Clinical trial NCT03665038
Conditions: Post Partum Depression
Sponsor: Sage Therapeutics
Start date: 2018-09-07; Completion date: 2021-01-08
Enrollment: 28 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a multi-center study evaluating the safety, tolerability, and pharmacokinetics of brexanolone in the treatment of adolescent female participants with postpartum depression (PPD).

Detailed description:

Arms: arm 1: Participants will receive a 60-hour single continuous IV infusion of brexanolone, at 30 mcg/kg/hour (0 to 4 hours), at 60 mcg/kg/hour (4 to 24 hours), at 90 mcg/kg/hour (24 to 52 hours), followed by a taper to 60 mcg/kg/hour (52 to 56 hours), and 30 mcg/kg/hour (56 to 60 hours) during the study.
Interventions: intervention 1: Brexanolone
Intervention descriptions: intervention 1: Administered as IV infusion.

Protocol documents:
Prot_000.pdf: 
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  






Protocol 547-PPD-304 
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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 
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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 
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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 
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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.   
 





SAP_001.pdf: 
Official Title: 
A Multicenter, Open-label Study Evaluating the Safety, Tolerability
and Pharmacokinetics  of Brexanolone in the Treatment of   Adolescent  
Subjects With Postpartum Depression
NCT Number: 
NCT03665038
Document Date: 
SAP Version 1.0: 10 March 2021


Clinical Study Report 
547-PPD-304
16.1 Study Information 
1 
9.
DOCUMENTATION OF STATISTICAL METHODS
547-PPD-304 SAP v1.0 05 March 2021


Statistical Analysis Plan (Methods) 
Sage Therapeutics, Inc. 
Study 547-PPD-304 
CONFIDENTIAL 
1 
 
SAGE THERAPEUTICS INCORPORATED  
Statistical Analysis Plan 
Methods 
Protocol Number 547-PPD-304 
A Multicenter, Open-label Study Evaluating the Safety, Tolerability, and 
Pharmacokinetics of Brexanolone in the Treatment of Adolescent Female Subjects 
with Postpartum Depression 
 
 
Author of SAP: 
, PhD 
 
 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, Massachusetts 02142 
Version: Version 1.0 
Date of SAP: 05 March 2021 
 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written consent of 
Sage Therapeutics Incorporated is strictly prohibited except to the extent required under applicable laws or regulations.  
Persons to whom the information is disclosed must be informed that the information is confidential and may not be further 
disclosed by them. 
 
 
DocuSign Envelope ID: 8DFD15FC-4639-415B-9718-995CA4ED61AB


Statistical Analysis Plan (Methods) 
Sage Therapeutics, Inc. 
Study 547-PPD-304 
CONFIDENTIAL 
 
2 
 
Authorization Signature Page 
 
A Multicenter, Open-label Study Evaluating the Safety, Tolerability, and Pharmacokinetics of Brexanolone in the Treatment 
of Adolescent Female Subjects with Postpartum Depression 
 
Author: 
 
 
 
 
 
 
 
Name:  
, PhD 
 
Date 
Position:  
 
 
 
Company:  Sage Therapeutics, Inc. 
 
 
 
 
 
Approved by: 
 
 
 
 
 
 
 
 
_______________________________________________ 
, PhD  
  
Sage Therapeutics, Inc. 
 
 
 
_________________ 
Date 
 
 
 
 
 
_______________________________________________ 
, MD 
 
Sage Therapeutics, Inc. 
 
 
 
 
 
_________________ 
Date 
 
 
 
 
 
_______________________________________________ 
, MD 
  
Sage Therapeutics, Inc. 
 
 
_________________ 
Date 
 
 
 
 
 
_______________________________________________ 
 
  
Sage Therapeutics, Inc. 
 
 
 
 
 
_________________ 
Date 
DocuSign Envelope ID: 8DFD15FC-4639-415B-9718-995CA4ED61AB
08-Mar-2021 | 12:43 EST
10-Mar-2021 | 15:07 EST
08-Mar-2021 | 21:15 EST
09-Mar-2021 | 14:20 EST
10-Mar-2021 | 10:10 EST


Statistical Analysis Plan (Methods) 
Sage Therapeutics, Inc. 
Study 547-PPD-304 
CONFIDENTIAL 
 
3 
 
1 
TABLE OF CONTENTS 
1 
Table of Contents ............................................................................................................. 3 
2 
List of Abbreviations ....................................................................................................... 5 
3 
Introduction...................................................................................................................... 7 
4 
Study Objectives .............................................................................................................. 7 
4.1 
Primary Objective ....................................................................................................... 7 
4.2 
Secondary Objectives ................................................................................................. 7 
 
 
5 
Study Endpoints ............................................................................................................... 7 
5.1 
Primary Endpoint ........................................................................................................ 7 
5.2 
Secondary Endpoints .................................................................................................. 7 
 
 
6 
Study Design ..................................................................................................................... 8 
6.1 
Overall Design ............................................................................................................ 8 
6.2 
Sample Size and Power .............................................................................................. 9 
6.3 
Randomization and blinding ....................................................................................... 9 
7 
Modifications .................................................................................................................... 9 
7.1 
Modifications from the Approved Clinical Study Protocol ....................................... 9 
7.2 
Modifications from the Approved Statistical Analysis Plan ...................................... 9 
7.3 
Modifications from the Approved DSMB Charter ..................................................... 9 
8 
Analysis Sets ................................................................................................................... 10 
8.1 
All Subjects Set ........................................................................................................ 10 
8.2 
Randomized/enrolled Set .......................................................................................... 10 
8.3 
Safety Set .................................................................................................................. 10 
8.4 
Efficacy Set .............................................................................................................. 10 
8.5 
Pharmacokinetics Set ................................................................................................ 10 
9 
Statistical Analysis ......................................................................................................... 10 
9.1 
General Considerations ............................................................................................ 10 
9.1.1 
Study Day Definition ........................................................................................ 11 
9.1.2 
Baseline Definition ........................................................................................... 11 
9.1.3 
Missing Data ..................................................................................................... 11 
9.1.3.1 
Adverse Events Onset Date ........................................................................ 11 
9.1.3.2 
Prior and Concomitant Medications Date .................................................. 12 
9.2 
Background Characteristics ...................................................................................... 13 
9.2.1 
Subject Disposition ........................................................................................... 13 
9.2.2 
Protocol Deviations .......................................................................................... 14 
9.2.3 
Demographics and Baseline Characteristics ..................................................... 14 
9.2.4 
Medical History ................................................................................................ 14 
9.2.5 
Study Drug Exposure and Compliance ............................................................ 14 
9.3 
Efficacy Analysis ...................................................................................................... 15 
9.3.1 
Definition of Efficacy Variables ....................................................................... 15 
 
 
9.3.2 
Definition of Other Efficacy Variable(s) .......................................................... 16 
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Statistical Analysis Plan (Methods) 
Sage Therapeutics, Inc. 
Study 547-PPD-304 
CONFIDENTIAL 
 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.3.3 
Visit Windows .................................................................................................. 19 
9.3.4 
Analysis of Efficacy Variable(s) ...................................................................... 22 
9.4 
Safety Analysis ......................................................................................................... 23 
9.4.1 
Visit Windows .................................................................................................. 23 
9.4.2 
Adverse Events ................................................................................................. 25 
9.4.3 
Prior and Concomitant Medications ................................................................. 26 
9.4.4 
Clinical Laboratory ........................................................................................... 26 
9.4.4.1 
Hematology, Serum Chemistry, Coagulation ............................................ 26 
9.4.4.2 
Hormones and Exploratory Biochemistry .................................................. 30 
9.4.4.3 
Pregnancy Test ........................................................................................... 30 
9.4.4.4 
Drugs of Abuse and Alcohol ...................................................................... 30 
9.4.5 
Electrocardiogram ............................................................................................ 30 
9.4.6 
Vital Signs ........................................................................................................ 31 
9.4.7 
Physical Examination ....................................................................................... 32 
 
 
9.5 
Pharmacokinetic Analysis ........................................................................................ 34 
9.5.1 
Collection schedule........................................................................................... 34 
9.5.2 
Derived Pharmacokinetic parameters ............................................................... 34 
9.5.3 
Handling of dropouts or missing data............................................................... 34 
9.5.4 
Pharmacokinetic statistical analysis ................................................................. 34 
9.5.5 
Data presentation .............................................................................................. 35 
10 Summary of Interim and Data Safety Monitoring Board Analyses ......................... 35 
11 References ....................................................................................................................... 36 
12 Appendices...................................................................................................................... 37 
12.1 Appendix A: Schedule of Assessments .................................................................... 37 
 
38 
 
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Statistical Analysis Plan (Methods) 
Sage Therapeutics, Inc. 
Study 547-PPD-304 
CONFIDENTIAL 
 
5 
 
2 
LIST OF ABBREVIATIONS 
Abbreviation or 
Specialist Term 
Explanation 
AE 
adverse event 
AESI 
adverse event of special interest 
ANCOVA 
analysis of covariance 
ATC 
anatomical therapeutic chemical 
AUC  
area under the concentration-time curve  
AUC∞  
area under the concentration-time curve from time zero to infinity  
 
 
BMI  
body mass index  
bpm 
beats per minute 
  
  
  
  
Cmax  
maximum (peak) plasma concentration  
CS 
clinically significant  
Css  
steady-state drug concentration in the plasma during oral intake  
Cavg 
steady-state drug concentration in the plasma 
  
  
CV 
coefficient of variation 
DSMB 
Data Safety Monitoring Board 
ECG  
electrocardiogram  
eCRF  
electronic case report form  
 
 
ET 
early termination 
FCS 
fully conditional specification 
GEE 
Generalized Estimating Equation 
 
  
  
HCG 
human chorionic gonadotropin 
HCRU 
healthcare resource utilization 
IV 
intravenous 
kg 
kilogram 
m 
meter 
  
  
Max 
maximum 
MedDRA  
Medical Dictionary for Regulatory Activities  
Min 
minimum 
mmHg 
millimeter of mercury 
MMRM  
mixed effects model for reported measures  
msec 
millisecond 
n  
number  
NCS 
not clinically significant 
PCS 
potentially clinically significant 
PCSC 
potentially clinically significant change 
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Statistical Analysis Plan (Methods) 
Sage Therapeutics, Inc. 
Study 547-PPD-304 
CONFIDENTIAL 
 
6 
 
PHQ-9 
Patient Health Questionnaire 
PK  
pharmacokinetic(s)  
PPD 
postpartum depression 
PT 
preferred term 
QTcF 
QT corrected with Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD  
standard deviation  
  
  
SI 
International System of Units 
SOC  
system organ class  
ss 
steady state 
TEAE  
treatment-emergent adverse event  
Tmax  
time at maximum (peak) plasma concentration  
WHO  
World Health Organization  
WHO-DDE  
World Health Organization-Drug Dictionary Enhanced 
 
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Statistical Analysis Plan (Methods) 
Sage Therapeutics, Inc. 
Study 547-PPD-304 
CONFIDENTIAL 
 
3 
INTRODUCTION 
This Statistical Analysis Plan (SAP) is based on the approved clinical study protocol Version 
4.0 dated 20 December 2019.  
The purpose of the SAP is to describe in detail the statistical methodology and the statistical 
analyses to be conducted for data presentation for Study 547-PPD-304, a multicenter, open-
label study evaluating doses up to 90 mcg/kg/h of brexanolone in adolescent female subjects 
with postpartum depression.   
All patients who received the active study treatment brexanolone will be presented, which 
includes patients who were randomized in the earlier versions of the protocol (Protocol 
Version 1.0, dated 23 January 2018, Version 2.0, dated 11 September, 2018, and Version 3.0 
dated 03 June 2019), and received the active study treatment, as well as the patients who are 
enrolled under Protocol Version 4.0, the open-label study.   
In addition, for the patients enrolled under the double blinded protocol versions (Protocol 
Version 1.0, dated 23 January 2018, Version 2.0, dated 11 September, 2018, and Version 3.0 
dated 03 June 2019), all of their data will be presented according to their randomized 
treatment arms (placebo and brexanolone).  
All analyses and summary outputs will be generated using SAS® version 9.4 (or higher).  
4 
STUDY OBJECTIVES  
4.1 
Primary Objective 
 To evaluate the safety and tolerability of brexanolone when administered to 
adolescent female subjects diagnosed with postpartum depression (PPD).  
4.2 
Secondary Objectives 
 To assess the plasma pharmacokinetic (PK) profile of brexanolone and, when 
appropriate, metabolites of brexanolone 
 
 
 
 
 
 
 
5 
STUDY ENDPOINTS 
5.1 
Primary Endpoint 
 Incidence of treatment-emergent adverse events (TEAEs) 
5.2 
Secondary Endpoints 
 PK parameters derived from plasma concentrations of brexanolone and, when 
appropriate, metabolites of brexanolone 
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 Mean  changes from baseline in clinical laboratory measures, vital signs, 
electrocardiogram (ECG) and concomitant medication use.  
 
6 
STUDY DESIGN  
6.1 
Overall 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 (from Day -14 through day -1, inclusive), a 
3-day (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).        
 
In Study 547-PPD-304, once subjects are confirmed as eligible for the study, subjects will be 
administered brexanolone. On the morning of dosing (Day 1), subjects will begin a 4-hour 
dose titration period of 30 mcg/kg/hour (0-4 hours), then 60 mcg/kg/hour (4-24 hours), then 
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90 mcg/kg/hour (24-52 hours); followed by a decrease to 60 mcg/kg/hour (52-56 hours), and 
30 mcg/kg/hour (56-60 hours) as shown in Table 1.   
Table 1: 
Infusion Rates for 547-PPD-304 
 
Infusion Rate (mcg/kg/hour) 
Time point 
Day 1 
0-4 hours 
Day 1 
4-24 hours 
Day 2-3 
24-52 hours 
Day 3 
52-56 hours 
Day 3 
56-60 hours 
Dose(mcg) 
30  
60  
90  
60  
30 
 
Total brexanolone dosing will occur over 60 hours. 
The end of the Treatment Period coincides with the beginning of the Follow-up Period.  
Follow-up visits will be conducted on Day 7, Day 14, Day 21, Day 30.  
6.2 
Sample Size and Power 
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.  
 
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. 
6.3 
Randomization and blinding 
In this open-label study, all subjects will be administered a single, continuous, 60-hour 
intravenous (IV) infusion of brexanolone starting on Day 1. 
 
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. 
7 
MODIFICATIONS  
7.1 
Modifications from the Approved Clinical Study Protocol 
Not applicable.  
 
7.2 
Modifications from the Approved Statistical Analysis Plan 
Not applicable. 
 
7.3 
Modifications from the Approved DSMB Charter 
DSMB Charter 1.0, dated 31 Oct 2018, specified periodic data review meetings to be 
scheduled quarterly after the first meeting.  
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DSMB Charter 2.0, dated 16 July 2019, updated the periodic data review meetings scheduled 
quarterly or when a minimum of five (5) new subjects are enrolled and 14-day visit data are 
available.   
BREXANOLONE DSMB Charter Version 1.0, dated 20 October 2020, a brexanolone 
program-wide DMC charter has been created to cover all ongoing brexanolone studies: 
547-PPD-304 and 547-ARD-301.  
8 
ANALYSIS SETS 
8.1 
All Subjects Set 
The All Subjects Set will include every subject who has given written informed consent.  
This set will be used for subject disposition.  
8.2 
Randomized/enrolled Set 
The Randomized/enrolled Set will include subjects who have been randomized in earlier 
double blinded versions of the protocol and subjects who are enrolled in the current open-
label version of the protocol.  Subjects will be classified according to randomized treatment 
for the double-blinded treatment and also for the active study treatment brexanolone they 
receive.   
8.3 
Safety Set 
The Safety Set will include all randomized/enrolled subjects who start the infusion of study 
drug.  Subjects will be classified according to actual treatment received.  This analysis set 
will be used for subject demographics and baseline characteristic summaries and all safety 
analyses. 
8.4 
Efficacy Set 
The Efficacy Set will include the subset of the Safety Set who have a valid baseline efficacy 
assessment and at least one post-baseline efficacy assessment.  
8.5 
Pharmacokinetics Set 
The PK Set will include all subjects in the Safety Set who have at least one evaluable 
post-baseline PK sample.  Subjects will be classified according to actual treatment received.  
This analysis set will be used for all PK analyses. 
9 
STATISTICAL ANALYSIS 
9.1 
General Considerations 
Unless otherwise specified, continuous endpoints will be summarized with number (n), 
mean, standard deviation (SD), median, minimum (min) and maximum (max).  The 
minimum and maximum will be reported with the same degree of precision (ie, the same 
number of decimal places) as the raw data.  Measures of location (mean and median) will be 
reported to 1 degree of precision more than the raw data.  Measures of spread (SD) will be 
reported to 2 degrees of precision more than the raw data.  In addition, change from baseline 
values will be calculated at each time point and summarized descriptively.  For categorical 
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endpoints, descriptive summaries will include counts and percentages.  Percentages will be 
presented to 1 decimal place except for 0%, which will be presented as “0”, and 100%, which 
will be presented as “100”.  
All analyses and summary outputs will be generated using SAS® version 9.4 (or higher). 
All subject data, including those derived, will be presented in the subject data listings.  The 
listings will display all subjects who were enrolled.  In general, the subject data listings will 
be sorted by randomized treatment group, subject number and assessment visit and date (and 
time, if applicable).  The summary tables will be presented descriptively by treatment group. 
9.1.1 Study Day Definition 
Study day is defined as follows:  
  The day when the study drug infusion is started is designated as Day 1. 
  For visit days after Day 1, study day = visit date – Day 1 date + 1. 
  For visit days prior to Day 1, study day = visit date – Day 1 date. Thus, study days for 
the screening visit are negative numbers.  There is no “Day 0”. 
9.1.2 Baseline Definition 
For the purpose of all safety and efficacy analyses where applicable, baseline is defined as 
the last non-missing measurement prior to the start of study drug administration. 
9.1.3 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 of the available non-missing data.  
 
subscales that were collected during protocol version 1.0-3.0 will be calculated, and the 
missing responses will be handled using the built-in scoring tool.   
Safety data will not be subject to any imputation and will be summarized on an observed 
basis. 
The following conventions will be used for missing adverse event (AE) dates 
(Section 9.1.3.1), and missing prior and concomitant medication dates (Section 9.1.3.2) for 
determining the TEAEs or for determining prior and concomitant medication.  The actual 
date will not be replaced by the imputed date.  
9.1.3.1 Adverse Events Onset Date 
If the AE onset date is completely missing in which the day, month, and year are all missing, 
do not impute a date but consider it as TEAE, unless the AE end date is before the initiation 
of treatment, in which case the AE will be considered prior.   
For the partial AE onset date and time, 
 If the year is present, but the month and day are missing: 
o If year of AE onset = year of initiation of the treatment, then set the 
month and day to the month and day of initiation of the blinded 
treatment 
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o If year of AE onset < year of initiation of the treatment, then set the 
month and day to December 31. 
o If year of AE onset > year of initiation of the treatment, then set the 
month and day to January 1. 
 If the year and month are present, but the day is missing: 
o If year and month of AE onset = year and month of initiation of the 
treatment, then set the day to the day of initiation of the treatment. 
o If year and month of AE onset < year and month of initiation of the 
treatment, then set the day to the last day of month 
o If year and month of AE onset > year and month of initiation of the 
treatment, then set the day to the first day of the month 
 If the year and day are present and the month is missing: 
o If year of AE onset = year of initiation of the treatment and 
o if day > the day of initiation of the treatment, then set the month to 
the month of initiation of the treatment 
o if day < day of initiation of the treatment, and 
 If the month of initiation of the treatment = December, then 
set the month to the month of initiation of the treatment, i.e. 
December. 
 If the month of initiation of the treatment < December, then 
set the month = the month of initiation of the treatment +1.  
o If year of AE onset < year of initiation of the treatment, then set the month 
to December. 
o If year > year of initiation of the treatment, then set the month to January. 
 If the year and day are present and the month is missing, then treat it as if the 
day is missing, and only the year is present. Follow the imputation rules for 
“year is known, but the month and day is unknown”. 
 When the year is missing, but the month and/or day is known, treat this date 
as missing; do not impute. 
The general rule is to impute the AE onset date as close as to the initiation of treatment date, 
with a preference to after the initiation of the treatment date.  If the imputed AE onset date is 
after the AE stop date, then set the onset date to the AE stop date. 
9.1.3.2 Prior and Concomitant Medications Date 
If the start date (or end date) of a medication is completely missing in which the year is 
unknown, then the start date (or end date) will not be imputed.  
 
For the partial start date of medication,  
o If the year is present and the month and day are missing, set the month and 
day to January 1. 
o If the year and day are present and the month is missing, set the month to 
January. 
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o If the year and month are present and the day is missing, set the day to the first 
day of the month. 
o If the imputed start date of medication is after the non-imputed end date of 
medication, then the start date will be set to the end date of medication. 
For the partial end date of medication, 
o If the year is present and the month and day are missing, set the month and 
day to December 31. 
o If the year and day are present and the month is missing, set the month to 
December. 
o If the year and month are present and the day is missing, set the day to the last 
day of the month. 
o If the imputed end date of medication is before the non-imputed start date of 
medication, then the end date will be set to the start date of medication. 
 
If both the start date and end date are imputed, and the imputed end date of medication  
contradicts with the imputed start date of medication, the general rule is to set the imputed 
month or day (either stop or start) to the non-imputed month and day (either stop or start) 
such that they will not contradict each other.  Then consider the following: 
o If the imputed end month = imputed start month, and 
 If the imputed end day < imputed start day, then the end day will be 
set to the start day of medication. 
o If the imputed end month < imputed start month, and 
 If the imputed end day > imputed start day, then the end month will be 
set to the start month of medication. 
 If the imputed end day < imputed start day 
 If the start month of the medication is not December, then the 
end month will be set to the start month of medication +1 
 If the start month of the medication = December, then the end 
month will be set to the start month of medication (December) 
and the end day will be the start day of the medication.  
9.2 
Background Characteristics  
9.2.1 Subject Disposition 
The analyses of subject disposition will use all subjects who provided written inform consent 
to the study. 
The summaries of subject disposition will include the number and percentage of subjects 
who were screened, screen failed, enrolled, randomized, received brexanolone injection or 
placebo, subjects who completed the study, who prematurely withdrew from the study, 
primary reasons for not completing the study, who completed infusion, who discontinued 
infusion prematurely, and primary reasons for discontinuing treatment. Study completion 
summary and treatment completion summary will be based on subjects who received study 
drug (Safety Set).  Percentages will be calculated based on the Safety Set. These data will be 
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provided by randomized treatment groups. If a subject is rescreened because the subject has 
been a screen failure the first time, the status of the subject will be determined from the 
second screening. In the count of screened subjects, this subject will be counted only once.   
The number and percentage of subjects will also be summarized for each reason for 
premature discontinuation.  In addition, the number of subjects whose data should be used for 
the planned analyses will be identified for each respective analysis set (ie, All Subject, 
Safety, Efficacy, and PK Sets). 
Study completion and discontinuation details, eligibility, treatment allocation, population 
assignment, and protocol deviations will be presented in listings. 
9.2.2 Protocol Deviations 
Protocol deviations identified during site monitoring will be captured on an electronic case 
report form (eCRF) and categorized by the study team as major and minor deviations, 
without any unblinding information.  The major deviations will be further categorized as 
major-efficacy, major-safety and major-Good Clinical Practice (GCP) deviations.  The major 
deviations will be summarized by type and by actual treatment received using the Safety Set.  
The minor deviations will be included in the listing.  
The list of protocol deviations that may affect efficacy will be identified and finalized by a 
study team review before database unblinding by a study team review, and will be 
documented as such.   
Any violation of inclusion/exclusion criteria will be presented in a data listing using the 
Randomized Set. 
9.2.3 Demographics and Baseline Characteristics 
Demographic data, such as age, gender, race and ethnicity, and baseline characteristics, such 
as height, weight, body mass index (body mass index [BMI], calculated as weight (kg)/ 
[height (m)2]), and baseline antidepressants use, will be listed and summarized using the 
Safety Set.  For this summary, as well as for the subsequent analyses, baseline antidepressant 
use will be defined as taking any medications belonging to the anatomical therapeutic 
chemical (ATC) 3 term N06A or N05A, or contain terms as ‘depression’, ‘postpartum 
depression’, ‘major depression’, postpartum depression (‘PPD’), ‘major depressive disorder’, 
or ‘major depressive mood’.   
Drug and alcohol, and pregnancy screening results will be collected and listed but not 
summarized, as they are considered part of the inclusion/exclusion criteria. 
9.2.4 Medical History 
Medical history collected at screening will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA), Version 23.0.  Medical history data will be summarized by 
system organ class (SOC) and preferred term (PT) and listed by subject using the Safety Set. 
9.2.5 Study Drug Exposure and Compliance 
Drug administration information collected on the eCRF will be listed by subject using the 
Safety Set.  Details will include dose, infusion rate and unit, start date/time of dose, and end 
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date/time of dose.  In Protocol Version 1.0-2.0, fusion administration sets were fully primed 
with admixture according to subject body weight, so the infusion rate for each infusion 
duration is fixed.  In Protocol Version 3.0 and 4.0, the infusion administration set was set as 
the same, but the infusion rates vary depending on subject body weight, with the 
target 1mg/mL concentration to achieve the recommended dose for each infusion duration.   
The dose categories and infusion rate for given dose are listed in Table 2. 
 
Table 2: 
Dose Categories and Infusion Rate for Given Dose of 547-PPD-304  
Dose 
Category 
Infusion Rate for Given Dose (mcg/kg/hour) 
Titration 
30 
(Day 1 0-4 hours) 
60 
(Day 1 4-24 hours) 
Maintenance 
90 
(Day 2 24 hours - Day 3 52 hours) 
Taper 
60 
(Day 3 52-56 hours) 
30 
(Day 3 56-60 hours) 
 
Overall exposure to study drug is defined as total number of hours treated with study drug 
during the study, which is calculated as the sum of actual exposure duration of each infusion 
segment. The exposure duration for a segment is defined as (end time of infusion – start time 
of infusion [in seconds])/3600.  
Exposure to study drug in each planned infusion rate segment (titration dose, maintenance 
dose, and tapering dose) is defined as the sum of actual exposure duration of each infusion 
segment within the infusion rate segment. 
Study drug compliance (%) is calculated as [actual total dose (in mcg/kg)/planned total dose 
(in mcg/kg)] x 100. 
Overall exposure to study drug, exposure to study drug in each infusion rate segment and 
study drug compliance will be summarized using the Safety Set.  
9.3 
Efficacy Analysis  
All efficacy analyses will be performed for the Efficacy Set unless otherwise specified. 
9.3.1 Definition of Efficacy Variables 
 
 
 
 
 
 
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9.3.3 Visit Windows    
The unscheduled or early termination (ET) visit will be mapped to a scheduled visit for 
analysis using the date/time of collection/assessment as a basis to determine study day/hour 
and then study day/hour will be mapped to the intended visit.  Once analysis visit windows 
get assigned, all visits, including scheduled visits, unscheduled visits, and ET visits will be 
eligible for being flagged as the “analyzed record” within the analysis window.  A subject’s 
individual analysis visit window could potentially contain more than 1 visit.  In the event of 
multiple visits falling within an analysis window or in case of a tie, the following rules will 
be used in sequence to determine the “analyzed record” for the analysis visit window: 
 If there is a scheduled visit/day for the analysis visit window, then the scheduled 
visit/day data will be used. 
 If there is no scheduled visit/day for the analysis visit window, the data closest to the 
scheduled study day/hour will be used. 
 If there is no scheduled visit/day for the analysis visit window and there are visits 
equally close to the day/hour of scheduled visit, the latest data will be used. 
The data not flagged as the “analyzed record” will also be listed in subject listings. 
The Follow-up Period in this version of the protocol was reduced from Day 90 ± 7 days to Day 
30 ± 3 days for consistency with the Follow-up Period in the adult PPD studies for brexanolone. 
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Tables 4 – 8 summarize the visit window for all the efficacy endpoint under both follow up 
schedules.  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.4 
Safety Analysis 
The primary objective is the safety and tolerability of brexanolone, as evaluated by TEAEs.  
Other safety endpoints include clinical laboratory tests, vital signs, ECGs and concomitant 
medication usage. 
 
Safety data will be listed by subject and summarized descriptively by treatment group.  All 
safety analyses will be performed on the Safety Set.  
The safety endpoints and variables considered in the summary tables for this study are 
summarized in Table 10. 
Table 10:  Safety Endpoints and Variables in the Summary Tables and Listings 
Safety Evaluation 
Incidence  
Actual 
Value 
Change from 
Baseline 
Abnormality/Clinical 
Significance (CS) 
AEs 
X 
* 
 
 
Concomitant Medications 
X 
* 
 
 
Laboratory assessments 
 
X 
X 
* 
ECG 
 
X 
X 
* 
Vital Signs 
 
X 
X 
* 
X = Safety Assessment will be summarized in tables 
* = Safety Assessment will be presented in individual subject data listings   
Abbreviations:AE=Adverse Event; ECG=electrocardiogram; 
 
  
 
9.4.1 Visit Windows 
The mapping rule of unscheduled or early termination (ET) visit and the rule of flagging 
“analyzed record” are the same as described in Section 9.3.3.  
Table 11 displays the visit windows for analysis of clinical laboratory parameters (including 
hematology, serum chemistry) parameters; Table 12 displays the visit windows for analysis 
of 12-lead ECG; Table 13 displays the visit windows for analysis of vital signs parameters; 
and Table 14 displays the visit windows for analysis of 
.  
Table 11: 
Visit Windows for Analysis of Clinical Laboratory Parameters 
Scheduled Visit 
Study Day/Hour of Expected Visit 
Study Day/Hour Window for Visit 
Baseline 
D -1 
D -7 to D1H0 
D3H72 
D3H72 
>D1H0, < D3H72 
D14 
D14 
>D4H0, < D33 
Note: D = Day, H = Hour. 
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Table 12: 
Visit Windows for Analysis of 12-lead Electrocardiogram Parameters 
Scheduled Visit 
Study Day/Hour of Expected Visit 
Study Day/Hour Window for Visit 
Screening 
D-1 
D-7 to D-1 
Baseline 
D1H0 
D1H0 
D3H72 
D3H72 
>D1H0, < D3H72 
D14 
D14 
>D4H0, < D33 
Note: D = Day, H = Hour. 
Table 13: 
Visit Windows for Analysis of Vital Signs Parameters 
Scheduled Visit 
Study Day/Hour of Expected Visit 
Study Day/Hour Window for Visit 
Screening 
D -1 
D -7 to D-1 
Baseline 
D1H0 
D1H0 
D1H2  
D1H2 
>D1H0, < D1H3 
D1H4 
D1H4 
>D1H3, < D1H6 
D1H8 
D1H8 
>D1H6, < D1H10 
D1H12 
D1H12 
>D1H10, < D1H18 
D1H24 
D1H24 
>D1H18, < D2H27 
D2H30 
D2H30 
>D2H27, < D2H33 
D2H36 
D2H36 
>D2H33, < D2H42 
D2H48 
D2H48 
>D2H42, < D3H51 
D3H54 
D2H54 
>D3H51, < D3H57 
D3H60 
D3H60 
>D3H57, < D3H66 
D3H72 
D3H72 
>D3H66, < D3H72 
D7 
D7 
>D4H0, < D10 
D14 
D14 
>D10, < D33 
Note: D = Day, H = Hour. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
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9.4.2 Adverse Events  
The analysis of AEs will be based on the concept of TEAEs.  A TEAE is defined as an AE 
with onset on or after the start of study drug infusion, or any worsening of a pre-existing 
medical condition/AE with onset on or after the start of study drug infusion.  
All adverse events will be coded using MedDRA version 23.0 or higher and summarized by 
SOC and PT.  Multiple occurrences of an AE are counted only once per subject per SOC and 
per PT for summary tables.  Incidences will be presented in order of decreasing frequency of 
the brexanolone group by SOC and PT.  Incidences will also be presented in order of 
decreasing frequency of the brexanolone group by PT only.  In addition, summaries will be 
provided by severity (mild, moderate, severe) and by causality (related, not related) to study 
drug (see protocol section 12.2.2 for definitions). TEAEs leading to treatment discontinuation 
and study discontinuation and Serious AEs (SAEs) (see protocol section 12.2.1.2 for 
definition) with onset after the start of randomized infusion will also be summarized. 
Summary tables of TEAEs will be presented by treatment and will summarize the number 
and percentage of subjects for the following: 
  Any TEAE 
  TEAEs by maximum severity to study drug (mild, moderate, severe) 
  Treatment-emergent serious AEs (SAEs) 
  TEAEs leading to discontinuation of study drug 
 TEAEs leading to withdrawal from study 
 AEs of special interest (AESIs), which include: 
o Excessive sedation 
o Loss of consciousness 
o Any sedation-related AE that leads to dose reduction, interruption, or 
termination 
Subjects will be counted only once within each SOC and PT at the maximum severity in the 
following order: severe, moderate, and mild.  An AE with missing severity will be 
considered as a severe AE.  The incidences will be presented by descending frequency of 
SOC and then, within a SOC, by descending frequency of PT based on the subject count, and 
in alphabetical order of PT if the incidence within a PT is a tie.   
Subjects will be counted only once within each SOC and PT at the strongest relationship to 
study drug in the following order: related, not related to study drug.  If the relationship 
between the AE and the study drug is determined to be “possible” or “probable”, the event 
will be considered as related to the study drug.  An AE with missing relationship to study 
drug will be considered as related to study drug.   
A summary of most frequent TEAE just by preferred term where the incidence is more than 
5% in any treatment group will be provided, sorted by decreasing overall frequency.  
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All AEs, SAEs (including those with onset or worsening before the start of randomized 
infusion), AEs leading to study drug discontinuation and AEs leading to death through the 
Day 30 Follow-up Visit (±3 days), and all AESIs will be listed.  
9.4.3 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 (WHO-DDE) dated March 2018, or 
later.  
 
Medications will be presented according to whether they are being taken prior to and/or 
during the study (concomitant): 
  Prior medications are defined as all medications taken prior to the infusion of study 
treatment.  
  Concomitant medications are defined as all medications taken on or after the infusion 
of study treatment starts through the Day 30 (±3 days) visit.  If medication dates are 
incomplete and it is not clear whether the medication was concomitant, it will be 
assumed to be concomitant. 
Note that medication that started prior to the infusion of study drug and continued after the 
start of infusion will be summarized as prior medication and separately as concomitant 
medication.  Details of prior and concomitant medications will be listed by subject, start date, 
and verbatim term. 
Medication summaries will be performed by ATC level 2 term and PT separately for “Prior” 
or “Concomitant” medications as defined above based on the Safety Set. 
Nonpharmacological interventions for PPD will be listed and summarized. 
 
9.4.4 Clinical Laboratory 
9.4.4.1  Hematology, Serum Chemistry, Coagulation 
Blood samples will be collected for coagulation at screening, and hematology and serum 
chemistry, throughout the study. Analytes to be evaluated are summarized in Table 15. 
 
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 Appendix A. 
 
Table 15: Summary of Laboratory Analytes 
 
Hematology 
Complete blood count (red blood cells, white blood cells with 
differentiation and absolute values, hemoglobin, hematocrit, reticulocytes, 
and platelets) 
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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, clinically significant (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. 
Summary tables will include descriptive statistics for the actual values and changes from 
baseline by scheduled time point in hematology, serum chemistry, and coagulation by 
treatment group.  Frequency counts and percentages will be presented over time for these 
categorical data by treatment.   
Shift analysis pre- and post-treatment will be presented for the following laboratory 
categories (low, normal and high).  
Number and percent of subjects with liver injury as defined by Hy’s law will be presented. 
Hy’s law is defined as ALT or AST > 3 times of upper limit of normal; and total bilirubin > 2 
times of upper limit of normal, and alkaline phosphatase < 2 time of upper limit of normal. 
All parameters will be converted to consistent units according to the International System of 
Units (SI) before summarization. 
All clinical laboratory results will be listed by subject and timing of collection.  Out-of-range 
values will be flagged as low, high, or abnormal, where applicable. 
The number and percentage of subjects with potentially clinically significant (PCS) values at 
any time after study drug infusion will be summarized by treatment group for the hematology 
and chemistry parameters defined in Table 16 and Table 17.  PCS laboratory values will also 
be listed by subject. 
 
 
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Table 16: 
Hematology Potentially Clinically Significant Values 
Laboratory  
Parameter 
Sex 
Units 
Criteria for PCS Values (Observed 
values) 
 
 
 
High  
Low  
Hemoglobin                Male 
g/L  
>185  
<115 
 
Female 
g/L  
>170 
<100 
Hematocrit    
Male 
Fraction of 1 
>0.55  
<0.385  
 
Female 
Fraction of 1 
>0.49 
<0.345 
Platelet count  
 
109/L  
>600 
<125 
White blood cell 
 
109/L  
>15  
<2.5  
Basophils  
 
109/L  
>0.5 
NA 
Eosinophils 
 
109/L 
>1.5 
NA 
Neutrophils  
 
109/L 
NA  
<1.5  
Lymphocytes  
 
109/L 
>6.0  
<0.5  
Monocytes  
 
109/L 
>1.4 
NA 
Abbreviations: PCS = Potentially Clinically Significant 
 
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Table 17: 
Chemistry Potentially Clinically Significant Values 
Laboratory  
Parameter 
Units 
Criteria for PCS Values (Observed values) 
 
 
High  
Low  
Albumin  
g/L  
>70  
<28  
Blood urea nitrogen  
mmol/L 
>10.71 
NA 
Calcium 
mmol/L 
>2.75 
<2.0 
Chloride 
mmol/L 
>120 
<90 
Creatinine 
mmol/L 
>3xULN or >3x Baseline 
 
Gamma Glutamyl 
Transferase  
 
>3xULN 
 
Glucose 
mmol/L 
>13.9 
<2.8 
Sodium  
mmol/L  
>150 
<132  
Potassium  
mmol/L  
>5.4  
<3.3  
Protein  
g/L 
 
<45 
Bicarbonate  
mmol/L  
>34  
<18  
Chloride  
mmol/L  
>120  
<90  
Phosphorus  
mmol/L 
>1.94 
<0.61 
Liver Function Tests 
(LFT) 
 
 
 
Bilirubin  
μmol/L  
>2xULN  
NA  
Aspartate 
Aminotransferase  
U/L  
>3xULN  
NA  
Alanine 
Aminotransferase  
U/L  
>3xULN  
NA  
Alkaline 
Phosphatase  
U/L  
>1.5xULN  
NA  
Abbreviations: PCS = Potentially Clinically Significant 
 
Liver function tests will be monitored closely for potentially clinically significant values, and 
will be summarized for occurrence any time post-baseline for the following parameters for 
these PCS threshold (for condition involving >1 parameter, the results need to be from the 
same timepoint): 
Alanine Aminotransferase: >3xULN, >5xULN, >10xULN 
Aspartate Aminotransferase: >3xULN, >5xULN, >10xULN 
Alanine Aminotransferase or Aspartate Aminotransferase: >3xULN, >5xULN, >10xULN 
Alkaline Phosphatase: >1.5xULN, >2xULN 
Total Bilirubin: >1.5xULN, >2xULN 
Total Bilirubin > 2xULN AND (Alanine Aminotransferase or Aspartate Aminotransferase 
>3xULN) 
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Total Bilirubin >2xULN AND Alkaline Phosphatase >2xULN AND (Alanine 
Aminotransferase or Aspartate Aminotransferase >3xULN) 
Any lab results considered clinically significant by the investigator will be captured as AEs 
events, hence will show up in AE displays. 
9.4.4.2 
 Hormones and Exploratory Biochemistry 
Blood samples will be collected and may be analyzed for estrogen, progesterone, 
progesterone metabolites, oxytocin, tryptophan, kynurenine, and markers of inflammation. 
9.4.4.3 
 Pregnancy Test 
All subjects will be tested for pregnancy by serum human chorionic gonadotropin (HCG) at 
the Screening Visit and by serum or urine HCG 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. Subjects 
with a positive pregnancy test at screening or Day 1 will be ineligible for study participation. 
Pregnancy test results will be listed by subject.  
9.4.4.4 
 Drugs of Abuse and Alcohol 
Urine assessment for select drugs of abuse will be performed (including amphetamines, 
barbiturates, benzodiazepines, cannabinoids, cocaine, opiates, and phencyclidine). A positive 
urine drug screen is exclusionary, unless deemed by the investigator to reflect a prescribed 
medication. Alcohol will be assessed via breathalyzer or urine dipstick. Drug screening and 
alcohol assessment results will be listed.  
9.4.5 Electrocardiogram 
A baseline 12-lead ECG will be performed during screening.  The following ECG parameters 
will be recorded: heart rate (bpm), pulse rate (PR) (msec), QRS (msec), QT (msec), and QT 
corrected with Fridericia’s formula (QTcF) (msec).  
QTcF (msec) is calculated as: QT (msec) / RR1/3, where RR = 60 / heart rate (bpm). 
All ECG results will be interpreted by the Investigator as ‘normal’ ‘abnormal, NCS’; or 
‘abnormal, CS’.  If ‘abnormal’, details will be provided. 
The actual value at each time point and change from baseline at each post-baseline time point 
will be summarized by treatment group.  The number and percentage of subjects with 
‘normal’, ‘abnormal, not clinically significant’ and ‘abnormal, clinically significant’ ECG 
results will be summarized at baseline and each post-baseline time point. 
All ECG data will be listed by subject and time of measurement.  Mean values of ECG 
parameters over time will be presented graphically by treatment group.  
Additionally, the number and percentage of subjects with PCS and potentially clinically 
significant change (PCSC) values will be summarized for such occurrence any time post-
baseline.  Potentially clinically significant values will be identified for ECG parameters as 
outlined in the following table.  This analysis includes triplicate values individually and is 
not based on average value.  In addition, any PCS value at any time post-baseline will be 
summarized as shown in Table 18. 
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Table 18: 
ECG Potentially Clinically Significant Values 
ECG 
Units 
Criteria for PCS Values (Observed 
values) 
Criteria for PCSC values 
(Change from Baseline) 
 
 
High  
Low  
Increase  
Decrease  
QTcF 
Interval 
msec  
>450 but < 480 
>480 but < 500 
>500 
NA  
> 30 to 60 
>60 
 
NA  
Abbreviations: PCS = Potentially Clinically Significant; PCS = Potentially Clinically Significant Change; 
NA=Not Available  
 
9.4.6 Vital Signs 
Vital signs include oral temperature (°C), respiratory rate (breaths/min), heart rate (bpm), and 
blood pressure (mmHg). 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 
Appendix A. A full set of vital signs will be obtained at all specified time points 
(±30 minutes), unless the subject is asleep between the hours of 23.00 h and 06.00 h. 
 
Additionally, respiratory rate, heart rate, and blood pressure should be collected for any 
subject that experiences an AESI 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. 
Additionally, the number and percentage of subjects with PCS and PCSC values will be 
summarized for such occurrence any time post-baseline. Potentially clinically significant 
values will be identified for vital sign parameters as outlined in the Table 19. 
 
 
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Table 19: 
Vital Signs Potentially Clinically Significant Values 
Vital Sign 
Units 
Criteria for PCS 
Values (Observed 
values) 
Criteria for PCSC values 
(Change from Baseline 
values) 
 
 
High  
Low  
Increase  
Decrease  
Heart rate (supine and 
standing) 
Beats/min  >120  
<40  
NA 
NA 
Systolic Blood 
Pressure (supine and 
standing)  
mmHg  
>180 
<90  
≥30 
≥30 
Diastolic Blood 
pressure (supine and 
standing)  
mmHg  
>110 
<50  
≥20 
≥20  
Supine - Standing 
Systolic Blood 
Pressure 
mmHg 
≥20 
 
 
 
Supine – Standing 
Diastolic Blood 
Pressure 
mmHg 
≥10 
 
 
 
PCS = Potentially Clinically Significant; PCS = Potentially Clinically Significant Change; NA=Not Available  
 
The change from supine to standing (Supine – Standing) vital signs – heart rate, systolic and 
diastolic blood pressure – will be summarized by scheduled assessment timepoint. 
Any vital signs results considered clinically significant by the investigator will be captured as 
adverse events, hence will show up in AE displays. 
  
9.4.7 Physical Examination 
Body weight and height will be measured at screening.  BMI will be programmatically 
calculated in the eCRF.  The date of assessment and study day of physical examinations will 
be listed.  
Note: Any condition present at the post-treatment physical examination that was not present 
at or worsened since the baseline examination is to be documented as an AE and will be 
presented in AE listings and tables. 
 
 
 
 
 
 
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9.5 
Pharmacokinetic Analysis 
Plasma will be collected to assay for concentrations of brexanolone. PK analyses will be 
performed using the PK set.  
9.5.1 Collection schedule 
Blood samples for PK analysis will be collected at pre-infusion and at 4 (before change in 
infusion rate, if applicable), 8, 12, 24 (before change in infusion rate, if applicable), 30, 36, 
48, 60 (before end of infusion), and 72 hours after the start of the infusion.  PK blood draws 
after the start of infusion will have a window of ±10 minutes. In the event of an unplanned 
dose adjustment, if feasible, an unscheduled PK sample should be collected just prior to the 
infusion rate change.  PK collection should also occur as soon as is feasible in the case of 
overdose. 
9.5.2 Derived Pharmacokinetic parameters 
The following PK parameters will be derived from the plasma concentrations of brexanolone 
(where evaluable): 
Table 20: 
Pharmacokinetic Parameters and Definitions 
AUC0-60 (or AUC) 
Area under the plasma concentration time curve from time 0 to 60 hours 
AUC∞ 
AUC from time 0 to infinity 
Cmax 
Maximum (peak) plasma concentration 
Tmax 
Time at maximum (peak) plasma concentration 
Css  
Steady-state drug concentration in the plasma during constant-rate infusion 
Thalf 
Half-life of first elimination phase of brexanolone 
CL/F 
Clearance of brexanolone 
Vss 
Steady state volume of distribution 
Vz/F 
Volume of distribution 
9.5.3 Handling of dropouts or missing data 
PK parameters will be provided by qPharmetra, LLC.  Please refer to the qPharmetra PK 
Analysis Plan for handling missing data.  
9.5.4 Pharmacokinetic statistical analysis 
The plasma concentrations along with time point deviation from scheduled time will be listed 
by subject. 
PK will be summarized using appropriate descriptive statistics.  PK plasma concentration 
equivalents that are BLQ will be set to zero. Plasma concentration values that are BLQ will 
be set to 0 for the calculation of descriptive statistics and the same will be considered for 
individual plots. If more than 50% of values at any given time point are BLQ, then only n, 
minimum, median and maximum will be reported. 
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All PK parameters will be summarized using n, geometric mean, geometric coefficient of 
variation (CV), CV, median, minimum, and maximum, all listed by subject.  
9.5.5 Data presentation 
Individual plasma PK concentrations and PK parameters will be presented with an 
appropriate number of significant figures as in the raw data.  If the raw value has > 3 
significant figures, use the following for representation.  
 For values > 100, display the whole number 
 For values < 100, display 3 significant figures  
The level of precision for each summary statistic will be presented as follows: 
 n: integer 
 Min, max: in same precision as individual data 
  Arithmetic mean, median, geometric mean: in 1 more level of precision than 
min/max 
 SD, standard error of mean (SEM): in 1 more level of precision than means/median 
  CV% and geometric CV%: 1 decimal place. 
The descriptive statistics will be generated as discussed above in Section 9.5.4. The 
following figures will be produced: 
  Mean ± SD plasma concentration-time profiles through Day 3, 72 hours will be 
plotted on linear and semi-logarithmic scales  
  Individual subject concentration-time profiles on linear and semi-logarithmic 
concentration scales 
  Spaghetti plots for each treatment through Day 3, 72 hours (linear and 
semi-logarithmic scale) 
10 SUMMARY OF INTERIM AND DATA SAFETY MONITORING BOARD ANALYSES 
The interim DSMB analysis will be summarized in a separate SAP. 
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11 REFERENCES 
Clinical Study Protocol: Version 4.0 (20 December 2019), Company: Sage Therapeutics Inc.  
 
  
  
  
 
 
 
 
 
 
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12 APPENDICES 
12.1 Appendix A: Schedule of Assessments 
 
 
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