENAL FUNCTIONING: Creatinine clearance (Calculated GFR) 
OTHER TESTS: Follicle-stimulating Hormone (FSH; postmenopausal women or if menopause 
is suspected; Screening visit only), 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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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. 
Day No. 
Aramisulpride and Esamisulpride PK and Plasma Prolactin 
Blood Sample Collection Times: 
1 
-22 to -2 
Baseline prolactin only 
2 
-1 
Predose for PK and prolactin 
4 
14 (± 2) 
Postdose* for PK and prolactin 
6 
42 (± 2) 
Postdose* for PK and prolactin 
7 
7 (± 2) days 
after last dose 
Follow-up**for PK and prolactin 
* 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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APPENDIX IV. PHARMACOGENOMICS SAMPLE 
COLLECTON AND HANDLING GUIDELINE 
Please refer to the Laboratory Investigator Manual for all collection and shipping instructions. 
BLOOD SAMPLES FOR POTENTIAL PHARMACOGENOMICS 
• 
A blood sample (approximately 4.0 mL) will be collected at Baseline (Visit 2) using a 
4 mL Vacutainer® (or equivalent) collection tube containing K2-EDTA as an 
anticoagulant. 
• 
The tubes containing blood samples will be labeled with the following information: unique 
barcode (if possible), protocol number, subject number, and sample date of collection. 
• 
Blood samples will be kept upright on wet ice upon blood draw and will be stored frozen at 
approximately -70°C within 10 min of collection until shipment to the appropriate 
laboratory. For sites without a -70°C freezer, samples should be shipped to the central 
laboratory within 24 hours of collection (prior to shipping, must be stored frozen at -20°C). 
• 
The blood samples for pharmacogenomics will be shipped in leak proof double-plastic 
sealed bags with approximately 20 pounds of dry ice placed in insulated shipping 
containers labeled on the outside with “Human Specimens/Non-infectious”. Packing 
material such as bubble wrap or other cushioning material will be placed around the 
samples to prevent breakage during shipping. Samples will be shipped in conformance with 
International Air Transport Association (IATA) regulations relating to the handling and 
shipping of hazardous goods. 
• 
The shipping details will be defined in the Laboratory Investigator Manual. 
 


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APPENDIX V. 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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APPENDIX VI. MINIMUM MADRS TOTAL SCORE CRITERIA 
AT BASELINE 
To be eligible for randomization, Baseline (Visit 2) MADRS total score must be ≥ 22 AND no 
more than a 25% decrease from the total score at Screening. (Refer to Table below for 
reference.) 
The following formula is to be utilized to determine the MADRS total score change at Baseline 
(Visit 2): 
MADRS total score at Screening - MADRS total score at Baseline
MADRS total score at Screening
× 100% 
 
MADRS total score 
at Screening (V1) 
MINIMUM Permissible 
MADRS total score at 
Baseline (V2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MADRS total 
score at Screening 
(V1) 
MINIMUM 
Permissible MADRS 
total score at Baseline 
(V2) 
22 
22 
42 
32 
23 
22 
43 
33 
24 
22 
44 
34 
25 
22 
45 
34 
26 
22 
46 
35 
27 
22 
47 
36 
28 
22 
48 
37 
29 
22 
49 
37 
30 
23 
50 
38 
31 
24 
51 
39 
32 
25 
52 
40 
33 
25 
53 
40 
34 
26 
54 
41 
35 
27 
55 
42 
36 
28 
56 
43 
37 
28 
57 
43 
38 
29 
58 
44 
39 
30 
59 
45 
40 
31 
60 
46 
41 
31 
- 
- 


Protocol SEP380-301, Version 3.00 
 
SEP-4199 CR 
Confidential and Proprietary 
117 
06 Dec 2022 
26. 
APPENDIX VII. PRE-BASELINE ELIGIBILITY REVIEW  
Subject information collected during the Screening Period will be reviewed by the Sponsor 
Eligibility Committee to inform Inclusion Criterion 19. For each subject who does not screen fail 
based on any other inclusion or exclusion criterion, sites are instructed to complete the following 
as soon as possible (within 2 working days, if possible). 
• Confirm the diagnosis of bipolar I disorder with at least 1 prior manic episode or 
manic episode with mixed features corroborated by medical records or documented 
correspondence with a treating psychiatrist or mental healthcare provider/staff, or 
information from a reliable informant who is familiar with the subject’s psychiatric 
history. 
• Confirm the diagnosis of a current major depressive episode corroborated by medical 
records or documented correspondence with a treating psychiatrist or mental 
healthcare provider/staff (if the subject has been evaluated during the current MDD 
episode), or information from a reliable informant who is familiar with the subject’s 
psychiatric history. 
• Send clinical laboratory samples to the centralized laboratory vendor. 
• Transmit ECG results to centralized cardiac safety vendor. 
• Upload all audio recordings and send all rating scales data to Sponsor’s designee. 
These include: 
o Lifetime Illness Characteristics Questionnaire and Bipolarity Index Score 
o Structured Interview for DSM-5 Clinical Trials (audio recording) 
o Montgomery-Asberg Depression Rating Scale – Self-rating Version 
o Montgomery-Asberg Depression Rating Scale (audio recording) 
o Young Mania Rating Scale 
o Columbia Suicide Severity Rating Scale 
o Clinical Global Impression - Bipolar Version -Severity of Illness 
• Complete the following Screening eCRFs or study-level forms: 
o Subject 
o Visit 
o Protocol Version 
o Demographics 
o Medical History 
o Psychiatric History 
o Family Psychiatric and Medical History 
o Prior and Concomitant Medications 
o Vital Signs 


Protocol SEP380-301, Version 3.00 
 
SEP-4199 CR 
Confidential and Proprietary 
118 
06 Dec 2022 
o Physical Examination 
o Neurological Examination 
o Inclusion/Exclusion Criteria 
o Screening Pass/Fail 
Complete the subject psychiatric narratives based on the subject’s self-report, information 
obtained from medical records, documented correspondence with a treating psychiatrist or 
mental healthcare provider/staff, or information provided by the highly reliable informant. The 
narrative should include information summarizing the chronological timeline of subject’s 
psychiatric history including a description of the manic episode and clinical presentation of 
current major depressive episode. 
 

SAP_001.pdf: 
Statistical Analysis Plan  
  
PROTOCOL SEP380-301 
Page 1 of 79 
 
 
 
 
 
Version Number: 
Final 
 
 
Version Date: 
08DEC2023 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
SEP380-301 
A Multi-region, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study 
Evaluating SEP-4199 Controlled Release (CR) for the Treatment of Major Depressive Episode 
Associated with Bipolar I Disorder (Bipolar I Depression) 
 
Phase: III 
 
 
 
 
VERSION NUMBER AND DATE: FINAL 
                                                         DECEMBER 08, 2023    
 
 
 
 


Statistical Analysis Plan  
  
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan Final (Dated 08DEC2023) for Protocol SEP380-301. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan  
  
PROTOCOL SEP380-301 
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Version Number: 
Final 
 
 
Version Date: 
08DEC2023 
 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan  
  
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Version Number: 
Final 
 
 
Version Date: 
08DEC2023 
 
MODIFICATION HISTORY 
 
 
Unique 
Identifie
r for 
this 
Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
V1.0 
08June2023 
 
Not Applicable – First Version 
V2.0 
03August2023 
 
Incorporated comments on the first 
draft. Added table of contents for TFL 
shells.  
V2.1 
18August2023 
 
Incorporated comments on the draft 
V2.0. added CV units for lab.   
V2.2 
10October2023 
 
Simplified the analysis plan because 
the small sample size due to study 
early termination.  
V2.3 
30October2023 
 
Incorporated comments on the draft 
V2.2.   
V2.4 
07Novmber2023 
 
Incorporated comments from SMP on 
the draft V2.3.   
Final 
08Decmber2023 
 
Incorporated comments on the draft 
V2.4.   
 
 
 


Statistical Analysis Plan  
  
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Version Date: 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ............................................................... 2 
MODIFICATION HISTORY ......................................................................................................... 4 
TABLE OF CONTENTS .............................................................................................................. 5 
1. 
INTRODUCTION ............................................................................................................. 10 
2. 
STUDY OBJECTIVES, ESTIMANDS, AND ENDPOINTS ............................................... 10 
2.1. 
Primary Efficacy Objective , Estimands, and Endpoints ............................................ 10 
2.2. 
Secondary Efficacy Objective, Estimand, and Endpoint ............................................ 11 
2.3. 
Additional Efficacy Objectives and Endpoints ............................................................ 11 
2.3.1 Additional Efficacy Objectives ........................................................................................................ 11 
2.3.2 Additional Efficacy Endpoints......................................................................................................... 12 
2.4. 
Safety Objectives and Endpoints .................................................................................. 12 
2.4.1  Safety Objectives ............................................................................................................................. 13 
2.4.2    Safety Endpoints ........................................................................................................................... 13 
2.5. 
Pharmacokinetic  and Pharmacodynamic Objectives and Endpoints ...................... 13 
2.5.1  Pharmacokinetic and Pharmacodynamic Objectives .................................................................. 14 
2.5.2  Pharmacokinetic and Pharmacodynamic Endpoints .................................................................. 14 
3. 
STUDY DESIGN .............................................................................................................. 14 
3.1. 
General Description ........................................................................................................ 14 
3.2. 
Method of assigning subjects to treatment groups .................................................... 15 
3.3. 
Blinding ............................................................................................................................ 15 
3.4. 
Determination of sample size ........................................................................................ 16 
3.5. 
Changes in the conduct of the study ............................................................................ 16 
3.6. 
Schedule of Events ......................................................................................................... 16 


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3.7. 
Changes to Analysis from Protocol .............................................................................. 16 
4. 
PLANNED INTERIM ANALYSIS AND SAFETY MONITORING ANALYSIS................... 17 
4.1. 
Data and Safety Monitoring Board (DSMB) .................................................................. 17 
4.2. 
Interim Analysis ............................................................................................................... 17 
5. 
ANALYSIS POPULATIONS ............................................................................................ 17 
5.1. 
Intention-to-Treat [ITT] Population ................................................................................ 17 
5.2. 
Safety [SAF] Population ................................................................................................. 18 
5.3. 
Pharmacokinetics (PK) Population ............................................................................... 18 
6. 
GENERAL CONSIDERATIONS ...................................................................................... 18 
6.1. 
Reference Start Date and Study Day ............................................................................. 18 
6.2. 
Baseline ............................................................................................................................ 18 
6.3. 
Derived Time points ........................................................................................................ 19 
6.4. 
Windowing Conventions ................................................................................................ 20 
6.5. 
Retests, Unscheduled Visits and Early Termination data........................................... 20 
6.6. 
Statistical Tests ............................................................................................................... 21 
6.7. 
Common Calculations .................................................................................................... 21 
6.8. 
Software Version ............................................................................................................. 21 
7. 
STATISTICAL CONSIDERATIONS ................................................................................ 21 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses ....................... 21 
7.2. 
Multicenter Studies ......................................................................................................... 21 
7.3. 
Missing data ..................................................................................................................... 22 
8. 
OUTPUT PRESENTATIONS ........................................................................................... 22 
9. 
DISPOSITION AND WITHDRAWALS ............................................................................. 22 
10. 
IMPORTANT PROTOCOL DEVIATIONS ........................................................................ 23 


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10.1. 
Deviations Related to PK Analysis ................................................................................ 23 
11. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .................................. 23 
11.1. 
Derivations ....................................................................................................................... 25 
12. 
MEDICAL HISTORY ....................................................................................................... 25 
13. 
PRIOR/CONCOMITANT/POST-TREATMENT MEDICATIONS ...................................... 25 
14. 
STUDY DRUG EXPOSURE ............................................................................................ 26 
14.1. 
Derivations ....................................................................................................................... 26 
15. 
STUDY DRUG COMPLIANCE ........................................................................................ 27 
15.1. 
Derivations ....................................................................................................................... 27 
16. 
EFFICACY OUTCOMES ................................................................................................. 28 
16.1. 
Primary Efficacy .............................................................................................................. 28 
16.1.1. 
Primary Efficacy Variable & Derivation ......................................................................... 28 
16.1.2. 
Missing Data Methods for Primary Efficacy Variable .................................................. 28 
16.1.3. 
Primary Analysis of Primary Efficacy Variable(s) ........................................................ 28 
16.1.4. 
Supportive Analysis of Primary Efficacy Variable(s) .................................................. 29 
16.2. 
Secondary Efficacy ......................................................................................................... 30 
16.2.1. 
Secondary Efficacy Variable & Derivations .................................................................. 30 
16.2.2. 
Missing Data Methods for Secondary Efficacy Variable(s)......................................... 30 
16.2.3. 
Analysis of Secondary Efficacy Variable ...................................................................... 30 
16.2.4. 
Supportive Analysis of Secondary Efficacy Variable .................................................. 30 
16.3. 
Additional Efficacy Endpoints Analyses ...................................................................... 31 
16.3.1. 
Additional Efficacy Variable Derivations ...................................................................... 31 
16.3.2. 
Missing Data Methods for Other Efficacy Variable(s) ................................................. 32 
16.3.3. 
Analysis of Additional Efficacy Variables..................................................................... 33 


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17. 
SAFETY OUTCOMES ..................................................................................................... 34 
17.1. 
Pretreatment and Adverse Events ................................................................................. 34 
17.1.1. 
All AEs .............................................................................................................................. 35 
17.1.2. 
AEs Leading to Discontinuation from Study Treatment Period ................................. 35 
17.1.3. 
Serious Adverse Events and Death ............................................................................... 35 
17.1.4. 
Adverse Events of Special Interest (AESI) ................................................................... 35 
17.2. 
Laboratory Evaluations .................................................................................................. 36 
17.2.1. 
Laboratory Reference Ranges and Potentially clinically significant (PCS) Criteria 37 
17.3. 
ECG Evaluations ............................................................................................................. 37 
17.3.1. 
ECG Specific Derivations ............................................................................................... 38 
17.3.2. 
ECG Potential Clinically Significant Criteria ................................................................ 39 
17.4. 
Vital Signs ........................................................................................................................ 39 
17.4.1. 
Vital Signs Potentially Clinically Significant Criteria ................................................... 40 
17.5. 
Physical And Neurological Examination ...................................................................... 41 
17.6. 
Other Safety Assessments ............................................................................................. 41 
17.6.1. 
Young Mania Rating Scale (YMRS) ............................................................................... 41 
17.6.2. 
Treatment-Emergent Mania ............................................................................................ 41 
17.6.3. 
Columbia Suicide Severity Rating Scale (C-SSRS) ..................................................... 41 
17.6.4. 
Abnormal Involuntary Movement Scale (AIMS) ........................................................... 44 
17.6.5. 
Barnes Akathisia Rating Scale (BARS) ......................................................................... 45 
17.6.6. 
Modified Simpson-Angus Scale (MSAS)....................................................................... 45 
17.6.7. 
Physician Withdrawal Checklist (PWC) ........................................................................ 45 
18. 
PHARMACOKINETIC ANALYSIS .................................................................................. 46 
18.1. 
Derivation ......................................................................................................................... 46 
19. 
DATA NOT SUMMARIZED OR PRESENTED ................................................................ 47 


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20. 
CHANGES IN THE ANALYSIS SPECIFIED IN THE STATISTICAL ANALYSIS PLAN .. 47 
21. 
REFERENCES ................................................................................................................ 48 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS........................................ 49 
APPENDIX 2. PARTIAL DATE CONVENTIONS.................................................................... 52 
APPENDIX 3. STATISTICAL MODEL SPECIFICATIONS ..................................................... 58 
APPENDIX 4. 
INTERNATIONALLY AGREED ORDER OF SYSTEM ORGAN CLASSES ....... 60 
APPENDIX 5. Adverse Event of Special Interest (AESI) ..................................................................... 61 
A5.1  Hyperprolactinemia-related AEs (Customized) ............................................................................ 61 
A5.2  Extrapyramidal Syndrome (EPS) related AEs (Broad) ................................................................. 62 
A5.3  Torsade de pointes/QT Prolongation (Broad and Narrow) related AEs ..................................... 63 
APPENDIX 6. PREDEFINED POTENTIALLY CLINICALLY  SIGNIFICANT (PCS) CRITERIA 
FOR LABORATORY VALUES ................................................................................................. 64 
APPENDIX 7. BLINDED DATA REVIEW (BDR) PROCESS .................................................. 66 
APPENDIX 8. EQ-5D-5L INDEX VALUE ............................................................................... 67 
APPENDIX 9. TABLE OF CONTENTS.................................................................................................... 68 
APPENDIX 10. Schedule of Events ......................................................................................................... 73 
 
 


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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of 
efficacy and safety data for Protocol SEP380-301. It describes the data to be summarized and 
analyzed, including specifics of the statistical analyses to be performed.  
Data and Safety Monitoring Board (DSMB) analysis plan will be described in separate documents. A 
Blind Data Review (BDR) Plan will be written to describe the process and the outputs to be delivered 
during the IPD/BDR meetings. 
This statistical analysis plan (SAP) is based on protocol version 3.0, dated 06 December 2022. 
Hereafter, this protocol version is referred to as the Clinical Study Protocol (CSP).  
All the final planned analyses specified in this SAP will be performed inhouse by SMPA following the 
analysis populations, final database lock, and unblinding of treatment. 
Some minor modifications may be necessary to the planned design of tables, figures, and listings to 
accommodate data collected during the actual study conduct. 
 
2. STUDY OBJECTIVES, ESTIMANDS, AND ENDPOINTS 
The objective of Study SEP380-301 is to evaluate the efficacy, safety, and tolerability of SEP-4199 CR 
formulation given as monotherapy at fixed doses of 200 mg/day and 400 mg/day compared with placebo 
in the treatment of subjects with major depressive episode associated with bipolar I disorder (bipolar I 
depression). 
2.1. PRIMARY EFFICACY OBJECTIVE , ESTIMANDS, AND ENDPOINTS 
Evaluate the efficacy of SEP-4199 CR in the reduction of depression symptoms, as measured using the 
Montgomery-Asberg Depression Rating Scale (MADRS). 
Table 1: Primary Objective, Estimand, and Endpoint 
Primary 
Objective 
Endpoint 
Evaluate the efficacy of SEP-4199 CR in the 
reduction of depression symptoms, as measured 
using the Montgomery-Asberg Depression Rating 
Scale (MADRS). 
Change from baseline to Week 6.in 
MADRS total score  
 
Estimand 
Population 
Subjects with major depressive episode associated with bipolar I disorder, as 
characterized by the inclusion/exclusion criteria of the study. For the efficacy 
analyses, the ITT population will be used to represent the population of interest. 
Treatments 
SEP-4199 CR formulation given as monotherapy at fixed doses of 200 mg/day 
and 400 mg/day compared with placebo for 6 weeks  
Intercurrent events 
The intercurrent event that is deemed to have an impact on the interpretation of 
the variable of interest is early withdrawal from study treatment for any reason. 


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This intercurrent event will be handled with the hypothetical strategy. The efficacy 
data after the last on-treatment visit will not be collected as these data are 
irrelevant to the treatment effect of interest. Rather, these data will be implicitly 
predicted based on the assumptions about how the data would evolve after 
treatment withdrawal. 
Population-level 
summary 
The difference in the change from baseline in MADRS total score.  
 
2.2. SECONDARY EFFICACY OBJECTIVE, ESTIMAND, AND ENDPOINT 
Evaluate the efficacy of SEP 4199 CR in global improvement of bipolar depression severity, as 
measured using the Clinical Global Impression-Bipolar Version-Severity of Illness, Depression scale 
(CGI-BP-S depression). 
Table 2: Secondary Objective, Estimand, and Endpoint 
Secondary 
Objective 
Endpoint 
Evaluate the efficacy of SEP 4199 CR in global 
improvement of bipolar depression severity, as 
measured using the Clinical Global Impression-
Bipolar Version-Severity of Illness, Depression 
scale (CGI-BP-S depression). 
Change from baseline to Week 6 in CGI-BP-S 
depression score. 
Estimand 
Population 
Subjects with major depressive episode associated with bipolar I disorder as 
characterized by the inclusion/exclusion criteria of the study. For the efficacy 
analyses, the ITT population will be used to represent the population of interest. 
Treatments 
SEP-4199 CR formulation given as monotherapy at fixed doses of 200 mg/day 
and 400 mg/day compared with placebo for 6 weeks. 
Intercurrent events 
The intercurrent event that is deemed to have an impact on the interpretation of 
the variable of interest is early withdrawal from study treatment for any reason. 
This intercurrent event will be handled with the hypothetical strategy. The efficacy 
data after the last on-treatment visit will not be collected as these data are 
irrelevant to the treatment effect of interest. Rather, these data will be implicitly 
predicted based on the assumptions about how the data would evolve after 
treatment withdrawal. 
Population-level 
summary 
The difference in the change from baseline to Week 6 in CGI-BP-S depression 
score. 
 
2.3. ADDITIONAL EFFICACY OBJECTIVES AND ENDPOINTS 
        2.3.1 Additional Efficacy Objectives 
• 
Assess the proportion of subjects with treatment response, defined as ≥ 50% reduction in 
MADRS total score. 


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• 
Assess the proportion of subjects with depression symptom remission, defined as a MADRS 
total score ≤ 12. 
• 
Assess the effect of treatment on the core symptoms of depression, as measured using the 
MADRS-6 subscale, defined as summation of items 1, 2, 3, 7, 8, and 9. 
• 
Assess the effect of treatment in the reduction of anxiety symptoms, as measured using the 
Hamilton Anxiety Rating Scale (HAM-A). 
• 
Assess the effect of treatment on subject self-rated depression symptom severity, as 
measured by the Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR16). 
• 
Assess the effect of treatment on functional impairment, as measured by the Sheehan 
Disability Scale (SDS). 
• 
Assess the effect of treatment on quality of life, as measured by the EuroQol-5 Dimension-5 
Level (EQ-5D-5L). 
• 
Assess the effect of treatment on anhedonia, as measured by the Snaith-Hamilton Pleasure 
Scale (SHAPS). 
 2.3.2 Additional Efficacy Endpoints 
• 
Change from Baseline in MADRS total score at Weeks 1, 2, and 4 
• 
Change from Baseline in CGI-BP-S depression score at Weeks 1, 2, and 4 
• 
The proportion of subjects with treatment response, defined as ≥ 50% reduction from Baseline 
in MADRS total score, at Week 6 
• 
The proportion of subjects meeting criteria for remission, defined as MADRS total score ≤ 12, 
at Week 6 
• 
Change from Baseline to Week 6 in the MADRS-6 core symptoms subscale 
• 
Change from Baseline in HAM-A total score at Weeks 1, 2, 4, and 6 
• 
Change from Baseline to Week 6 in the QIDS-SR16 total score 
• 
Change from Baseline to Week 6 in the SDS total score 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) at 
Week 6 
• 
Change from Baseline to Week 6 in the EQ-5D-5L Index score and VAS score 
• 
Change from Baseline to Week 6 in the SHAPS total score 
2.4. SAFETY OBJECTIVES AND ENDPOINTS 


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   2.4.1  Safety Objectives 
• 
Determine the incidence of adverse events (AEs), discontinuation due to AEs, serious AEs 
(SAEs), and adverse events of special interest (AESI). 
• 
Evaluate safety and tolerability using physical examinations, 12-lead electrocardiograms 
(ECG), vital signs, clinical laboratory tests, prolactin levels, metabolic parameters, body 
weight, and body mass index (BMI). 
• 
Monitor for akathisia and extrapyramidal symptoms (EPS) using the Abnormal Involuntary 
Movement Scale (AIMS), Barnes Akathisia Scale (BARS), and Modified Simpson-Angus 
Scale (SAS). 
• 
Monitor for treatment-emergent mania or hypomania, defined as a Young Mania Rating Scale 
(YMRS) score of ≥ 16 on any 2 consecutive visits or at the final assessment, or an AE of 
mania or hypomania. 
• 
Monitor for suicidality using the Columbia-Suicide Severity Rating Scale (C-SSRS). 
• 
Evaluate potential withdrawal symptoms using the Physician’s Withdrawal Checklist (PWC). 
  2.4.2    Safety Endpoints 
• 
The incidence of overall AEs, discontinuation due to AEs, and SAEs 
• 
The incidence of hyperprolactinemia-related AESI by sex and overall 
• 
Clinical laboratory evaluations (serum chemistry, hematology, thyroid panel, and urinalysis) 
• 
Clinical evaluations (vital signs including orthostatic effects, and 12-lead ECGs) 
• 
Change and percent change from Baseline to Week 6 in body weight (kg) 
• 
Change from Baseline to Week 6 in BMI (kg/m2) 
• 
Changes from Baseline in metabolic parameters, including glucose, hemoglobin A1c (HbA1c), 
insulin, Homeostatic Model Assessment for Insulin (HOMA-IR), total cholesterol, high density 
lipoprotein (HDL), low density lipoprotein (LDL), and triglycerides at Week 6 
• 
Incidence of treatment-emergent mania, defined as a YMRS total score ≥ 16 at two 
consecutive visits or at final visit, or an AE of hypomania or mania 
• 
Mean changes from Baseline and the proportion of subjects with worsening on the movement 
disorders scales: AIMS, BARS, and modified SAS at Week 6 
• 
Frequency and severity of suicidal ideation and suicidal behavior as assessed by the C-SSRS 
• 
Occurrence of potential symptoms of withdrawal from SEP-4199 CR measured by change 
from Week 6 in the PWC total score at the safety Follow-up Visit 
2.5. PHARMACOKINETIC AND PHARMACODYNAMIC OBJECTIVES AND 
ENDPOINTS 


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   2.5.1  Pharmacokinetic and Pharmacodynamic Objectives 
• 
Evaluate the therapeutic plasma concentration range of SEP-4199 CR taken as 200 mg/day 
and 400 mg/day for treatment of major depressive episode associated with bipolar I disorder. 
• 
Perform population pharmacokinetic (Pop-PK) analysis using plasma concentrations of 
SEP-4199 CR 200 mg/day and 400 mg/day. 
• 
Evaluate the relationship between SEP-4199 PK and plasma prolactin levels for SEP-4199 
CR 200 mg/day and 400 mg/day. 
• 
Explore the exposure-response relationship of SEP-4199 CR 200 mg/day and 400 mg/day 
and symptoms as measured by MADRS using population pharmacokinetic (PK)/ 
pharmacodynamic (PD) methods. 
2.5.2  Pharmacokinetic and Pharmacodynamic Endpoints 
• 
Plasma concentrations of aramisulpride and esamisulpride 
• 
Plasma concentrations of prolactin 
3. STUDY DESIGN 
3.1. GENERAL DESCRIPTION 
SEP380-301 is a randomized, double-blind, placebo-controlled, parallel-group study designed to 
evaluate the efficacy, safety, and tolerability of treatment with SEP 4199 CR at fixed doses of 200 
mg/day or 400 mg/day compared with placebo for the treatment of major depressive episode associated 
with bipolar I disorder (bipolar I depression). The study is projected to randomize approximately 522 
subjects in North America, Latin America, Japan, and Europe to SEP 4199 CR 200 mg/day, SEP 4199 
CR 400 mg/day, and placebo treatment groups in a 1:1:1 ratio, resulting in approximately 174 
subjects/group. 
The study will consist of a Screening Period (up to 21 days), a 6 week double-blind Treatment Period 
(42 days), and a Follow-up Period (7 [± 2] days after the last study drug dose), as shown in the following 
figure. If necessary, subjects may return to the clinic at any time for an unscheduled visit. Subjects who 
complete the Treatment Period are eligible to enroll directly into a long-term open-label safety extension 
study (SEP380-303) of SEP 4199 CR. Those subjects who prematurely discontinue or who complete 
the Treatment Period and choose not to enroll in the long-term open-label safety extension study will 
have a follow-up safety Visit 7 (± 2) days after their last dose of double-blind study drug. 


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Figure 1   Study Schematic  
 
Abbreviations: CR = controlled release; EOT = end of treatment; V = visit; Wk = week 
Note: Subjects who do not enroll in long-term open-label safety extension study will have Visit 7. For 
Japan, there is an extra visit on Day 1. 
3.2. METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS 
Subjects who successfully meet eligibility criteria will be randomly assigned to receive SEP 4199 CR 
200 mg/day, SEP 4199 CR 400 mg/day, or matching placebo in a double blind fashion in a 1:1:1 ratio. 
The randomization will be balanced using permuted blocks with stratification factor of countries. The 
stratification process will be handled in an Interactive Web Response Systems (IXRS). 
At the Baseline Visit (Visit 2), the treatment code, which is linked to the randomization schedule, will be 
assigned by the IXRS designated by the Sponsor. A unique subject number will be assigned by the 
IXRS when a subject enters the Screening Period. Each subject will be given one subject number 
comprised of 9 digits. Each subject number will specify the study (3 digits), site (3 digits), and subject (3 
digits) (eg, 301001001 would denote: Study 301, Site 001, and Subject 001). If a subject does not meet 
study entry criteria, his or her subject number cannot be reassigned to another subject. 
Subjects may be screened up to a maximum of 3 times, if judged appropriate by the Investigator and 
approved by the Medical Monitor. Each time the subject is rescreened, they will be reconsented and 
receive a new subject number, which cannot be reassigned to another subject. Subjects who do not 
pass Inclusion Criterion#12 (ie, subject meets an additional inclusion criterion at Baseline that will 
remain blinded to clinical site Investigators and staff) may not be re-screened. 
3.3. BLINDING 
Subjects, Investigators, clinical site staff, persons performing the assessments, clinical operations 
personnel (including the Sponsor’s bioanalytical manager), data analysts, personnel at central 
laboratories (including imaging), and the Sponsor will remain blinded to randomization scheme until 
blinding is formally broken for all subjects. For this to occur, all subjects must have completed the study 
and the study database must be locked. 
Randomization data are kept strictly confidential until the time of unblinding and will not be accessible by 


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anyone else involved in the study with the following exceptions: bioanalytical laboratory personnel 
involved in the analysis of PK samples, Data and Safety Monitoring Board (DSMB) members involved in 
regular review of safety data, external statistical staff involved in preparing materials for DSMB reviews, 
and the Sponsor’s clinical trials materials management. 
Prolactin levels will be masked in regular lab data transfer for any assessment collected after the first 
study drug dose and until database is locked and treatment is unblinded (that is to say, prolactin 
assessed prior to the first study drug dose will be unmasked and available for study personnel during 
the study). 
The identity of the treatments will be concealed by the use of study drugs that are all identical in 
packaging, labeling, schedule of administration, and appearance. 
Plasma concentrations of aramisulpride, esamisulpride, and total amisulpride will not be disclosed 
before unblinding. In any case that concentration data transfer to the Sponsor becomes necessary prior 
to the database lock, then the concentration data can only be shared with the Sponsor’s bioanalytical 
project manager with dummy subject IDs. 
3.4. DETERMINATION OF SAMPLE SIZE 
The sample size is estimated based on the primary efficacy endpoint, the change from Baseline in 
MADRS total score at Week 6. Based on the Phase 2 Study SEP380-201 results for both planned and 
post-hoc analyses of the primary endpoint, assuming a common standard deviation (SD) of 10 and a 
mean improvement of 3.5 (effect size 0.35) and 3.5 (effect size 0.35) over placebo for SEP 4199 CR 
200 mg and 400 mg dose groups, respectively, with a randomization ratio of 1:1:1 for placebo, SEP 
4199 CR 200 mg and 400 mg, a sample size of 165 subjects per treatment group will provide at least 
80% conjunctive power to reject both null hypotheses of no difference between SEP 4199 CR doses 
and placebo and at least 90% power to reject at least one individual null hypothesis after multiplicity 
adjustment for two comparisons of the primary endpoint using the enhanced mixture truncated 
Hochberg gatekeeping procedure (Kordzakhia 2018) with truncation parameter 0.5 and 2-sided Type I 
error of 0.05. An upward adjustment of approximately 5% is assumed to compensate for subjects who 
are randomized but have no post-Baseline efficacy assessment. Thus, a total sample of approximately 
174 subjects per group (522 subjects in total) will be randomized. The sample size calculation is based 
on 100,000 Monte Carlo computer simulations. 
3.5. CHANGES IN THE CONDUCT OF THE STUDY 
Effective 10-Oct-2023 the Sponsor has decided to discontinue SEP380-301 & SEP380-303 studies early 
based on numerous considerations including operational feasibility of conducting and completing the 
studies in a timely manner. There were no emergent safety, tolerability or efficacy issues associated with 
the investigational study medication (SEP-4199 CR) that contributed to this decision.  
3.6. SCHEDULE OF EVENTS 
Schedule of events can be found in Section 1, Table 2 Schedule of Assessments of the CSP. This table 
is also included in APPENDIX 14 of the SAP.  There is an additional visit for Japan on Day1 which 
checks study drug compliance and ECG. 
3.7. CHANGES TO ANALYSIS FROM PROTOCOL 


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Because of the small sample size due to study early termination, the following main changes will be made 
for this study: 
1. Except for disposition, demographics, some key efficacy and safety variables, combined SEP-
4199 CR vs. placebo will be performed for the efficacy analyses using ITT population and safety 
analyses using Safety population. 
2. Only include Safety population,  ITT population, and PK population, no analyses using PP 
population and Follow-up population will be performed. 
3. Except for PWC, follow-up period analysis will not be performed. 
4. No subgroup analyses and sensitivity analyses will be performed.     
5. No multiple comparisons for the primary and secondary efficacy endpoints will be performed. 
6. SDS subscale scores and proportion of subjects meeting functional remission criteria per the SDS 
subscales will not be analyzed. 
7. AE will not be summarized by high-level term (HLT). 
8. Rank ANCOVA analysis will not performed for selected lab, vital signs, and ECG parameters.  
9. To be consistent with AIMS and BARS, MSAS will be analyzed by total score.  
4. PLANNED INTERIM ANALYSIS AND SAFETY MONITORING ANALYSIS 
The following interim analysis and safety monitoring analysis will be performed for this study. 
4.1. DATA AND SAFETY MONITORING BOARD (DSMB) 
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 DSMB may review blinded, 
unblinded, or partially unblinded data, but the Sponsor (with the exception of the relevant members of 
the pharmacovigilance team responsible for reporting Suspected Unexpected Serious Adverse 
Reactions [SUSARs]), the CRO, and the Investigators will remain blinded until the official unblinding of 
the database. The membership of the DSMB and its mandate will be described in a separate DSMB 
charter. 
4.2. INTERIM ANALYSIS  
Other than the DSMB safety reviews, there is no interim analysis planned for this study. 
5. ANALYSIS POPULATIONS 
Agreement and authorization of subjects included/ excluded from each analysis population will be 
conducted prior to database lock and the unblinding of the study treatment.  
5.1. INTENTION-TO-TREAT [ITT] POPULATION 
The intention-to-treat (ITT) population will consist of subjects who are randomized and received at least 
one dose of study medication and have both baseline and at least one post-Baseline assessment in 
either MADRS or CGI-BP-S depression scores. The ITT population is the primary population for efficacy 
analyses, ie, unless otherwise specified, all efficacy analyses will be based on the ITT population. 
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5.2. SAFETY [SAF] POPULATION 
The safety population will consist of all subjects who randomized and receive at least one dose of study 
medication. Subjects will be analyzed according to modal dose (the predominant treatment) received. 
The modal dose or predominant treatment is defined as the treatment to which the subject is exposed 
for the greatest duration during the treatment period. This will generally be the same as the randomized 
treatment group, unless the subject takes incorrect study medication during their entire participation in 
the study. 
5.3. PHARMACOKINETICS (PK) POPULATION 
The PK population includes all subjects who are randomized, receive at least 1 dose of study drug, and 
have any post-Baseline PK concentrations of SEP-4199 CR. PK samples collected from placebo 
subjects will not be analyzed. 
The PK analysis will be based on the PK population. 
Population PK (Pop-PK) analysis methods will be used to characterize the PK/PD profiles in subjects 
treated with SEP 4199. These methods will be described in a separate document and will not be 
included in the SAP. 
 
6. GENERAL CONSIDERATIONS 
6.1. REFERENCE START DATE AND STUDY DAY 
Reference start date is defined as the day of the first dose of study drug, (Day 1 is the day of the first 
dose of study drug), and will appear in every listing where an assessment date or event date appears.  
Study Day will be calculated from the reference start date, and will be used to show start/ stop day of 
assessments and events.  
• 
If the date of the assessment  or event is on or after the reference date then:  
Study Day = (date of assessment or event – reference date) + 1. 
 
• 
If the date of the assessment or event is prior to the reference date then:  
Study Day = (date of assessment or event – reference date). 
In the situation where the assessment or event date is partial or missing, Study Day, and any 
corresponding durations will appear partial or missing in the listings. Partial assessment or event dates 
will be presented as is in the listings. 
6.2. BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing value taken prior to the first dose 
of study medication (including unscheduled assessments).  


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Whenever available, the time information should be accounted for in the derivation of baseline values. In 
the case where time isn’t available and the date of the last non-missing value and the reference start 
date coincide, that value will be considered the baseline. Adverse Events and medications commencing 
on the reference start date will be considered postbaseline. 
6.3. DERIVED TIME POINTS 
As per protocol, Visit 6 can be an End of Treatment (EOT) visit or an Early Termination (ET) visit. If a 
subject terminates early, his/her ET visit will be mapped to the next planned assessment visit if it is within 
the window of the next planned assessment visit and within 7 days after treatment discontinuation. This 
applies to both efficacy and safety data. If assessments from an ET visit cannot be mapped to the next 
planned assessment visit, these assessments will be excluded from any mixed model for repeated 
measures (MMRM). No follow-up visit data will be included in any MMRM/ANCOVA analyses. In the case 
of the ET being out of window of the next planned visit, it will be mapped to an unscheduled visit as 
appropriate. 
 
All applicable by-visit efficacy and safety tables will include descriptive statistics for the Follow-up visit 
and the “Last Observation Carried Forward (LOCF) visit”. The “Last Observation Carried Forward 
(LOCF) visit” is defined as the post-baseline visit at which the last non-missing observation is collected 
for a subject for a given parameter, including unscheduled visits or unmapped ET visits, but excluding 
follow-up visit. The “Last Observation Carried Forward (LOCF) visit” will be excluded from any MMRM 
analyses. 
For remapping of the ET visits, see Table 3 below.  
Table 3: Mapping of the ET visit. 
Parameter 
Early Termination Day Criteria 
Week 
Analysis Visit 
ECG, Vital Sign, YMRS, C-SSRS, 
Concomitant Medication, Last 
dose of Benzodiazepines/ 
Sedatives/Hypnotics 
1 ≤ study day ≤ 9 
1 
Week 1 
10 ≤ study day ≤ 16 
2 
 Week 2 
17 ≤ study day ≤ 30 
4 
Week 4  
31 ≤ study day ≤ 44 
6 
Week 6  
MADRS, CGI-BP-S, HAM-A  
1 ≤ study day ≤ 9 
1 
Week 1 
10 ≤ study day ≤ 16 
2 
Week 2 
17 ≤ study day ≤ 30 
4 
Week 4 
31 ≤ study day ≤ 44 
6 
Week 6 
QIDS-SR16, SDS, EQ-5D-5L, 
SHAPS, AIMS, BARS, MSAS 
Weight, BMI, Waist 
Circumference, PWC, HbA1C, 
Lipid panel, Serum Insulin, 
HOMA-IR, CRP 
31 ≤ study day ≤ 44 
6 
Week 6 
Hematology, Serum Chemistry*, 
Urinalysis, Serum Prolactin, PK, 
Plasma Prolactin 
10 ≤ study day ≤ 16 
2 
Week 2 
31 ≤ study day ≤ 44 
6 
Week 6 


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* Except for parameters listed above such as HbA1C, Lipid panel, Serum Insulin, HOMA-IR, CRP.
Abbreviations: AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating Scale; BMI = Body Mass Index;
CGI-BP-S = Clinical Global Impression Bipolar Version, Severity of Illness; C-SSRS = Columbia-Suicide Severity Rating Scale;
ECG = 12-Lead Electrocardiogram; ET = Early Termination; EQ-5D = EuroQoL-5D; HAM-A = Hamilton Rating Scale for Anxiety;
MADRS = Montgomery-Asberg Depression Rating Scale;  PWC =  Physician’s Withdrawal Checklist; QIDS-SR16 = Quick Inventory
of Depressive Symptomatology – Self-Report; SAS = Modified Simpson-Angus Scale; SDS = Sheehan Disability Scale; YMRS =
Young Mania Rating Scale.
All planned visits will be mapped to weeks and analysis visits for summaries and statistical analyses 
where applicable (Table 4).  
Table 4: Mapping of planned visits. 
Planned Visit 
Analysis Week 
Analysis Visit 
Visit 1 
-1
Screening 
Visit 2 
0 
Baseline 
Visit 2 (day 1 Japan) 
Day 1 
Visit 3 
1 
Week 1 
Visit 4 
2 
Week 2 
Telephone Contact 1 (TC1) 
3 
TC1 
Visit 5 
4 
Week 4 
Telephone Contact 2 (TC2) 
5 
TC2 
Visit 6 
6 
Week 6 
Visit 7 
7 
Follow-up 
Original visit collected on the case report forms (CRFs) will be displayed in the listings. 
6.4. WINDOWING CONVENTIONS
Apart from early termination data (see Section 6.3), no visit windowing will be performed during the 
analysis for this study. Data will be summarized by analysis visit and analyzed by week where 
applicable (see Section 6.3). 
6.5. RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA 
In general, for by-visit summaries, data recorded at the scheduled visits will be presented. 
Unscheduled assessments will not be included in by-visit summaries. Unscheduled assessments 
collected prior to the first dose of study drug will contribute to the derivation of the baseline value. 
Unscheduled assessments collected postbaseline will contribute to the derivation of LOCF endpoint, 
potentially clinically significant (PCS) postbaseline value, and best/worst case value where required (eg, 
shift tables). 
In the case of a retest, the assessment recorded under the scheduled visit will be used for by-visit 
summaries, and the assessment(s) recorded under unscheduled visit(s) will be presented in listings 
only. 
Early termination data collected postbaseline will be assigned to the next planned visit for that 
assessment as explained in Section 6.3. This mapping will be implemented to all early termination data 


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points used in the efficacy and safety analyses. 
Listings will include scheduled, unscheduled (including retests), and early termination data with original 
dates and visits displayed. 
6.6. STATISTICAL TESTS 
All statistical inference will be performed with 2-sided tests at the significance level of 0.05 and 2-sided 
95% confidence intervals (CIs) whenever appropriate. All data will be summarized by treatment group 
and visit as appropriate. All subject data will be presented in data listings by subject. 
6.7. COMMON CALCULATIONS 
For quantitative assessments, change from baseline will be calculated as:  
• 
Assessment Value at Visit X – Baseline Value 
and percentage change from baseline will be calculated as:  
• 
100 (Assessment Value at Visit X – Baseline Value)/Baseline Value. 
6.8. SOFTWARE VERSION 
All analyses will be conducted using Statistical Analysis System (SAS®) version 9.4 or higher (SAS 
Institute, Inc., Cary, North Carolina). 
7. STATISTICAL CONSIDERATIONS 
7.1. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED IN 
ANALYSES 
The following covariates are used in the analyses. For details of their inclusion in the models, see 
specific analysis sections. 
• 
Baseline value of the variable to be analyzed 
7.2. MULTICENTER STUDIES 
This study will be conducted by multiple investigators at multiple centers in the Europe, Japan, North 
America, and Latin America. 
When specified, statistical analysis will be adjusted for region with centers within the region pooled. 
Region will be categorized as follows:  
• 
USA 
• 
Europe 


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• 
Japan 
7.3. MISSING DATA 
For the MMRM models, missing observations are treated as missing at random (MAR) and no 
imputation for missing data will be applied.   
Unless otherwise specified, any individual missing item in any scale will not be imputed. When 
calculating a total score, subscale score, or any assessment with more than one item, if one or more 
items are missing at a visit, then the associated score (ie, total score or subscale score) will be set to 
missing. For additional details, see the individual scale description sections. 
Handling of missing efficacy data, if any, is described in Sections 16.1.2, 16.2.2, 16.3.2. 
Handling of missing safety data, if any, is described in Sections 17.1.1.1, 17.1.1.2, and 17.6. 
Handling of missing PK data if any is described in Section 18. 
See APPENDIX 2 for details of incomplete/missing dates. 
8. OUTPUT PRESENTATIONS 
APPENDIX 1 shows conventions for presentation of data in outputs.  
The shells 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 in separate documents. 
9. DISPOSITION AND WITHDRAWALS 
All subjects who provide informed consent will be accounted for in this summary. 
Subject disposition will be presented for the screened subjects described by the randomized treatment 
group (where applicable) and overall for all subjects. The number and percentage of subjects who were 
screened, screen-failed (with reasons for screen failure), randomized, randomized but not dosed, 
received study medication, completed or discontinued (with reasons for discontinuation) from the study 
treatment period, and completed the follow-up visit, and completed the treatment period but not the 
follow-up visit will be presented. The number of subjects with non-missing change from baseline at 
Week 6 of MADRS total score and the number of subjects with non-missing change from baseline at 
Week 6 of CGI-BP-S depression score will also be presented. 
With respect to the above, the following definitions apply: 
• 
Screened Subjects: Any subject who signed the study specific informed consent and 
completed at least 1 study-related procedure. 
• 
Screen failure: Subjects who signed the study specific informed consent but either failed to 
meet screening requirements or was successfully screened but was not randomized. 
• 
Randomized Subjects: Any subject who was randomized into the treatment period of the 
study and was assigned a randomization number. 
The number of subjects randomized will also be described by site, country, and region by treatment 
group and overall. The number of subjects who complete (including remotely versus in-person, for  


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Week 6 and the Follow-up visit only) and discontinue from the study medication before or at a given 
visit, along with reasons for study medication discontinuation will be described by the treatment group 
and overall using randomized subjects.  
The number of subjects in each population will also be described. 
10. IMPORTANT PROTOCOL DEVIATIONS 
A complete list of subjects who meet at least one of important protocol deviations (IPDs) criteria, will be 
identified through a blinded data review meeting (BDRM) prior to database lock. Details of the IPD 
categories and criteria are provided in the IPD specifications document.  IPDs will be identified for all 
randomized subjects and presented in a data listing. 
In addition, the number and percentage of subjects within each IPD category will be summarized for the 
SAF population by the actual treatment group.  
 
10.1. DEVIATIONS RELATED TO PK ANALYSIS 
Changes to the procedures or events, which may impact the quality of the PK data, may be considered 
significant protocol deviations and will be described within the clinical study report body text. These 
changes or events will include any circumstances that will alter the evaluation of the PK. Examples 
include, but may not be limited to, sample processing errors that lead to inaccurate bioanalytical results, 
and/or inaccurate dosing on the day of PK sampling. In the case of a significant protocol deviation or 
event, PK data collected for the affected dose group will be excluded from the study summary and 
inferential results but listed, if appropriate. Other changes to the procedures or events which do not 
impact the quality of the PK data will not be considered significant. A common example of a non-
significant protocol deviation is a missed blood sample or deviations from blood collection times. 
11. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be presented for the SAF population. The data 
will be presented by treatment group (SEP-4199 CR 200 mg/day, SEP-4199 CR 400 mg/day, all SEP-
4199 CR, and Placebo) and overall by the predominant treatment received.  
No statistical testing will be carried out for demographic or other baseline characteristics. 
The following demographic and other baseline characteristics will be reported for this study: 
• 
Age (years) - calculated relative to date of informed consent, as a continuous variable and 
categorically: 
o 
< 55 years 
o 
 ≥ 55 years 
• 
Gender 
• 
Race  
o 
American Indian or Alaska Native 


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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 
Bulgaria 
o 
Romania 
o 
USA 
o 
Japan  
• 
Region 
o 
USA 
o 
Europe 
o 
Japan 
• 
Weight (kg) 
• 
Height (cm) 
• 
BMI (kg/m2), as a continuous variable and categorically: 
o 
Underweight: < 18.5 
o 
Normal: 18.5 to < 25.0 
o 
Overweight: 25.0 to < 30.0 
o 
Obese:  ≥ 30.0 
• 
Baseline MADRS total score, as a continuous variable 
• 
Baseline CGI-BP-S depression score, as a continuous variable  
Demographic data collected for all screened subjects will be listed.  
The following psychiatric history data will be summarized for the SAF population in a separate table: 
• 
Age at onset of bipolar I disorder 
• 
Time since initial onset of bipolar I disorder, in years, calculated relative to date of informed 
consent (see APPENDIX 2 for partial date imputation rules) 
• 
Time since onset of current episode of major depression associated with bipolar I disorder 
symptoms, in months, calculated relative to date of informed consent (see APPENDIX 2 for 
partial date imputation rules) 
• 
Frequency distribution of number of prior hospitalizations for Bipolar I depression (0, 1, 2, 3, 
and 4 or more) to date of informed consent (see APPENDIX 2 for partial date imputation 
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•
Frequency distribution of DSM-5 code in ascending numeric order
•
Bipolar I diagnosis subtype (Bipolar I disorder without rapid Cycling and Bipolar I disorder
with rapid cycling)
•
Number and percentage of subjects with any other psychiatric disorders
Summaries of subjects’ family psychiatric history will also be presented for the Safety population.    
Other psychiatric Disorder data will be summarized for SAF population in a separate table by 
summarizing Diagnosis and DSM-5 codes. 
11.1. DERIVATIONS 
•
Time since initial onset of bipolar disorder (years):
(Date of informed consent – date of initial onset of bipolar disorder) / 365.25 
•
Time since initial onset of current episode of major depression (months):
(Date of informed consent – date of initial onset of current episode of major depression) / 30.4375 
12. MEDICAL HISTORY
Medical History information will be presented for the SAF populations by treatment group (all SEP-4199 
CR and Placebo) and overall. The data will be presented by the predominant treatment received. 
Medical and surgical history information, including both past and concomitant medical conditions and 
major surgical history, as collected on the Medical History CRF form, will be coded using MedDRA, 
Version 24.1 or higher, and presented by SOC and PT. Medical History will be sorted alphabetically by 
SOC and by decreasing frequency of PT in the All SEP-4199 CR column. 
Summaries of subjects’ family medical history will be presented for the Safety population.  
Reproductive history of females will also be summarized for SAF population in a separate table. 
13. PRIOR/CONCOMITANT/POST-TREATMENT MEDICATIONS
Medications will be coded to Anatomical Therapeutic Chemical (ATC) levels and Preferred Names using 
World Health Organization Drug Dictionary Global, Version SEP 2021. Medications will be presented for 
the SAF population and coded to indication-specific Anatomical Therapeutic Chemical (ATC) Level 3 
and Preferred Name. If ATC level 3 is missing, then ATC level 2 will be used. Medication will be sorted 
alphabetically by ATC level 3 and by decreasing frequency of Preferred Name in the All SEP-4199 CR 
column. 
Whenever available, the time information should be accounted for in the derivation of prior, concomitant, 
and post-treatment medications, see APPENDIX 2 for the handling of partial dates for medications. In 
the case where it is not possible to define a medication as prior, concomitant, or post-treatment, the 
medication will be classified by the worst case; ie, prior, concomitant, and post-treatment.  
•
Prior medications are medications which started prior to the first dose of study medication.


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• 
Concomitant medications are medications that:  
o 
Started prior to, at the time of, or after the first dose of study medication, AND 
o 
Started before or at the date (day) of the last dose of study drug, AND  
o 
Ended at the time of or after the first dose of study drug or were ongoing at the end of 
the study.  
• 
Post-treatment medications are medications which ended after the day of the last dose of 
study drug or ongoing. 
Prior and concomitant medication use will be summarized by treatment group (all SEP-4199 CR and 
Placebo) by ATC Level 3 classification and Preferred Name using the SAF population. Subjects with 
multiple uses of a medication will be counted only once for a given ATC level 3 class or Preferred 
Name. Number and percentage of subjects who take concomitant benzodiazepines, sedatives, or 
hypnotics will be summarized by visit (including follow-up visit) and overall. Prior, concomitant, and post-
treatment medications will be provided in data listings. 
14. STUDY DRUG EXPOSURE 
Exposure to study drug will be calculated as the number of days from first dose date to last dose date. 
Duration of exposure to study drug will be summarized for the SAF population. 
The date of first study drug administration will be taken from the CRF “Study Drug Administration / Drug 
Accountability” form.  
The date of last study drug will be retrieved as the latest date among “Study Drug Administration / Drug 
Accountability” and “Subject Disposition - End of Study” forms. For subjects who are lost to follow-up, 
and for whom the last dose date is unknown, the last contact date will be used. 
Interruptions and compliance are not taken into account for duration of exposure.  
Overall number of tablets taken will be summarized by treatment group (SEP-4199 CR 200 mg/day, 
SEP-4199 CR 400 mg/day, all SEP-4199 CR, and Placebo) as a continuous variable. 
Duration of exposure to study medication in days will be summarized both as a continuous variable and 
categorically, and by planned visit days: 
• 
Number and percentage of subjects with drug exposure ≥ 4, ≥ 7, ≥ 14, ≥ 21, ≥ 28, ≥ 35, and 
≥ 42 days; 
• 
Number and percentage of subjects with drug exposure for 1 - 3, 4 - 6, 7 - 13, 14 - 20, 21 -
 27, 28 - 34, 35 - 41 and ≥ 42 days. 
Total person years of exposure will be calculated by treatment group (SEP-4199 CR 200 mg/day, SEP-
4199 CR 400 mg/day, all SEP-4199 CR, and Placebo). 
14.1. DERIVATIONS 
• 
Duration of exposure (days) 
Last dose of study drug – First dose of study drug + 1. 
• 
Person years of exposure 


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Sum of total exposure (days) for all subjects within each treatment group / 365.25 
• 
Overall number of tablets taken 
Sum of number of dispensed tablets – Sum of number of returned tablets, if any returned 
tablets is missing then overall number of tablets taken is set to missing 
15. STUDY DRUG COMPLIANCE  
Compliance to study drug will be presented by treatment group (all SEP-4199 CR and Placebo) for the 
SAF population. 
Percent compliance will be calculated by visit and overall on the number of subjects with non-missing 
compliance data. For each postbaseline visit, if the number of tablets returned is missing, the 
corresponding compliance will be set as missing. Overall compliance will be set to missing if one or 
more blister cards are not returned to the site for accountability. 
Non-compliance is defined as less than 75% or more than 125% non-missing compliance. Subjects with 
missing compliance will not be classified as non-compliant but described in the categorical analysis. 
Compliance will be summarized both as a continuous variable (ie, mean percentage) and categorically 
(ie, number and percentage of subjects who are compliant vs. non-compliant, or with compliance 
< 75%, 75% - 125%, > 125%, and missing). 
Subject level treatment compliance will be listed. 
15.1. DERIVATIONS 
Compliance with study drug will be calculated for each period defined by study visits (ie, per-visit 
compliance) and overall. 
Per-visit compliance for the period defined by visit (V-1) and visit V will be calculated as: 
# Tablets dispensed at Visit (V-1) - # Tablets returned at Visit V 
# Tablets should be taken per day × ൫Date of Visit V - Date of Visit (V-1)൯ × 100% 
For week 1, the date of first dose of study medication will be used instead of date of visit (V-1).  Two 
tablets per day are supposed to be taken. If number tablets dispensed at Visit (V-1) and/or number 
tablets returned at Visit V are missing, per-visit compliance will not be calculated for the period 
impacted. 
If a subject discontinued from the study in between Visit (V-1) and Visit V except for subjects lost to 
follow-up in which case ET visit was not done, then the above formula will be modified to: 
# Tablets dispensed at Visit (V-1) - # Tablets returned at Visit ET  
# Tablets should be taken per day × ൫Date of Visit ET - Date of Visit (V-1)൯ × 100% 
The per-visit compliance calculated above will contribute to the summary of per-visit compliance for the 
period defined by visit (V-1) and visit V. 
Overall compliance will be calculated as: 
Total # tablets dispensed - Total # tablets returned
# Tablets should be taken per day × Duration of Exposure × 100% 
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If number tablets dispensed and/or number tablets returned are missing at 1 or more visits, overall 
compliance will not be calculated. 
16. EFFICACY OUTCOMES  
16.1. PRIMARY EFFICACY 
16.1.1. PRIMARY EFFICACY VARIABLE & DERIVATION 
The primary efficacy endpoint is the change from baseline in the MADRS total score at Week 6.  
The MADRS is a clinician-rated assessment of the subject’s level of depression. The measure contains 
10 items that measure apparent and reported sadness, inner tension, reduced sleep and appetite, 
difficulty concentrating, lassitude, inability to feel, and pessimistic and suicidal thoughts. Each item is 
scored in a range of 0 to 6 points, with higher scores indicating increased depressive symptoms. Total 
score will be equal to the sum of the 10 items (range between 0 and 60). MADRS is assessed at 
Visit 1/Screening, Visit 2/Baseline/Week 0, Visit 3/Week 1, Visit 4/Week 2, Visit 5/Week 4, and 
Visit 6/Week 6. 
16.1.2. MISSING DATA METHODS FOR PRIMARY EFFICACY VARIABLE 
The MADRS total score at a visit will be set to missing at that visit if any one item is missing. The 
primary efficacy variable, change from baseline in MADRS total score at Week 6, will be set to missing if 
MADRS score at Week 6 is missing or baseline value is missing. The same applies to all other visits.  
The primary analysis of the primary efficacy variable will use an MMRM which makes an MAR 
assumption to the missing MADRS total score. Early termination data will be mapped as described in 
Section 6.3. Missing data will not be imputed. 
16.1.3. PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE(S) 
The primary efficacy estimand is defined as the efficacy of all SEP-4199 CR  over placebo for 6 weeks, 
calculated as the difference in the primary efficacy endpoint between all SEP-4199 CR treatment group 
and the placebo treatment group in the ITT population. This estimand provides an estimate of the 
efficacy of all SEP-4199 CR over placebo, should a subject be able to tolerate and adhere to treatment 
for 6 weeks.  
The 4 attributes of the primary efficacy estimand are as follows: 
A. Population of interest: ITT subjects with major depressive episode associated with bipolar 
I disease (bipolar I disorder) defined through the inclusion/exclusion criteria.  
B. The variable of interest (endpoint): change from baseline in MADRS total score at 
Week 6 
C. Intercurrent events (and how to handle them)  
The estimand is based on the effect of treatment in the hypothetical absence of any intercurrent events, 
ie, if all subjects had adhered to treatment up to Week 6. This includes events where a subject 
continues the study regardless of the intercurrent event(s) (eg, subject received a prohibited medication 
during the treatment period and was not discontinued from the study) and/or events that cause the 


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subject to discontinue from the study.  
Any intercurrent event where subject continues the study regardless of the intercurrent event will be 
ignored for the primary analysis and the primary efficacy data will be analyzed as is. 
The statistical analysis for intercurrent events that lead to treatment discontinuation rests on an 
assumption about assessments that would have been observed under the hypothetical setting where a 
subject does not discontinue from treatment. For example, a subject who discontinues treatment before 
Week 6 in the all SEP-4199 CR treatment group is assumed to behave similar to a subject who 
completes the study up to Week 6 in the same SEP-4199 CR treatment group using the MMRM 
analysis based on the MAR assumption. The assumption for subjects in the placebo group is made 
similarly. 
D. Population level summary of the variable:  
Difference in means of change from baseline in MADRS total score at Week 6 comparing all SEP-4199 
CR treatment group to placebo  
The efficacy of SEP-4199 CR in terms of the MADRS total score will be evaluated using the following  
null hypothesis:  
H1: There is no difference in mean change from baseline at Week 6 on the MADRS total score in 
the all SEP-4199 CR treatment group compared to Placebo.  
The alternative hypothesis for the null hypothesis is that there is a difference.  
The primary efficacy endpoint will be analyzed for the ITT population using an MMRM analysis, with 
change from baseline in the MADRS total score as the response variable and with factors for treatment 
group, week, region, baseline MADRS total score, and the treatment-by-week interaction. This analysis 
method makes an MAR assumption to the missing primary efficacy endpoints. The Kenward Roger 
approximation will be used to estimate denominator degrees of freedom. An unstructured covariance 
matrix will be used for the within-subject correlation. Heterogeneous Toeplitz and Toeplitz, and 
Compound Symmetry will be assumed sequentially in case the model fails to convergence. The first 
covariance structure to yield convergence will be used in the analysis. For the primary efficacy endpoint, 
two models are used: one for all SEP-4199 CR versus placebo, one for each SEP-4199 CR dose group 
versus placebo group. 
The Least Square (LS) mean treatment difference of change from baseline at Week 6, their 2-sided 
95% CIs, and the associated p-value will be calculated based on the MMRM.  
At each postbaseline visit, effect-size will be presented. Based on the MMRM, effect size at a visit will be 
calculated as the absolute value of the LS means difference from placebo divided by the model estimate 
of the pooled SD at the visit, which is obtained from the square root of the diagonal element, associated at 
the visit, from the covariance matrix (R matrix of subjects with MADRS total score at all visits). 
16.1.4. SUPPORTIVE ANALYSIS OF PRIMARY EFFICACY VARIABLE(S) 
The primary efficacy endpoint will be analyzed using an analysis of covariance (ANCOVA) on the ITT 
population as supportive analysis for each scheduled postbaseline visit and also Week 6 LOCF 
endpoint. The model will include terms for treatment, region, and baseline MADRS total score as 
covariate. The LS mean of treatment difference (all SEP-4199 CR group minus placebo), the 2-sided 
95% CIs, and the associated p-values will be obtained from the model.  
Based on the ANCOVA, effect size at a visit will be calculated as the absolute value of the LS means 
difference from Placebo divided by the model estimate of the pooled standard error (the standard error 
of the LS mean difference divided by the square root of the sum of inverse sample sizes of change from 
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16.2. SECONDARY EFFICACY 
The secondary efficacy analyses will be performed for the ITT population.  
16.2.1. SECONDARY EFFICACY VARIABLE & DERIVATIONS 
The secondary efficacy variable is change from baseline in Clinical Global Impression Bipolar Version, 
Severity of Illness (CGI-BP-S) Score (Depression). 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. The CGI-BP-S score takes one of the following values: 1 (normal, not at all ill), 2 (borderline 
mentally ill), 3 (mildly ill), 4 (moderately ill), 5 (markedly ill), 6 (severely ill), 7 (among the most extremely 
ill patients). CGI-BP-S is assessed at Visit 2/Baseline/Week 0, Visit 3/Week 1, Visit 4/Week 2, Visit 
5/Week 4, and Visit 6/Week 6. 
16.2.2. MISSING DATA METHODS FOR SECONDARY EFFICACY VARIABLE(S) 
The secondary efficacy variable, change from baseline in CGI-BP-S depression score at Week 6, will be 
set to missing if the CGI-BP-S depression score at Week 6 is missing or baseline value is missing. The 
same applies to all other visits. The analysis of the secondary efficacy variable will use a MMRM which 
makes an MAR assumption to the missing secondary efficacy endpoints. Early termination data will be 
mapped as described in Section 6.3. Missing data will not be imputed. 
16.2.3. ANALYSIS OF SECONDARY EFFICACY VARIABLE 
The secondary efficacy estimand for this study is the difference in means of change from baseline in the 
CGI-BP-S depression score at Week 6 comparing all SEP-4199 CR treatment group to placebo in ITT 
population with major depressive episode associated with bipolar I disease (bipolar I disorder) defined 
through the inclusion/exclusion criteria, should a subject be able to tolerate and adhere to treatment up 
to Week 6.  
The efficacy of SEP-4199 CR in terms of the CGI-BP-S depression score will be evaluated using the 
following null hypothesis: 
H2: There is no difference in mean change from baseline at Week 6 on the CGI-BP-S depression 
score in the all SEP-4199 CR treatment group compared to Placebo.  
The alternative hypothesis for the null hypothesis is that there is a difference.  
The secondary efficacy endpoint (change from Baseline in CGI-BP-S depression score at Week 6) will 
be analyzed with an MMRM model similar to the one used in the primary efficacy analysis (adjusted with 
the corresponding Baseline). For the secondary efficacy endpoint, two models are used: one for all 
SEP-4199 CR versus placebo, one for each SEP-4199 CR dose group versus placebo group. The LS 
mean treatment difference of change from Baseline at Week 6, the 2-sided 95% CIs, and the associated 
p-value will be calculated based on the model.  
The CGI-BP-S mania and overall bipolar illness scores will only be presented in listings. 
16.2.4. SUPPORTIVE ANALYSIS OF SECONDARY EFFICACY VARIABLE 
ANCOVA analysis as described in Section 16.1.4 will also be produced for the secondary endpoint. 


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16.3. ADDITIONAL EFFICACY ENDPOINTS ANALYSES 
All the additional efficacy endpoints will be analyzed using the ITT population. 
16.3.1. ADDITIONAL EFFICACY VARIABLE DERIVATIONS 
16.3.1.1. MADRS-6 Core Symptoms Subscale Score 
The MADRS-6 core symptoms subscale score is the six-item MADRS subscale score, calculated as the 
sum of the following items: Apparent sadness, reported sadness, inner tension, lassitude, inability to 
feel, and pessimistic thoughts (item numbers 1, 2, 3, 7, 8, and 9,  and possible score range between 0 
to 36). MADRS-6 is assessed at Visit 1/Screening, Visit 2/Baseline/Week 0, Visit 3/Week1, Visit 4/Week 
2, Visit 5/Week 4, and Visit 6/Week 6. 
16.3.1.2. Hamilton Rating Scale for Anxiety (HAM-A) 
The HAM-A is a rating scale developed to quantify the severity of anxiety symptomatology. The 14 items 
are: anxious mood, tension, fears, insomnia, intellectual, depressed mood, somatic (muscular), somatic 
(sensory), cardiovascular symptoms, respiratory symptoms, gastrointestinal symptoms, genitourinary 
symptoms, autonomic symptoms, and behavior at interview. Each of the 14 items is rated on a 5-point 
scale, ranging from 0 (not present) to 4 (very severe). The HAM-A total score is the sum of the 14 
individual items and ranges from 0 to 56. A higher score is associated with a greater degree of anxiety. 
A score of ≥14 has been suggested to indicate clinically significant anxiety (Rush 2000). If 1 or more 
items are missing at a visit, the total score will be set to missing. HAM-A is assessed at 
Visit 2/Baseline/Week 0, Visit 3/Week 1, Visit 4/Week 2, Visit 5/Week 4, and Visit 6/Week 6. 
16.3.1.3. Quick Inventory of Depressive Symptomatology – Self-Report 16-Item (QIDS-
SR16) 
The QIDS-SR16 is a 16-item self-report measure of depressive symptomatology which uses a 
computerized assessment interface for administration. The scoring system for the QIDS-SR16 converts 
responses from 16 separate items into nine DSM-IV symptom criterion domains. Each item is rated 0 to 
3. 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 equals the sum of the nine individual domain scores and 
ranges from 0 to 27. Higher score indicates worse depression symptoms. The nine domains comprise: 
depressed mood (Item 5); concentration/decision making (Item 10); self outlook (Item 11); suicidal 
ideation (Item 12); decreased interest (Item 13); decreased energy (Item 14); sleep disturbance (initial, 
middle, and late insomnia or hypersomnia) (Items 1 to 4); appetite/weight disturbance (Items 6 to 9); 
and psychomotor disturbance (Items 15 and 16). The total score will be set to missing if one or more 
domain scores are missing at a visit. The appetite/weight disturbance symptom domain score will be set 
to missing if three or more items are missing at a visit, given the planned skip pattern of items 6 to 9, 
and the remaining symptom domain scores will be set to missing if one or more items within the 
respective domain are missing. QIDS-SR16 is assessed at Visit 2/Baseline/Week 0 and Visit 6/Week 6. 
16.3.1.4. Sheehan Disability Scale (SDS) 
Three items are self-rated using an 11-point visual analog scale ranging from 0 to 10 to assess disability 
across three domains: work/school, social life, and family life; the three items will be summarized 
individually in addition to the SDS total score. The SDS total score is calculated as the sum of the 
3 items and ranges from 0 (unimpaired) to 30 (highly impaired). If one or more items are missing at a 
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authors of the scale recommend setting the total score to missing (Sheehan 2008). Number of days lost 
due to symptoms, and number of days underproductive due to symptoms are also collected. SDS is 
assessed at Visit 2/Baseline/Week 0 and Visit 6/Week 6. 
16.3.1.5. EuroQoL 5-D (EQ-5D-5L) 
The 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 consists of a descriptive system and the EQ VAS.  
The descriptive system comprises five 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, corresponding to scores of 1 to 5, respectively. 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. The digits for the five dimensions can be combined into a 5-digit number 
that describes the patient’s health state. An index value (a weighted scoring of the 5 dimension scores 
with a possible range from 0 to 1) will be assigned to each observed health state using the US value set 
as defined in APPENDIX 9. 
The EQ VAS records the patient’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 reflect the patient’s own judgment. 
EQ-5D-L is assessed at Visit 2/Baseline/Week 0 and Visit 6/Week 6. 
16.3.1.6. Snaith-Hamilton Pleasure Scale (SHAPS) 
The SHAPS (Snaith 1995) is a subject-reported questionnaire that will be administered at Visit 2/ 
Baseline/ Week 0 and Visit 6/Week 6. 
The SHAPS is a 14 item scale that assesses 4 domains of hedonic experience: interests/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 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.  
16.3.1.7. MADRS responders 
A MADRS responder is defined as achieving a ≥ 50% reduction from the baseline total score at Week 6 
and Week 6 (LOCF). The MADRS total score percentage change will be defined as (value at 
postbaseline visit – baseline value) x 100 / (baseline value). Subjects having a negative percentage 
change indicate improvement in MADRS total score.  
16.3.1.8. MADRS remission 
A MADRS remission is defined as a MADRS total score of ≤ 12 at Week 6 and Week 6 (LOCF).  
16.3.2. MISSING DATA METHODS FOR OTHER EFFICACY VARIABLE(S) 
Any individual missing item in any scale will not be imputed.  


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For MADRS-6, HAM-A, SDS, SHAPS, and YMRS, if 1 or more items are missing at a visit, the total 
score will be set to missing. Similarly, if an individual domain score for EQ-5D-5L is missing, the index 
value cannot be calculated. 
For QIDS-SR16, the total score will be set to missing if 1 or more domain scores are missing at a visit. 
The appetite/weight disturbance symptom domain score will be set to missing if 3 or more items are 
missing at a visit, given the planned skip pattern of items 6 to 9, and the remaining symptom domain 
scores will be set to missing if 1 or more items within the respective domain are missing. 
16.3.3. ANALYSIS OF ADDITIONAL EFFICACY VARIABLES 
16.3.3.1. Change from baseline in MADRS-6 subscale score at Week 6  
The MADRS-6 subscale score and change from baseline will be summarized by time point for each 
treatment group. Change from baseline at Week 6 will be analyzed by the MMRM method described for 
primary endpoint with baseline MADRS-6 subscale score as covariate (see Section 16.1.3). 
16.3.3.2. Change from baseline in HAM-A total score at Week 6  
The HAM-A total score and change from baseline will be summarized by time point for each treatment 
group. Change from baseline at Week 6 will be analyzed by the MMRM method described for primary 
endpoint with baseline HAM-A total score as covariate (see Section 16.1.3). 
16.3.3.3. Change from baseline in QIDS-SR16 total score at Week 6  
The QIDS-SR16 total score and change from baseline will be summarized by timepoint for each 
treatment group. Change from baseline at Week 6 will be analyzed by the ANCOVA method described 
for primary endpoint with baseline QIDS-SR16 total score as covariate (see Section 16.1.4). 
16.3.3.4. Change from baseline in SDS total score at Week 6  
The SDS total score and change from baseline will be summarized by time point for each treatment 
group. Change from baseline at Week 6 will be analyzed by the ANCOVA model described in Section 
16.1.4 with baseline SDS total score as covariate. 
16.3.3.5. Change from baseline in EQ-5D-5L Scores at Week 6  
The EQ dimension scores, VAS score, and index score and change from baseline will be summarized 
by time point for each treatment group. Change from baseline of EQ VAS and index score at Week 6 
will be analyzed by the ANCOVA model described in Section 16.1.4 with baseline EQ VAS and baseline 
index score as a covariate, respectively. 
16.3.3.6. Change from baseline in SHAPS total score at Week 6  
The SHAPS total score and change from baseline will be summarized by time point for each treatment 
group. Change from baseline at Week 6 will be analyzed by the ANCOVA model described in Section 
16.1.5.1 with baseline SHAPS total score as covariate. 
16.3.3.7. MADRS responders at Week 6 
The MADRS total score responder proportions at Week 6 will be compared between the two treatment 
groups using logistic regression. This model will include treatment and region as fixed effects and 


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baseline MADRS score as a covariate. If the model fails to converge, the model will be attempted 
without region first, and if still not converging then without baseline MADRS total score. Effect size and 
Number Needed to Treat (NNT) will be provided.  
Between group effect size will be defined as: Natural Log(odds ratio)xsqrt(3)/pi 
The NNT will be derived as 1/Risk Reduction where Risk Reduction (RR) = (all SEP-4199 CR treatment 
group – placebo response rate). The NNT results will be provided in whole numbers with any fractional 
values rounded up to the nearest whole number. 
The 95% CI will also be presented (only when the lower and upper limits are of the same sign) and are 
computed by taking the reciprocal of the 95% lower and upper bound of the RR. The lower confidence 
limit will be rounded down to the largest integer value that is less than the computed estimate, and the 
upper confidence limit will be rounded up to the smallest integer value that is greater than the computed 
estimate.  
16.3.3.8. MADRS remission at Week 6 
Remission incidence rate, defined as MADRS total score ≤12, will be analyzed similarly to the MADRS 
responder analysis (see Section 16.3.3.7).  
17. SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the SAF population. 
There will be no statistical comparisons between the treatment groups for safety data, unless otherwise 
specified within the relevant section.  
17.1. PRETREATMENT AND ADVERSE EVENTS 
Pretreatment events and AEs will be coded using the MedDRA central coding dictionary, Version 24.1 
or higher. 
Adverse events are untoward medical occurrences that occurred on or after the first dose of study 
medication, with a missing start date and a stop date on or after first dose of study medication, or with 
both a missing start and stop date. Untoward medical occurrences that started between informed 
consent and prior to the first dose of study medication are pre-treatment events. 
Whenever available, the time information should be accounted for in the derivation of AEs vs. 
pretreatment events. In the case where time isn’t available, untoward medical occurrences that started 
on or after the day of the first dose of study drug will be considered AEs; those that started before the 
day of the first dose of study drug will be considered pretreatment.  
See APPENDIX 2 for handling of partial dates for AEs. In the case where it is not possible to define an 
untoward medical occurrence as an AE or pretreatment event, it will be classified by the worst case, ie, 
AE.  
An overall summary of the incidence of AEs within each of the categories described in the following 
sections will be provided as specified in the templates, including summary of SAEs. The overall 
incidence summary will also be provided for AEs related to study drug. 
Listings will be provided for all AEs, AEs leading to discontinuation of study drug, AEs leading to 
discontinuation from the study, serious adverse events (SAEs), and AEs leading to death. A listing for 
pretreatment events will also be presented.  


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For incidence summaries, each subject will be counted only once within each SOC and PT. Adverse 
Events will be sorted alphabetically by SOC and then by decreasing frequency of PT within each SOC 
based on the All SEP-4199 CR treatment group. For the incidence summary table by SOC and PT, 
each subject will be counted only once within each SOC and PT, and AEs will be sorted alphabetically 
by SOC, and then by decreasing frequency of PT within each  SOC based on the All SEP-4199 CR  
group. If not otherwise specified, all summaries will present incidence (number of subjects and 
percentages) and number of events. 
17.1.1. ALL AES  
Adverse events will be summarized by SOC and PT for AE incidence and number of events. A listing of 
all AEs will be presented. 
Adverse events will also be presented by maximum severity and by strongest relationship to the study 
drug as specified in the sections below. 
17.1.1.1. Severity 
Severity is classified as mild/ moderate/severe (increasing severity). Adverse events with a missing 
severity will be summarized as severe. If a subject reports an AE more than once within the same 
SOC/PT, the AE with the worst severity will be used in the corresponding severity summaries. For this 
summary, AEs will be presented by SOC and PT. 
17.1.1.2. Relationship to Study Drug 
Relationship to study drug, as indicated by the investigator, is classed as “not related”/ “possible”/ 
“probable”/ “definite” (increasing strength of relationship). A “related” AE is defined as an AE with a 
relationship to the study drug of “possible”, “probable” or “definite”. A “not related” AE is defined as an 
AE with a relationship to the study drug of “not related”. Adverse events with a missing relationship to 
the study drug will be regarded as “related” to the study drug. If a subject reports the same AE more 
than once within the same SOC/PT, the AE with the strongest relationship to study drug will be used in 
the corresponding relationship summaries. For this summary, AEs will be presented in 2 categories, 
related and not related, by SOC and PT. 
17.1.2. AES LEADING TO DISCONTINUATION FROM STUDY TREATMENT PERIOD 
Adverse events leading to discontinuation from the study treatment period are AEs with “Caused Study 
Discontinuation” = “Yes” on the AE CRF page for subjects with reason for discontinuation as AE on the 
Study Disposition CRF page or AE action taken=”Drug Withdrawn”. A summary of AEs leading to 
discontinuation from the study treatment period by SOC and PT will be presented. A listing of AEs 
leading to discontinuation from the study treatment period will be presented. 
17.1.3. SERIOUS ADVERSE EVENTS AND DEATH 
Serious AEs are those AEs recorded as “Serious” on the AE CRF page. AEs leading to death are those 
AEs which are recorded as having an outcome of “Fatal” on the AE CRF page. Summaries of SAEs 
(including deaths) by SOC and PT will be prepared. A listing of SAEs (including deaths) will be 
presented. 
17.1.4. ADVERSE EVENTS OF SPECIAL INTEREST (AESI) 


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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. AE SMQs and 
clustered PTs will be summarized by category (and sub-category, when applicable) and preferred term. 
 
17.2. LABORATORY EVALUATIONS 
All summaries will be based on the SAF population. Laboratory data to be reported for this study include 
Hematology, Serum Chemistry (including lipid panel and thyroid panel), Urinalysis, Urine drug 
screening, Hemoglobin (HbA1c), Serum Prolactin, Serology, Serum Insulin, C-Reactive Protein (CRP), 
and urine pregnancy test. A list of laboratory assessments to be included in the outputs is included in 
section 21 of the CSP. Urine drug screening, serum FSH, serology, and urine pregnancy test will only 
be listed. 
Presentations will use both international system of units (SI) and conventional (CV) units.  
Quantitative laboratory measurements reported as “< X”, ie, below the lower limit of quantification 
(BLQ), or “> X”, ie, above the upper limit of quantification (ULQ), will be converted to X for the purpose 
of quantitative summaries, but will be presented as recorded, ie, as “< X” or “> X” in listings. 
The following summaries will be provided for laboratory data: 
• 
By-visit summary of observed values and changes from baseline for continuous data in 
hematology, chemistry, and urinalysis.  
• 
By visit summary of the number and percentage of subjects in each outcome category for 
categorical data in urinalysis (if applicable).  
• 
Shift in laboratory results (chemistry, hematology, urinalysis) from baseline to Week 6 
according to the reference range criteria. The normal reference ranges from the central 
laboratory will be used to determine whether the laboratory test value is below, within, or 
above the normal range. Urinalysis will be presented as normal or abnormal (including low, 
high, abnormal) in the shift table. 
• 
Number and percentage of subjects with at least one potentially clinically significant (PCS) 
postbaseline laboratory value (see Section 17.2.1 and APPENDIX 7) will be presented by 
treatment group. The period of evaluation is the double-blind treatment period, including 
unscheduled visits. Subjects will be represented in the count of a particular PCS category if 
they have met that criteria at least once postbaseline, regardless of their baseline value.  
Serum prolactin results will be summarized overall and separately by gender. Glucose, insulin, 
and lipid panel results, along with a derived variable for homeostasis model assessment of insulin 
resistance (HOMA-IR) will be summarized for fasting only and overall (fasting, non-fasting, or 
fasting status unknown combined) status. HOMA-IR will be derived based on glucose and insulin 
results as: HOMA-IR = Glucose (mg/dL) x Insulin (mU/L) / 405 (Matthews 1985). The following 
conversion factors will be used if needed:  


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     Glucose (mg/dL) = Glucose (mmol/L) × 18.015588; 
     Insulin (mU/L) = Insulin (pmol/L) × (1/6). 
HbA1c will also be summarized.  
All laboratory data will be provided in data listings, with the values outside the reference ranges flagged. 
17.2.1. LABORATORY REFERENCE RANGES AND POTENTIALLY CLINICALLY 
SIGNIFICANT (PCS) CRITERIA 
Quantitative laboratory measurements will be compared with the relevant laboratory reference ranges in 
SI units and categorized as: 
• 
Low: Below the lower limit of the laboratory reference range.  
• 
Normal: Within the laboratory reference range (upper and lower limit included). 
• 
High: Above the upper limit of the laboratory reference range. 
For laboratory parameters with categorical outcomes, measurements will be compared with the relevant 
laboratory reference values and categorized as normal or abnormal.  
In addition to the high and low quantitative laboratory assignments (as identified by means of the 
laboratory reference ranges), Potentially clinically significant (PCS) quantitative safety (and other) 
laboratory assessments will also be identified in accordance with the predefined Potentially clinically 
significant (PCS) criteria as presented in APPENDIX 7.  
17.3. ECG EVALUATIONS 
Results from the central ECG 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 Interval (msec) 
• 
QT Interval (msec) 
• 
QTcF Interval (msec) [derived] 
• 
QTcB Interval (msec) [derived] 
• 
Heart rate (HR) (beats/min) 
• 
ECG findings 
• 
Overall assessment of ECG (investigator’s judgment): 


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o 
Normal 
o 
Abnormal, clinically Significant (CS) 
o 
Abnormal, not clinically significant (NCS) 
The following summaries will be provided for ECG data for the SAF population: 
• 
By visit summary of observed values and changes from baseline (for quantitative 
measurements) 
• 
By visit and overall (including unscheduled visits) summary of ECG overall assessment 
results. Percentage of subjects will be based on the number of subjects with ECG overall 
assessment available at the given time point. Any unscheduled ECG that occurs after first 
dose will be included in the overall post-treatment summaries. 
• 
Shift in ECG overall assessments from baseline to Week 6.  
• 
Number and percentage of subjects with QTc levels in each of the QTc categories 
The number and percentage of subjects with QTc values in the following QTc interval prolongation 
categories will be identified, same criteria apply to both QTcF and QTcB: 
• 
 > 450 msec for males \  >470 msec for females at any postbaseline time point (including 
unscheduled visits) not present at baseline 
• 
 > 480 msec for male or females at any postbaseline time point (including unscheduled 
visits) not present at baseline 
• 
 > 500 msec for males or females at any postbaseline time point (including unscheduled 
visits) not present at baseline 
• 
≥ 30 msec and < 60 msec increase from baseline for at least one postbaseline 
measurement (including unscheduled visits) 
• 
≥ 60 msec increase from baseline for at least one postbaseline measurement (including 
unscheduled visits) 
All ECG parameters, overall interpretation, and findings will be provided in data listings. A listing 
displaying ECG values for subjects with at least 1 prolonged QTc will be produced. 
17.3.1. ECG SPECIFIC DERIVATIONS 
The following 3 measures are provided by the ECG vendor and those provided values will be analyzed.  
If one of these values is missing and derivation in the course of analysis is needed, the following 
derivations may be used: 
• 
Bazett’s Correction of QT interval (msec) 
𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄 (msec) =
𝑄𝑄𝑄𝑄 (𝑚𝑚𝑚𝑚)
ඥ𝑅𝑅𝑅𝑅 (𝑚𝑚𝑚𝑚)/1000
 
• 
Fridericia’s Correction of QT interval (msec) 


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𝑄𝑄𝑄𝑄𝑄𝑄𝑄𝑄 (msec) =
𝑄𝑄𝑄𝑄 (𝑚𝑚𝑚𝑚)
ඥ𝑅𝑅𝑅𝑅 (𝑚𝑚𝑚𝑚)/1000
3
 
• 
RR Interval – If RR Interval is not available it will be derived from HR as follows, for the 
derivation of the QTc corrections 
𝑅𝑅𝑅𝑅 (msec) =  1000 ∗
60
𝐻𝐻𝐻𝐻 (𝑏𝑏𝑏𝑏𝑏𝑏) 
17.3.2. ECG POTENTIAL CLINICALLY SIGNIFICANT CRITERIA 
Potentially clinically significant ECG measurements will be identified in accordance with the following 
predefined PCS criteria: 
Table 5: Predefined ECG PCS criteria 
ECG Parameter 
PCS Low 
PCS High 
Heart Rate (beats/min) 
< 50  
> 100  
PR Interval (msec) 
-- 
> 210  
QRS Duration (msec) 
-- 
> 120  
 
17.4. VITAL SIGNS 
The following vital signs measurements will be reported for this study: 
• 
Supine Systolic Blood Pressure (mmHg) 
• 
Standing Systolic Blood Pressure (mmHg) 
• 
Supine Diastolic Blood Pressure (mmHg) 
• 
Standing Diastolic Blood Pressure (mmHg) 
• 
Supine Pulse Rate (beats/min) 
• 
Standing Pulse Rate (beats/min) 
• 
Respiratory Rate (breaths/min) 
• 
Temperature (C) 
• 
Weight (kg) 
• 
BMI (kg/m2) 
• 
Waist circumference (cm) 


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The following summaries will be provided for vital signs data for the SAF population: 
• 
Observed value and change from baseline by visit including the follow-up visit.  
• 
BMI Categories will be described by visit. 
• 
Number and percentage of subjects with at least one PCS vital sign value (see Section 
17.4.1) post Baseline. The period of evaluation is the double-blind treatment period, 
including unscheduled visits. Subjects will be counted in a particular PCS category if they 
met that PCS criteria at least once post Baseline, regardless of their Baseline value.  
• 
The number and percentage of subjects with orthostatic hypotension and orthostatic 
tachycardia will be summarized by treatment for baseline and the overall postbaseline 
period, as well as by visit. As specified in Section 6.3, any orthostatic hypotension or 
tachycardia events that occurred at the early termination visit will be assigned to the next 
planned visit. Orthostatic hypotension is defined as a decrease of ≥ 20 mmHg in systolic 
blood pressure or ≥ 10 mmHg in diastolic blood pressure after the subject had been 
standing for at least 2 to 4 minutes, compared to the systolic and diastolic blood pressures 
measured in the supine position, respectively. Orthostatic tachycardia is defined as a heart 
rate increase of at least 20 beats per minute (bpm) after the subject was standing for at least 
2 to 4 minutes, compared to the heart rate measured in the supine position and a heart rate 
> 100 bpm after the subject was standing for at least 2 to 4 minutes. Standing vital signs will 
be used as collected on the CRFs. 
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. 
 
17.4.1. VITAL SIGNS POTENTIALLY CLINICALLY SIGNIFICANT CRITERIA 
Potentially clinically significant vital sign measurements will be identified in accordance with the 
following predefined PCS criteria: 
Table 6. Predefined Potentially Clinically Significant vital sign criteria. 
Parameter 
Name 
Low 
Decrease from 
Baseline 
High 
Increase from 
Baseline 
Systolic BP 
≤ 90 mmHg 
≥ 20 mmHg 
≥ 180 mmHg 
≥ 20 mmHg 
Diastolic BP 
≤ 50 mmHg 
≥ 15 mmHg 
≥ 105 mmHg 
≥ 15 mmHg 
Pulse rate 
≤ 50 bpm 
≥ 15 bpm 
≥ 120 bpm 
≥ 15 bpm 
Respiration Rate  
≤ 10 
breaths/min 
≥ 50% 
≥ 25 
breaths/min 
≥ 50% 
Weight 
 
≥ 7% 
 
≥ 7% 
Temperature 
N/A 
 
≥ 38.3 °C 
≥ 0.8°C 
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baseline 
Note:  A vital sign measurement is PCS Low if it is below the specified lower limit and decreased from baseline orPCS High if it is 
above the specified upper limit and increased from baseline. 
17.5. PHYSICAL AND NEUROLOGICAL EXAMINATION 
As all physical and neurological findings will be recoded as medical history or AEs, no specific analysis 
of physical and neurological examination will be performed.  
17.6. OTHER SAFETY ASSESSMENTS 
17.6.1. YOUNG MANIA RATING SCALE (YMRS) 
The YMRS is an 11-item instrument used to assess the severity of mania in patients with a diagnosis of 
bipolar disorder. The 11 items are: Elevated Mood, Increased Motor Activity Energy, Sexual Interest, 
Sleep, Irritability, Speech (Rate and Amount), Language-Thought Disorder, Content, Disruptive-
Aggressive Behaviour, Appearance and Insight. The YMRS is a clinician-rated assessment. Ratings are 
based on patient self-reporting, combined with clinician observation (accorded greater score). Seven 
items are rated on a 5-point scale, ranging from 0 to 4, and four items are rated on a 9-point scale, 
ranging from 0 to 8. 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. If one or more items are missing at a visit, 
the total score will be set to missing. YMRS is assessed at Visit 1/Screening, Visit 2/Baseline/Week 0, 
Visit 3/Week 1, Visit 4/Week 2, Visit 5/Week 4, Visit 6/Week 6, and Visit 7/Follow-up/Week 7. 
The YMRS total score and change from baseline will be summarized by time point for each treatment 
group. Change from baseline over time will be analyzed by the MMRM method described for primary 
endpoint with baseline YMRS total score as covariate (see Section 16.1.3). 
 
17.6.2. TREATMENT-EMERGENT MANIA 
Treatment-emergent mania is defined as a YMRS score ≥ 16 on any 2 consecutive post-Baseline visits 
or at the final assessment, or an AE of mania or hypomania during the double blind treatment period. If 
a subject has no reported AE of mania or hypomania and has no post-Baseline assessment of YMRS, 
incidence of treatment-emergent mania will be set to missing. The mania indicator will be set to 1 if the 
subject exhibits post-baseline mania, and 0 if the subject does not experience post-baseline mania and 
has at least 1 non-missing post-baseline YMRS total score, and missing otherwise.  
Number and percentage of patients with treatment-emergent mania will be summarized by treatment 
group for the SAF population. The proportion of subjects with treatment-emergent mania will be 
analyzed using the logistic regression model including factors of treatment, region, and Baseline YMRS 
total score as a covariate. Wald chi-square p-values for tests of significance associated with each effect 
(treatment, geographic region, and baseline YMRS total score) will also be presented. This analysis will 
be performed for the SAF population.  
17.6.3. COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS) 


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The C-SSRS is a tool designed to systematically assess and track suicidal behavior and suicidal 
ideation for life time, past 3 months (90 days) prior to the screening visit, and throughout the study. The 
strength of this suicide classification system is in its ability to comprehensively identify suicidal events 
while limiting the over-identification of suicidal behavior. The C-SSRS Baseline/Screening Version is 
used at the screening visit and the C-SSRS Since Last Visit Version is used from Visit 2 (lead-in) 
onward. Subjects with Type 4 (active suicidal ideation with some intent to act, without specific plan) or 
Type 5 (active suicidal ideation with specific plan and intent) suicidal ideation during the study will be 
discontinued from the study and referred to a mental health professional. C-SSRS is assessed at Visit 
1/Screening, Visit 2/Baseline/Week 0, Visit 3/Week 1, Visit 4/Week 2, Visit 5/Week 4, Visit 6/Week 6, 
and Visit 7/Follow-up/Week 7. 
C-SSRS includes four sections: Suicidal Ideation, Intensity of Ideation, Suicidal Behavior, and Answer 
for Actual Suicide Attempts.  
The following outcomes are C-SSRS categories and have binary responses (yes/no). The categories 
are re-ordered from the scale to facilitate the definitions of the C-SSRS endpoints, and to provide clarity 
in the presentation of the results. 
Suicidal ideation is measured by 5 categories, representing 5 subtypes of suicidal ideation with 
increasing severity: 
• 
Category 1: Wish to be Dead 
• 
Category 2: Non-specific Active Suicidal Thoughts 
• 
Category 3: Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
• 
Category 4: Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
• 
Category 5: Active Suicidal Ideation with Specific Plan and Intent 
Suicidal behavior is measured by 5 categories, representing 5 subtypes of suicidal behavior: 
• 
Category 6: Preparatory Acts or Behavior 
• 
Category 7: Aborted Attempt 
• 
Category 8: Interrupted Attempt 
• 
Category 9: Actual Attempt (non-fatal) 
• 
Category 10: Completed Suicide 
The 10 categories above are not mutually exclusive. Subjects will be counted in each category for which 
they have an event. 
Self-injurious behavior without suicidal intent is a non-suicide-related C-SSRS outcome, and also has a 
binary response (yes/no). 
For the purpose of C-SSRS analysis, “baseline” and “postbaseline” are defined as follows. 
Time point 
Study Visit 
C-SSRS Version 
Derivation Rule 
Baseline 
Screening/Visit 1 
Baseline/Screening – Past 3 
Months 
Most severe 
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Visit 2/Baseline* 
Since Last Visit 
Post-
baseline 
All postbaseline visits up 
to and including Visit 
6/Week 6, including 
unscheduled visits 
Since Last Visit 
Most severe 
outcome 
* Note: The Visit 2/Baseline C-SSRS assessment must be administered prior to the first dose of study 
medication in order to be used in the C-SSRS Baseline derivation.  
C-SSRS composite endpoints will be derived for each time point of interest (ie, baseline, postbaseline, 
and each study visit) as follows: 
• 
Any suicidal ideation: A “yes” answer to any one of the 5 suicidal ideation questions on C-
SSRS (Categories 1-5). 
• 
Any suicidal behavior: A “yes” answer to any one of the 5 suicidal behavior questions on the 
C-SSRS (Categories 6-10). 
• 
Any Suicidal Ideation or Behavior: 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 (ie, baseline, postbaseline, 
each study visit including follow-up visit) is defined as the maximum suicidal ideation category (1-5) 
present for the time of interest. If no ideation is present a score of 0 is assigned. A suicidal ideation 
score of 4 or 5 is considered serious. 
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. 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. 
The number and percentage of subjects with any suicidality, any suicidal ideation, and any suicidal 
behavior in the SAF population will be presented for: 
• 
Baseline (as defined above) 
• 
Postbaseline (as defined above) 
• 
Each scheduled study visit: Screening (lifetime; past 3 months), Week 1, Week 2, Week 4, 
Week 6. 
Shift in suicidal ideation score from Baseline to the overall post-Baseline period, to each of the 
scheduled visits will be presented.  
The following comparative endpoints will also be presented, where “Treatment emergence” is used for 
outcomes that include events that first emerge or worsen, and “Emergence” is used for outcomes that 
include events that first emerge. 
• 
Treatment-emergent suicidal ideation compared to recent history: An increase in the maximum 
suicidal ideation score during treatment from the maximum suicidal ideation category at Baseline 
(C-SSRS scales taken during the specified pre-treatment period; excludes “lifetime” scores from 
the Baseline C-SSRS scale or Baseline/Screening C-SSRS scale). 


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• 
Treatment-emergent serious suicidal ideation compared to recent history: An increase in the 
maximum suicidal ideation score to 4 or 5 on the C-SSRS during treatment from not having 
serious suicidal ideation (scores of 0-3) at Baseline (C-SSRS scales taken during the specified 
pre-treatment period; excludes “lifetime” scores from the Baseline C-SSRS scale or 
Baseline/Screening C-SSRS scale). 
• 
Emergence of serious suicidal ideation compared to recent history: An increase in the maximum 
suicidal ideation score to 4 or 5 on the C-SSRS during treatment from no suicidal ideation (scores 
of 0) at Baseline (CSSRS scales taken during the specified pre-treatment period; excludes 
“lifetime” scores from the Baseline C-SSRS scale or Baseline/Screening C-SSRS scale). 
• 
Improvement in suicidal ideation at a time point of interest compared to Baseline: An improvement 
in this endpoint can be considered as a decrease in suicidal ideation score at the time point of 
interest (e.g., the last measurement during treatment) from the baseline measurement (e.g., the 
measurement taken just prior to treatment). This analysis should only be performed for studies in 
which a baseline C-SSRS can be defined (i.e., having improvement from the worse event over a 
lifetime is not clinically meaningful). 
• 
Treatment-emergent suicidal behavior compared to all prior history: The occurrence of suicidal 
behavior (categories 6-10) during treatment from not having suicidal behavior (categories 6-10) 
prior to treatment (includes “lifetime” and/or “screening” scores from the Baseline C-SSRS scale, 
Screening C-SSRS scale, or Baseline/Screening C-SSRS scale, and any “Since Last Visit” from 
the Since Last Visit C-SSRS scales taken prior to treatment). 
Responses to each question will be listed. 
17.6.4. 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, upper and lower 
extremity movements, and trunk movements. Three other items assess the subject at a global level, and 
two items assess dental status. The individual items on the AIMS are rated from 0 = ‘None’ to 4 = 
‘Severe’. The (non-global) total AIMS score is the sum of items 1 through 7. The possible range for the 
total AIMS score is 0 to 28. Items 8 through 12 are not included in the total AIMS score. Higher values of 
the total AIMS score indicate increased severity in abnormal movement. If 1 or more of the AIMS total 
score items are missing at a visit, the score will be set to missing. Item 8, representing global severity 
score, will be summarized separately. AIMS is assessed at Visit 2/Baseline/Week 0 and Visit 6/Week 6. 
All summaries and analyses will be based on the SAF population. Descriptive statistics for observed 
value and change from baseline will be displayed at week 6 and Week 6 (LOCF) by treatment group. 
AIMS total score will be analyzed using ANCOVA based on the change from baseline to Week 6 and 
Week 6 (LOCF) similar to the primary efficacy endpoint, with the respective baseline values as covariate 
(see Section 16.1.4).  
The AIMS total score at Week 6 and Week 6 (LOCF) will also be classified as ‘abnormal’ if either: at 
least two items have a response of ‘mild’ or higher; or at least one item has a response of ‘moderate’ or 
higher. Otherwise, non-missing total scores will be classified as ‘normal’. This is a modification of the 
Schooler-Kane Criteria for Tardive Dyskinesia (Schooler 1982). Shifts from baseline will be summarized 
at Week 6 and Week 6 (LOCF), postbaseline overall (based on maximum severity), and treatment 
group. 
Frequency distribution of AIMS global severity score will be provided at Week 6 and Week 6 (LOCF)  
and treatment group. Postbaseline AIMS global severity scores will be classified as ‘worsened’, 
‘unchanged’, or ‘improved’, relative to a subject’s baseline score. A higher score than that of baseline 


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would be classified as ‘worsened’. Conversely, a lower score would be classified as ‘improved’. These 
postbaseline changes will be summarized at Week 6 and Week 6 (LOCF)  and treatment group. 
17.6.5. BARNES AKATHISIA RATING SCALE (BARS)  
The BARS is a rating scale geared toward assessment of neuroleptic-induced akathisia, though it can 
be used to measure akathisia associated with other drugs as well. The BARS consists of four items, 
including one item assessing objective restlessness, two items targeting subjective restlessness 
(awareness and related distress), and one global clinical assessment item. All items are anchored and 
utilize a 4-point scale, except for the global rating which has a 6-point scale (from absence of akathisia 
through severe akathisia). The subjective and objective items are summed to yield a total score. The 
BARS 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 at a visit are missing the 
total will not be calculated. BARS is assessed at Visit 2/Baseline/Week 0 and Visit 6/Week 6. 
All summaries and analyses will be based on the SAF population. Descriptive statistics for observed 
value and change from baseline in BARS total score and global clinical assessment score will be 
displayed at each visit by treatment group. The BARS total score and global clinical assessment score 
will be analyzed using ANCOVA based on the change from baseline to Week 6 similar to the primary 
efficacy endpoint, with the respective baseline values as covariate (see Sections 16.1.4).  
Categorical scores for the four BARS items will be summarized with number and percentage of 
observations at Week 6 and Week 6 (LOCF)  and treatment group.  
The postbaseline BARS Global Clinical Assessment of Akathisia responses will be classified as 
‘worsened’, ‘unchanged’, or ‘improved’, relative to a subject’s baseline response. A higher score than 
that of baseline would be classified as ‘worsened’. Conversely, a lower score would be classified as 
‘improved’. Shifts from baseline will be summarized at Week 6 and Week 6 (LOCF)  and treatment 
group.  
17.6.6. MODIFIED SIMPSON-ANGUS SCALE (MSAS)  
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). The 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 items are missing at a visit the SAS total score will be set to missing. MSAS is 
assessed at Visit 2/Baseline/Week 0 and Visit 6/Week 6. 
All summaries and analyses will be based on the SAF population. Descriptive statistics for observed 
value and change from baseline in MSAS total score will be displayed at each visit by treatment group. 
The MSAS total score will be analyzed using ANCOVA based on the change from baseline to Week 6 
similar to the primary efficacy endpoint, with the baseline MSAS total score value as covariate (see 
Sections 16.1.4). 
The MSAS total score at each visit will also be classified as ‘abnormal’ if it exceeds 3 (Rush 2000). 
Otherwise, non-missing total scores will be classified as ‘normal.’ Shifts from baseline will be 
summarized at Week 6 and Week 6 (LOCF) and treatment group. 
17.6.7. PHYSICIAN WITHDRAWAL CHECKLIST (PWC) 
The Physician Withdrawal Checklist (PWC) is used to evaluate symptoms of withdrawal after 
discontinuation of study drug. The scale includes 20 symptoms and each symptom is assessed on a 4 


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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.  
This checklist will be assessed at the end of treatment visit (Visit 6/Week 6) and Visit 7/Follow-up visit. 
All summaries and analyses will be based on the Safety population. To assess withdrawal effect per 
PWC symptoms, the PWC total score will be summarized using descriptive statistics by visit and 
treatment group. The number and percentage of subjects with a “Present” response (mild, moderate, or 
severe) will be provided for each of the 20 PWC items. In addition, responses of mild, moderate and 
severe will be summarized separately at each visit.  
18. PHARMACOKINETIC ANALYSIS 
All PK analysis will be performed using PK population. 
Blood sample for plasma concentrations of R-amisulpride, S-amisulpride, total amisulpride, and/or 
plasma prolactin measurement will be collected at Visit 1/Screening (only for plasma prolactin), 
Visit 2/Baseline/Week 0, Visit 4/Week 2, Visit 6/Week 6, and Visit 7/Follow-up/Week 7. The PK 
collection times from Predose on Week 0 to Follow-up and deviations and/or any values excluded from 
analysis will be presented in data listings. 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 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 6.3 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 by dose.  
18.1. 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 


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19. DATA NOT SUMMARIZED OR PRESENTED 
Disposition, demographics, and pretreatment events will be listed for screened subjects including the 
screen failures. A randomized subject’s any premedication data from his/her screen failed period will be 
included in ADaM and in Tables/Listings. Any pre-treatment medical occurrences from the subject’s 
screen failed period will be excluded from ADAE and all other screen failed period data will be excluded 
from any baseline calculations for the later randomized subject. The information on scales collected on 
paper is not included in ADaM and in Tables/Listings.  Other data that are collected on screen failures 
will not be presented, but will be available in the clinical study database and SDTM domains.  
 
20. CHANGES IN THE ANALYSIS SPECIFIED IN THE STATISTICAL 
ANALYSIS PLAN 
Any changes or deviations during the analysis and reporting process from the statistical analysis plan 
designed will be described and justified in the final report. 


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21. REFERENCES 
Buckland ST, Burnham KP, Augustin NH. Model selection an integral part of inference. Biometrics. 
1997;53:603–618. 
Dmitrienko A, Koch GG. Analysis of clinical trials using SAS: A practical Guide. Second Edition. SAS 
Press: Cary, NC. 2017. 
Dmitrienko A, Molenberghs G, Chuang-Stein C, Offen W. Analysis of Clinical Trials Using SAS: A 
Practical Guide. SAS Press: Cary, NC. 2005. 
Diggle PJ, Heagerty P, Liang KY, Zeger SL. The analysis of Longitudinal Data. Oxford, England: 2nd 
Edition. Oxford University Press. 2002. 
Loebel A, Cucchiaro J, Silva R, Kroger H, Hsu J, Sachs G. Lurasidone monotherapy in the treatment of 
bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014 
Feb;171(2):160 8. 
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model 
assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin 
concentrations in man. Diabetologia. 1985;28 (7):412–9. 
O’Kelly M, Ratitch B. Clinical Trials with Missing Data: A Guide for Practitioners. John Wiley & Sons. 
2014. 
R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical. 
Computing, Vienna, Austria. URL https://www.R-project.org/. 2017. 
Rush A, Pincus H, First M, Blacker D, Endicott J, Keith S, Phillips K, Ryan N, Smith G, Tsuang M, 
Widiger T, Zarin D. Handbook of Psychiatric Measures, Washington D.C: American Psychiatric 
Association. 2000. 
Rush J, Pincus H, First M, Blacker D, Endicott J, Keith S, Phillips K, Ryan N, Smith G, Tsuang M, 
Widiger T, Zarin D. Handbook of Psychiatric Measures. American Psychiatric Association. 2000;554-
556. 
Schooler NR, Kane JM. Research Diagnoses for Tardive Dyskinesia. Arch. Gen. Psychiatry. 
1982;39:486-487. 
Sheehan KH, Sheehan DV, Assessing treatment effects in clinical trials with the Discan metric of the 
Sheehan Disability Scale. International Clinical Psychopharmacology. 2008;23:70-83. 
 
 
 


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Version Number: 
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Version Date: 
08DEC2023 
 
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: 
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. 
o 
The width of the entire output should match the linesize (134) 
• 
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” (eg, 99.99% is presented as 
“>99.9”); and cases where percent < 0.1% will be presented as “<0.1” (eg, 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. 
• 
P-values: 


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o 
P-values should be reported to four decimal places, except values <1.0000 but 
>0.9999 will be presented as ‘>0.9999’ ; and values <0.0001 will be presented as 
‘<0.0001’. Rounding will be applied after the <0.0001 and >0.9999 rule. 
• 
Ratios: 
o 
Ratios should be reported to one more decimal place than the raw data. 
• 
Spacing: 
o 
There must be a minimum of 1 blank space between columns (preferably 2). 
• 
Missing values: 
o 
A “0” should be used to indicate a zero frequency. 
o 
A blank will be used to indicate missing data in an end-of-text table or subject listing. 
• 
Figures: 
o 
Figures should be provided in RTF files using the SAS Output Delivery System 
(ODS), as Computer Graphics Metafile (CGM) formatted graphical output generated 
by SAS. 
o 
The image should be clear and of high quality when viewed in the Word document, 
and when printed. 
o 
In general, boxes around the figures should be used. 
• 
Footers should be defined as follows: 
o 
A continuous line of underscores (‘_’) will follow the body of the table or listing prior to 
any footnotes at the bottom of the page. 
o 
Table footnotes should be defined using compute statements in the proc report, and 
should appear directly after the body of the table. 
o 
If text wraps across more than one line (for a note), the first letter for all lines of text 
after the first one will be indented to align beneath the first letter of the text in the first 
line. 
DATES & TIMES 
Depending on data available, dates and times will take the form YYYY-MM-DDThh:mm:ss. 
SPELLING FORMAT 
English US. 
PRESENTATION OF TREATMENT GROUPS 
For outputs, treatment groups will be represented as follows and in that order: 
Treatment Group 
For Tables, Graphs and Listings 
Placebo 
Placebo 


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Treatment Group 
For Tables, Graphs and Listings 
SEP-4199 CR 200 mg 
SEP-4199 
CR 
200 
mg 
(applies 
to 
disposition, 
demographic, some key efficacy and safety tables, and 
listings) 
SEP-4199 CR 400 mg 
SEP-4199 
CR 
400 
mg 
(applies 
to 
disposition, 
demographic, some key efficacy and safety tables, and 
listings) 
All SEP-4199 CR 
All SEP-4199 CR (only applies to tables and graphs ) 
LISTINGS 
All listings will be sorted by the following (unless otherwise indicated in the template): 
• 
Randomized/Actual treatment received as applicable, displaying SEP-4199 CR first and 
then placebo.  
• 
Subject ID,  
• 
Original date/time (where applicable) - listings of AEs, concomitant medications, medical 
histories etc should be sorted in chronological order, with earliest AE, medication or history 
coming first, 
• 
For listings where non-randomized subjects are included, these will appear in a category 
after the randomized treatment groups labelled ‘Not Randomized’. 
 
 








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of the first dose of the study medication then impute as January 1. 
Then apply the rule from one of both dates that are known. 
Partial 
Partial 
Impute start date: 
CRF questions: ‘Started prior to First Dose?’ = Yes; ‘Started after last dose of study 
medication?’ = No. 
• 
If only the day is unknown, impute as 1st day of the month.  
• 
If the month and day are unknown, impute as  January 1. 
CRF questions: ‘Started prior to First Dose?’ = No; ‘Started after last dose of study 
medication?’ = Yes. 
• 
If only the day is unknown, impute as the later of (first day of the month, end 
of treatment + 1). 
• 
If month and day are unknown, impute as the later of  (January 1, end of 
treatment + 1). 
CRF questions: ‘Started prior to First Dose?’ = No; ‘Started after last dose of study 
medication?’ = No. 
• 
If only the day is unknown, and the month of start date is the same as the 
month of the first dose of the study medication then impute  as the first dose 
date of the study medication. 
• 
If only the day is unknown, and the month of start date is after the month of 
the first dose of the study medication then impute  as the 1st day of the  
month. 
• 
If the month and day are unknown, and the year of start date is the same as 
the year of the first dose of the study medication then impute  as the first 
dose date of the study medication. 
• 
If the month and day are unknown, and the year of start date is after the year 
of the first dose of the study medication then impute as January 1. 
Impute stop date as: 
• 
If only the day is unknown, and the month of the stop date is not the same 
as the month of the last  study visit, then impute  as the last day  of the  
month. 
• 
If only the day is unknown, and the month of the stop date is the same as 
the month of the last study visit, then impute  as the last study visit date. 
• 
If the month and day are unknown, and the year of the stop date is not the 
same as the year of the last study visit, then impute  as  December 31. 
• 
If the month and day are unknown, and the year of the stop date is the same 
as the year of the last  study visit, then impute as the last  study visit date. 
Then apply the rule from one of both dates are known. 
Partial 
Missing 
Impute start date as: 
CRF questions: ‘Started prior to First Dose?’ = Yes; ‘Started after last dose of study 
medication?’ = No. 
• 
If only the day is unknown, impute as 1st day of the month.  
• 
If the month and day are unknown, impute 1st January. 
CRF questions: ‘Started prior to First Dose?’ = No; ‘Started after last dose of study 
medication?’ = Yes. 
• 
If only the day is unknown, impute as the later of (first day of the month; end 
of treatment + 1). 
• 
If month and day are unknown, impute as the later of (January 1; end of 
treatment + 1). 
CRF questions: ‘Started prior to First Dose?’ = No; ‘Started after last dose of study 
medication?’ = No. 
• 
If only the day is unknown, and the month of start date is the same as the 
month of the first dose of the study medication then impute as the first dose 
date of the study medication. 
• 
If only the day is unknown, and the month of start date is after the month of 
the first dose of the study medication then impute  as the 1st day of the  
month. 
• 
If the month and day are unknown, and the year of start date is the same as 
the year of the first dose of the study medication then impute as the first 
dose date of the study medication. 
• 
If the month and day are unknown, and the year of start date is after the year 
of the first dose of the study medication then impute as January 1. 




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PARTIAL DATE IMPUTATION RULES FOR  PSYCHIATRICS HISTORY:  
Partial dates of first symptoms, initial diagnosis of Bipolar I disorder, onset of last manic episode, and 
onset of current major depressive episode, will be imputed as follows:  
(1) If year and month are known, and if the year or month is before Screening, use the 15th of the month; 
otherwise, if the month is the month of Screening, use the 1st of the month.  
(2) If only year is known, and it is before the year of Screening, use June 30th of that year; If only year is 
known and it is same as the year of Screening, use Jan 1.   
This imputation rule will be applied to calculation of duration of initial symptoms of bipolar I disorder, initial 
diagnosis of bipolar I disorder, onset of last manic episode, and onset of current major depressive 
episode. 
 
 


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APPENDIX 3. STATISTICAL MODEL SPECIFICATIONS 
MIXED MODEL FOR REPEATED MEASURES (MMRM) 
Ods graphics on; 
PROC MIXED DATA=XXX plots=(studentpanel(marginal)  pearsonpanel(marginal)); 
CLASS SUBJID REGION TRTPN WEEK; 
MODEL TOTCFB = TOTBL REGION TRTPN WEEK TRTPN*WEEK / DDFM=KR RESIDUAL OUTPM=OUTRESIDUAL; 
REPEATED WEEK/TYPE=UN SUBJECT=SUBJID; 
LSMEANS TRTPN*WEEK /PDIFF CL; 
RUN; 
*Where WEEK = Week 1, Week 2, Week 4, Week 6; 
Ods graphics off; 
 
In case the MMRM model assuming the unstructured covariance variance structure fails to converge, 
Heterogeneous Toeplitz and Toeplitz, and Compound Symmetry covariance structure will be assumed 
sequentially. The first covariance structure to yield convergence will be used in the analysis.  
PROC MIXED empirical; 
CLASS SUBJID REGION TRTPN WEEK; 
MODEL TOTCFB = TOTBL REGION TRTPN WEEK TRTPN*WEEK / RESIDUAL OUTP=OUTRESIDUAL; 
REPEATED WEEK/TYPE=TOEPH  SUBJECT=SUBJID; 
REPEATED WEEK/TYPE=TOEP SUBJECT=SUBJID; 
REPEATED WEEK/TYPE=CS SUBJECT=SUBJID; 
LSMEANS TRTPN*WEEK /PDIFF CL COV; 
RUN; 
 
Within-group effect size will be calculated as the observed value of LS mean of change from baseline 
divided by SD, obtained as the SE of the LS Mean multiplied by the square root of the treatment group 
change from baseline sample size at each visit. Between-group effect size at a visit will be calculated as 
the observed value of the LS means difference from Placebo divided by the model estimate of the 
pooled SD at the visit, which is obtained from the square root of the diagonal element, associated at the 
visit, from the covariance matrix (R matrix of subjects with MADRS total score at all visits). Although the 
variance-covariance estimates are calculated differently depending on the covariance structure being 
applied for the model, the diagonal of the R matrix will contain the variance estimate at each visit that 
can be used for the effect size calculations regardless of the covariance structure. 
 
 


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ANALYSIS OF COVARIANCE (ANCOVA) 
PROC MIXED; 
BY WEEK; 
CLASS TRTPN REGION; 
MODEL TOTCFB = TRTPN REGION TOTBL; 
LSMEANS TRTPN / PDIFF CL; 
RUN; 
 
LOGISTIC REGRESSION 
* Placebo is reference; 
PROC LOGISTIC DESCENDING; 
CLASS TRTPN REGION / PARAM=REF; 
MODEL RESP = TRTPN REGION TOTBL; 
RUN; 
 
 
 














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APPENDIX 7. BLINDED DATA REVIEW (BDR) PROCESS 
The blinded review of the SEP380-301 data will be conducted prior to unblinding in order to permit the 
checking and assessment of data for the purposes of identifying additional information for analyses 
specified in the SAP. This process will be completed prior to unblinding. 
This review will be performed by appropriate personnel including, but not limited to a biostatistician and 
an MD. Relevant outputs will be generated shortly before/after database soft lock in order to facilitate 
the blinded review process. 
Any changes to the planned analysis based on a blinded review of data will be documented with 
detailed explanation for deviations from the pre-defined plans. Decisions made at this meeting will be 
documented prior to unblinding to be incorporated into the analysis. 
The BDR process will include review of analysis populations. In addition, the IPD review process 
detailed in the IPD specification document will help identify any IPDs. 
 
 


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APPENDIX 8. EQ-5D-5L INDEX VALUE 
EQ-5D-5L health states, defined by the EQ-5D-5L descriptive system, will be converted into a single 
index value using an appropriate value set. For international trials, EuroQol recommends applying a 
single value set or crosswalk to all study sites. US value set will be used for US, Europe, and Japan for 
this study. 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 9. TABLE OF CONTENTS 
DISPOSITION, WITHDRAWALS, IPD, BASELINE AND EXPOSURE DATA  
Table 14.1.1.1 Subject Disposition (All Subjects Screened) 
Table 14.1.1.2 Subject Discontinuation by Visit (All Subjects Randomized)  
Table 14.1.1.3 Number of Subjects Randomized by Region, Country, and Site (All Subjects 
Randomized)  
Table 14.1.2.1 Analysis Populations (All Subjects Randomized) 
Table 14.1.2.2 Important Protocol Deviations (Safety Population)  
Table 14.1.3.1 Demographics and Other Baseline Characteristics (Safety Population)  
Table 14.1.4.1 Psychiatric History (Safety Population) 
Table 14.1.4.2 Psychiatric History - Other psychiatric disorders at baseline (Safety Population)  
Table 14.1.4.3 Family Psychiatric History (Safety Population)  
Table 14.1.5.1 Medical and Surgical History (Safety Population)  
Table 14.1.6.1 Prior Medications (Safety Population)  
Table 14.1.6.2 Concomitant Medications (Safety Population)  
Table 14.1.6.3 Summary of Concomitant Benzodiazepines, Sedatives, or Hypnotics Use (Safety 
Population) 
Table 14.1.7.1 Exposure to Study Medication (Safety Population) 
Table 14.1.7.2 Study Medication Compliance (Safety Population)  
EFFICACY DATA 
Table 14.2.1.1 MADRS Total Score – Mixed Model for Repeated Measures Analysis of Change from 
Baseline over Time (ITT Population)  
Table 14.2.1.2 MADRS Total Score – ANCOVA of Change from Baseline over Time (ITT Population)  
Table 14.2.2.1 CGI-BP-S Depression Score – Mixed Model for Repeated Measures Analysis of Change 
from Baseline over Time (ITT Population)  
Table 14.2.2.2 CGI-BP-S Depression Score – ANCOVA of Change from Baseline over Time (ITT 
Population)  
Table 14.2.3.1 MADRS-6 Subscale Score – Mixed Model for Repeated Measures Analysis of Change 
from Baseline over Time (ITT Population)  
Table 14.2.3.2.1 MADRS Responders at Week 6 and Week 6 (LOCF) – Logistic Regression (ITT 
Population) 
Table 14.2.3.2.2 MADRS Remission at Week 6 and Week 6 (LOCF) – Logistic regression (ITT 
Population)  
Table 14.2.3.3 HAM-A Total Score – Mixed Model for Repeated Measures Analysis of Change from 
Baseline over Time (ITT Population)  
Table 14.2.3.4 QIDS-SR16 Total Score – ANCOVA of Change from Baseline at Week 6 and Week 6 
(LOCF) (ITT Population) 
Table 14.2.3.5.1 SDS Total Score – ANCOVA of Change from Baseline at Week 6 and Week 6 (LOCF)  


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(ITT Population) 
Table 14.2.3.6.1 EQ-5D-5L VAS Score – ANCOVA of Change from Baseline at Week 6 and Week 6 
(LOCF) (ITT Population) 
Table 14.2.3.6.2 EQ-5D-5L Index Value – ANCOVA of Change from Baseline at Week 6 and Week 6 
(LOCF) (ITT Population) 
Table 14.2.3.6.3 EQ-5D-5L Dimension Score – Observed Value and Change from Baseline at Week 6 
and Week 6 (LOCF) (ITT Population) 
Table 14.2.3.7 SHAPS Total Score – ANCOVA of Change from Baseline at Week 6 and Week 6 (LOCF)  
(ITT Population) 
SAFETY DATA  
Table 14.3.1.1 Adverse Event Overall Summary (Safety Population)  
Table 14.3.1.2 Adverse Events, by System Organ Class and Preferred Term (Safety Population)  
Table 14.3.1.3.1 Adverse Events, by System Organ Class and Preferred Term, by Maximum Severity 
(Safety Population) 
Table 14.3.1.3.2 Adverse Events, by System Organ Class and Preferred Term, by Relationship to Study 
Medication (Safety Population) 
Table 14.3.1.4 Adverse Events of Special Interest (AESI) by Preferred Term (Safety Population) 
Table 14.3.1.5 Adverse Events Leading to Discontinuation from Study Treatment Period, by System 
Organ Class and Preferred Term (Safety Population)  
Table 14.3.2.1 Serious Adverse Events, by System Organ Class and Preferred Term (Safety 
Population)  
Table 14.3.4.1.1.1 Clinical Chemistry Laboratory Data in SI Units – Observed Value and Change from 
Baseline (Safety Population)  
Table 14.3.4.1.1.2 Clinical Chemistry Laboratory Data in CV Units – Observed Value and Change from 
Baseline (Safety Population)  
Table 14.3.4.1.2 Clinical Chemistry Laboratory Data – Shift from Baseline to Week 6 (Safety Population) 
Table 14.3.4.2.1.1 Hematology Laboratory Data in SI Units – Observed Value and Change from 
Baseline (Safety Population)  
Table 14.3.4.2.1 Hematology Laboratory Data in CV Units – Observed Value and Change from Baseline 
(Safety Population)  
Table 14.3.4.2.2 Hematology Laboratory Data – Shift from Baseline to Week 6 (Safety Population)  
Table 14.3.4.3.1 Urinalysis Laboratory Data – Observed Value and Change from Baseline (Safety 
Population)  
Table 14.3.4.3.2 Urinalysis Laboratory Data (Categorical Values) – By Visit Summary (Safety 
Population)  
Table 14.3.4.3.3 Urinalysis Laboratory Data – Shift from Baseline to Week 6 (Safety Population)  
Table 14.3.4.4.1 Number and Percentage of Subjects with Potentially Clinically Significant (PCS)  Post-
Baseline Laboratory Values in SI Units (Safety Population) 
Table 14.3.4.4.2 Number and Percentage of Subjects with Potentially Clinically Significant (PCS)  Post-
Baseline Laboratory Values in CV Units (Safety Population)  
Table 14.3.5.1.1 Electrocardiogram (ECG) Parameters – Observed Value and Change from Baseline 


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(Safety Population)  
Table 14.3.5.1.2 Electrocardiogram (ECG) Overall Assessment – By Visit Summary (Safety Population)  
Table 14.3.5.1.3 Electrocardiogram (ECG) Overall Assessment – Shift from Baseline to Week 6 (Safety 
Population)  
Table 14.3.5.1.4 Incidence of Potentially Clinically Significant (PCS)  Electrocardiogram (ECG) Results 
(Safety Population)  
Table 14.3.5.2.1 Vital Signs – Observed Value and Change from Baseline (Safety Population)  
Table 14.3.5.2.2 BMI Categories – By Visit Summary (Safety Population)  
Table 14.3.5.2.3 Number and Percentage of Subjects with Potentially Clinically Significant (PCS) Post-
Baseline Vital Signs (Safety Population)  
Table 14.3.5.2.4 Incidences of Orthostatic Hypotension and Orthostatic Tachycardia (Safety Population)  
Table 14.3.5.3.1 C-SSRS – Any Suicidal Ideation, Suicidal Behavior, and Suicidality by Visit (Safety 
Population)  
Table 14.3.5.3.2 C-SSRS – verall Post-baseline Subject Incidence of Treatment-Emergent Changes in 
Suicidality (Safety Population)  
Table 14.3.5.4.1 AIMS Total Score – ANCOVA of Change from Baseline at Week 6 and Week 6 (LOCF) 
(Safety Population)  
Table 14.3.5.4.2 AIMS Total Score –  Shift from Baseline (Safety Population)  
Table 14.3.5.4.3 AIMS Global Severity Score –  Categorical Summary (Safety Population)  
Table 14.3.5.4.4 AIMS Global Severity Score –  Categorical Change from Baseline (Safety Population) 
Table 14.3.5.5.1 BARS Total Score – ANCOVA of Change from Baseline at Week 6 and Week 6 
(LOCF) (Safety Population)  
Table 14.3.5.5.2 BARS Items –  Categorical Summary (Safety Population)  
Table 14.3.5.5.3 BARS Global Clinical Assessment – Categorical Change from Baseline (Safety 
Population)  
Table 14.3.5.6.1 MSAS Total Score – ANCOVA of Change from Baseline at Week 6 and Week 6 
(LOCF) (Safety Population)  
Table 14.3.5.6.2 MSAS Total Score – Shift from Baseline (Safety Population)  
Table 14.3.5.7.1 YMRS Total Score – Mixed Model for Repeated Measures Analysis of Change from 
Baseline over Time (Safety Population)  
Table 14.3.5.7.2 YMRS Total Score - Treatment-Emergent Mania (Safety Population)  
Table 14.3.5.8.1 Physician Withdrawal Checklist (PWC) Total Score – Observed value (Safety 
Population)  
Table 14.3.5.8.2 Physician Withdrawal Checklist (PWC) Symptoms – Categorical Summary (Safety 
Population)  
Table 14.3.5.9.1 SEP-4199 Plasma Concentrations (ng/mL) by Scheduled Time (PK Population) 
Table 14.3.5.9.2 Plasma Prolactin Concentrations (ng/mL) by Scheduled Time (PK Population)  
 
Figure 14.1 Time to Study Drug Discontinuation (ITT Population)  


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Figure 14.2.1.1 MADRS Total Score – LS Mean (95% CI) of Change from Baseline over Time Based on 
MMRM Estimates (ITT Population)  
Figure 14.2.1.2 MADRS Total Score – LS Mean (95% CI) of Change from Baseline over Time Based on 
ANCOVA Estimates (ITT Population) 
Figure 14.2.2.1 CGI-BP-S Depression Score – LS Mean (95% CI) of Change from Baseline over Time 
Based on MMRM Estimates (ITT Population)  
Figure 14.2.2.2 CGI-BP-S Depression Score – LS Mean (95% CI) of Change from Baseline over Time 
Based on ANCOVA Estimates (ITT Population) 
  
Listing 16.1.7 Randomization Scheme and Codes (Randomized Subjects)  
Listing 16.2.1.1 Subject Disposition (Screen Failures)  
Listing 16.2.1.2 Subject Disposition (Randomized Subjects)  
Listing 16.2.1.3 Protocol Version and Study Medication Blinding Status (Randomized Subjects)  
Listing 16.2.1.4 Analysis Population Assignment (Randomized Subjects)  
Listing 16.2.2.1 Major and Critical Protocol Deviations (Randomized Subjects)  
Listing 16.2.2.2 Inclusion Criteria (Randomized Subjects) 
Listing 16.2.2.3 Exclusion Criteria (Randomized Subjects)  
Listing 16.2.3.2 Subjects Excluded from Pharmacokinetic Analyses (Randomized Subjects) 
Listing 16.2.4.1 Demographics and other Baseline Characteristics (Randomized Subjects)  
Listing 16.2.4.2 Psychiatric History (Randomized Subjects)  
Listing 16.2.4.3 Family Psychiatric History (Randomized Subjects)  
Listing 16.2.4.4 Other Psychiatric disorder (Randomized Subjects)  
Listing 16.2.4.5 Medical and Surgical History (Randomized Subjects) 
Listing 16.2.4.6 Prior, Concomitant, and Post-treatment Medications (Randomized Subjects)  
Listing 16.2.4.7 Timing of Last Dose of Benzodiazepines / Sedatives / Hypnotics (Randomized Subjects)
  
Listing 16.2.5.1 Drug Accountability (Randomized Subjects)  
Listing 16.2.5.2 Randomized and Predominant Study Medication (Randomized Subjects)  
Listing 16.2.6.1 Montgomery Asberg Depression Rating Scale (MADRS) (Randomized Subjects)  
Listing 16.2.6.2 Clinical Global Impression – Severity Bipolar Version (CGI-BP-S) (Randomized 
Subjects)  
Listing 16.2.6.3 Hamilton Rating Scale for Anxiety (HAM-A) (Randomized Subjects)  
Listing 16.2.6.4 Quick Inventory of Depressive Symptomatology – Self-Report (QIDS-SR16) 
(Randomized Subjects)  
Listing 16.2.6.5 Sheehan Disability Scale (SDS) (Randomized Subjects)  
Listing 16.2.6.6 EuroQol 5D-5L (EQ-5D-5L) (Randomized Subjects) 
Listing 16.2.6.7 Snaith-Hamilton Pleasure Scale (SHAPS) (Randomized Subjects) 


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Listing 16.2.7.1 Pre-treatment Events (Screen Failures) 
Listing 16.2.7.2 Pre-Treatment Events (Randomized Subjects)  
Listing 16.2.7.3 All Adverse Events (Safety Population)  
Listing 16.2.7.4 Serious Adverse Events (Safety Population)  
Listing 16.2.7.5 Adverse Events Leading to Discontinuation from Study Treatment Period (Safety 
Population)  
Listing 16.2.7.6 Adverse Events Leading to Death (Safety Population)  
Listing 16.2.8.1 Central Laboratory Data – Clinical Chemistry (Safety Population)  
Listing 16.2.8.2 Central Laboratory Data – Hematology (Safety Population)  
Listing 16.2.8.3 Central Laboratory Data – Urinalysis (Safety Population)  
Listing 16.2.8.4 Central Laboratory Data – Other (Safety Population)  
Listing 16.2.8.5 Central Laboratory Data – Urine Drug Screening (Safety Population) 
Listing 16.2.8.6 Central Laboratory Data – Potentially Clinically Significant (PCS) Values (Safety 
Population)  
Listing 16.2.8.7 Vital Signs (Safety Population)  
Listing 16.2.8.8 Vital Signs – Potentially Clinically Significant (PCS) Values (Safety Population) 
Listing 16.2.8.9 Electrocardiogram (ECG) Results (Safety Population) 
Listing 16.2.8.10 Electrocardiogram (ECG) Results – Overall Assessment (Safety Population)  
Listing 16.2.8.11 Columbia-Suicide Severity Rating Scale (C-SSRS) (Safety Population) 
Listing 16.2.8.12 Pregnancy Test Results (Safety Population)  
Listing 16.2.8.13 Serum Follicle Stimulating Hormone (FSH) Test Results (Safety Population)  
Listing 16.2.8.14 Young Mania Rating Scale (YMRS) (Safety Population)  
Listing 16.2.8.15 Abnormal Involuntary Movement Scale (AIMS) (Safety Population)  
Listing 16.2.8.16 Barnes Akathisia Rating Scale (BARS) (Safety Population)  
Listing 16.2.8.17 Modified Simpson-Angus Scale (MSAS) (Safety Population)  
Listing 16.2.8.18 Physician Withdrawal Checklist (PWC) (safety Population)  
Listing 16.2.8.19 Plasma SEP-4199 Concentrations (Safety Population)  
Listing 16.2.8.20 Plasma Prolactin Concentration (Safety Population)  
Listing 16.2.8.21 Plasma Concentrations for Subjects Excluded from Pharmacokinetic Analysis (Safety 
Population)  
Listing 16.2.8.22 Visit Information (Randomized Subjects)  
Listing 16.2.8.23 Comments Information (Randomized Subjects) 
  
Statistical Appendix 16.1.9.2.1: Supportive Output for Table 14.2.1.1.2 MADRS Total Score – Mixed 
Model for Repeated Measures Analysis of Change from Baseline over Time (ITT Population)  
Statistical Appendix 16.1.9.2.2: Supportive Output for Table 14.2.2.1 CGI-BP-S Score – Mixed Model for 
Repeated Measures Analysis of Change from Baseline over Time (ITT Population)  


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APPENDIX 10. SCHEDULE OF EVENTS 
 


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Visit 1 
Visit 2a 
Visit 3 
Visit 4 
TC1b 
Visit 5 
TC2b 
Visit 6c 
Visit 7d 
Screening 
Washoute 
Baseline 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
EOT/ET 
Follow-up 
Day 
-22 to -2 
Day -1 
Day 7 
(± 2) 
Day 14 (± 
2) 
Day 21 (± 
2) 
Day 28 (± 
2) 
Day 35 (± 
2) 
Day 42 (± 
2) 
7 (± 2) 
days after 
last dose 
Obtain informed consent 
X 
 
 
 
 
 
 
 
 
Obtain informed consent for 
duplicate subject check (where 
local regulations allow) 
X 
 
 
 
 
 
 
 
 
Obtain informed consent for 
optional 
pharmacogenomic 
sampling, if applicable 
 
X 
 
 
 
 
 
 
 
Lifetime Illness Characteristics 
Questionnairef 
X 
 
 
 
 
 
 
 
 
Montgomery-Asberg Depression 
Rating Scale, Self-rating version 
(MADRS-S)f 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
Duplicate Subject Check 
X 
 
 
 
 
 
 
 
 
Pre-Baseline Eligibility Reviewg 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Psychiatric Historyh 
X 
 
 
 
 
 
 
 
 
Family Psychiatric and Medical 
History 
X 
 
 
 
 
 
 
 
 
Structured Clinical Interview for 
DSM-5-Clinical Trial Version 
(SCID-5-CT)i 
X 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
 
 
 
X 
X 


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Visit 1 
Visit 2a 
Visit 3 
Visit 4 
TC1b 
Visit 5 
TC2b 
Visit 6c 
Visit 7d 
Screening 
Washoute 
Baseline 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
EOT/ET 
Follow-up 
Day 
-22 to -2 
Day -1 
Day 7 
(± 2) 
Day 14 (± 
2) 
Day 21 (± 
2) 
Day 28 (± 
2) 
Day 35 (± 
2) 
Day 42 (± 
2) 
7 (± 2) 
days after 
last dose 
Neurological Examination 
X 
X 
 
 
 
 
 
X 
X 
Prior/Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subject Eligibility Checkj  
 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Dispense Study Drug  
 
X 
X 
X 
 
X 
 
 
 
Study Drug Accountabilityk 
 
 
X 
X 
 
X 
 
X 
 
Schedule Next Visitl 
X 
X 
X 
X 
 
X 
 
X 
 
EFFICACY ASSESSMENTS 
 
 
 
 
 
 
 
 
 
Montgomery-Asberg Depression 
Rating Scale (MADRS)m 
X 
X 
X 
X 
 
X 
 
X 
 
Hamilton Anxiety Rating Scale 
(HAM-A)n 
 
X 
X 
X 
 
X 
 
X 
 
Quick Inventory of Depressive 
Symptomatology-Self-Report 
(QIDS-SR16) 
 
X 
 
 
 
 
 
X 
 
Sheehan Disability Scale (SDS) 
 
X 
 
 
 
 
 
X 
 
EuroQol - 5 Dimension - 5 Level 
(EQ-5D-5L) 
 
X 
 
 
 
 
 
X 
 
Snaith-Hamilton Pleasure Scale 
(SHAPS) 
 
X 
 
 
 
 
 
X 
 
Clinical 
Global 
Impression-
Bipolar 
Version-Severity 
of 
Illness (CGI-BP-S)o 
X 
X 
X 
X 
 
X 
 
X 
 


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Visit 1 
Visit 2a 
Visit 3 
Visit 4 
TC1b 
Visit 5 
TC2b 
Visit 6c 
Visit 7d 
Screening 
Washoute 
Baseline 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
EOT/ET 
Follow-up 
Day 
-22 to -2 
Day -1 
Day 7 
(± 2) 
Day 14 (± 
2) 
Day 21 (± 
2) 
Day 28 (± 
2) 
Day 35 (± 
2) 
Day 42 (± 
2) 
7 (± 2) 
days after 
last dose 
SAFETY ASSESSMENTS 
 
 
 
 
 
 
 
 
 
Vital Sign Measurementsp 
X 
X 
X 
X 
 
X 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
Weight and Body Mass Indexq 
X 
X 
 
 
 
 
 
X 
X 
Waist Circumference 
 
X 
 
 
 
 
 
X 
 
Pretreatment 
Event/ 
Adverse Events Monitoringr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
X 
X 
X 
 
X 
 
X 
X 
Serum Chemistrys 
X 
X 
 
X 
 
 
 
X 
X 
Hematology 
X 
X 
 
X 
 
 
 
X 
X 
Urinalysis 
X 
X 
 
X 
 
 
 
X 
X 
Serum Prolactint 
X 
X 
 
X 
 
 
 
X 
X 
Hemoglobin A1c (HbA1c) 
X 
X 
 
 
 
 
 
X 
 
Lipid Panel s 
X 
X 
 
 
 
 
 
X 
 
Serum Insulins 
X 
X 
 
 
 
 
 
X 
 
High 
Sensitivity 
C-Reactive 
Protein (hs-CRP) 
X 
X 
 
 
 
 
 
X 
 
Hepatitis B/C Panel 
X 
 
 
 
 
 
 
 
 
Thyroid Panel  
X 
X 
 
 
 
 
 
X 
 
Serum 
Follicle 
Stimulating 
Hormone 
(postmenopausal 
women or if menopause is 
suspected) 
X 
 
 
 
 
 
 
 
 


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Visit 1 
Visit 2a 
Visit 3 
Visit 4 
TC1b 
Visit 5 
TC2b 
Visit 6c 
Visit 7d 
Screening 
Washoute 
Baseline 
Week 1 
Week 2 
Week 3 
Week 4 
Week 5 
Week 6 
EOT/ET 
Follow-up 
Day 
-22 to -2 
Day -1 
Day 7 
(± 2) 
Day 14 (± 
2) 
Day 21 (± 
2) 
Day 28 (± 
2) 
Day 35 (± 
2) 
Day 42 (± 
2) 
7 (± 2) 
days after 
last dose 
Serum Pregnancy Test (females 
of childbearing potential)u 
X 
 
 
 
 
 
 
 
 
Urine Pregnancy Test (females of 
childbearing potential)u,v 
 
X 
 
X 
 
 
 
X 
X 
Urine Drug Screenv 
X 
 
 
 
 
 
 
 
 
Rapid Urine Drug Testv 
 
X 
 
X 
 
 
 
X 
X 
Young 
Mania 
Rating 
Scale 
(YMRS)w 
X 
X 
X 
X 
 
X 
 
X 
X 
Physician’s Withdrawal Checklist 
(PWC)x 
 
 
 
 
 
 
 
X 
X 
Columbia-Suicide 
Severity 
Rating Scale (C-SSRS)y 
X 
X 
X 
X 
 
X 
 
X 
X 
Abnormal Involuntary Movement 
Scale (AIMS) 
 
X 
 
 
 
 
 
X 
 
Barnes Akathisia Scale (BARS) 
 
X 
 
 
 
 
 
X 
 
Modified Simpson-Angus Scale 
(SAS) 
 
X 
 
 
 
 
 
X 
 
Blood Sampling for Plasma PK 
and Plasma Prolactint,z 
X 
X 
 
X 
 
 
 
X 
X 
Optional Blood Sampling for 
Pharmacogenomic Testingaa 
 
X 
 
 
 
 
 
 
 
Abbreviations: BMI = body mass index; eCRF = electronic case report form; DSM-5 = The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; EOT = End of 
Treatment; ET = Early Termination; hCG = human chorionic gonadotropin; PK = pharmacokinetics; TC = telephone call. 
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 additional visit for Japan on Day 1 which checks study drug compliance and ECG. 
 


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a Visit 2 is defined as the Baseline Visit. Study drug will be dispensed at Visit 2/Day -1, and subjects will be instructed to take their first dose of study drug the following morning 
(Day 1). 
b A telephone call at Day 21 and Day 35 to ascertain adverse events and concomitant medications since last visit. 
c Visit 6 is the End of Treatment/Early Termination visit. Subjects who discontinue the study prior to Visit 6 will have all Visit 6 procedures performed at the time of 
discontinuation. 
d Subjects who discontinue early from the study or complete the study and do not enter the extension study (SEP380-303) will have a safety Follow-up Visit (7 [± 2] days after 
their last dose of study drug). 
e Screening assessments may occur over multiple days. Hospitalization during the Screening Period will not be allowed, except where required by local regulations or when 
determined to be clinically indicated based on the subject’s psychiatric history and current psychiatric symptoms. Medical justification must be provided to the Medical Monitor 
and the Medical Monitor must approve the request for hospitalization. In such cases, a maximum of 7 days’ hospitalization during washout of prior medications in the Screening 
Period will be allowed. An extension of the Screening Period by up to 7 days may be allowed, with prior approval from the Medical Monitor. 
f Following Informed Consent, the Lifetime Illness Characteristics Questionnaire and the MADRS-S will be completed by the subject prior to other assessments at Screening. 
Subject must have a MADRS-S total score ≥ 22 at Screening. 
g For the pre-Baseline review by the Sponsor Eligibility Committee, sites will be required to submit specific Screening information for CRO and Sponsor review, prior to 
proceeding to Baseline. Details are provided in Section 26, Appendix VII of the protocol. 
h Includes a psychiatric history form that will include variables related to duration of illness, treatment response (eg, prior medications used to treat bipolar disorder) and other 
similar variables. 
i The SCID-5-CT will be used to support the DSM-5 diagnosis and must be administered by a qualified rater at the site. 
j Subject eligibility check in IXRS is to be performed prior to randomization, but after all scales are completed, to confirm Blinded Inclusion Criterion 12 is met.  
k Clinical site staff will record the date and time of the 3 doses prior to the study visit in the source (all visits) and eCRF (Visit 4 [Day 14] and Visit 6 [Day 42] only), based on 
subject self-report. 
l Instruct subject to record dosing date and time of the last 3 doses prior to the study visit on the blister pack wallet or other format and bring back all used/unused study drug and 
packaging to next visit. 
m Subjects must have a MADRS total score ≥ 22 at Screening (Visit 1) and Baseline (Visit 2). Subjects who demonstrate a decrease (improvement) of ≥ 25% in MADRS total 
score from Screening (Visit 1) to Baseline (Visit 2) must be screen failed. 
n The Structured Interview Guide for the HAM-A (SIGH-A) will be used for administration of the HAM-A. 
o Subjects must have a CGI-BP-S depression score ≥ 4 at Screening (Visit 1) and Baseline (Visit 2). 
p 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. Respiratory rate and temperature will also be measured. 
q BMI will be calculated by clinical site staff at Screening (Visit 1) and recorded in the eCRF. At Baseline (Visits 2), Visit 6/EOT/ET (Day 42), and Visit 7 (Follow-up), BMI does 
not need to be calculated by the clinical site staff as it will be calculated in the analysis. 
r Events occurring prior to first dose of study drug are programmatically identified as pretreatment events. Events occurring after first dose of study drug are programmatically 
identified as adverse events. 
s Subjects are required to fast for at least 8 hours prior to sample collection for laboratory testing at Baseline (Visit 2) and Visit 6/EOT/ET (Day 42). Fasting for 8 hours prior to 
Screening (Visit 1) is also recommended to avoid potential retests. 
t Prolactin levels (serum and plasma) will be masked for any assessment collected after the first study drug dose. Prolactin levels prior to the first study drug dose will be 
unmasked. 
u For females of childbearing potential, any positive urine ß-hCG test should be confirmed by serum β-hCG. 
v 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. 
w To be eligible for enrollment, subjects must have a YMRS total score ≤ 12 at Screening (Visit 1) and Baseline (Visit 2). 


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x The PWC will be completed for early termination subjects and subjects who complete the study and do not rollover into Study SEP380-303; it will not be completed for subjects 
who rollover into Study SEP380-303. 
y At the Screening visit (Visit 1), the “Baseline/Screening” version will be completed; for all subsequent visits, the “Since Last Visit” version of the C-SSRS will be administered. 
z Blood sample for SEP-4199 population pharmacokinetic analysis for R- and S-enantiomers and/or plasma prolactin measurement will be collected at Screening (Visit 1), Baseline 
(Visit 2), Visit 4 (Day 14), Visit 6/EOT/ET (Day 42), and Visit 7/Follow-up (7 ± 2 days after last dose), with a record of the time of last 3 administered doses on the eCRF at 
Visit 4 (Day 14) and Visit 6/EOT/ET (Day 42). 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. 
aa Blood sampling for pharmacogenomic testing will be requested but is not required for participation in the study.