A Multicenter, Open-Label Study Evaluating the Safety, Tolerability, and Pharmacokinetics of Brexanolone in the Treatment of Adolescent Female Subjects With Postpartum Depression
Phase: PHASE3
Conditions: Post Partum Depression
Sponsor: Supernus Pharmaceuticals, Inc.

Official Title: 
A Multicenter, Open-label Study Evaluating the Safety, Tolerability, and 
Pharmacokinetics of Brexanolone in the Treatment of Adolescent Female 
Subjects With Postpartum Depression
NCT Number: 
NCT03665038
Document Date: 
Protocol Version 4.0: 20 December 2019

Clinical Study Report 
547-PPD-304
16.1 Study Information 
1 
1.
PROTOCOL AND AMENDMENTS
Version Number 
Date 
Title 
Initial 
Version 1.0, 23 
January 2018 
A Multicenter, Double-Blind, Placebo-Controlled Study Evaluating 
the Efficacy, Safety, 
Tolerability, and Pharmacokinetics of Brexanolone in 
the Treatment of Adolescent Female Subjects with Postpartum 
Depression   
Amendment 1 
Version 2.0, 11 
September 2018 
A Multicenter, Double-Blind, Placebo-Controlled Study Evaluating 
the Efficacy, Safety, 
Tolerability, and Pharmacokinetics of Brexanolone in 
the Treatment of Adolescent Female Subjects with Postpartum 
Depression  
Amendment 2 
Version 3.0, 03 
June 2019 
A Multicenter, Double-Blind, Placebo-Controlled Study Evaluating 
the Efficacy, Safety, 
Tolerability, and Pharmacokinetics of Brexanolone in 
the Treatment of Adolescent Female Subjects with Postpartum 
Depression  
Amendment 3 
Version 4.0, 20 
December 2019 
A Multicenter, Open-Label Study Evaluating the Safety, 
Tolerability, and Pharmacokinetics of Brexanolone in 
the Treatment of Adolescent Female Subjects with Postpartum 
Depression  

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INVESTIGATOR’S AGREEMENT 
 
I have read the Clinical Protocol 547-PPD-304 and agree to conduct the study as outlined.  I 
agree to maintain the confidentiality of all information received or developed in connection with 
this protocol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date (DD Month YYYY) 
 
 

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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Sage Therapeutics 
215 First Street  
Cambridge, MA  02142 
Name of Study drug: 
Brexanolone 
Name of Active Ingredient: 
Brexanolone (USAN), also known as allopregnanolone (scientific name) 
Title of Study: A Multicenter, Open-Label Study Evaluating the Safety, Tolerability, and 
Pharmacokinetics of Brexanolone in the Treatment of Adolescent Female Subjects with Postpartum 
Depression 
Study center(s):  A global study at up to 50 sites  
Phase of development: 3 
Objectives:  
Primary Objective: 
• 
The primary objective of the study is to evaluate the safety and tolerability of brexanolone when 
administered to adolescent female subjects diagnosed with PPD. 
Secondary Objectives: 
• 
To assess the plasma pharmacokinetic (PK) profile of brexanolone and, when appropriate, 
metabolites of brexanolone 
 
 
 
 
 
Methodology:  
In previous Versions 1 through 3 of this protocol, subjects were randomly assigned to active or 
placebo study drug in a blinded manner. With the current Amendment 3/Version 4, the study has been 
converted to an open-label study where all subjects will receive brexanolone. 
This is a Phase 3, open-label study designed to evaluate the safety, tolerability and PK, of 
brexanolone in adolescent female subjects diagnosed (by Structured Clinical Interview for DSM-5 
Axis I Disorders [SCID-5]) with PPD.  Subjects will be administered a single, 60-hour continuous IV 
infusion of brexanolone.  

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Screening Period:  
The Screening Period begins with the informed consent process at the Screening Visit, which can 
occur on any one calendar day of a 14-day window (from Day -14 through Day -1, inclusive).  
Subjects will undergo procedures at the Screening Visit to determine eligibility, including completion 
of the 
 
Treatment Period:  
The Treatment Period is the period from the start of the assessments on Day 1 prior to initiation of 
brexanolone through the 72-hour assessments on Day 3. The 60-hour infusion will be administered as 
follows: 30 mcg/kg/hour (Hour 0 to 4), then 60 mcg/kg/hour (Hour 4 to 24), then 90 mcg/kg/hour 
(Hour 24 to 52), followed by 60 mcg/kg/hour (Hour 52 to 56), and 30 mcg/kg/hour (Hour 56 to 60).  
A programmable peristaltic infusion pump will be used to ensure accurate delivery of brexanolone. 
Due to the risk of excessive sedation and sudden loss of consciousness, for the duration of the 
infusion, subjects will be monitored for hypoxia using continuous pulse oximetry equipped with an 
alarm, and will be assessed for excessive sedation by a healthcare provider every 2 hours during 
planned, non-sleep periods. Subjects must not be the primary caregiver of dependents and must be 
accompanied during any interactions with their child(ren) that occur during the infusion. 
If excessive sedation occurs at any time during the infusion, the infusion will be stopped until the 
symptoms resolve. The infusion may be resumed at the same or lower dose as clinically appropriate. 
The infusion will be immediately stopped if pulse oximetry reveals hypoxia. After an episode of 
hypoxia, the infusion should not be resumed. Subjects will remain confined through the completion of 
the brexanolone infusion and Hour 72 assessments. If deemed medically appropriate by the 
investigator, subjects may be discharged after completing the Hour 72 assessments. Subjects will be 
cautioned against engaging in potentially hazardous activities requiring mental alertness, such as 
driving, until any sedative effects have dissipated.  
For lactating subjects, the investigator and subject should weigh the developmental and health 
benefits of breastfeeding during the infusion against any potential adverse effects on the breastfed 
child from brexanolone or from the underlying maternal condition. Subjects may continue to 
breastfeed or express milk to feed their infant during the infusion if the benefit is deemed to outweigh 
the risk. During the study, a qualified lactation consultant will be made available to subjects upon 
request.  
Safety and efficacy assessments will be performed as outlined in the Schedule of Assessments (Table 
2); blood samples will be collected and will be analyzed for concentrations of brexanolone and may 
be analyzed for concentrations of brexanolone metabolites.   
Follow-up Period: Follow-up visits will be conducted through Day 30. Psychiatric review for 
worsening symptoms of depression will be available during the study and psychiatric follow-up after 
the end of the study will be arranged as needed by the Investigator and will be documented. 
An independent data safety monitoring board will monitor the clinical data for safety signals 
throughout the study. In order to perform their monitoring function, the board will have access to all 
safety data as necessary. 
Number of subjects (planned):  
Qualified subjects 15 to 17 years old (inclusive) will be enrolled in the study. Enrollment will 
continue until approximately 20 subjects have been treated with brexanolone. The planned sample 
size of 20 includes those subjects who received brexanolone as blinded study drug during earlier 
versions of the protocol when the study was a randomized, double-blind, placebo-controlled study.   

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Diagnosis and main criteria for inclusion:  
Inclusion criteria: 
1. Subject (and parent/guardian, per local regulations) has signed the appropriate informed 
consent form prior to any study-specific procedures being performed. 
2. Subject is ambulatory, female, and it is confirmed that she will be 15 to 17 years of age 
(inclusive) through completion of study drug infusion. 
3. Subject agrees to adhere to the study requirements.   
4.  (Removed) 
5. Subject has had a major depressive episode that began no earlier than the third trimester and 
no later than the first 4 weeks following delivery, as diagnosed by SCID-5. 
6. Subject has a 
 total score of ≥20 at screening and Day 1 (prior to initiation of the 
study drug infusion).  
7. Subject is ≤6 months postpartum at screening.   
8. Subject is willing at screening to delay the start of any new pharmacotherapy regimens, 
including antidepressant or antianxiety medication until the study drug infusion and 72-hour 
assessments have been completed. 
9. If the subject is taking medications administered to treat the symptoms of depression or 
anxiety (such as anxiolytics or antidepressants), these must be at a stable dose from 30 days 
prior to dosing until the completion of the 72-hour assessments. 
10. Subject agrees to use one of the following methods of contraception during participation in 
the study and for 30 days following the end of the study drug infusion, unless she is surgically 
sterile (either bilateral tubal ligation, bilateral oophorectomy and/or hysterectomy) or does not 
engage in sexual relations which carry a risk of pregnancy: 
• 
Combined oral, intravaginal, or transdermal (estrogen and progesterone containing) 
hormonal contraception associated with inhibition of ovulation 
• 
Oral, injectable, or implantable progesterone-only hormonal contraception associated 
with inhibition of ovulation 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
11. Subject agrees not to be the primary caregiver of any dependents during the infusion.  
Exclusion criteria: 
1. Subject has a positive pregnancy test at screening or Day 1 (prior to initiation of the study 
drug infusion).   
2. Subject’s most recent pregnancy resulted in a miscarriage, still birth, or neonatal death; or 
subject has terminated parental rights (eg, child has been placed for adoption).  
3. Subject has end stage renal disease.   
4. Subject is in hepatic failure. 
5. Subject is anemic (hemoglobin ≤10 g/dL).   

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6. Subject has untreated or inadequately treated hypothyroidism or hyperthyroidism. 
7. Subject has known allergy to progesterone or allopregnanolone.   
8. Subject has active psychosis per Investigator assessment.   
9. Subject has attempted suicide during current episode of PPD.   
10. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder.   
11. Subject has current/active alcohol or drug abuse (including benzodiazepines) within the 30 
days prior to screening as assessed by the Investigator.  A positive urine drug screen is 
exclusionary unless deemed by the investigator to reflect a prescribed medication. 
12. Subject has exposure to another investigational medication or device within 30 days prior to 
screening.   
13. Subject has previously participated in this study or any other study employing brexanolone, 
SAGE-217, ganaxolone, any other compound containing allopregnanolone, or has received 
treatment with ZULRESSOTM. 
14. Subject is investigative site personnel, sponsor personnel, or an immediate member of their 
family (spouse, parent, child, or sibling whether biological or legally adopted). 
15. Subject has received electroconvulsive therapy within 14 days prior to screening and/or plans 
to receive electroconvulsive therapy before the Study Day 7 visit. 
Study drug, Dosage and Mode of Administration:  
Brexanolone will be administered as a single, continuous, 60-hour intravenous (IV) infusion, 
administered according to the following dose regimen.  
Time point 
Day 1 
0 to 4 hours 
Day 1 
4 to 24 hours 
Day 2-3 
24 to 52 hours 
Day 3 
52 to 56 hours 
Day 3 
56 to 60 hours 
Dose 
30 mcg/kg/hour 60 mcg/kg/hour 90 mcg/kg/hour 60 mcg/kg/hour 30 mcg/kg/hour 
Reference therapy, dosage and mode of administration:  
This is an open-label study with no control group.  
Duration of participation: Each subject’s involvement is up to 47 days, including a maximum 
14-day Screening Period, a 3-day Treatment Period (60 hours of treatment and an additional 12 hours 
for completion of 72-hour assessments), and a Follow-up Period through Day 30 (±3 days). 
Criteria for evaluation: 
Primary Endpoint 
• Incidence of treatment-emergent adverse events 
Secondary Endpoints  
• PK parameters derived from plasma concentrations of brexanolone and, when 
appropriate, metabolites of brexanolone 
 
 
 

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Pharmacokinetic Set 
The PK Set is defined as all subjects in the Safety Set for whom at least one evaluable post-baseline 
PK sample is available. The PK parameters, which will include AUC0-60, AUC∞, Cmax, tmax, Css, and 
Cavg, will be summarized by descriptive statistics, including n, mean, SD, median, minimum, and 
maximum values, and listed by subject. In addition, PK data collected in this study may be combined 
with data from other studies in adolescent and adult subjects for population-PK and exposure-
response analyses.   
PK analyses may include determination of plasma concentration of brexanolone if a serious AE 
occurs. 
Sample Size Calculation 
No formal sample size calculation was made for this study. The planned sample size of 20 adolescent 
subjects treated with brexanolone should be appropriate to characterize the PK and safety profile. 
 

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Table 2: 
Schedule of Assessments 
Study Procedure 
Screening 
Period 
Treatment Period/Inpatient Stay 
(Day 1 to Day 3) 
Follow-up Period 
Visit Days D -14 to -1 
D1 
D1 
D1 
D1 
D1 
D1 
D2 
D2 
D2 
D3 
D3 
D3 
D7 
(±1d) 
D14 and/or 
ET 
(±2d) 
D21 
(±3d) 
D30 
(±3d) 
Hour 
 
H0* 
H2 
H4 
H8 
H12 
H24 
H30 
H36 
H48 
H54 
H60 
H72 
 
 
 
 
Informed consent process a 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCID-5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination b 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
Body weight 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Clinical laboratory 
assessments c 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
Drug and alcohol test d 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy teste 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Vital signs f 
X 
Xg 
X 
X 
X 
X 
Xg 
Xg 
X 
X 
X 
X 
X 
X 
Xg 
 
 
12-lead ECG  
X 
X 
 
 
 
 
 
 
 
 
 
 
X h 
 
X 
 
 

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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
PROTOCOL SIGNATURE PAGE .................................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................4 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............14 
TABLE OF CONTENTS ...............................................................................................................14 
LIST OF TABLES .........................................................................................................................17 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................18 
5. 
INTRODUCTION ......................................................................................................20 
5.1. 
Background of Postpartum Depression and Unmet Medical Need ............................20 
5.2. 
Brexanolone ................................................................................................................20 
5.3. 
Dose Justification ........................................................................................................21 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................22 
6.1. 
Primary Objective .......................................................................................................22 
6.2. 
Secondary Objective ...................................................................................................22 
6.3. 
 
6.4. 
Endpoints ....................................................................................................................22 
6.4.1. 
Primary Endpoint ........................................................................................................22 
6.4.2. 
Secondary Endpoints ..................................................................................................22 
6.4.3. 
 
7. 
INVESTIGATIONAL PLAN .....................................................................................24 
7.1. 
Overall Study Design ..................................................................................................24 
7.2. 
Number of Subjects ....................................................................................................25 
7.3. 
Treatment Assignment ................................................................................................25 
7.4. 
Dose Adjustment Criteria ...........................................................................................25 
7.5. 
Study Termination ......................................................................................................26 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................27 
8.1. 
Subject Inclusion Criteria ...........................................................................................27 

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8.2. 
Subject Exclusion Criteria ..........................................................................................28 
8.3. 
Subject Withdrawal, Early Discontinuation of Study Drug, and Study 
Termination .................................................................................................................28 
8.3.1. 
Subject Withdrawal from the Study ...........................................................................28 
8.3.2. 
Discontinuation of Study Drug ...................................................................................29 
8.3.3. 
Replacement of Subjects .............................................................................................29 
9. 
TREATMENT OF SUBJECTS ..................................................................................30 
9.1. 
Study Drug ..................................................................................................................30 
9.2. 
Prior/Concomitant Medications and Restrictions .......................................................30 
9.3. 
Treatment Adherence ..................................................................................................30 
9.4. 
Blinding and Randomization ......................................................................................31 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................32 
10.1. 
Description of Study Drug ..........................................................................................32 
10.2. 
Study Drug Packaging and Labeling ..........................................................................32 
10.3. 
Study Drug Storage .....................................................................................................32 
10.4. 
Preparation of Study Drug for Dosing ........................................................................33 
10.5. 
Study Drug Administration .........................................................................................33 
10.6. 
Study Drug Accountability .........................................................................................33 
10.7. 
Study Drug Handling and Disposal ............................................................................33 
11. 
ASSESSMENT OF EFFICACY AND PHARMACOKINETICS .............................34 
11.1. 
Efficacy Assessments .................................................................................................34 
 
 
 
 
 
 
 
 
 
 
 
 
11.2. 
Pharmacokinetic Assessments ....................................................................................35 
12. 
ASSESSMENT OF SAFETY .....................................................................................37 
12.1. 
Safety and Tolerability Assessments ..........................................................................37 
12.1.1. 
Demographic/Medical History ...................................................................................37 
12.1.2. 
Vital Signs ..................................................................................................................37 
12.1.3. 
Weight, Height and Body Mass Index ........................................................................37 

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12.1.4. 
Physical Examination .................................................................................................37 
12.1.5. 
Electrocardiogram .......................................................................................................38 
12.1.6. 
Laboratory Assessments .............................................................................................38 
12.1.6.1. 
Pregnancy Test ............................................................................................................38 
12.1.6.2. 
Drugs of Abuse and Alcohol ......................................................................................39 
12.1.6.3. 
Hormones and Exploratory Biochemistry ..................................................................39 
12.1.7. 
Continuous Pulse Oximetry ........................................................................................39 
12.1.8. 
Monitoring for Excessive Sedation ............................................................................39 
 
 
12.2. 
Adverse and Serious Adverse Events .........................................................................39 
12.2.1. 
Definition of Adverse Events .....................................................................................39 
12.2.1.1. 
Adverse Event .............................................................................................................39 
12.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................40 
12.2.2. 
Relationship to Study Drug ........................................................................................41 
12.2.3. 
Recording AEs ............................................................................................................41 
12.2.4. 
Pregnancy ...................................................................................................................42 
12.2.5. 
Overdose .....................................................................................................................42 
12.2.6. 
Immediate Reporting SAEs ........................................................................................42 
12.2.7. 
Adverse Events of Special Interest .............................................................................43 
13. 
STATISTICS ..............................................................................................................44 
13.1. 
Data Analysis Sets ......................................................................................................44 
13.2. 
Handling of Missing Data ...........................................................................................44 
13.3. 
General Considerations ...............................................................................................44 
13.4. 
Demographics and Baseline Characteristics ...............................................................44 
13.5. 
Preliminary Analyses ..................................................................................................44 
13.6. 
Efficacy Analyses .......................................................................................................45 
13.7. 
Safety Analyses ..........................................................................................................45 
13.7.1. 
Adverse Events ...........................................................................................................45 
13.7.2. 
Clinical Laboratory Evaluations .................................................................................45 
13.7.3. 
Physical Examinations ................................................................................................45 
13.7.4. 
Vital Signs ..................................................................................................................45 
13.7.5. 
12-Lead Electrocardiogram ........................................................................................45 
13.7.6. 
Prior and Concomitant Medications ...........................................................................45 

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13.8. 
Determination of Sample Size ....................................................................................46 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................47 
14.1. 
Audits and Inspections ................................................................................................47 
14.2. 
Institutional Review Board/ Independent Ethics Committee .....................................47 
14.3. 
Data Safety Monitoring Board ....................................................................................47 
14.4. 
Study Monitoring ........................................................................................................47 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................49 
16. 
ETHICS ......................................................................................................................50 
16.1. 
Ethics Review .............................................................................................................50 
16.2. 
Ethical Conduct of the Study ......................................................................................50 
16.3. 
Written Informed Consent ..........................................................................................50 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................51 
17.1. 
Inspection of Records .................................................................................................51 
17.2. 
Retention of Records ..................................................................................................51 
17.3. 
Confidentiality ............................................................................................................51 
18. 
PUBLICATION POLICY ..........................................................................................53 
19. 
REFERENCES ...........................................................................................................54 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Schedule of Assessments ............................................................................................11 
Table 3: 
Abbreviations and Specialist Terms ...........................................................................18 
Table 4: 
Infusion Rate ...............................................................................................................33 
Table 5: 
Summary of Laboratory Analytes ..............................................................................38 
 

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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 3: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
AE 
adverse event 
AESI 
adverse event of special interest 
 
 
 
 
 
 
CS 
clinically significant  
 
 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, fifth 
edition  
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
  
 
ET 
early termination 
GABAA 
γ-aminobutyric acid-ligand gated chloride channel 
GCP 
Good Clinical Practice 
 
 
 
 
ICD 
International Classification of Diseases 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
intravenous 
 
 
MDD 
major depressive disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
pharmacokinetic(s) 
PPD 
postpartum depression 
SAE 
serious adverse event 

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Abbreviation or Specialist Term 
Explanation 
SAP 
statistical analysis plan 
SBECD 
sulfobutylether-β-cyclodextrin 
SCID-5 
Structured Clinical Interview for DSM-5 Axis I Disorders 
SD 
standard deviation 
SUSARs 
suspected unexpected serious adverse reactions 
TEAE 
treatment-emergent adverse event 
 

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5. 
INTRODUCTION 
5.1. 
Background of Postpartum Depression and Unmet Medical Need 
Postpartum depression (PPD) is a serious mood disorder estimated to affect approximately 10 to 
20 percent of women giving birth globally. In the United States, estimates of new mothers 
identified with PPD each year vary by state from 8 to 20 percent with an overall average of 11.5 
percent (Ko et al 2017). Postpartum depression is defined in both the International Classification 
of Diseases (ICD)-10 and Diagnostic and Statistical Manual of Mental Disorders (DSM-5 2013) 
as a major depressive episode in the postpartum period with marked impairment in functioning. 
PPD often co-occurs with anxiety. PPD is a leading cause of maternal mortality (Savitz 2011) 
and, by affecting maternal functioning, poses serious risks to the emotional, cognitive, 
behavioral, and physical development of the infant and siblings (CPS 2004; Noorlander 2008).  
Findings from several studies implicate that peripartum fluctuations in reproductive hormones 
(in particular, the major progesterone metabolite, allopregnanolone) have a pivotal 
pathophysiological role in PPD. There is no evidence that the pathophysiology of PPD in 
adolescents differs from that in adults. 
Current standard of care for PPD includes pharmacological therapies, most often antidepressants 
approved for major depressive disorder (MDD), combined with counseling, behavioral, and other 
nonpharmacological interventions (Altshuler 2001). While tricyclic antidepressants and/or 
selective serotonin reuptake inhibitors (SSRIs) are both commonly used, SSRIs tend to be 
preferred due to better safety data while breastfeeding (Altshuler 2001). However, the evidence 
for efficacy of MDD antidepressants in PPD is generally based on data from the MDD 
population (Austin 2013). Limited randomized data are available evaluating the effectiveness of 
MDD antidepressants in PPD (De Crescenzo, 2014). Thus, based on the level of available 
evidence, there is a considerable need for improved pharmacological therapy for PPD.   
Allopregnanolone is a potent positive allosteric modulator of synaptic and extrasynaptic 
γ-aminobutyric acid-ligand gated chloride channel (GABAA) receptors. Plasma allopregnanolone 
concentrations rise in concert with progesterone throughout pregnancy, reaching the highest 
physiological concentrations in the third trimester (Maguire 2009). After childbirth, these 
concentrations decrease abruptly (Nappi 2001). Failure of GABAA receptors to adapt to these 
changes at parturition has been postulated to have a role in triggering postpartum depression 
(Maguire 2008). Allopregnanolone and pharmacologically similar compounds have been shown 
to have profound effects on anxiety and depression in animal models (Paul 1992; Maguire 2008). 
5.2. 
Brexanolone 
The brexanolone drug product is a proprietary formulation of brexanolone drug substance (also 
referred to as allopregnanolone) and excipients. Allopregnanolone is an endogenous, naturally 
occurring neuroactive steroid formed in the corpus luteum of the ovary, adrenal cortex, and 
central nervous system (Holzbauer 1985; Paul 1992; Ottander 2005). Allopregnanolone is a 
metabolite of progesterone created by the actions of 5-α reductase and 3-α hydroxy-steroid 
dehydrogenase. Allopregnanolone is a potent positive allosteric modulator of both synaptic and 
extra-synaptic GABAA receptors.   

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Nonclinical toxicology studies largely illustrate the sedative and anesthetic effects of 
allopregnanolone and/or brexanolone at higher equivalent doses than the proposed dose for the 
current study. Pharmacokinetic data in animals indicate a short half-life of brexanolone and rapid 
clearance with a moderate volume of distribution and cerebral levels higher than plasma. Clinical 
evidence to date demonstrates a clinically meaningful improvement in depressive symptoms in 
subjects with PPD following a 60-hour infusion of brexanolone compared with placebo. 
Brexanolone (brand name ZULRESSOTM) was approved by the US Food and Drug 
Administration on 19 March 2019 for the treatment of PPD in adults. Refer to the Investigator’s 
Brochure for detailed description of clinical and nonclinical studies with brexanolone. 
5.3. 
Dose Justification 
Sage has completed three placebo-controlled studies of brexanolone in adult women with PPD, 
all of which demonstrated statistical improvement in depressive symptoms for brexanolone as 
compared with placebo (see Investigator’s Brochure). All three studies employed a maintenance 
dose of 90 mcg/kg/h and this dose was well tolerated. Because the 90 mcg/kg/h maintenance 
dose was safe and effective in adult women with PPD, this dose has been chosen for this study of 
brexanolone in adolescents with PPD. 

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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
In previous Versions 1 through 3 of this protocol, subjects were randomly assigned to active or 
placebo study drug in a blinded manner. With the current Amendment 3/Version 4, the study has 
been converted to an open-label study where all subjects will receive brexanolone.  
This is a Phase 3, open-label study designed to evaluate the safety, tolerability, and PK, of 
brexanolone in adolescent female subjects diagnosed (by Structured Clinical Interview for DSM-
5 Axis I Disorders [SCID-5]) with PPD.  Subjects will be administered a single, 60-hour 
continuous IV infusion of brexanolone.  Each subject’s involvement is up to 47 days, including a 
maximum 14-day Screening Period, a 3-day Treatment Period (60 hours of treatment and an 
additional 12 hours for completion of 72-hour assessments), and a Follow-up Period through Day 
30 (± 3 days). 
The Screening Period begins with the informed consent process at the Screening Visit, which can 
occur on any one calendar day of a 14-day window (from Day -14 through Day -1, inclusive). 
Depending on age at screening and local regulations, subjects will either sign an informed 
consent form, or will sign an adolescent assent form and their parent/guardian will sign a 
parental informed consent form.  Subjects will undergo procedures at the Screening Visit to 
determine eligibility, including completion of the 
. 
The Treatment Period is the period from the start of the assessments on Day 1 prior to initiation 
of the brexanolone intravenous (IV) infusion through the 72-hour assessments on Day 3. The 60-
hour infusion will be administered as follows: 30 mcg/kg/hour (Hour 0 to 4), then 60 
mcg/kg/hour (Hour 4 to 24), then 90 mcg/kg/hour (Hour 24 to 52), followed by 60 mcg/kg/hour 
(Hour 52 to 56), and 30 mcg/kg/hour (Hour 56 to 60). A programmable peristaltic infusion pump 
will be used to ensure accurate delivery of brexanolone. 
Due to the risk of excessive sedation and sudden loss of consciousness, for the duration of the 
infusion, patients will be monitored for hypoxia using continuous pulse oximetry equipped with 
an alarm, and will be assessed for excessive sedation by a healthcare provider every 2 hours 
during planned, non-sleep periods. Subjects must not be the primary caregiver of dependents and 
must be accompanied during any interactions with their child(ren) that occur during the infusion. 
If excessive sedation occurs at any time during the infusion, the infusion will be stopped until the 
symptoms resolve. The infusion may be resumed at the same or lower dose as clinically 
appropriate. See Section 7.4 for details on dose adjustment criteria. The infusion will be 
immediately stopped if pulse oximetry reveals hypoxia. After an episode of hypoxia, the infusion 
should not be resumed.   
Subjects will remain confined through the completion of the brexanolone infusion and Hour 72 
assessments. If deemed medically appropriate by the investigator, subjects may be discharged 
after completing the Hour 72 assessments.  Subjects will be cautioned against engaging in 
potentially hazardous activities requiring mental alertness, such as driving, until any sedative 
effects have dissipated. 
For lactating subjects, the investigator and subject should weigh the developmental and health 
benefits of breastfeeding during the infusion against any potential adverse effects on the 

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breastfed child from brexanolone or from the underlying maternal condition. Subjects may 
continue to breastfeed or express milk to feed their infant during the infusion if the benefit is 
deemed to outweigh the risk. During the study, a qualified lactation consultant will be made 
available to subjects upon request. 
Safety and efficacy assessments will be performed as outlined in the Schedule of Assessments 
(Table 2). Blood samples will be collected and will be analyzed for concentrations of 
brexanolone and may be analyzed for concentrations of brexanolone metabolites. 
Follow-up visits will be conducted on Day 7, Day 14, Day 21, and Day 30.  Psychiatric review 
for worsening symptoms of depression will be available during the study and psychiatric follow-
up after the end of the study will be arranged as needed by the Investigator and will be 
documented. 
An independent data safety monitoring board (DSMB) will monitor the clinical data for safety 
signals throughout the study. In order to perform their monitoring function, the DSMB will have 
access to all safety data as necessary. 
7.2. 
Number of Subjects 
Qualified subjects 15 to 17 years old (inclusive) will be enrolled in the study. Enrollment will 
continue until approximately 20 subjects have been treated with brexanolone. The planned 
sample size of 20 includes those subjects who received brexanolone as blinded study drug during 
earlier versions of the protocol when the study was a randomized, double-blind, placebo-
controlled study.  
7.3. 
Treatment Assignment 
In this open-label study, subjects will be administered a single, continuous, 60-hour intravenous 
(IV) infusion of brexanolone starting on Day 1. 
7.4. 
Dose Adjustment Criteria 
If excessive sedation occurs at any time during the infusion, the infusion will be stopped until the 
symptoms resolve. The infusion may be resumed at the same or lower dose as clinically 
appropriate. The infusion will be immediately stopped if pulse oximetry reveals hypoxia. After 
an episode of hypoxia, the infusion should not be resumed.  
• For subjects who do not tolerate the 90 mcg/kg/hour dose, a reduction to 60 
mcg/kg/hour may be considered during the time period when the 90 mcg/kg/hour is 
scheduled to occur. 
Any sedation-related AEs that lead to dose interruption, termination, or reduction should be 
recorded as AEs of special interest (AESIs), and should be reported in an expedited manner as 
outlined in Section 12.2.7. 
If other intolerable adverse events occur, the infusion will be stopped until the symptoms resolve. 
The infusion may be resumed at the same or lower dose as clinically appropriate. 
A plasma sample for PK analysis should be drawn at the time that the dose is adjusted or the 
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7.5. 
Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons including the occurrence of AEs or other findings suggesting unacceptable risk to 
subjects, or for administrative reasons. In the event of study termination, Sage Therapeutics will 
provide written notification to the Investigator. Investigational sites must promptly notify their 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) and initiate 
withdrawal procedures for participating subjects.   

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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
The following inclusion criteria must be met for individuals to be eligible for the study.   
1. Subject (and parent/guardian, per local regulations) has signed the appropriate informed 
consent form prior to any study-specific procedures being performed. 
2. Subject is ambulatory, female, and it is confirmed that she will be 15 to 17 years old 
(inclusive) through completion of study drug infusion. 
3. Subject agrees to adhere to the study requirements.   
4. (Removed) 
5. Subject has had a major depressive episode that began no earlier than the third trimester 
and no later than the first 4 weeks following delivery, as diagnosed by SCID-5.   
6. Subject has a 
 total score of ≥20 at screening and Day 1 (prior to initiation of the 
study drug infusion).  
7. Subject is ≤6 months postpartum at screening.   
8. Subject is willing at screening to delay the start of any new pharmacotherapy regimens, 
including antidepressant or antianxiety medication until the study drug infusion and 72-
hour assessments have been completed. 
9. If the subject is taking medications administered to treat the symptoms of depression or 
anxiety (such as anxiolytics or antidepressants), these must be at a stable dose from 30 
days prior to dosing until the completion of the 72-hour assessments. 
10. Subject agrees to use one of the following methods of contraception during participation 
in the study and for 30 days following the end of the study drug infusion, unless she is 
surgically sterile (either bilateral tubal ligation, bilateral oophorectomy and/or 
hysterectomy) or does not engage in sexual relations which carry a risk of pregnancy: 
• Combined oral, intravaginal, or transdermal (estrogen and progesterone 
containing) hormonal contraception associated with inhibition of ovulation 
• Oral, injectable, or implantable progesterone-only hormonal contraception 
associated with inhibition of ovulation 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner 
11. Subject agrees not to be the primary caregiver of any dependents during the infusion. 

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8.2. 
Subject Exclusion Criteria 
Subjects will be excluded if they meet any of the following exclusion criteria.   
1. Subject has a positive pregnancy test at screening or Day 1 (prior to initiation of the study 
drug infusion).   
2. Subject’s most recent pregnancy resulted in a miscarriage, still birth, or neonatal death; or 
subject has terminated parental rights (eg, child has been placed for adoption).  
3. Subject has end stage renal disease.   
4. Subject is in hepatic failure. 
5. Subject is anemic (hemoglobin ≤10 g/dL).   
6. Subject has untreated or inadequately treated hypothyroidism or hyperthyroidism. 
7. Subject has known allergy to progesterone or allopregnanolone.   
8. Subject has active psychosis per Investigator assessment.   
9. Subject has attempted suicide during current episode of PPD.   
10. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder.   
11. Subject has current/active alcohol or drug abuse (including benzodiazepines) within the 
30 days prior to screening as assessed by the Investigator.  A positive urine drug screen is 
exclusionary, unless deemed by the investigator to reflect a prescribed medication. 
12. Subject has exposure to another investigational medication or device within 30 days prior 
to screening.   
13. Subject has previously participated in this study or any other study employing 
brexanolone, SAGE-217, ganaxolone, any other compound containing allopregnanolone, 
or has received treatment with ZULRESSOTM. 
14. Subject is investigative site personnel, sponsor personnel, or an immediate member of 
their family (spouse, parent, child, or sibling whether biological or legally adopted). 
15. Subject has received electroconvulsive therapy within 14 days prior to screening and/or 
plans to receive electroconvulsive therapy before the Study Day 7 visit. 
8.3. 
Subject Withdrawal, Early Discontinuation of Study Drug, and 
Study Termination 
The reasons for study drug discontinuation and/or subject withdrawal from the study must be 
recorded on the appropriate electronic Case Report Form (eCRF). The Investigator must notify 
the Sponsor and/or the Medical Monitor immediately when a subject has been 
discontinued/withdrawn for any reason, including withdrawal due to an AE. 
8.3.1. 
Subject Withdrawal from the Study 
Subjects may withdraw from the study at any time for any reason without compromising the 
subject’s medical care.  The Investigator will also withdraw subjects for safety, behavioral, 

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compliance, or administrative reasons or upon termination of the study.  Subjects who withdraw 
should, if possible, complete an early termination visit, which includes the assessments for the 
Day 14 visit (see Table 2). 
8.3.2. 
Discontinuation of Study Drug  
If it is necessary to discontinue the study drug earlier than planned, subjects should continue to 
remain in the study and be followed per protocol to capture safety and efficacy assessments for 
the duration of the study period. 
8.3.3. 
Replacement of Subjects 
Subjects who initiate the study drug infusion and who subsequently withdraw for any reason will 
not be replaced. 

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9. 
TREATMENT OF SUBJECTS 
9.1. 
Study Drug 
Subjects will be administered a single continuous 60-hour infusion of brexanolone. 
9.2. 
Prior/Concomitant Medications and Restrictions 
Subjects may receive standard of care for adolescent patients diagnosed with PPD, including 
psychosocial interventions. Any concomitant medication determined medically necessary for the 
welfare of the subject may be given at the discretion of the Investigator at any time during the 
study. Where feasible, changes to psychotropic medications may be made only as outlined in the 
paragraph below.   
Concomitant use of opioids, CNS depressants, such as benzodiazepines, or other drugs 
interacting with the GABAA receptor are permitted if on stable recommended dose but should be 
used with caution during infusions of brexanolone, as there may be an increased risk of sedation-
related events.  Subjects that are receiving medications administered to treat the symptoms of 
depression or anxiety (such as anxiolytics or antidepressants) must have been initiated at least 30 
days prior to dosing and must remain at a stable dose until completion of the 72-hour 
assessments.  Any new medication for depression or anxiety initiated after the 72-hour 
assessments are completed must be preceded by a discussion between the investigator and the 
Medical Monitor. 
Subjects on high doses of benzodiazepines may be at increased risk for sedation-like AEs if 
administered concomitantly with brexanolone. These subjects may be considered for eligibility 
based on specific discussions between the Investigator and the Medical Monitor. All patients 
should be monitored during the infusion for any events of excessive sedation. 
The following interventions will be recorded on the appropriate eCRF: 
• All medications taken from 60 days prior to informed consent through the final study 
visit 
• All psychoanaleptic and psycholeptic medications (including anxiolytics or 
antidepressants) taken in the previous 6 months prior to informed consent through the 
final study visit 
• All medications used to treat the current episode of PPD regardless of timing through 
the final study visit 
• All nonpharmacological interventions used to treat the current episode of PPD 
regardless of timing through the final study visit 
9.3. 
Treatment Adherence 
Study drug will be prepared by a pharmacist or designee, administered as a continuous IV 
infusion, and the dose actually received will be documented in the study record. There should be 
no adjustments in dosing except as described in Section 7.4. 

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9.4. 
Blinding and Randomization 
This is an open-label study. This study was previously conducted (in Protocol Versions 1 
through 3) as a randomized placebo-controlled double-blind study.  An independent DSMB will 
have access to all safety data as necessary. 

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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Description of Study Drug 
As supplied, the brexanolone drug product is a sterile, clear, colorless 5 mg/mL solution of 
brexanolone and 250 mg/mL sulfobutyl-ether-beta-cyclodextrin buffered with 10 mM citrate at a 
pH of 6.0, supplied in single-dose 20 mL vials for IV administration. The composition and 
pharmaceutical quality of the study drug will be maintained according to the current Good 
Manufacturing Practice and Good Clinical Practice (GCP) guidelines and available for review in 
the study medication documentation.   
10.2. 
Study Drug Packaging and Labeling 
Brexanolone will be provided to the sites.   
The product is aseptically processed, sterile filtered, and filled into 20 mL Type 1 parenteral 
glass vials with West FluroTec® coated stopper container closure systems, under current Good 
Manufacturing Practice conditions. Brexanolone is intended to be used as a single-use vial.   
Study drug labels with all required information and conforming to all applicable regulatory 
requirements will be prepared by the Sponsor.   
10.3. 
Study Drug Storage 
The investigator or designee should refer to the Pharmacy Manual for instructions on 
acknowledging receipt of study drug.  
Study drug vials should be stored under refrigerated conditions (2 to 8°C). The vials must be 
carefully stored safely and separately from other drugs. The study drug may not be used for any 
purpose other than the present study.   
The Investigator or designee will be responsible for ensuring appropriate storage, dispensing, 
inventory, and accountability of all clinical supplies.  An accurate, timely record of the 
disposition of all clinical supplies must be maintained. The supplies and inventory must be 
available for inspection by the designated representatives of the Sponsor or the Sponsor’s 
representatives on request, and must include the information below: 
• The identification of the subject to whom the drug was dispensed 
• The date(s) and quantity of the drug dispensed to the subject 
• The product lot/batch number 
The preparation of the study drugs must be documented on a ‘Drug Preparation and Dispensing 
Log Form’ or similar form.   
The drug inventory and any clinical supplies that have been destroyed must be documented.  
This documentation must include at least the information below or as agreed with the Sponsor: 
• The number of prepared units 
• The number of administered units 
• The number of unused units 

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• The number of units destroyed at the end of the study 
• The date, method, and location of destruction 
10.4. 
Preparation of Study Drug for Dosing 
The Pharmacist or designee will be responsible for preparing study drug (brexanolone) for 
subject dosing. The prepared admixture will be administered at room temperature.   
Refer to the Pharmacy Manual for specific instructions regarding requirements for IV bags and 
labeling, infusion sets, infusion preparation and administration instructions.   
10.5. 
Study Drug Administration  
Subjects will receive a 60-hour continuous IV infusion of brexanolone.   
The specific infusion dose of study drug will be calculated based on weight (obtained at 
screening) for each subject and administered according to the dose regimen in Table 4.   
Table 4: 
Infusion Rate 
Time point 
Day 1 
0 to 4 hours 
Day 1 
4 to 24 hours 
Day 2 to 3 
24 to 52 hours 
Day 3 
52 to 56 hours 
Day 3 
56 to 60 hours 
Dose 
30 mcg/kg/hour 
60 mcg/kg/hour 
90 mcg/kg/hour 
60 mcg/kg/hour 
30 mcg/kg/hour 
Dosing should begin in the morning (on Day 1) to avoid the dose increase to 90 mcg/kg/hour late 
in the day, and to avoid awakening subjects during the night for completion of study 
assessments.   
Refer to the Pharmacy Manual for complete details on preparation and administration. 
10.6. 
Study Drug Accountability 
The Pharmacist or designee will maintain accurate records of all investigational drug product 
supplies received, stored, dispensed, and discarded.  Accurate records will be kept regarding the 
volume of study drug used for each IV preparation, as well as the required infusion dose (or 
doses), and the date and time of preparation. Reasons for departure from the expected dosing 
regimen must be recorded. To satisfy regulatory requirements regarding drug accountability, all 
study medication needs to be reconciled in full.   
10.7. 
Study Drug Handling and Disposal 
The pharmacist or designee for drug accountability is to document the date and time of 
preparation of test article and for which subject the study drug was intended (ie, record subject 
initials and birth date or another unique identifier).   
At the end of the study, any unused study drug will be retained or returned to the Sponsor for 
destruction or destroyed locally per the Sponsor’s directions; disposition of study drug will be 
documented.   

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The plasma samples will be drawn from the arm contralateral to that used for study drug 
administration. Instructions on sample collection, processing methods, storage, and shipping 
conditions for subject-specific plasma PK kits will be provided in the study laboratory manual. 

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12.
ASSESSMENT OF SAFETY
12.1. 
Safety and Tolerability Assessments
Safety and tolerability of study drug will be evaluated by incidence of treatment-emergent 
adverse events as well as changes from baseline in vital signs measurements, clinical laboratory 
measures, ECGs, concomitant medication usage, and
   
The following assessments will be performed at the time points specified in the Schedule of 
Assessments (Table 2). 
12.1.1. 
Demographic/Medical History 
Medical history will be collected and listed by subject. Age, race, and ethnic origin will be 
recorded. The diagnosis of PPD will be determined using the SCID-5. Subjects will be 
specifically asked about the following depression, anxiety, and other diagnoses per DSM-5: 
generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress 
disorder, major depressive disorder, persistent depressive disorder, postpartum depression, 
bipolar disorder, seasonal affective disorder, psychotic depression, premenstrual dysphoric 
disorder, situational depression, atypical depression, menstrual migraine, other Axis 1 and Axis 2 
disorders, pregnancy history (including number of pregnancies, number of births, methods of 
delivery, and birth complications) and PPD episodes.   
12.1.2. 
Vital Signs 
Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure. Heart 
rate and blood pressure to be collected in supine position at all scheduled time points as well as 
in the standing position at specific time points listed in Table 2. 
Additionally, respiratory rate, heart rate, and blood pressure should be collected for any subject 
that experiences an AESI (defined in Section 12.2.7) as soon as is feasible after the onset of the 
event and recorded as unscheduled in the eCRF. Collection of vital signs should occur per local 
clinical practice, at a minimum until the subject regains consciousness. 
12.1.3. 
Weight, Height and Body Mass Index 
Body weight and height will be measured; body mass index will be programmatically calculated 
in the eCRF.   
12.1.4. 
Physical Examination 
Physical examinations of major body systems will be undertaken and recorded. Any clinically 
significant finding present at the post-screening physical examination that was not present at or 
worsened since the screening examination will be documented as an AE. Major body systems to 
be included in the screening physical examination are head, eye, ear, nose and throat, heart, 
lungs, abdomen, and extremities; as well as cognitive and neurological examination, and mental 
status examination. Post-screening physical examinations may be symptom directed. 

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12.1.5. 
Electrocardiogram 
Twelve-lead ECGs will be performed. The Investigator will record if the ECG is normal; 
abnormal, not clinically significant; or abnormal, clinically significant (CS). If Abnormal, details 
of the abnormality will be provided (ie, first-degree AV block, bundle branch block). The 
standard intervals (heart rate, PR, QRS, QT, and QTcF) will be recorded for all ECGs.   
12.1.6. 
Laboratory Assessments 
Blood samples will be collected for hematology, serum chemistry, and coagulation. Analytes to 
be evaluated are summarized in Table 5.  
All blood samples will be sent to the central laboratory.  Subjects may be considered eligible for 
the study based on results reported by a local laboratory; however, screening samples must also 
be sent to the central laboratory. Both local and central screening laboratories must adhere to the 
visit window provided in Table 2.   
Table 5: 
Summary of Laboratory Analytes 
Hematology 
complete blood count (red blood cells, white blood cells with differentiation 
and absolute values, hemoglobin, hematocrit, reticulocytes, and platelets) 
Coagulation 
(at Screening 
only) 
activated partial thromboplastin time, prothrombin time, and international 
normalized ratio 
Biochemistry 
serum electrolytes (sodium, potassium, chloride, bicarbonate or total carbon 
dioxide, calcium, and phosphorus) renal function tests (creatinine and blood 
urea nitrogen); liver function tests (total bilirubin, alkaline phosphatase, 
aspartate aminotransferase, alanine aminotransferase, and gamma glutamyl 
transferase); thyroid stimulating hormone; total protein; albumin and glucose 
(fasting or non-fasting) 
All clinical laboratory test results outside the reference range will be interpreted by the 
Investigator as abnormal, not clinically significant; or abnormal, CS.  Screening results 
considered abnormal and CS at the Screening Visit may make the subject ineligible for the study 
pending review by the Investigator or Medical Monitor. Clinically significant abnormal results 
after screening will be considered and reported as AEs.  
12.1.6.1. Pregnancy Test 
All subjects will be tested for pregnancy by serum human chorionic gonadotropin at the 
Screening Visit and by serum or urine human chorionic gonadotropin at other scheduled time 
points.  Subjects may be considered eligible for the study based on serum pregnancy test results 
reported by a local laboratory; however, screening samples must also be sent to the central 
laboratory. Both local and central screening laboratories must adhere to the visit window 
provided in Table 2.   

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product. In clinical studies, an AE can include an undesirable medical condition occurring at any 
time, including baseline or washout periods, even if no study treatment has been administered. 
A treatment-emergent adverse event (TEAE) is an AE that occurs after the first administration of 
any study drug.  The term study drug includes any Sage Therapeutics study drug, a comparator, 
or a placebo administered in a clinical trial. 
Laboratory abnormalities and changes from baseline in vital signs (including ECGs) are 
considered AEs if they result in discontinuation or interruption of study treatment, are clinically 
significant and require therapeutic medical intervention, meet protocol specific criteria (if 
applicable) and/or if the Investigator considers them to be clinically significant and adverse 
events. Laboratory values and vital signs that meet the criteria for a serious adverse event (SAE) 
should be reported in an expedited manner.  
Laboratory values and vital signs that are clearly attributable to another AE do not require 
discrete reporting (e.g. electrolyte disturbances in the context of dehydration, chemistry and 
hematologic disturbances in the context of sepsis, etc.). 
12.2.1.2. Serious Adverse Event (SAE) 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is immediately life-threatening (Note: The term “life threatening” refers to an event in 
which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it were more severe.) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
An SAE may also be any other medically important event that, in the opinion of the Investigator, 
may jeopardize the subject or may require medical intervention to prevent one of the outcomes 
listed above. (Examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization). 
All SAEs that occur from the signing of the consent form(s) through the end of study 
participation, whether or not they are related to the study drug, must be recorded on forms 
provided by Sage Therapeutics. Serious adverse events occurring after the subject’s final study 
visit should be reported to the Sponsor or Sponsor’s designee only if the investigator considers 
the SAE to be related to study drug. 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the subject is hospitalized. The site must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or on a waiting list to be scheduled) prior to obtaining the subject’s 
consent to participate in the study. 

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• The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress, in the opinion of the 
Investigator, between the subject’s consent to participate in the study and at the time 
of the procedure or treatment.  
• The prescheduled or elective procedure or a routinely scheduled treatment is the sole 
reason for the intervention or hospital admission.  
If a subject is hospitalized due to local requirements for administration of the study treatment, the 
hospitalization should not be considered an SAE unless one of the requirements above is met. 
12.2.2. 
Relationship to Study Drug 
The Investigator must make the determination of relationship to the study drug for each AE (not 
related, possibly related or probably related).  The Investigator should decide whether, in his or 
her medical judgment, there is a reasonable possibility that the event may have been caused by 
the study drug. If no valid reason exists for suggesting a relationship, then the AE should be 
classified as “not related.” If there is any valid reason, even if undetermined, for suspecting a 
possible cause-and-effect relationship between the study drug and the occurrence of the AE, then 
the AE should be considered at least “possibly related.”   
 
Not 
Related: 
No relationship between the experience and the administration of study drug; related to 
other etiologies such as concomitant medications or subject’s clinical state. 
Possibly 
Related: 
A reaction that follows a plausible temporal sequence from administration of the study 
drug and follows a known response pattern to the suspected study drug.  
The reaction might have been produced by the subject’s clinical state or other modes 
of therapy administered to the subject, but this is not known for sure. 
Probably 
Related: 
A reaction that follows a plausible temporal sequence from administration of the study 
drug and follows a known response pattern to the suspected study drug.  
The reaction cannot be reasonably explained by the known characteristics of the 
subject’s clinical state or other modes of therapy administered to the subject. 
If the relationship between the AE/SAE and the study drug is determined to be “possible” or 
“probable”, the event will be considered related to the study drug for the purposes of expedited 
regulatory reporting. 
12.2.3. 
Recording AEs 
Information about AEs will be collected from the signing of the consent form(s) until the final 
visit of the study for that subject.  All AEs will be followed until the event is resolved, 
considered stable, or the Investigator determines the event is no longer clinically significant.   
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site.  The AE term should be reported in standard medical terminology when 
possible.  For each AE, the Investigator will evaluate and report the onset (date and time), 
resolution or clinical plateau (date and time), intensity, causality, action taken, outcome, and 
whether or not it caused the subject to discontinue the study drug or withdraw early from the 
study.   

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Intensity will be assessed according to the following scale: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities) 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.2.1.2. An AE of severe intensity 
may not be considered serious. 
12.2.4. 
Pregnancy 
Based on findings from animal studies of other drugs that enhance GABAergic inhibition, 
brexanolone may cause fetal harm. Should a pregnancy occur, it must be reported within 24 
hours of identification and recorded on the Sage Therapeutics pregnancy form. Pregnancy in 
itself is not regarded as an AE unless there is a suspicion that a study drug may have interfered 
with the effectiveness of a contraceptive medication. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented even if the subject was 
discontinued from the study. All reports of congenital abnormalities/birth defects are SAEs. 
Spontaneous miscarriages should also be reported and handled as SAEs. Elective abortions 
without complications should not be handled as AEs. 
12.2.5. 
Overdose 
An overdose is any dose of study treatment given to a subject or taken by a subject that exceeds 
the dose described in protocol. Overdoses are not considered AEs and should not be recorded as 
an AE on the eCRF; however, all overdoses must be recorded on an Overdose form and sent to 
Sage or designee within 24 hours of the site becoming aware of the overdose. An overdose must 
be reported to Sage or designee even if the overdose does not result in an AE. If an overdose 
results in an AE, the AE must be recorded. 
12.2.6. 
Immediate Reporting SAEs 
All SAEs (regardless of causality) will be recorded from the signing of the consent form(s) until 
the final visit of the study for that subject. Serious adverse events occurring after the subject’s 
final study visit should be reported to the Sponsor or Sponsor’s designee only if the investigator 
considers the SAE to be related to study drug. 
All SAEs must be reported to Sage Therapeutics, or designee, immediately. A written account of 
the SAE must be sent to Sage Therapeutics within 24 hours of the first awareness of the event by 
the Investigator and/or his/her staff. The Investigator must complete, sign and date the SAE 
report form, verify the accuracy of the information recorded on the SAE report form with the 
corresponding source documents, and send a copy to Sage Therapeutics, or designee.   
Additional follow-up information, if required or available, must be sent to Sage Therapeutics, or 
designee. within 24 hours of receipt; a follow-up SAE form should be completed and placed with 
the original SAE information and kept with the appropriate section of the eCRF and/or study file.   

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Sage Therapeutics, or designee, is responsible for notifying the relevant regulatory authorities of 
certain events. It is the Principal Investigator’s responsibility to notify the IRB/EC of all SAEs 
that occur at his or her site. Investigators will also be notified of all suspected, unexpected, 
serious, adverse reactions (SUSARs) that occur during the clinical study or from other studies 
with brexanolone. Each site is responsible for notifying its ethics committee of these SUSARs. 
Sage or designee will submit SUSARs  to regulatory agencies according to local law.  
12.2.7. 
Adverse Events of Special Interest 
The following events are considered AESIs and should be reported on the AESI form within 72 
hours.  
• Excessive sedation  
• Loss of consciousness 
• Any sedation-related AE that leads to dose reduction, interruption, or termination 
If the AESI also qualifies as an SAE an SAE form should be submitted per the guidelines per 
Section 12.2.6.  

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13. 
STATISTICS 
Planned statistical analyses are provided in brief below. A separate statistical analysis plan (SAP) 
will provide a detailed description of the analyses to be performed in the study. The SAP will be 
finalized and approved prior to database lock. 
13.1. 
Data Analysis Sets 
The Efficacy Set will be defined as all subjects who initiate study drug infusion and have at least 
one post-baseline efficacy evaluation. Efficacy data will be analyzed using appropriate 
descriptive statistics and pre-specified statistical methods; subject listings will be provided for all 
efficacy data.  
The Safety Set, defined as all subjects administered study drug, will be used to provide 
descriptive summaries of safety data. 
The PK Set is defined as all subjects in the Safety Set for whom at least one evaluable post-
baseline PK sample is available. 
13.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data. All subjects will be used in the analyses, as 
per the analysis sets, using all non-missing data available. 
13.3. 
General Considerations 
Except where noted, baseline is defined as the last measurement prior to the start of study drug 
infusion.   
Continuous endpoints will be summarized with number (n), mean, standard deviation (SD), 
median, minimum, and maximum. In addition, change from baseline values will be calculated at 
each time point and summarized descriptively. For categorical endpoints, descriptive summaries 
will include counts and percentages.   
13.4. 
Demographics and Baseline Characteristics 
Demographic data, such as age, race, and ethnicity, and baseline characteristics, such as height, 
weight, and body mass index, will be summarized using the Safety Set.   
Pregnancy results will be listed but not summarized.   
Medical history will be listed by subject. Medical history will be coded using Medical Dictionary 
for Regulatory Activities (MedDRA) Version 19.1 or higher. 
13.5. 
Preliminary Analyses 
In order to conduct the preliminary analyses, the sponsor may lock and unblind the data from 
subjects enrolled during earlier versions of the protocol when the study was a randomized, 
double-blind, placebo-controlled study, before the open-label study finishes.  

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13.6. 
Efficacy Analyses 
The change from baseline in 
total score and binary efficacy endpoints, including 
Responder and Remission, will be appropriately summarized.   
13.7. 
Safety Analyses 
13.7.1. 
Adverse Events 
The analysis of AEs will be based on the concept of TEAEs, as defined in Section 12.2.1.1. The 
incidence of TEAEs will be summarized overall and by MedDRA Version 19.1 or higher, 
System Organ Class, and preferred term.  In addition, summaries will be provided by severity 
(mild, moderate, severe) and by causality (related, not related) to study drug.   
TEAEs leading to study drug discontinuation, study withdrawal, or dose modifications will also 
be summarized. All SAEs will be summarized. 
All AEs and SAEs (including those with onset or worsening before the start of study drug) 
through the final study visit will be listed.   
13.7.2. 
Clinical Laboratory Evaluations 
Clinical laboratory results will be listed by subject and timing of collection. Mean changes from 
baseline in clinical laboratory measures will be evaluated.   
13.7.3. 
Physical Examinations 
The study date of physical examinations will be listed. Any clinically significant finding present 
at the post-screening physical examination that was not present at or worsened since the 
screening examination will be documented as an AE. 
13.7.4. 
Vital Signs 
Vital sign results will be listed by subject and timing of collection. Mean changes from baseline 
(predose) in vital signs will be evaluated by time point.   
13.7.5. 
12-Lead Electrocardiogram 
The following ECG parameters will be listed for each subject: heart rate, PR, QRS, QT, and 
QTcF. Any clinically significant abnormalities or changes in ECGs should be listed as an AE. 
ECG findings will be listed by subject and visit.   
13.7.6. 
Prior and Concomitant Medications 
Medications will be recorded at each study visit during the study and will be coded using World 
Health Organization-Drug dictionary enhanced September 2016, or later.   
Those medications taken prior to the initiation of the study drug infusion but not continuing 
beyond the initiation of the study drug infusion will be denoted “Prior”. Those medications taken 
prior to the initiation of the study drug infusion and continuing beyond the initiation of the study 
drug infusion will be denoted “Prior” and “Concomitant (ie, those with a start date before the 
first dose of study drug that are ongoing or with a stop date on or after the first dose of study 

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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Audits and Inspections 
Authorized representatives of Sage Therapeutics, a regulatory authority, an IEC or an IRB may 
visit the site to perform audits or inspections, including source data verification.  The purpose of 
a Sage Therapeutics or designee audit or inspection is to systematically and independently 
examine all study-related activities and documents to determine whether these activities were 
conducted, and data were recorded, analyzed, and accurately reported according to the protocol, 
GCP guidelines of the International Council on Harmonisation (ICH), and any applicable 
regulatory requirements.  The Investigator should contact Sage Therapeutics immediately if 
contacted by a regulatory agency about an inspection.   
14.2. 
Institutional Review Board/ Independent Ethics Committee  
The Principal Investigator must obtain IRB/IEC approval for the investigation.  Initial IRB/IEC 
approval, and all materials approved by the IRB/IEC for this study, including the consent 
form(s), and recruitment materials, must be maintained by the Investigator and made available 
for inspection.   
14.3. 
Data Safety Monitoring Board 
An independent DSMB will monitor the clinical data for safety signals throughout the study.  In 
order to perform their monitoring function the DSMB will have access to all safety data as 
necessary. 
The composition and procedures for the board will be described in a separate DSMB Charter. 
14.4. 
Study Monitoring 
A representative of Sage Therapeutics or designee will visit the investigational study site to:   
• Determine the adequacy of the facilities 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of Sage Therapeutics or designee or its 
representatives. This will be documented in a Clinical Study Agreement between 
Sage Therapeutics and the Investigator.   
During the study, a monitor from Sage Therapeutics or designee will have regular contacts with 
the investigational site in order to: 
• Provide information and support to the Investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the eCRFs, and that study drug accountability checks are being 
performed 
• Perform source data verification. This includes a comparison of the data in the eCRFs 
with the subject’s medical records at the hospital or practice, and other records 

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relevant to the study. This will require direct access to all original records for each 
subject (eg, clinic charts). 
• Record and report any protocol deviations not previously sent to Sage Therapeutics or 
designee; and 
• Confirm AEs, AESIs, and SAEs have been properly documented on eCRFs and 
confirm AESIs and SAEs have been forwarded to Sage Therapeutics or designee in 
the protocol specified timelines and those SAEs that met criteria for reporting have 
been forwarded to the IRB.   
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 

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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Investigator and institution will permit study-related monitoring, audits, IRB/IEC review, 
and regulatory inspections as requested by Food and Drug Administration or other regulatory 
agencies, the Sponsor, or the Sponsor’s designee, including direct access to source 
data/documents (ie, original medical records, laboratory reports, hospital documents, progress 
reports, signed consent form(s)) in addition to eCRFs.   
Quality assurance and quality-control systems with written standard operating procedures will be 
followed to ensure this study will be conducted and data will be generated, documented 
(recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory 
requirements.   
The site’s dedicated study monitor will arrange to visit the Investigator at regular intervals during 
the study. The monitoring visits must be conducted according to the applicable ICH and GCP 
guidelines to ensure protocol adherence, quality of data, drug accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities. 
During these visits, eCRFs and other data related to the study will be reviewed and any 
discrepancies or omissions will be identified and resolved. The study monitor will be given 
access to study-relevant source documents (including medical records) for purposes of source 
data verification. 
During and/or after completion of the study, quality-assurance officers named by Sage 
Therapeutics or the regulatory authorities may wish to perform on-site audits. The Investigator is 
expected to cooperate with any audit and provide assistance and documentation (including 
source data) as requested. 
Quality control will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. 
Agreements made by the Sponsor with the Investigator/institution and any other parties involved 
with the clinical study will be in writing in a separate agreement. 

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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the consent form(s), must be approved or 
given a favorable opinion in writing by an IRB or IEC as appropriate. The Investigator must 
submit written approval to Sage Therapeutics or designee before he or she can enroll any subject 
into the study.   
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit subjects for the study. The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB or IEC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the study drug. 
Sage Therapeutics or designee will provide this information to the Principal Investigator.   
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines.   
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and its most recent amendment (2008) and are consistent with ICH/GCP 
and other applicable regulatory requirements.   
16.3. 
Written Informed Consent 
All subjects will complete an informed consent process. Depending on age at screening and local 
regulations, the process will either require the subject to sign an informed consent form, or for 
the subject to sign an adolescent assent form and a parent/guardian to sign a parental informed 
consent form. 
The Investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risk, and benefit of the study.  Subjects must also 
be notified that they are free to discontinue from the study at any time.  The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided 
before completing the informed consent process.   
The consent forms, as specified by the clinical site’s IRB/IEC, must follow the Protection of 
Human Subjects regulations listed in the Code of Federal Regulations, Title 21, Part 50. 
The subject’s signed and dated informed consent must be obtained before conducting any study 
procedures.   
The Investigator(s) must maintain the original, signed consent form(s).  A copy of the signed 
consent form(s) must be given to the subject and/or parent/guardian.   

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17. 
DATA HANDLING AND RECORDKEEPING 
Procedures for data handling (including electronic data) used in this protocol will be documented 
in a Data Management Plan.   
Electronic CRFs will be completed for each study subject.  It is the Investigator’s responsibility 
to ensure the accuracy, completeness, and timeliness of the data reported in the subject’s eCRF.  
Source documentation supporting the eCRF data should indicate the subject’s participation in the 
study and should document the dates and details of study procedures, AEs, and subject status.   
The Investigator will have access to the electronic data capture system and will receive a copy of 
the subject eCRF data at the end of the study.  For subjects who discontinue or terminate from 
the study, the eCRFs will be completed as outlined in the eCRF completion guidelines.  
17.1. 
Inspection of Records 
Sage Therapeutics or designee will be allowed to conduct site visits to the investigational 
facilities for the purpose of monitoring any aspect of the study.  The Investigator agrees to allow 
the monitor to inspect the drug storage area, study drug stocks, drug accountability records, 
subject charts and study source documents, and other records related to study conduct.   
17.2. 
Retention of Records 
The Investigator must maintain all documentation relating to the study for a period of 2 years 
after the last marketing application approval or, if not approved, 2 years following the 
discontinuance of the test article for investigation.  If it becomes necessary for Sage Therapeutics 
or the Regulatory Authority to review any documentation relating to the study, the Investigator 
must permit access to such records.  If the Investigator withdraws from the responsibility of 
keeping the study records, custody must be transferred to an appropriate person willing to accept 
the responsibility.  The Sponsor must be notified in writing if a custodial change occurs.   
17.3. 
Confidentiality 
To maintain subject privacy, all eCRFs, study reports and communications will identify the 
subject by the assigned subject number.  The Investigator will grant monitor(s) and auditor(s) 
from the Sponsor or its designee and regulatory authority(ies) access to the subject’s original 
medical records for verification of data gathered on the eCRFs and to audit the data collection 
process.  The subject’s confidentiality will be maintained and will not be made publicly available 
to the extent permitted by the applicable laws and regulations.   
Subjects will be notified that registration information, results, and other information about this 
study will be submitted to ClinicalTrials.gov or other clinical trial database as required by local 
regulation, a publicly available trial registry database; however, protected health information of 
individual subjects will not be used.   
All information regarding the study drug supplied by Sage Therapeutics to the Investigator is 
privileged and confidential information.  The Investigator agrees to use this information to 
accomplish the study and will not use it for other purposes without consent from the Sponsor.  It 
is understood that there is an obligation to provide the Sponsor with complete data obtained 
during the study.  The information obtained from the clinical study will be used towards the 

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development of the study drug and may be disclosed to regulatory authorities, other 
Investigators, corporate partners, or consultants, as required.   

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18. 
PUBLICATION POLICY 
All information concerning brexanolone is considered confidential and shall remain the sole 
property of Sage Therapeutics.  The Investigator agrees to use this information only in 
conducting the study and shall not use it for any other purposes without written approval from 
Sage Therapeutics.  No publication or disclosure of study results will be permitted except as 
specified in a separate, written agreement between Sage Therapeutics and the Investigator.