Conditions: Postpartum Depression
Keywords: Postpartum Care
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 276
Healthy volunteers: no

Brief summary:
The primary purpose of this study was to determine if treatment with SAGE-217 reduces depressive symptoms in participants with severe postpartum depression (PPD) compared to placebo as assessed by the change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D) total score at Day 15 and to evaluate the safety and tolerability of SAGE-217 compared to placebo as assessed by the incidence of adverse events, vital sign measurements, clinical laboratory evaluations, electrocardiogram (ECG) parameters, and the Columbia Suicide Severity Rating Scale (C-SSRS).

Detailed description:
This study was previously posted by Sage Therapeutics. In November 2023, sponsorship of the trial was transferred to Biogen.

Arms:
arm 1: Participants received SAGE-217, 15 milligrams (mg), oral solution, twice daily (BID) for first 2 days followed by SAGE-217, 15 or 20 mg, oral solution, BID, starting on Day 3 for up to 14 days as tolerated. arm 2: Participants received SAGE-217 matching placebo, capsules, orally, once daily, for up to 14 days. arm 3: Participants received SAGE-217, 30 mg, capsules, orally, once daily, for up to 14 days.

Interventions: intervention 1: SAGE-217 15/20 mg Oral Solution intervention 2: Placebo intervention 3: SAGE 217 30 mg Capsules
Intervention descriptions: intervention 1: SAGE-217, 15 mg oral solution, BID for Days 1 to 2 followed by 20 mg oral solution BID for Days 3 to 14. If not tolerated, 15 mg for the rest of study (Days 3 to 14). intervention 2: SAGE-217 matching placebo, capsules, orally, once daily, for up to 14 days. intervention 3: SAGE-217, 30 mg, capsules, orally, once daily, for up to 14 days.

Protocol document:
Prot_000.pdf: 
 
Official Title: 
A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-
Controlled Study Evaluating the Efficacy, Safety, and Pharmacokinetics of 
SAGE-217 in the Treatment of Adult Female Subjects With Severe 
Postpartum Depression 
NCT Number: 
 
NCT02978326 
 
Document Date: 
 
Protocol Version 9.0: 02 July 2018 
 
 
 
 
 
 
 






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INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for SAGE-217. I have read the Clinical 
Protocol 217-PPD-201 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 


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CONTACTS IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Telephone Number 
Clinical Research Organization Premier Research  
512-686-1256 
 


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2. 
SYNOPSIS 
Name of Sponsor: 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Protocol No. 217-PPD-201 
Phase: 3 
Name of Investigational Product: 
SAGE-217 Capsules 
Name of Active Ingredient: 
SAGE-217  
Title of the Protocol: 
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PARALLEL-GROUP, PLACEBO-
CONTROLLED STUDY EVALUATING THE EFFICACY, SAFETY, AND 
PHARMACOKINETICS OF SAGE-217 IN THE TREATMENT OF ADULT FEMALE SUBJECTS 
WITH SEVERE POSTPARTUM DEPRESSION 
Study Sites: Approximately 60 sites in the United States 
Primary Efficacy Objective: 
To determine if treatment with SAGE-217 reduces depressive symptoms in subjects with severe 
postpartum depression (PPD) compared to placebo as assessed by the change from baseline in the 
17-item Hamilton Rating Scale for Depression (HAM-D) total score at Day 15. 
Secondary Efficacy Objectives: 
• 
To determine if treatment with SAGE-217 Capsules 30 mg QD reduces depressive 
symptoms in subjects with severe PPD compared to placebo as assessed by the change 
from baseline in the HAM-D total score at all other time points.  
• 
To determine if treatment with SAGE-217 Capsules 30 mg QD reduces depressive 
symptoms compared to placebo as assessed by HAM-D response, HAM-D remission, 
change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total 
score, Clinical Global Impression – Improvement (CGI-I) response, and changes from 
baseline in HAM-D subscales and individual item scores at Day 15 and all other time 
points.  
• 
To determine if treatment with SAGE-217 Capsules 30 mg QD reduces anxiety symptoms 
compared to placebo as assessed by changes from baseline in Hamilton Anxiety Rating 
Scale (HAM-A) total score Day 15 and all other time points.  
Safety Objective: 
• 
To evaluate the safety and tolerability of SAGE-217 compared to placebo as assessed by 
the incidence of adverse events, vital sign measurements, clinical laboratory evaluations, 
electrocardiogram (ECG) parameters, and the Columbia Suicide Severity Rating Scale 
(C-SSRS).  


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Name of Sponsor: 
Sage Therapeutics 
215 First Street 
Cambridge, MA 02142 
Protocol No. 217-PPD-201 
Phase: 3 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
Study Design and Methodology:  
This is a multicenter, randomized, double-blind, parallel-group, placebo-controlled study of the 
efficacy, safety, and pharmacokinetics of SAGE-217 in adult subjects diagnosed with severe PPD.  
The study will be conducted in 2 parts. One subject was enrolled and dosed in Part A before it was 
closed to enrollment (see Protocol Amendment 2, Version 3.0); the current amendment describes 
Part B only.  
Screening Period: 
The Screening Period will begin with the signature of the informed consent form (ICF). The diagnosis 
of depression will be determined using the Structured Clinical Interview for Diagnostic and Statistical 
Manual of Mental Disorders-5 (DSM-5) Axis I Disorders (SCID-I). Eligibility will be determined by 
applying the inclusion/exclusion criteria. A full medical and family history will be taken including 
recording of all major depression episodes, other Axis I and Axis II disorders, and postpartum 
depression episodes in immediate female family members.  
Treatment Period:  
Once subjects are confirmed as eligible for the study, they will be randomized to active study drug or 
placebo on a 1:1 basis.  
Randomized subjects will receive 30 mg QD of study drug (SAGE-217 Capsules or placebo). Those 
subjects who cannot tolerate 30 mg QD will receive 20 mg QD for the remainder of the Treatment 
Period. Subjects who experience intolerable adverse events (AEs) at the 20 mg QD dose level may be 
discontinued from study treatment at the discretion of the Investigator. Subjects will be instructed to 




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Name of Sponsor: 
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215 First Street 
Cambridge, MA 02142 
Protocol No. 217-PPD-201 
Phase: 3 
per DSM-5, diagnosed by Structured Clinical Interview for (DSM-5) Axis I Disorders (SCID-
I).  
8. Subject has a HAM-D total score of ≥26 at screening and Day 1 (prior to randomization).  
9. Subject is ≤6 months postpartum.  
10. Subject is willing to delay start of other antidepressant or anxiety medications and any new 
pharmacotherapy regimens, including as-needed benzodiazepine anxiolytics, until after the 
Treatment Period ends and all Day 15 assessments have been completed.  
11. Subject has no detectable hepatitis B surface antigen (HBsAg), no detectable anti-hepatitis C 
virus (HCV), detectable anti-HCV but negative viral load, and no detectable human 
immunodeficiency virus (HIV) antibody at screening.  
12. Subject agrees to use 1 of the following methods of contraception during participation in the 
study and for 30 days following the last dose of study drug, unless they are surgically sterile:  
• 
Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation. 
• 
Oral, injectable, or implantable progestogen-only hormonal contraception associated with 
inhibition of ovulation.  
• 
Intrauterine device. 
• 
Intrauterine hormone-releasing system. 
• 
Bilateral tubal occlusion. 
• 
Vasectomized partner. 
 
Exclusion Criteria: 
Subjects will be excluded if they meet any of the following exclusion criteria.  
1. Subject has a recent history or active clinically significant manifestations of metabolic, hepatic, 
renal, hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, 
dermatological, urogenital, neurological, or eyes, ears, nose, and throat disorders, or any other 
acute or chronic condition that, in the Investigator’s opinion, would limit the subject’s ability 
to participate in or complete this clinical study.  
2. Subject has a known allergy to SAGE-217 Capsule or its excipients.  
3. Subject has active psychosis per Investigator assessment.  
4. Subject has attempted suicide associated with the current episode of PPD.  
5. Subject has a medical history of seizures.  


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Protocol No. 217-PPD-201 
Phase: 3 
6. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder.  
7. Subject has a history of active alcoholism or drug addiction (including benzodiazepines) in the 
12 months prior to screening.  
8. Subject has had exposure to another investigational medication or device within 30 days prior 
to screening.  
9. Subject has prior participation in any SAGE-547 or SAGE-217 clinical study.  
10. Subject who presents for the study while currently receiving psychotropic medications that are 
used with the intent to treat depressive symptoms such as antidepressants, atypical 
antipsychotics, etc., which have not been taken at the same dose for at least 30 days prior to 
Day 1. (Subjects presenting for the study who have stopped taking these medications within the 
30 days prior to the start day of study drug may be eligible if they will be off of the 
medications for longer than 5 half-lives until the start day of study drug).  
11. Use of any known strong inhibitors of cytochrome P450 (CYP)3A4 within 14 days or 5 half-
lives (whichever is longer) or consumed grapefruit juice, grapefruit, Seville oranges, or 
products containing these within 14 days prior to receiving the first dose of study drug and 
throughout the study.  
12. Subject has a positive urine drug test at the screening visit. 
13. Use of any CYP inducers, such as rifampin, carbamazepine, ritonavir, enzalutamide, efavirenz, 
nevirapine, phenytoin, phenobarbital or St John’s Wort, within 14 days or 5 half-lives 
(whichever is longer) prior to the first dose of study drug and throughout the study. 
14. Subject plans to undergo elective surgery during participation in the study. 
Investigational Product, Dosage, and Mode of Administration:  
SAGE-217 Capsules are available as hard gelatin capsules containing a white to off-white powder. In 
addition to the specified amount of SAGE-217 Drug Substance, active SAGE-217 Capsules contain 
croscarmellose sodium, mannitol, silicified microcrystalline cellulose, and sodium stearyl fumarate as 
excipients. Capsules will be available in 10-mg, 20-mg, and 30-mg strengths in order to provide 
treatment doses of 20 mg and 30 mg. Subjects will be administered 2 capsules per dose. 
Reference Therapy, Dosage, and Mode of Administration:  
Matched placebo capsules containing only the above-listed capsule excipients will be provided. 
Subjects will be administered 2 placebo capsules per day, to maintain blinding.  
Duration of Participation:  
Up to 76 days (14 days of treatment) 
Randomization: 
Subjects will be randomized to receive SAGE 217 or matching placebo in a 1:1 ratio.  






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Name of Sponsor: 
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Protocol No. 217-PPD-201 
Phase: 3 
Binary efficacy endpoints, including responder and remission endpoints, will be summarized and 
analyzed using the generalized estimating equation method.  
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA™) 
Version 19.1 or higher. The overall incidence of adverse events will be displayed by System Organ 
Class, preferred term, and treatment. The incidence of adverse events will also be presented by 
maximum severity and relationship to study drug. Vital signs, clinical laboratory measures, ECG, 
concomitant medication usage, and C-SSRS data will be summarized by treatment, where applicable. 
Out-of-range safety endpoints may be categorized as low or high, where applicable. Safety data will be 
summarized and examined for possible relationships between subject characteristics and plasma 
SAGE-217 concentrations, as appropriate. Suicidality data collected using the C-SSRS at baseline and 
at each visit during the active Treatment Period will be listed for all subjects. The C-SSRS listings will 
include behavior type and/or category for suicidal ideation and suicidal behavior of the C-SSRS. 
Sample Size Calculation: 
Assuming a 2-sided test at an alpha level of 0.05, a sample size of approximately 65 subjects per 
treatment group would provide 90% power to detect a placebo-adjusted treatment difference of 
approximately 4 points in the primary endpoint, change from baseline in HAM-D total score at Day 15 
assuming standard deviation (SD) of 7 points.  
Assuming a 10% dropout and a 1:1 randomization ratio, approximately 72 randomized subjects per 
treatment group will be required to obtain 130 evaluable subjects. Evaluable subjects are defined as 
those randomized subjects who received study drug and have a valid baseline and at least 1 post-
baseline HAM-D assessment. Additional subjects may be randomized if the dropout rate is higher than 
10%. 






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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............15 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................20 
5. 
INTRODUCTION ......................................................................................................22 
5.1. 
Background of Postpartum Depression and Unmet Medical Need ............................22 
5.2. 
SAGE-217 ...................................................................................................................23 
5.3. 
Potential Benefits and Risks .......................................................................................23 
5.4. 
Dose Justification ........................................................................................................24 
5.4.1. 
Safety Measures ..........................................................................................................24 
5.4.2. 
Safety Instructions ......................................................................................................24 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................25 
6.1. 
Primary Efficacy Objective ........................................................................................25 
6.2. 
Secondary Efficacy Objectives ...................................................................................25 
6.3. 
Safety Objectives ........................................................................................................25 
 
 
 
 
7. 
INVESTIGATIONAL PLAN .....................................................................................27 
7.1. 
Overall Study Design ..................................................................................................27 
7.2. 
Blinding and Randomization ......................................................................................27 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................29 
8.1. 
Subject Inclusion Criteria ...........................................................................................29 
8.2. 
Subject Exclusion Criteria ..........................................................................................30 
8.3. 
Subject Withdrawal Criteria .......................................................................................31 
8.3.1. 
Study Drug Withdrawal ..............................................................................................31 
8.3.2. 
Criteria for Study Termination ...................................................................................31 
9. 
TREATMENT OF SUBJECTS ..................................................................................32 
9.1. 
Number of Subjects ....................................................................................................32 
9.2. 
Treatment Assignment ................................................................................................32 


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9.3. 
Dose Adjustment Criteria ...........................................................................................32 
9.4. 
Prior/Concomitant Medications and Restrictions .......................................................32 
9.4.1. 
Prior/Concomitant Medications ..................................................................................32 
9.4.2. 
Restricted Medications ...............................................................................................33 
9.4.3. 
Other Restrictions .......................................................................................................33 
9.5. 
Treatment Compliance ................................................................................................34 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................35 
10.1. 
Study Drug ..................................................................................................................35 
10.2. 
Batch Formula for SAGE-217 Capsules.....................................................................35 
10.3. 
Study Drug Packaging and Labeling ..........................................................................35 
10.4. 
Study Drug Storage .....................................................................................................35 
10.5. 
Administration ............................................................................................................35 
10.6. 
Study Drug Accountability .........................................................................................36 
10.7. 
Study Drug Handling and Disposal ............................................................................36 
11. 
ASSESSMENT OF EFFICACY ................................................................................37 
11.1. 
Primary Efficacy Outcome Measure - Hamilton Rating Scale for Depression 
(HAM-D) ....................................................................................................................37 
11.2. 
Secondary Efficacy Outcome Measures .....................................................................37 
11.2.1. 
Montgomery-Åsberg Depression Rating Scale (MADRS) ........................................37 
11.2.2. 
Clinical Global Impression (CGI) ..............................................................................38 
11.2.3. 
Hamilton Anxiety Rating Scale (HAM-A) .................................................................38 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13. 
ASSESSMENT OF SAFETY .....................................................................................41 


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13.1. 
Safety and Tolerability Parameters .............................................................................41 
13.1.1. 
Demographic/Medical History ...................................................................................41 
13.1.2. 
Vital Signs ..................................................................................................................41 
13.1.3. 
Weight and Height ......................................................................................................41 
13.1.4. 
Physical Examination .................................................................................................41 
13.1.5. 
Electrocardiogram (ECG) ...........................................................................................41 
13.1.6. 
Laboratory Assessments .............................................................................................42 
13.1.6.1. 
Hematology .................................................................................................................42 
13.1.6.2. 
Blood Chemistry .........................................................................................................42 
13.1.6.3. 
Urinalysis ....................................................................................................................42 
13.1.6.4. 
Virus Serology ............................................................................................................42 
13.1.6.5. 
Hormones and Exploratory Biochemistry ..................................................................43 
13.1.6.6. 
Pregnancy Test ............................................................................................................43 
13.1.6.7. 
Genetic Testing ...........................................................................................................43 
13.1.6.8. 
Drugs of Abuse and Alcohol ......................................................................................43 
13.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................43 
13.2. 
Adverse and Serious Adverse Events .........................................................................44 
13.2.1. 
Definition of Adverse Events .....................................................................................44 
13.2.1.1. 
Adverse Event .............................................................................................................44 
13.2.1.2. 
Suspected Adverse Reaction .......................................................................................44 
13.2.1.3. 
Serious Adverse Event ................................................................................................44 
13.3. 
Relationship to Study Drug ........................................................................................45 
13.4. 
Recording Adverse Events .........................................................................................45 
13.5. 
Reporting Adverse Events ..........................................................................................46 
13.6. 
Emergency Identification of Study Drug ....................................................................46 
14. 
STATISTICS ..............................................................................................................48 
14.1. 
Data Analysis Sets ......................................................................................................48 
14.2. 
Handling of Missing Data ...........................................................................................48 
14.3. 
General Considerations ...............................................................................................48 
14.4. 
Demographics and Baseline Characteristics ...............................................................48 
14.5. 
Primary Efficacy Endpoint .........................................................................................48 
14.6. 
Secondary Efficacy Endpoints ....................................................................................49 
14.6.1. 
Efficacy Analyses .......................................................................................................49 


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14.6.2. 
Safety Analyses ..........................................................................................................49 
14.6.2.1. 
Adverse Events ...........................................................................................................49 
14.6.2.2. 
Clinical Laboratory Evaluations .................................................................................50 
14.6.2.3. 
Physical Examinations ................................................................................................50 
14.6.2.4. 
Vital Signs ..................................................................................................................50 
14.6.2.5. 
12-Lead Electrocardiogram ........................................................................................50 
14.6.2.6. 
Prior and Concomitant Medications ...........................................................................50 
14.6.2.7. 
Columbia Suicide Severity Rating Scale ....................................................................50 
 
 
14.8. 
Determination of Sample Size ....................................................................................51 
14.9. 
Changes from Protocol Specified Analyses ...............................................................51 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................52 
15.1. 
Study Monitoring ........................................................................................................52 
15.2. 
Audits and Inspections ................................................................................................52 
15.3. 
Institutional Review Board (IRB) ...............................................................................53 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................54 
17. 
ETHICS ......................................................................................................................55 
17.1. 
Ethics Review .............................................................................................................55 
17.2. 
Ethical Conduct of the Study ......................................................................................55 
17.3. 
Written Informed Consent ..........................................................................................55 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................56 
18.1. 
Inspection of Records .................................................................................................56 
18.2. 
Retention of Records ..................................................................................................56 
18.3. 
Confidentiality ............................................................................................................56 
19. 
PUBLICATION POLICY ..........................................................................................58 
20. 
LIST OF REFERENCES ............................................................................................59 
21. 
APPENDICES ............................................................................................................61 
APPENDIX 1. DEPRESSION AND ANXIETY DISORDERS LIST .......................................62 
APPENDIX 2. PRIOR AND CONCOMITANT ANTIDEPRESSANT MEDICATION 
LIST ............................................................................................................................63 
 
 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Schedule of Events .....................................................................................................13 
Table 3: 
Abbreviations and Specialist Terms ...........................................................................20 
 


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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 
BMI 
body mass index 
CGI-I 
Clinical Global Impression – Improvement 
CGI-S 
Clinical Global Impression – Severity 
Cmax  
maximum plasma concentration 
CS 
clinically significant  
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
cytochrome P450  
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
GABA 
γ-aminobutyric- acid 
GABAA 
γ-aminobutyric- acid-ligand gated chloride channel 
GCP 
Good Clinical Practice 
GEE 
generalized estimating equation 
HAM-A 
Hamilton Anxiety Rating Scale 
HAM-D 
Hamilton Rating Scale for Depression 
HBsAg  
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Council on Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 


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Abbreviation or Specialist Term 
Explanation 
LS 
least squares 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed effects model for repeated measures 
MTD 
maximum tolerated dose 
NCS 
not clinically significant 
NF  
National Formulary 
PPD 
postpartum depression 
QD 
once daily 
QTcF 
QT interval calculated using the Fridericia method 
SAD 
single ascending dose 
SCID-I 
Structured Clinical Interview for DSM-5 Axis I Disorders 
SD 
standard deviation 
SOC 
System Organ Class 
SSRIs 
serotonin reuptake inhibitors 
SUSAR 
suspected, unexpected, serious, adverse reaction 
TEAE 
treatment-emergent adverse event 
tmax  
time at maximum (peak) plasma concentration 
WHO-DD 
World Health Organization-Drug dictionary 


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5. 
INTRODUCTION 
5.1. 
Background of Postpartum Depression and Unmet Medical Need 
Postpartum depression (PPD) is defined as the occurrence of major depressive episode within 
4 weeks of delivery (DSM-IV 1994) or up to a year after giving birth (Okun 2013). In Diagnostic 
and Statistical Manual of Mental Disorders (DSM-5), the onset specifier includes the entire 
pregnancy as well as 4 weeks following delivery (DSM-5 2013). There are 2 entry criteria for the 
diagnosis of depression (depressed mood and/or loss of interest) and 7 associated symptoms of 
depression (appetite problems, sleep problems, motor problems, lack of concentration, loss of 
energy, poor self-esteem, and suicidality). To be diagnosed with severe PPD, women must 
present at least 5 symptoms of depression (DSM-5 2013). Most women experience onset of 
symptoms within the first 3 months following delivery, and PPD is most prevalent at 10 to 
14 weeks following childbirth (Okun 2013). The overall incidence of PPD is estimated at around 
15% to 20%, with up to 10% being considered severe (Edge 2007; O’Hara 2014). Although 
frequently recognized in the postpartum period, depressive episodes can also begin in the last 
trimester or earlier during pregnancy (Meltzer-Brody 2011).  
Converging preclinical and clinical evidence (Luscher 2011) implicates deficits in GABAergic 
neurotransmission in the pathophysiology of depressive disorders including PPD. Furthermore, 
several pieces of experimental data implicate deficiencies in the normal regulation of 
endogenous neuroactive steroid in depressive disorders (Maguire 2008; Maguire 2009). It is 
thought that the large increase in progesterone-derived neurosteroids during pregnancy and their 
precipitous decrease at parturition may have considerable effects on γ-aminobutyric acid-gated 
chloride channel (GABAA) receptors during pregnancy and postpartum leading to PPD. The 
dynamic trafficking of extrasynaptic (δ-containing) GABAA receptors may be an important 
compensatory mechanism to changing neurosteroid levels during healthy pregnancies, and this 
trafficking pattern may be disrupted in PPD (Maguire 2008; Maguire 2009). In a preclinical 
model of PPD, mice lacking GABAA receptor δ-subunits (Gabrd -/- mice) exhibit postpartum-
specific phenotypes including reduced tonic inhibition, neuronal hyperexcitability, depressive-
like behaviors, and profound deficits in maternal care (Maguire 2008; Maguire 2009). In this 
model, the onset of depression-like behaviors occurred only in the postpartum period and 
included a significant increase in pup mortality due to maternal neglect and cannibalism, 
analogous to the increase in infanticide observed in human women with PPD. These data suggest 
that augmenting extrasynaptic GABAA receptor function may provide a therapeutic benefit in 
PPD.  
Current standard of care for severe PPD comprises cautious use of pharmacological therapies in 
nursing mothers combined with other interventions. Evidence for efficacy of tricyclic 
antidepressants and/or selective serotonin reuptake inhibitors (SSRIs) is based on use in the 
general population rather than any extensive studies in PPD (Austin 2013), and SSRIs tend to be 
preferred due to better data on safety while breastfeeding (Altshuler 2001). Based on the level of 
evidence for antidepressants in major depressive disorder (Kirsch 2008; Fournier 2010), there is 
a considerable need for improved pharmacological therapy for PPD.  
Drugs may be combined with a number of counseling, behavioral, and other nonpharmacological 
therapy approaches, which are generally used as the first-line therapy in less severe PPD 
(Altshuler 2001). Urgent referral and potentially admission are recommended for mothers at risk 


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of self-harm, with their infants, if such facilities exist (Austin 2013). Therapeutic options in 
severe PPD are currently limited, and it is not clear whether the current standard of care impacts 
the natural history of the disease, although most women recover within a year.  
5.2. 
SAGE-217 
SAGE-217 is a synthetic neuroactive steroid and a positive allosteric modulator of GABAA 
receptors, the major class of inhibitory neurotransmitter receptors in the brain and representing 
the most highly expressed synaptic and extrasynaptic inhibitory receptors in the mammalian 
brain. Consistent with the actions of other GABAA receptor potentiators 
(Rudolph and Knoflach 2011), SAGE-217 exhibits potent anticonvulsant, anxiolytic, and 
sedative activity when administered in vivo and pharmacological data provide evidence that 
SAGE-217 is a potent and efficacious neuroactive steroid and potentiator of multiple subtypes of 
GABAA receptors. 
To date, the safety, tolerability, efficacy, and pharmacokinetics (PK) of SAGE-217 (Oral 
Solution and Capsules) have been evaluated in Phase 1 studies and in Phase 2 studies (either 
complete or ongoing) in subjects with Essential Tremor, Parkinson’s Disease, Postpartum 
Depression and Major Depressive Disorder. The maximum tolerated dose (MTD) was 30 mg 
SAGE-217 Oral Solution in the Phase 1 multiple-ascending dose study and is the target 
therapeutic dose in clinical development with the capsule formulation. Based on a Phase 1 
relative bioavailability study of SAGE-217 Oral Solution and Capsules, exposures with 
SAGE-217 Capsules were lower than or equal to exposures observed at the same dose with 
SAGE-217 Oral Solution.  
SAGE-217 has been generally well tolerated to date, based on available data from the Phase 1 
and 2 studies. The most common treatment-emergent adverse events were sedation, somnolence, 
and dizziness. Most adverse events were reported as mild or moderate in intensity and resolved 
by the end of the study. A single suspected, unexpected, serious, adverse reaction (SUSAR) has 
been reported to date: an event of transient confusion leading to discontinuation of study drug in 
a subject with essential tremor who received the SAGE-217 Oral Solution. 
Refer to the Investigator’s Brochure for detailed background information on SAGE-217. 
5.3. 
Potential Benefits and Risks 
Protocol 217-PPD-201 is the first clinical study of SAGE-217 evaluating the efficacy, safety, and 
pharmacokinetics in subjects with PPD. Thus, the potential benefits in this population are 
unknown, although the risks are likely to be similar to those noted in the Investigator’s Brochure. 
Known risks of severe PPD include maternal suicide, infanticide, decreased maternal bonding 
with the infant, resulting in poor attachment (Lindahl 2005; McLearn 2006; Austin 2007; 
Meltzer-Brody 2014). It has also been demonstrated that effects of PPD extend to the paternal 
mood and, as a result, negatively impact the functioning of the entire family (Paulson 2010).  
In order to mitigate risks associated with this study, dose adjustments based on tolerability are 
allowed in the protocol.  
In the 217-CLP-103 study, SAGE-217 was found to be generally well-tolerated with no serious 
adverse events (AEs) reported during the treatment and follow-up periods. The most frequent AE 


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observed was sedation that was mild, transient, and occurred within 1 to 4 hours and generally 
dissipated by 8 hours.  
In conclusion, the known safety profile, coupled with exclusion of high-risk patients with 
attempted suicide associated with the current episode of depression, are expected to place this 
protocol at a favorable benefit to risk ratio.  
5.4. 
Dose Justification 
5.4.1. 
Safety Measures 
SAGE-217 has been generally well tolerated to date (see Section 5.2). 
Dose reductions are permitted during the study. During the treatment period, subjects will 
receive study drug as long as there are no dose-limiting safety/tolerability concerns. Dose 
adjustments should be made according to the process outlined in Section 9.3. 
In addition, as SAGE-217 is a central nervous system-active compound, the Columbia Suicide 
Severity Rating Scale (C-SSRS) will be used to monitor emergence or regression of suicidal 
ideation as means of detecting adverse effects on mood.  
5.4.2. 
Safety Instructions 
The study will be conducted on an outpatient basis. All doses will be self-administered by the 
subject at home. Adverse events will be collected throughout the subject’s participation. If safety 
concerns arise, the Investigator may hospitalize the subjects as clinically indicated. 
Instructions to the subject must include warnings about avoiding activities for which sedative 
effects of the study drug may impair performance, such as interactions with the infant, driving a 
motor vehicle, and operating machinery.  








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treatment allocation. Randomization will be performed centrally via an interactive response 
technology (IRT) system.  
Randomization schedules will be generated by an independent statistician. The allocation to 
treatment group (SAGE-217 or placebo) will be based on the randomization schedule. The 
randomization schedules will be kept strictly confidential, accessible only to authorized 
personnel until the time of unblinding. 
In the event of a medical emergency, the pharmacist and/or designated pharmacy staff may 
reveal actual study drug contents to the Investigator, who should also alert Sage of the 
emergency (see Section 13.6 for more details related to unblinding). In all cases where the study 
drug allocation for a subject is unblinded, pertinent information (including the reason for 
unblinding) must be documented in the subject’s records and on the electronic case report form 
(eCRF). If the subject or study center personnel (other than pharmacist and/or designated 
pharmacy staff) have been unblinded, the subject will be terminated from the study.  
 


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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 has signed an ICF prior to any study-specific procedures being performed.  
2. Subject is an ambulatory female between 18 and 45 years of age, inclusive.  
3. Subject is in good physical health and has no clinically significant findings, as 
determined by the Investigator, on physical examination, 12-lead ECG, or clinical 
laboratory tests.  
4. Subject agrees to adhere to the study requirements.  
5. Subject either must have ceased lactating at screening or, if still lactating or actively 
breastfeeding at screening, must agree to temporarily cease giving breast milk to her 
infant(s) from just prior to receiving study drug through Day 21, allowing for a 7-day 
washout after the last dose of study drug.  
6. Subject must have a negative pregnancy test at screening and Day 1 prior to the start of 
study drug administration.  
7. 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, and meets criteria for major 
depressive episode per DSM-5, diagnosed by Structured Clinical Interview for (DSM-5) 
Axis I Disorders (SCID-I).  
8. Subject has a HAM-D total score of ≥26 at screening and Day 1 (prior to randomization).  
9. Subject is ≤6 months postpartum.  
10. Subject is willing to delay start of other antidepressant or anxiety medications and any 
new pharmacotherapy regimens, including as-needed benzodiazepine anxiolytics, until 
after the Treatment Period ends and all Day 15 assessments have been completed.  
11. Subject has no detectable hepatitis B surface antigen (HBsAg), no detectable anti-
hepatitis C virus (HCV), detectable anti-HCV but negative viral load, and no detectable 
human immunodeficiency virus (HIV) antibody at screening.  
12. Subject agrees to use 1 of the following methods of contraception during participation in 
the study and for 30 days following the last dose of study drug, unless they are surgically 
sterile:  
• Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation. 
• Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation.  
• Intrauterine device. 
• Intrauterine hormone-releasing system. 
• Bilateral tubal occlusion. 


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• Vasectomized partner. 
8.2. 
Subject Exclusion Criteria 
Subjects will be excluded if they meet any of the following exclusion criteria.  
1. Subject has a recent history or active clinically significant manifestations of metabolic, 
hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, 
musculoskeletal, dermatological, urogenital, neurological, or eyes, ears, nose, and throat 
disorders, or any other acute or chronic condition that, in the Investigator’s opinion, 
would limit the subject’s ability to participate in or complete this clinical study.  
2. Subject has a known allergy to SAGE-217 Capsule or its excipients.  
3. Subject has active psychosis per Investigator assessment.  
4. Subject has attempted suicide associated with the current episode of PPD.  
5. Subject has a medical history of seizures.  
6. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder.  
7. Subject has a history of active alcoholism or drug addiction (including benzodiazepines) 
in the 12 months prior to screening.  
8. Subject has had exposure to another investigational medication or device within 30 days 
prior to screening.  
9. Subject has prior participation in any SAGE-547 or SAGE-217 clinical study.  
10. Subject who presents for the study while currently receiving psychotropic medications 
that are used with the intent to treat depressive symptoms such as antidepressants, 
atypical antipsychotics, etc., which have not been taken at the same dose for at least 
30 days prior to Day 1. (Subjects presenting for the study who have stopped taking these 
medications within the 30 days prior to the start day of study drug may be eligible if they 
will be off of the medications for longer than 5 half-lives until the start day of study 
drug).  
11. Use of any known strong inhibitors of cytochrome P450 (CYP)3A4 within 14 days or 5 
half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, Seville oranges, 
or products containing these within 14 days prior to receiving the first dose of study drug 
and throughout the study.  
12. Subject has a positive urine drug test at the screening visit. 
13. Use of any CYP inducers, such as rifampin, carbamazepine, ritonavir, enzalutamide, 
efavirenz, nevirapine, phenytoin, phenobarbital or St John’s Wort, within 14 days or 
5 half-lives (whichever is longer) prior to the first dose of study drug and throughout the 
study. 
14. Subject plans to undergo elective surgery during participation in the study. 


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8.3. 
Subject Withdrawal Criteria 
If there is an adverse event or medical reason for the withdrawal, the subject should be followed 
medically until the condition has either resolved or is stable. Details of the reason for withdrawal 
should be recorded in the subject’s eCRF.  
Subjects who withdraw should, if possible, complete the Early Termination Visit, including a 
physical examination, the appropriate investigations, vital signs, clinical laboratory tests 
 
 as outlined for the Day 21 visit (Table 2). All details of the Early Termination 
Visit should be recorded in the subject’s medical source documents.  
8.3.1. 
Study Drug Withdrawal 
Participation in the study is strictly voluntary. Subjects are free to discontinue the study at any 
time without giving their reason(s).  
A subject must be withdrawn from the study treatment in the event of any of the following: 
• Withdrawal of the subject’s consent; 
• New onset of a condition that would have met exclusion criterion, is clinically 
relevant and affects the subject’s safety, and discontinuation is considered necessary 
by the Investigators or Sage; 
• Occurrence of intolerable adverse events;  
• Intake of nonpermitted concomitant medication; 
• Subject noncompliance;  
• Significant protocol deviation determined in consultation with the Medical Monitor. 
If a subject failed to attend scheduled assessments during the course of the study, the 
Investigators must determine the reasons and the circumstances as completely and accurately as 
possible and document this in the subject’s source documents.  
Subjects may be withdrawn from the study if there is concern for the subject’s safety or it is 
determined that the subject is no longer a qualified participant.  
Subjects who withdraw or are withdrawn from the study will be replaced only if they withdraw 
prior to dosing. Subjects who are withdrawn from the study, fail to return or are no longer 
qualified will not be replaced.  
8.3.2. 
Criteria for Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons, including the occurrence of adverse events 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) and initiate withdrawal procedures for 
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9. 
TREATMENT OF SUBJECTS 
9.1. 
Number of Subjects 
Approximately 140 subjects with severe PPD will be randomized in a 1:1 ratio for approximately 
70 subjects per treatment group. Additional subjects may be enrolled in order to ensure there are 
130 evaluable subjects. Evaluable subjects are defined as those randomized subjects receiving 
study drug with valid baseline and at least 1 post-baseline HAM-D assessment. 
9.2. 
Treatment Assignment 
This is a double-blind study. Eligible subjects will be randomly assigned to receive SAGE-217 
or matched placebo on a 1:1 basis. Subjects, clinicians, and study team will be blinded to 
treatment allocation.  
Dose adjustments will only be allowed as described in Section 9.3.  
9.3. 
Dose Adjustment Criteria 
During the Treatment Period, subjects will be able to receive study drug as long as there are no 
dose-limiting safety/tolerability concerns. Subjects who cannot tolerate 30 mg QD will receive 
20 mg QD for the remainder of the Treatment Period. Subjects who experience intolerable AEs 
at the 20 mg QD dose level may be discontinued from study treatment at the discretion of the 
Investigator.  
Dose adjustments will be made based on tolerability as assessed by occurrence of a severe AE or 
a moderate AE of special interest (sedation, somnolence, dizziness, euphoric mood, confusion, 
drowsiness, inebriation (feeling drunk), or fatigue) judged by the investigator to be related to 
study drug. If a dose adjustment is deemed necessary by the Investigator at any time during the 
treatment period, the subject will return to the site to return any remaining current dose and for 
the adjusted dose to be dispensed. 
9.4. 
Prior/Concomitant Medications and Restrictions 
9.4.1. 
Prior/Concomitant Medications 
In this study, psychotropic medications refer to central nervous system active medications taken 
to help depressive symptoms, and include antidepressants, benzodiazepines, and hypnotic agents. 
Subjects presenting to the study on psychotropic medications may be eligible to participate if the 
same dose of the medications has been taken at least 30 days prior to Day 1; these subjects must 
remain at their same dose until completion of the Day 15 assessments. Those subjects on 
benzodiazepines and hypnotic agents may be considered for eligibility based on specific 
discussions between the Investigator and Sage to ensure safety. Subjects on other psychotropic 
medications, including stimulants, antipsychotics (if used for the purpose of treating psychotic 
symptoms), and mood stabilizers, are not eligible to participate in this study. Atypical 
antipsychotic use may be approved if it has been prescribed to augment the effects of 
antidepressants. 
Any concomitant medication determined necessary for the welfare of the subject may be given at 
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Section 9.4.2. All medications taken from 3 months prior to informed consent through the 
Day 45 visit should be recorded on the eCRF. Prior medications (ie, those taken prior to signing 
of ICF) that required washout for study entry will also be documented.  
9.4.2. 
Restricted Medications 
Restrictions on specific classes of medications include the following: 
• Initiation of new antidepressant therapy is prohibited upon admission to the study 
center for those eligible subjects who desire study participation. Those subjects 
already taking an antidepressant at the time of study entry (and meeting all study 
inclusion criteria) will be permitted to remain on the pre-existing antidepressant at 
their current dose if they were taking this dose at least 30 days prior to Day 1.  
• Benzodiazepines are to be avoided as much as possible. Eligible subjects taking a 
stable dose of benzodiazepine at least 30 days prior to Day 1 will be discussed on a 
case-by-case basis with Sage to determine eligibility. Subjects may be permitted to 
continue to take their current dose of the benzodiazepine (to prevent acute 
withdrawal), but no new benzodiazepine use will be permitted during the course of 
the study.  
• The use of hypnotics for sleep/insomnia such as Ambien® and trazodone is to be 
avoided; use of hypnotics will be discussed on a case-by-case basis with Sage.  
• Anticonvulsants are prohibited. Atypical antipsychotics are allowed only if the 
indication has been for the treatment of the depressive episode and not for treatment 
of psychotic symptoms. 
• Use of any known strong inhibitors of cytochrome P450 (CYP)3A4 within 14 days or 
5 half-lives (whichever is longer) prior to receiving the first dose of study drug and 
throughout the study. 
• Use of any CYP inducers, such as rifampin, carbamazepine, ritonavir, enzalutamide, 
efavirenz, nevirapine, phenytoin, phenobarbital or St John’s Wort, within 14 days or 
5 half-lives (whichever is longer) prior to the first dose of study drug and throughout 
the study. 
9.4.3. 
Other Restrictions 
The consumption of grapefruit juice, grapefruit, Seville oranges, or products containing these 
within 14 days prior to receiving the first dose of study drug and throughout the study is 
prohibited. 
Subjects are prohibited from giving their breast milk to infant(s) from just prior to receiving 
study drug through Day 21, allowing for a 7-day washout after the last dose of study drug. 
Subjects are prohibited from undergoing elective surgery during participation in the study. 


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9.5. 
Treatment Compliance 
Study drug will be dispensed by the site. Study drug administration will be monitored via a 
follow-up call from the site each evening (within approximately 1 hour following the scheduled 
evening dose) on Days 1-14. Any reasons for noncompliance will be documented, including: 
• Missed visits;  
• Interruptions in the schedule of administration; and 
• Nonpermitted medications. 
The time at which study procedures are conducted should follow the protocol timelines as 
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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
SAGE-217 Capsules are available as hard gelatin capsules containing a white to off-white 
powder. In addition to SAGE-217 Drug Substance, the SAGE-217 Capsules contain 
croscarmellose sodium, mannitol, silicified microcrystalline cellulose, and sodium stearyl 
fumarate as excipients. Capsules will be available in 10-mg, 20-mg, and 30-mg strengths in order 
to provide treatment doses of 20 mg and 30 mg. Subjects will be administered 2 capsules per 
dose. 
Matching placebo capsules are hard gelatin capsules for oral administration containing only the 
excipients listed above for the active capsule treatment. Subjects will receive 2 placebo capsules 
per dose. 
10.2. 
Batch Formula for SAGE-217 Capsules 
In addition to SAGE-217 Drug Substance, the SAGE-217 Capsules contain croscarmellose 
sodium, mannitol, silicified microcrystalline cellulose, and sodium stearyl fumarate as 
excipients.  
Matching placebo capsules contain only the excipients listed above for the active capsule 
treatment.  
10.3. 
Study Drug Packaging and Labeling 
The composition and pharmaceutical quality of the investigational product 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. All study drug will 
be labeled conforming to the applicable Code of Federal Regulations guidelines. SAGE-217 
Capsules and matched placebo capsules will be provided to the sites in subject-specific kits 
containing appropriately labeled bottles. Study drug will be dispensed by the appropriate site 
staff per the Pharmacy Manual.  
10.4. 
Study Drug Storage 
SAGE-217 Capsules and matched placebo capsules are to be stored at room temperature, safely 
and separately from other drugs. 
The study drug may not be used for any purpose other than the present study. After the study is 
completed, all unused study drug must be retained, returned as directed, or destroyed on site per 
Sage’s instructions.  
10.5. 
Administration 
Subjects will self-administer study drug (30 mg SAGE-217 or placebo) daily for 14 days on an 
outpatient basis. Subjects will be instructed to take the study drug each evening with food at 8:00 
PM ±30 minutes. If dosing occurs >30 minutes but <60 minutes before/after the scheduled time, 
this would constitute a protocol deviation. If the dose is not administered within <60 minutes 
after the scheduled dose, the subject will skip the dose and take the next scheduled dose on the 


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following day. Compliance with study drug administration will be monitored via a follow-up 
phone call from the site each evening (within approximately 1 hour following the scheduled 
evening dose) on Days 1-14. Subjects who tolerate 30 mg QD will receive this dose for the rest 
of the Treatment Period. Those subjects who cannot tolerate the 30 mg QD dose will have a dose 
reduction and receive 20 mg QD for the rest of the Treatment Period (see Section 9.3 for dose 
adjustment criteria).  
10.6. 
Study Drug Accountability 
Upon receipt of study drug, the Investigator or designee will inspect the materials and follow the 
instructions regarding receipt in the Pharmacy Manual. A copy of the shipping documentation 
will be kept in the study files.  
The study drug provided is for use only as directed in this protocol. The Investigator or designee 
must maintain a record of all study drug received, used, and discarded. It must be clear from the 
records which subject received which kit of active or placebo treatment. 
If a dose adjustment is deemed necessary by the Investigator at any time during the treatment 
period (see Section 9.3 for dose adjustment criteria), the subject will be instructed to return to the 
site to return any remaining current dose and for the adjusted dose to be dispensed. 
Sage or designee will be permitted access to the study supplies at any time within usual business 
hours and with appropriate notice during or after completion of the study to perform drug 
accountability reconciliation.  
10.7. 
Study Drug Handling and Disposal 
At the end of the study, all used and unused study drug will be reconciled and returned to Sage 
Therapeutics for destruction or destroyed locally; disposition of study drug will be documented. 
A copy of the inventory record of any clinical supplies that have been received, dispensed or 
destroyed must be documented by the site as directed. This documentation must include at least 
the information below: 
• The number of dispensed units; 
• The number of administered units; 
• The number of unused units; 
• The number of units destroyed at the end of the study; 
• The date, method, and location of destruction. 


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11. 
ASSESSMENT OF EFFICACY 
For all efficacy assessments, the baseline values will be calculated as the last recorded value 
prior to the start of randomized study drug administration. Change from baseline values will be 
calculated as the assessment score minus the baseline value. Change from baseline values will be 
calculated for each item and total score.  
Subject-rated and clinician-rated scales are to be completed according to the Schedule of Events 
(Table 2). 
11.1. 
Primary Efficacy Outcome Measure - Hamilton Rating Scale for 
Depression (HAM-D) 
The primary outcome measure will be the change from baseline in 17-item HAM-D total score at 
the end of the Treatment Period (Day 15).  
The 17-item HAM-D will be used to rate the severity of depression in subjects who are already 
diagnosed as depressed (Hamilton 1960). The 17-item HAM-D comprises individual ratings 
related to the following symptoms: depressed mood (sadness, hopeless, helpless, worthless), 
feelings of guilt, suicide, insomnia (early, middle, late), work and activities, retardation 
(slowness of thought and speech; impaired ability to concentrate; decreased motor activity), 
agitation, anxiety (psychic and somatic), somatic symptoms (gastrointestinal and general), 
genital symptoms, hypochondriasis, loss of weight, and insight. The HAM-D assessments are to 
be completed at the scheduled clinic visits 12 hours ±1 hour following the evening dose. Every 
effort should be made for the same rater to perform all HAM-D assessments for an individual 
subject.  
The HAM-D total score will be calculated as the sum of the 17 individual item scores.  
In addition to the primary efficacy endpoint of change from baseline in HAM-D total score, 
several secondary efficacy endpoints will be derived for the HAM-D. Hamilton Rating Scale for 
Depression subscale scores will be calculated as the sum of the items comprising each subscale. 
Hamilton Rating Scale for Depression response will be defined as having a 50% or greater 
reduction from baseline in HAM-D total score. Hamilton Rating Scale for Depression remission 
will be defined as having a HAM-D total score of ≤7.  
11.2. 
Secondary Efficacy Outcome Measures 
Secondary efficacy assessments include evaluation of depressive and anxiety symptom severity 
by the MADRS (Section 11.2.1), CGI (Section 11.2.2 ), and HAM-A (Section 11.2.3).  
11.2.1. 
Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS is a ten-item diagnostic questionnaire that psychiatrists use to measure the severity 
of depressive episodes in subjects with mood disorders. It was designed as an adjunct to the 
HAM-D that would be more sensitive to the changes brought on by antidepressants and other 
forms of treatment than the Hamilton Scale.  
Higher MADRS scores indicate more severe depression, and each item yields a score of 0 to 6. 
The overall score ranges from 0 to 60 (McDowell 2006; Müller-Thomsen 2005). 




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13. 
ASSESSMENT OF SAFETY 
The study will be conducted on an outpatient basis. Subjects will be instructed to self-administer 
the study drug with food each evening. Adverse events will be collected throughout the subject’s 
participation. If safety concerns arise, the Investigator may hospitalize the patients as clinically 
indicated. Instructions to the subject must include warnings about avoiding activities for which 
sedative effects of the study drug may impair performance, such as interactions with the infant, 
driving a motor vehicle, and operating machinery. 
If daily monitoring calls reveal AEs, the PI will be notified and the subjects may be brought in 
for evaluation at the PI’s discretion. During these visits, if the PI determines that dose adjustment 
is needed, subjects will be dispensed the lower dose (20 mg) for the remaining dosing period. 
13.1. 
Safety and Tolerability Parameters 
Safety and tolerability of study drug will be evaluated by vital signs measurements, clinical 
laboratory measures, physical examination, ECGs, concomitant medication usage, C-SSRS, and 
adverse event reporting. All safety and tolerability parameters will be assessed according to the 
Schedule of Events (Table 2). 
13.1.1. 
Demographic/Medical History 
Age, race, and ethnic origin will be recorded at the Screening visit. The diagnosis of depression 
will be determined using the SCID-I. A full medical and family history, including recording of 
depression and anxiety diagnoses and all major depression episodes (and for the subject, 
depression and anxiety treatment history [medication, hospitalization]), other Axis I and Axis II 
disorders, and postpartum depression episodes in immediate female family members (siblings, 
parents, and grandparents), will be recorded at the Screening visit. Subjects will be specifically 
asked about the depression or anxiety diagnoses listed in Appendix 1 and use of antidepressants 
listed in Appendix 2. 
13.1.2. 
Vital Signs 
Vital signs include respiratory rate, oral temperature, and supine (for at least 5 minutes prior to 
the measurement) and standing systolic and diastolic blood pressure and heart rate. Vital signs 
may be repeated at the discretion of the Investigator as clinically indicated.  
13.1.3. 
Weight and Height 
Body weight and height will be measured at the Screening visit; weight will also be measured on 
Days 15 and 21.  
13.1.4. 
Physical Examination 
A physical examination of all major body systems will be undertaken and recorded.  
13.1.5. 
Electrocardiogram (ECG) 
A 12-lead ECG will be assessed; the standard intervals as well as any abnormalities will be 
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13.1.6. 
Laboratory Assessments 
Blood and urine samples will be collected for hematology, serum chemistry, coagulation, select 
hormone parameters, and urinalysis. Where consent is given, an optional blood sample for 
hormone and exploratory biochemistry testing and optional genetic sample for biomarker testing 
will be collected at the Screening visit, Day 8 and Day 15.  
Serum and urine samples for pregnancy tests will also be collected. These assessments should be 
performed as outlined below.  
All samples will be analyzed at the central laboratory. Subjects may be considered eligible for 
the study based on local laboratory results; however, screening samples must also be sent to the 
central laboratory. Both local and central screening labs must adhere to the visit window 
provided in the Schedule of Events.  
All clinical laboratory test results outside the reference range will be interpreted by the 
Investigator as abnormal, not clinically significant (NCS) or abnormal, clinically significant 
(CS). Screening results considered abnormal, CS recorded at the Screening visit may make the 
subject ineligible for the study pending review by the Medical Monitor. Clinical laboratory 
results that are abnormal, CS during the study but within normal range at baseline and/or indicate 
a worsening from baseline will be considered adverse events, assessed according to 
Section 13.2.1, and recorded in the eCRF.  
13.1.6.1. Hematology 
Hematology tests will include complete blood count, including red blood cells, white blood cells 
with differentiation, hemoglobin, hematocrit, reticulocytes, and platelets. The coagulation panel 
will include activated partial thromboplastin time, prothrombin time, and international 
normalized ratio.  
13.1.6.2. Blood Chemistry 
Serum chemistry tests will include serum electrolytes; glucose; renal function tests, including 
creatinine, blood urea nitrogen, bicarbonate or total carbon dioxide; liver function tests, 
including alkaline phosphatase, total bilirubin, aspartate aminotransferase, and alanine 
aminotransferase; total protein; albumin; and thyroid stimulating hormone.  
13.1.6.3. Urinalysis 
Urinalysis will include assessment of protein, hemoglobin, glucose, ketones, bilirubin, 
urobilinogen, leukocyte esterase, nitrites, color, turbidity, pH, and specific gravity.  
13.1.6.4. Virus Serology 
Subjects will be screened for hepatitis (HBsAg and anti-HCV) and HIV prior to being enrolled in 
the study. If subjects are positive for anti-HCV, reflex RNA testing (viral load) for HCV should 
be conducted; those subjects with positive anti-HCV may be enrolled only if the viral load is 
negative. 


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13.1.6.5. Hormones and Exploratory Biochemistry 
Optional blood samples will be collected and may be analyzed for stress hormone levels, 
kynurenine biochemistry, and markers of inflammation. Future research may suggest other 
biochemical pathways as candidates for influencing not only response to SAGE-217 but also 
susceptibility to disorders for which SAGE-217 may be evaluated. Thus, the exploratory 
biochemistry may involve study of additional unnamed molecular pathways, but only as related 
to disease susceptibility and drug action.  
13.1.6.6. Pregnancy Test 
Women of childbearing potential will be tested for pregnancy by serum pregnancy test at the 
Screening visit and by urine pregnancy test on Day 1 (predose), and at the follow-up visit. A 
urine pregnancy test will also be performed as part of the early termination assessments for 
subjects who discontinue the study early. If a subject becomes pregnant during the study, the 
process for reporting the pregnancy and guidance for collection of information related to the 
pregnancy is outlined in the Safety Management Plan.  
13.1.6.7. Genetic Testing 
Where consent is given, an optional genetic sample for biomarker testing will be collected at the 
Screening visit.  
The objective of this research is to collect and store blood samples for possible DNA extraction 
and exploratory research into how genes or specific genetic variation may influence response (ie, 
distribution, safety, tolerability, and efficacy) to SAGE-217. Specific genetic variations of 
interest include but are not limited to: classes of metabolizing enzymes (eg, cytochrome P450 
supra-family genes), genes encoding enzymes involved in the production and metabolism of 
SAGE-217 (eg, AKR1C4 [3α-hydroxysteroid dehydrogenase]), genes associated with the GABA 
receptor (eg, GABRA1-A6, GABRB1-B3, GABRD, GABRE, GABRG1-3), and genes 
associated with the production and degradation of GABA.  
Future research may suggest other genes or gene categories as candidates for influencing not 
only response to SAGE-217 but also susceptibility to disorders for which SAGE-217 may be 
evaluated. Thus, the genetic research may involve study of additional unnamed genes or gene 
categories, but only as related to disease susceptibility and drug action.  
13.1.6.8. Drugs of Abuse and Alcohol 
A urine sample for assessment of selected drugs of abuse (including amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, opiates, and phencyclidine) and a serum (screening) or 
breath sample (predose on Day 1) for alcohol screen will be collected. Use of benzodiazepines at 
screening is not necessarily exclusionary, as subjects will be allowed to take psychotropics at a 
stable dose that have been initiated within 30 days prior to informed consent (see Section 9.4).  
13.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011). This scale 
consists of a baseline evaluation that assesses the lifetime experience of the subject with suicidal 
ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last 


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study visit. The C-SSRS includes ‘yes’ or ‘no’ responses for assessment of suicidal ideation and 
behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being 
the most severe).  
The “Baseline/Screening” C-SSRS form will be completed at screening (lifetime history and past 
24 months). The “Since Last Visit” C-SSRS form will be completed at all subsequent time 
points, as outlined in Table 2.  
13.2. 
Adverse and Serious Adverse Events 
13.2.1. 
Definition of Adverse Events 
13.2.1.1. Adverse Event 
An adverse event is the development of an undesirable medical condition or the deterioration of 
a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. In clinical studies, an adverse event 
can include an undesirable medical condition occurring at any time, including baseline or 
washout periods, even if no study treatment has been administered. 
13.2.1.2. Suspected Adverse Reaction 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event. For the purposes of Investigational New Drug safety 
reporting, “reasonable possibility” means there is evidence to suggest a causal relationship 
between the drug and the adverse event. Suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a drug.  
13.2.1.3. Serious Adverse Event 
A serious adverse event is an adverse event occurring during any study phase and at any dose of 
the investigational product, comparator or placebo, that fulfills 1 or more of the following: 
• It results in death 
• It is immediately life-threatening 
• It requires inpatient hospitalization or prolongation of existing hospitalization 
• It results in persistent or significant disability or incapacity 
• It results in a congenital abnormality or birth defect 
• It is an important medical event that may jeopardize the subject or may require 
medical intervention to prevent 1 of the outcomes listed above. 
All serious adverse events that occur after any subject has been enrolled, whether or not they are 
related to the study, must be recorded for the duration of the study on the SAE form provided by 
Sage Therapeutics or designee.  


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13.3. 
Relationship to Study Drug 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each adverse event (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 investigational product. If no valid reason 
exists for suggesting a relationship, then the adverse event 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 investigational product and the occurrence of the adverse event, then the 
adverse event should be considered “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 adverse event/serious adverse event and the investigational 
product is determined to be “possible” or “probable”, the event will be considered to be related 
to the investigational product for the purposes of expedited regulatory reporting.  
13.4. 
Recording Adverse Events 
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. Clinically significant changes in laboratory values, blood pressure, and pulse 
need not be reported as adverse events unless they prompt corrective medical action by the 
Investigator, constitute a serious adverse event, or lead to discontinuation of administration of 
study drug.  
Information about adverse events will be collected from the signing of the ICF until the final 
visit of the study for that subject. Adverse events that occur after the first administration of study 
drug will be denoted as treatment-emergent adverse events (TEAEs).  
All adverse events regardless of Investigator-determined causality, should be followed until the 
event is resolved or the Investigator determines the event is stable or no longer clinically 
significant.  
The adverse event term should be reported in standard medical terminology when possible. For 
each adverse event, the Investigator will evaluate and report the onset (date and time), resolution 
or clinical plateau (date and time), severity, causality, action taken, outcome, and whether or not 
it caused the subject to discontinue the study.  
Severity 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) 


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• Severe (incapacitating, with inability to perform normal activities) 
13.5. 
Reporting Adverse Events 
All serious adverse events (regardless of causality) will be recorded from the signing of the ICF 
until the Day 45 Follow-up visit. Any serious adverse events considered possibly or probably 
related to the investigational product and discovered by the Investigator at any time after the 
study should be reported. All serious adverse events must be reported to Sage or Sage’s designee 
immediately in writing within 24 hours of the first awareness of the event. The Investigator must 
complete, sign and date the serious adverse event form, verify the accuracy of the information 
recorded on the serious adverse event form with the corresponding source documents, and send a 
copy to Sage Therapeutics or designee.  
Additional follow-up information, if required or available, should be sent to Sage Therapeutics 
or designee within 24 hours of receipt; a follow-up serious adverse event form should be 
completed and placed with the original serious adverse event information and kept with the 
appropriate section of the eCRF and/or study file.  
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 of all serious 
adverse events that occur at his or her site if applicable per the IRB’s requirements. Investigators 
will also be notified of all unexpected, serious, drug-related events (7-/15-Day Safety Reports) 
that occur during the clinical study. Each site is responsible for notifying its IRB of these 
additional serious adverse events.  
13.6. 
Emergency Identification of Study Drug 
During the study, the blind is to be broken only when the safety of a subject is at risk and the 
treatment plan is dependent on the study treatment received. Unless a subject is at immediate 
risk, the Investigator must make diligent attempts to contact Sage prior to unblinding the study 
treatment administered to a subject. Any request from the Investigator about the treatment 
administered to study subjects must be discussed with Sage. If the unblinding occurs without 
Sage’s knowledge, the Investigator must notify Sage as soon as possible and no later than the 
next business morning. All circumstances surrounding a premature unblinding must be clearly 
documented in the source records. Unless a subject is at immediate risk, any request for the 
unblinding of individual subjects must be made in writing to Sage and approved by the 
appropriate Sage personnel, according to standard operating procedures. The blinding of the 
study will be broken after the database has been locked. Electronic copies of the randomization 
code will be made available to the laboratory performing the bioanalytical analyses in order to 
allow for limited analysis of samples from subjects receiving placebo.  
In the event of a medical emergency or pregnancy, the Investigator will discuss with the Medical 
Monitor if unblinding is warranted for medical management of the subject. If there is agreement 
to unblind treatment assignment, the unblinding procedure described in the Safety Management 
Plan for the study will be followed. If the Investigator is unable to contact the Medical Monitor 
in a medical emergency, and it is deemed clinically necessary by the Investigator, the treatment 
group for that subject may be unblinded in the interactive response technology system. 


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In all cases where the study drug allocation for a subject is unblinded, pertinent information must 
be documented in the subject’s records and on the eCRF. If the subject or study center personnel 
(other than unblinded personnel designated to dispense the study drug) have been unblinded, the 
subject will be permanently discontinued from the study.  




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fixed effects. All post-baseline time points will be included in the model. The primary 
comparison will be between SAGE-217 Capsule and placebo at the 15-day time point. Model-
based point estimates (ie, least squares [LS] means), 95% confidence intervals, and p-values) 
will be reported where applicable. An unstructured covariance structure will be used to model 
the within-subject errors. Compound symmetry covariance structure will be used if there is a 
convergence issue with the unstructured covariance model.  
14.6. 
Secondary Efficacy Endpoints 
14.6.1. 
Efficacy Analyses 
Similar to those methods described for the primary endpoint in Section 14.5, MMRM will be 
used for the analysis of the following variables: changes from baseline in MADRS total score, 
HAM-A total score, 
, and select individual item and subscale 
scores. For each model, the comparison of interest will be between SAGE-217 capsule and 
placebo at the 15-day time point. Model-based point estimates (ie, LS means), 95% confidence 
intervals, and p-values will be reported.  
Generalized estimating equation (GEE) methods will be used for the analysis of the following 
binary variables: HAM-D response (define as ≥50% reduction from baseline in HAM-D total 
score), HAM-D remission (defined as ≤7.0 HAM-D total score), and CGI-I response. 
Generalized estimating equation models will include terms for center, treatment, baseline score, 
assessment time point, and time point-by-treatment as explanatory variables. The comparison of 
interest will be the difference between SAGE-217 Capsules and placebo at the 15-day time point. 
Model-based point estimates (ie, odds ratios), 95% confidence intervals, and p-values will be 
reported. For the CGI-I response analysis, baseline CGI-S score will be included in the model.  
Descriptive statistics for all scores, change from baseline values, and response variables will be 
presented by treatment and assessment time point. Summaries will include n, mean, SD, median, 
minimum, and maximum.  
14.6.2. 
Safety Analyses 
Safety and tolerability of SAGE-217 will be evaluated by adverse events, concomitant 
medication usage, changes from baseline in vital signs, clinical laboratory evaluations, and 12-
lead ECG. Suicidality will be monitored by the C-SSRS. Safety data will be listed by subject and 
summarized by treatment group. All safety summaries will be performed on the Safety Set.  
14.6.2.1. Adverse Events 
The analysis of adverse events will be based on the concept of TEAEs. A TEAE is defined as an 
adverse event with onset after the start of study drug, or any worsening of a pre-existing medical 
condition/adverse event with onset after the start of study drug and until 7 days after the last 
dose. The incidence of TEAEs will be summarized overall and by Medical Dictionary for 
Regulatory Activities (MedDRA) Version 19.1 or higher System Organ Class (SOC) and 
preferred term. Incidences will be presented in order of decreasing frequency for the SAGE-217 
treatment group. In addition, summaries will be provided by severity (mild, moderate, severe) 
and by causality (related, not related) to study drug (see Section 13.3).  


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Treatment-emergent adverse events leading to discontinuation and serious adverse events (see 
Section 13.2.1.3 for definition) with onset after the start of randomized study drug will also be 
summarized.  
All adverse events and serious adverse events (including those with onset or worsening before 
the start of randomized study drug) through the Day 45 Follow-up visit will be listed. 
14.6.2.2. 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 summarized.  
14.6.2.3. Physical Examinations 
Any clinically significant change in physical examination compared to those observed at 
screening should be noted as an adverse event.  
14.6.2.4. Vital Signs 
Vital sign results will be listed by subject and timing of collection. Mean changes from 
randomization in vital signs will be summarized by time point.  
14.6.2.5. 12-Lead Electrocardiogram 
The following ECG parameters will be listed for each subject: heart rate, PR, QRS, QT, QTc, 
and QT interval calculated using the Fridericia method (QTcF). Any clinically significant 
abnormalities or changes in ECGs should be listed as an adverse event. Electrocardiogram 
findings will be listed by subject and visit.  
14.6.2.6. 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 (WHO-DD) September 2016, 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 those taken prior to the first dose of 
study drug. Concomitant medications are defined as those with a start date on or after the first 
dose of study drug, or 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 drug. If medication dates are incomplete and 
it is not clear whether the medication was concomitant, it will be assumed to be concomitant.  
Details of prior and concomitant medications will be listed by subject, start date, and verbatim 
term.  
14.6.2.7. Columbia Suicide Severity Rating Scale 
Suicidality data collected on the C-SSRS at baseline and by visit during the Treatment Period 
will be listed for all subjects. Listings will include behavior type and/or category for Suicidal 
Ideation and Suicidal Behavior of the C-SSRS.  




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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
Study Monitoring 
Before an investigational site can enter a subject into the study, a representative of Sage 
Therapeutics or designee will visit the investigational study site to:  
• Determine the adequacy of the facilities; and 
• 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 for the following: 
• 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 investigational product 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 
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 adverse events and serious adverse events have been properly documented 
on eCRFs and confirm any serious adverse events have been forwarded to Sage 
Therapeutics or designee and those serious adverse events 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. 
15.2. 
Audits and Inspections 
Authorized representatives of Sage Therapeutics, a regulatory authority, an Independent Ethics 
Committee (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 of Technical Requirements for Pharmaceuticals for Human Use (ICH), and any 
applicable regulatory requirements. The Investigator should contact Sage Therapeutics 
immediately if contacted by a regulatory agency about an inspection.  


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15.3. 
Institutional Review Board (IRB) 
The Principal Investigator must obtain IRB approval for the investigation. Initial IRB approval 
and all materials approved by the IRB for this study, including the subject consent form and 
recruitment materials, must be maintained by the Investigator and made available for inspection.  


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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Investigator and institution will permit study-related monitoring, audits, IRB review, and 
regulatory inspections as requested by the Food and Drug Administration, Sage, or Sage’s 
designee, including direct access to source data/documents (ie, original medical records, 
laboratory reports, hospital documents, progress reports, signed ICFs) 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 Sage 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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17. 
ETHICS 
17.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, 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 with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. 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.  
17.2. 
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.  
17.3. 
Written Informed Consent 
The Principal 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 signing the ICF.  
As additional assessments, the ICF will contain provisions for optional consent for the collection 
of blood samples for hormone and biomarker testing during screening and the collection of 
breast milk for biobanking 
 purposes. The ICF, as specified by the clinical site’s 
IRB, 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 Principal Investigator(s) must maintain the original, signed ICF. A copy of the signed ICF 
must be given to the subject.  
 


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18. 
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, adverse events, 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 much as possible, and the reason for the discontinuation 
or termination clearly and concisely specified on the appropriate eCRF. 
18.1. 
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.  
18.2. 
Retention of Records 
The Principal 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 
discontinuation 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.  
18.3. 
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 Sage 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, a publicly available trial registry database; 
however, protected health information of individual subjects will not be used.  


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All information regarding the investigational product 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 
Sage. It is understood that there is an obligation to provide Sage with complete data obtained 
during the study. The information obtained from the clinical study will be used towards the 
development of the investigational product and may be disclosed to regulatory authorities, other 
Investigators, corporate partners, or consultants, as required.  


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19. 
PUBLICATION POLICY 
All information concerning SAGE-217 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.  


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20. 
LIST OF REFERENCES 
Altshuler LL, Cohen LS, Moline ML, et al. Treatment of depression in women: a summary of the 
expert consensus guidelines. J Psychiatr Pract. 2001;7(3):185-208. 
Austin MP, Kildea S, Sullivan E. Maternal mortality and psychiatric morbidity in the perinatal 
period: challenges and opportunities for prevention in the Australian setting. Med J Aust. 
2007;186:36–47. 
Austin MP, Middleton P, Reilly NM, Highet NJ. Detection and management of mood disorders 
in the maternity setting: the Australian Clinical Practice Guidelines. Women Birth. 2013;26(1):2-
9.  
Cox JL, Holden JM, Sagovsky R. Detection of postnatal depression. Development of the 10-item 
Edinburgh Postnatal Depression Scale. Br J Psychiatry. 1987;150:782-6. 
DSM-IV. Diagnostic and statistical manual of mental disorders (4th ed.). American Psychiatric 
Association 1994. Arlington, VA: American Psychiatric Association Publishing. 
DSM-5. Diagnostic and statistical manual of mental disorders (5th ed). American Psychiatric 
Association 2013. Arlington, VA: American Psychiatric Publishing. 
Edge D. Ethnicity, psychosocial risk, and perinatal depression-a comparative study among inner-
city women in the United Kingdom. J Psychosom Res. 2007;63(3):291-5.  
Fournier JC, DeRubeis RJ, Hollon SD, et al. Antidepressant drug effects and depression 
severity—a patient-level meta-analysis. JAMA. 2010;303:47-53.  
Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32:50-5.  
Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56-62.  
Kirsch I, Deacon BJ, Huedo-Medina TB, et al. Initial Severity and Antidepressant Benefits: A 
Meta-Analysis of Data Submitted to the Food and Drug Administration. PLoS Med. 2008; 5(2): 
e45.  
Lindahl V, Pearson JL, Colpe L. Prevalence of suicidality during pregnancy and the postpartum. 
Arch Womens Ment Health. 2005;8:77–87. 
Luscher B, Shen Q, Sahir N. The GABAergic deficit hypothesis of major depressive disorder. 
Mol Psychiatry. 2011;16(4):383-406.  
Maguire J, Mody I. GABA(A)R plasticity during pregnancy: Relevance to postpartum 
depression. Neuron. 2008;59(2);207-13.  
Maguire J, Ferando I, Simonsen C, Mody I. Excitability changes related to GABAA receptor 
plasticity during pregnancy. J Neurosci. 2009;29(30):9592-601.  
McDowell, I. Measuring Health: A guide to rating scales and questionnaires. 2006: 3rd Ed. New 
York: Oxford University Press.  
McLearn KT, Minkovitz CS, Strobino DM, et al. Maternal depressive symptoms at 2 to 
4 months post partum and early parenting practices. Arch Pediatr Adolesc Med. 
2006;160:279-84. 




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CONFIDENTIAL 
 
61 
 
 
  
 
21. 
APPENDICES 


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62 
 
 
  
 
APPENDIX 1. DEPRESSION AND ANXIETY DISORDERS LIST 
Purpose: It is important to have a complete medical history of the subjects’ prior diagnoses for 
depression or anxiety. Please review this list with each subject and record any medical history on 
the appropriate case report form.  
 
Generalized Anxiety Disorder 
Obsessive-Compulsive Disorder 
Panic Disorder 
Posttraumatic Stress Disorder 
Major Depressive Disorder 
Persistent Depressive Disorder 
Bipolar Disorder 
Seasonal Affective Disorder 
Psychotic Depression 
Premenstrual Dysphoric Disorder 
Situational Depression 
Atypical Depression 
Schizophrenia 
Postpartum Depression 
 
 


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CONFIDENTIAL 
 
63 
 
 
  
 
APPENDIX 2. PRIOR AND CONCOMITANT ANTIDEPRESSANT 
MEDICATION LIST 
 
Purpose: It is important to have a complete history of the subjects’ prior therapies for depression. 
Please review the following list of examples of common therapies for depression with each 
subject and record any experience with these or any therapies for depression on the appropriate 
case report form.  
 
Celexa (citalopram) 
Prozac, Sarafem (fluoxetine) 
Zoloft (sertraline) 
Cymbalta (duloxetine)  
Effexor XR (venlafaxine) 
Wellbutrin (bupropion) 
Elavil (amitriptyline) 
Pamelor (nortriptyline) 
Lexapro (escitalopram) 
Luvox (fluvoxamine) 
Oleptro, Desyrel (trazodone) 
Paxil, Pexeva, Brisdell (paroxetine) 
Remeron, Remeron Soltab (mirtazapine) 
 

SAP_001.pdf: 
 
Official Title: 
A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-
Controlled Study Evaluating the Efficacy, Safety, and Pharmacokinetics of 
SAGE-217 in the Treatment of Adult Female Subjects With Severe 
Postpartum Depression 
NCT Number: 
 
NCT02978326 
 
Document Date: 
 
SAP Version 1.0: 11 December 2018 
 
 
 
 
 
 
 


Sage Therapeutics, Inc. 
Statistical Analysis Plan 
Methods 
Protocol 217-PPD-201 
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PARALLEL-GROUP, 
PLACEBO-CONTROLLED STUDY EVALUATING THE EFFICACY, 
SAFETY, AND PHARMACOKINETICS OF SAGE-217 IN THE TREATMENT 
OF ADULT FEMALE SUBJECTS WITH SEVERE POSTPARTUM 
DEPRESSION 
Author of SAP: 
, MStat 
Version: Version 1.0 
Date of SAP: 11 DECEMBER 2018 
Sponsor 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, Massachusetts 02142 
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written consent of 
Sage Therapeutics, Inc 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.










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2
LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION OR DESCRIPTION 
AE 
adverse event 
AR(1) 
autoregressive 
ATC 
Anatomical Therapeutic Chemical 
BAI 
Beck Anxiety Index 
BID 
twice daily 
BMI 
body mass index 
BLQ 
below the limit of quantification 
%CV 
percent coefficient of variation 
CGI-I 
Clinical Global Impression of Improvement 
CGI-S 
Clinical Global Impression of Severity 
CI 
confidence interval 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CS 
compound symmetry 
CSR 
clinical study report 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
HAM-A 
Hamilton Anxiety Rating Scale 
HAM-D 
Hamilton Rating Scale for Depression 
HEOR 
Health economics outcomes 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model for repeated measures 
LLOQ 
lower limit of quantitation 
LS 
least squares 
PPD 
postpartum depression 
PT 
preferred term 
QTcF 
QT-interval for ECG corrected for heart rate (Fridericia) 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
System Organ Class 
SSS 
Stanford Sleepiness Scale 
TEAE 
treatment emergent adverse event 
ULOQ 
upper limit of quantitation 
VC 
variance components 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 










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7
MODIFICATIONS 
7.1 
Modifications to the Approved Clinical Study Protocol 
The following changes from the clinical study protocol (version 9.0, dated July 2, 2018) have been made 
in this SAP: 
1.
2.
The protocol (Section 14.6.2.1) defines the upper limit for a TEAE as 7 days after last dose of
study drug, whereas Section 13.4 of the protocol defines TEAEs as any AE occurring after first
administration of study drug.  Per Sage’s request, this SAP follows Section 13.4 of the protocol in
defining TEAEs.
3.
The protocol does not have MADRS response and remission as secondary endpoints, but this was
requested to be analyzed. Additionally, subgroup analyses of selected efficacy endpoints were
requested by the Sponsor.
4.
The protocol has the All Randomized Set as a data analysis set, used to analyze subject
disposition, demographics, and baseline characteristics summaries; however, per Sage’s request,
subject disposition includes all enrolled subjects, and demographics and baseline characteristics
will be analyzed using subjects in the Safety Set and the Efficacy Set.
5.
Only one subject was enrolled and dosed in Part A before it was closed to enrollment. Therefore,
data collected in Part A will only be listed.
6.
Changes to the original and subsequent sample size estimates: Each amendment in which there
was a change to the desired study power and placebo-adjusted treatment difference for this study
was guided by clinical information external from this study. This information includes (1)
comments from the Agency during the brexanolone PPD Program Breakthrough Therapy (BTD)
designation (BTD) meeting, (2) study results from the brexanolone program (547-PPD-202B and
202C) and (3) study results from the SAGE-217 MDD program (217-MDD-201B). The original
sample size calculation used 10% alpha level 80% power with treatment difference and SD of 10
points each (based on observed data from SAGE-547-PPD-202A). Following discussions with
the FDA related to BTD for brexanolone, comments were incorporated into the SAGE-217 PPD
study to use alpha 5% which led to a decrease in the power to 72%. Consequently, following the
availability of study result from SAGE-217-MDD-201 Part B that showed 7.5 points (smaller
than 10 points) placebo-adjusted treatment difference, the SAGE-217 PPD-201 study sample size
was increased to maintain study power at the pre-specified 80%. Finally, to position the study as a
potential pivotal study, Sage took the opportunity to increase study power to 90% based on a
placebo-adjusted treatment difference of 4 points, SD = 7 points (per pooled SAGE-547-PPD-
202A, 202B, 202C 90 mg dose data). This was described in Amendment 6 of the protocol and
SAP (Section 6.2).
7.
Sensitivity analysis was added in case more than 10% of subjects are missing HAM-D scores at
Day 15.
8.
Per protocol analysis is added.
9.
7.2 
Modifications to the Approved Statistical Analysis Plan 
This is the first version of the SAP. 




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Categorical (qualitative) variables will be summarized using the number and proportion of each possible 
value.  In general, the denominator for the percentage calculation will be based upon the total number of 
subjects in the study population for the treatment group, unless otherwise specified. 
The minimum and maximum will be reported with the same degree of precision (ie, the same number of 
decimal places) as the observed data.  Measures of location (mean and median) will be reported to 1 
degree of precision more than the observed data and measures of spread (standard deviation) will be 
reported to 2 degrees of precision more than the observed data. 
Percentages will be presented to 1 decimal place unless otherwise specified.  Assessments done on 
unscheduled visits or on unscheduled parameters will not be summarized but will be listed unless 
otherwise specified. 
Treatment received or randomized treatment is defined as SAGE-217 or placebo.  If the subject took any 
dose of SAGE-217 during the study, she will be considered under SAGE-217 for treatment received.  All 
background summaries will be presented by randomized treatment and overall subjects.  All safety 
summaries will be presented by treatment received.  All efficacy summaries will be presented by 
treatment group.  
 
In the summary table and figures, the visit presented will follow the most recent protocol amendment. 
Any assessment under visits designated in the previous protocol will be included in the listing. 
All final, planned analyses identified in the protocol and in this SAP will be performed after all relevant 
study data have been processed and integrated into the analysis database, analysis populations have been 
finalized, and the database has been locked.  Any post-hoc, exploratory analysis performed to support 
planned study analyses, which are not identified in this SAP, will be documented and reported in 
Section 9.8 of the CSR.  Any results from these unplanned analyses (post-hoc) will also be clearly 
identified in the text of the CSR. 
All statistical tests will be performed as 2-sided tests with a significance level (alpha) of 0.05. 
All collected data for both study parts will be presented in listings and will be sorted by study part and 
subject.  
If partial dates occur, the convention for replacing missing dates for the purposes of calculating derived 
variables will be as follows: 
The following conventions will be used for incomplete or missing medication dates to determine whether 
the medications were concomitant:  
Concomitant Medication 
If the start date (or end date) of medication is completely missing (ie, in which the day, month, and year 
are all unknown) or only the day is known, then the start date (or end date) will not be imputed and the 
medication will be considered to be concomitant. 
For the partial start date of medication: 
o
If the year is present and the month and day are missing, then the month and day will be set to
January 1.
o
If the year and day are present and the month is missing, then the month will be set to
January.
o
If the year and month are present and the day is missing, then the day will be set to the 1st
day of 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.


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For the partial end date of medication: 
o
If the year is present and the month and day are missing, then the month and day will be set to
December 31.
o
If the year and day are present and the month is missing, then the month will be set to
December. If the year and month are present and the day is missing, then the day will be set
to the last day of the month.
Adverse Event 
If AE start dates are completely missing or partially missing, the following date imputation rules will be 
applied for the determination of treatment-emergence: 
If an AE onset date is completely missing (ie, in which the day, month, and year are all 
unknown), then the AE onset date and time will be set to the date and time of initiation of the 
treatment. 
For partial AE start dates: 

When the year is known, but the  month and day is unknown, then:
o
If the year matches the year of first dose date and the end date (if present) is after first
dose date, or AE is ongoing, then impute as the month and day of the first dose date.
o
If the year of AE onset < year of initiation of the treatment, then the month and day will
be set to December 31st.
o
If the year of AE onset > the year of initiation of treatment, then the month and day will
be set to January 1st.

When the year and day are present and the month is missing:
o
If the year of AE onset = the year of initiation of the treatment, then the month will be set
to the month of initiation of the treatment.
o
If the year of AE onset < the year of initiation of the treatment, then the month will be set
to December.
o
If the year of AE onset > the year of initiation of the treatment, then the month will be
set to January.

If the year and month are known, but the day is unknown, then:
o
If the year of AE onset = the year of initiation of the treatment and:

the month of AE onset = the month of initiation of the treatment, then the day
will be set to the day of initiation of the treatment.

the month of AE onset < the month of initiation of the treatment, then the day
will be set to the last day of month.

if the month of AE onset > the month of initiation of the treatment, then the day
will be set to the 1st day of month.
o
If the year of AE onset < the year of initiation of the treatment, then the day will be
set to the last day of month.
o
If the year of AE onset > the year of initiation of the treatment, then the day will be
set to the 1st day of month.
If the imputed AE onset date is after the AE stop date, then the onset date will be set to the stop date. 


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If an AE has a missing severity or relationship to study drug, no imputations will be performed.  No 
missing data will be imputed unless otherwise specified. 
In general, for quantitative laboratory values reported as ‘<X’ or ‘≤X’, the lower limit of quantitation 
(LLOQ) will be used for analysis (ie, a value of X will be used in the analysis for lab values reported as 
‘<X’ or ‘≤X’). Similarly, for quantitative laboratory values reported as ‘>X’ or ‘≥X’, the upper limit of 
quantitation (ULOQ) will be used for analysis (ie, a value of X will be used in the analysis for lab values 
reported as ‘>X’ or ‘≥X’).  
For analysis purposes, repeat laboratory rest results will not be used unless the original laboratory value is 
missing or indicated as invalid, in which case the first non-missing repeat laboratory value will be used 
for data analysis. 
The last measurement before the start of blinded study drug administration will be used as the baseline 
observation for all calculations of change from baseline. 
9.2 
Background Characteristics 
9.2.1 
Subject Disposition 
All subjects who sign the ICF will be accounted for in this study.  The number of subjects enrolled (ie, 
screened) will be summarized by overall subjects. The number of subjects randomized and who received 
study drug, treatment group, and overall subjects. The number and percentage of subjects who completed 
the study, who withdrew from the study early (as well as the reason for withdrawal), and in each analysis 
population will be summarized by part, treatment group and overall subjects. 
All disposition information will be included in a listing. 
9.2.2 
Demographics and Baseline Characteristics 
Demographics, such as age, age categories (18-24, 25-45), child-bearing potential, race, and ethnicity, and 
baseline characteristics such as height, weight, body mass index (BMI), BMI Categories (≤18.4, 18.5-
24.9, 25-29.9, ≥30 kg/m2 ), Baseline antidepressant use (Yes, No), family history of PPD (Yes, No) and 
onset of PPD (3rd trimester, within 4 weeks of delivery) will be summarized by treatment group and 
overall subjects.  
Subjects who marked more than one race will be summarized in a “More than One Race” category. The 
demographic and baseline characteristics table will be generated for subjects in the Safety Set and 
Efficacy Set.  
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding 
system (version 19.1 or higher).  Frequencies and percentages of subjects with a previous depression or 
anxiety diagnosis will have the following summarized by treatment group and overall subjects for 
subjects in the Efficacy Set: type of depression or anxiety diagnosis, number of episodes of PPD (1, 2, 3, 
>3), number of hospitalizations (1, 2, 3, >3) as a result of depression or anxiety, and number of subjects
with a family member with a history of psychiatric conditions.
Hepatitis, human immunodeficiency virus (HIV), drug and alcohol, and pregnancy screening results will 
be listed, but not summarized as they are considered part of the inclusion/exclusion criteria. 
Medical history and psychiatric family history will be listed. 
9.2.3 
Prior and Concomitant Medications 
Concomitant medications will be coded using World Health Organization Drug Dictionary Enhanced 
(WHO-DDE) (September 2016). 
Frequencies and percentages of medications used in the study will be summarized as follows: 


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
Prior medication: medication with a start date before the first dose of study drug (including
medications with a missing start date but a non-missing end date in this time period).

Concomitant medication: medication with a start date on or after the first dose of study drug, or
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 drug.  If medication dates are incomplete and it is not clear whether
the medication was concomitant, it will be assumed to be concomitant.
Details of prior and concomitant medications will be listed by study part, treatment group, subject, start 
date, and verbatim term.  All medications will be summarized by Anatomic Therapeutic Chemical (ATC) 
class and preferred term (PT).  Furthermore, all medications will be summarized by treatment group and 
overall subjects in. Subjects will be counted once per ATC and PT. 
Antipsychotic and antidepressant medications (ie, all medications belonging to the ATC 3 codes N05A 
and N06A respectively) used at treatment start (ie, a prior medication that is ongoing at treatment start) 
will be summarized and listed in a similar manner as prior and concomitant medications. 
Any new antidepressant medication or dose reduced/increased will be identified and summarized by study 
period (treatment period, and follow-up period) and treatment group. 
Different flags identifying antidepressants and antipsychotics will be included in the prior and 
concomitant medications listing.   
Medication summaries will be based on the Efficacy Set. 
9.2.4 
Study Drug Exposure and Compliance 
For all of the below formulas, i = individual subject for the entire treatment period (unless otherwise 
specified). 

Total drug exposure in mg for SAGE-217 will be calculated as:
∑𝐴𝑐𝑡𝑢𝑎𝑙 𝐷𝑜𝑠𝑒𝑠 𝑇𝑎𝑘𝑒𝑛
𝑖
 (𝑚𝑔)

Total drug exposure for placebo subjects is zero.

Average daily dose in mg/day will be calculated as:
∑𝐴𝑐𝑡𝑢𝑎𝑙 𝐷𝑜𝑠𝑒𝑠 𝑇𝑎𝑘𝑒𝑛
𝑖
 (𝑚𝑔)
∑𝐷𝑎𝑦𝑠 𝑜𝑛 𝑆𝑡𝑢𝑑𝑦 𝐷𝑟𝑢𝑔
𝑖
× 100

Total days of exposure will be calculated as:
∑𝐷𝑎𝑦𝑠 𝑜𝑛 𝑆𝑡𝑢𝑑𝑦 𝐷𝑟𝑢𝑔
𝑖

Percent of the planned exposure received  will be calculated as:
∑𝐴𝑐𝑡𝑢𝑎𝑙 𝐷𝑜𝑠𝑒𝑠 𝐸𝑥𝑝𝑜𝑠𝑢𝑟𝑒
𝑖
 (𝑚𝑔)
∑𝑃𝑙𝑎𝑛𝑛𝑒𝑑 𝐸𝑥𝑝𝑜𝑠𝑢𝑟𝑒 (𝑚𝑔)
𝑖
× 100
where  ∑𝐷𝑎𝑦𝑠 𝑜𝑛 𝑆𝑡𝑢𝑑𝑦 𝐷𝑟𝑢𝑔 
𝑖
= last dose date – first dose date +1. For subjects who 
complete the treatment, planned exposure is  14 days of treatment planned, times X mg for 
subjects randomized to SAGE-217, where X=30 for subjects randomized to 30mg, or  
X=20 for if subjects had dose reduction to 20mg. For subjects who discontinued the 
treatment early, the planned exposure is calculated as the number of doses planned up to the 
point of discontinuation. ∑𝐴𝑐𝑡𝑢𝑎𝑙 𝐷𝑜𝑠𝑒𝑠 𝐸𝑥𝑝𝑜𝑠𝑢𝑒 
𝑖
 (𝑚𝑔) = sum of all actual doses taken on 


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each day. If a subject only took one capsule on a given day, the actual dose is assumed to be 
30mg if the planned dose is 30mg on that day or 10 mg if the planned dose is 20 mg on that day. 

Study drug compliance (%) is defined as the number of capsules taken, divided by the number of
capsules planned to be taken, times 100.  Planned number of capsules taken is 28 for 14 days of
two-per-day treatment for subjects who completes the treatment period.  For subjects who
discontinue the treatment early, the planned number of capsules is (Last dose date – First dose
date + 1) x 2.  If a kit is not returned, compliance will be left missing.
Total drug exposure (mg), average daily dose (mg/day), total days of exposure, Percent of the planned 
exposure received and compliance (%) will be summarized descriptively by treatment group and 
overall. 
Study drug dosing and compliance information (including unplanned dose adjustments) will be listed. 
Any other study drug noncompliance such as missing visits, interruptions in the schedule of 
administration, and nonpermitted medications will be listed in the protocol deviations listing. 
9.3 
Efficacy Analysis 
The primary efficacy variable for this study is the change from baseline in HAM-D total score at the end 
of the Treatment Period (Day 15).  
The secondary efficacy variables for this study include: 

Change from baseline in HAM-D total score at all time points other than Day 15;

HAM-D response defined as 50% or greater reduction from baseline in HAM-D total score;

HAM-D remission defined as a HAM-D total score of ≤7;

Change from baseline in MADRS total score at Day 15 and other time points;

Change from baseline in CGI-S total score at Day 15 and other time points;

CGI-I response defined as “very much improved” or “much improved”;

Change from baseline in HAM-A total score at day 15 and other time points;

Changes from baseline in HAM-D subscales and individual item scores at Day 15 and other time
points
 
Efficacy analyses will be based on Efficacy Set using randomized treatment as treatment group.  
For the windowing of visit in the efficacy analysis, please refer to section 9.3.4. 
9.3.1 
Analysis of Primary Efficacy Variable 
9.3.1.1
Description of Primary Efficacy Variable 
The primary outcome measurement is the change from baseline in 17-item HAM-D total score at the end 
of the Treatment Period (Day 14), based on the Day 15 morning assessment.  


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The 17-item HAM-D will be used to rate the severity of depression in subjects who are already diagnosed 
as depressed (Hamilton 1960).  The 17-item HAM-D comprises individual ratings related to the following 
symptoms: depressed mood (sadness, hopeless, helpless, worthless), feelings of guilt, suicide, insomnia 
(early, middle, late), work and activities, retardation (slowness of thought and speech; impaired ability to 
concentrate; decreased motor activity), agitation, anxiety (psychic and somatic), somatic symptoms 
(gastrointestinal and general), genital symptoms, hypochondriasis, loss of weight, and insight.  The 
HAM-D assessments are to be completed within ±30 minutes of the scheduled time point, but before 
starting dosing on Day 1.  Every effort should be made for the same rater to perform all HAM-D 
assessments for an individual subject.  If more than 3 individual items are missing, the HAM-D total 
score will not be calculated and will be left as missing.  If less than or equal to 3 individual item scores 
are missing, the missing item scores will be imputed by the maximum possible value of the item or the 
mean of all other available item scores, whichever is smaller.  Imputed individual scores will be rounded 
to the nearest integer. 
Assessments of insomnia items during the Treatment Period will be rated relative to the “last night’s 
sleep”.  The HAM-D total score will be calculated as the sum of the 17 individual item scores.   
The HAM-D subscales are Core, Anxiety, Bech-6, and Meier.  Refer to following table for details on 
HAM-D Subscales and Items for Calculating Each Subscale score: 
HAM-D Subscales 
Items 
Calculation 
Core 
Depressed mood 
Feeling of guilt 
Suicide 
Work and activities 
Retardation 
Sum of the 5-item responses/20 x 100.  
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale.  
Anxiety 
Anxiety psychic 
Anxiety somatic 
Somatic symptoms gastrointestinal 
Somatic symptoms general 
Hypochondriasis 
Loss weight 
Sum of the 6-item responses/18 x 100.  
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale.  
Bech-6 
Depressed mood 
Feeling of guilt 
Work and activities 
Retardation 
Anxiety psychic 
Somatic symptoms general 
Sum of the 6-item responses/22 x 100.  
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale.  
Meier 
Depressed mood 
Feeling of guilt 
Work and activities 
Retardation 
Agitation 
Anxiety psychic 
Sum of the 6-item responses/24 x 100.  
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale.  


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Before PA4, the HAM-D will be collected in the clinic at Screening; before dosing on Day 1; 12 hours ± 
1 hour following the evening dose on Days 2, 3, 4, 5, 6, 8, and 15; and in the morning on Days 21 and 45. 
On or after PA4, the HAM-D will be collected at the scheduled clinic visits at Screening; before dosing 
on Day 1; 12 hours (±1 hour) following the previous evening’s dose on Days 3, 8, and 15; and in the 
morning on Days 21 and 45. 
9.3.1.2
Visit Windows for the Primary Variable 
For efficacy analyses, unscheduled measurements will only be included if a scheduled measurement is not 
available and the unscheduled measurement falls on the same study day. Visit windows are defined in 
Section 9.3.4. 
9.3.1.3
Primary Analysis 
Observed values and change/percent change from baseline to the Day 15 morning assessment (Day 15 – 
Baseline, and all other time points) in HAM-D total score and individual item scores will be summarized 
by treatment group.  Lower scores postdose indicate improvement in depressive symptoms. 
The difference between treatment groups in change from baseline to Day 15 in HAM-D total score will be 
evaluated by an MMRM with treatment, baseline HAM-D total score, baseline antidepressant use, 
assessment time point, and time point-by-treatment interaction as fixed effects. All post-baseline time 
points that are collected subjects both before and after release of PA4 (ie, Days 3, 8, 15, 21, and 45) will 
be included in the model; however, the primary comparison will be between SAGE-217 and placebo at 
the Day 15 time point.   
In comparing the visit value to baseline within each treatment group, least squares (LS) mean change 
from baseline will be presented along with associated 95% confidence interval (CI).  In comparing 
treatments (SAGE-217 minus placebo), LS mean differences in change from baseline will be presented 
along with associated 95% CI and pairwise treatment P value.  An unstructured covariance structure will 
be used to model the within-subject errors.  The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom. 
If there is a convergence issue with the unstructured covariance model, Toeplitz, compound symmetry or 
Autoregressive (1) (AR[1]) covariance structure will be used, following this sequence until convergence 
is achieved. If the model still does not converge with AR(1) structure, no results will be reported. When 
the covariance structure is not UN, the sandwich estimator for the variance-covariance matrix will be 
derived, using the EMPIRICAL option in the PROC MIXED statement in SAS. 
The LS mean change from baseline (and 95% CI of the mean) in HAM-D total score based on MMRM 
results will be plotted over time by treatment group.   
9.3.1.4
Supportive Analyses 
The change from baseline in HAM-D total scores will be analyzed by MMRM methods similar to the 
primary endpoint, as described in Section 9.3.1.3, with the addition of pooled center in the model. Pooling 
of centers is described in Section 9.3.5. 
9.3.1.5
Multiplicity Adjustment 
No adjustments for multiplicity will be performed for this Phase 3 trial.  Only the primary endpoint 
analysis will be treated as a formal hypothesis test, and the secondary endpoints will be considered as 
supportive of the primary endpoint. 
9.3.1.6
Sensitivity Analysis 
1) Sensitivity analyses will be carried out to investigate the impact of missing data if more than
10% of subjects are missing primary endpoint assessment (ie, HAM-D total score at Day 15).


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A dropout reason based imputation will be used.  An analysis of covariance (ANCOVA) model, 
including treatment, baseline antidepressant use, and baseline HAM-D total score, will be used to 
assess the treatment difference in change from baseline in HAM-D total score at Day 15 (MI 
imputed data).  The missing change from baseline in HAM-D total score at Day 15 will be 
imputed using multiple imputation. 
Imputation distribution: 
The imputation distribution for the missing change from baseline in HAM-D total score at Day 
15 will be a normal distribution.  All treated subjects will be classified as non-missing category, 
missing category 1, or missing category 2, based on the following rules: 
 Non-missing category: Subject with non-missing change from baseline in HAM-D total 
score at Day 15. 
 Missing category 1: Subject discontinued due to adverse events, physician decision, 
protocol violation or other, and is missing change from baseline in HAM-D total score at 
Day 15. 
 Missing category 2: Subject discontinued due to pregnancy, study terminated by sponsor, 
or withdrawal by subject, and is missing change from baseline in HAM-D total score at 
Day 15, or subject completed study but is missing change from baseline in HAM-D total 
score at Day 15. 
Imputation algorithm: 
Missing values of change from baseline in HAM-D total score at Day 15 will be imputed 
separately within each treatment group using the following missing reason based algorithm: 
 Missing category 1: randomly draw a sample from the normal distribution N(µ75, σ2), 
where µ75 is the 75th percentile of the non-missing change from baseline in HAM-D total 
score and σ2 is the sample variance estimated using the non-missing change at Day 15.  
This represents a conservative approach since higher values of change from baseline 
represents worse outcome. 
 Missing category 2: randomly draw a sample from the normal distribution N(µ, σ2), 
where µ is the mean of the non-missing change from baseline in HAM-D total score at 
Day 15 and σ2 is the sample variance estimated using the non-missing change at Day 15. 
Analysis model: 
The complete MI method is described below: 
 Impute missing values using the normal distribution specified in the above algorithm to 
form a complete dataset (imputed dataset).  After imputation, all Efficacy Set subjects 
will have non-missing change from baseline in HAM-D total score at Day 15. 
 Repeat the process K (K=5) times, using the procedure described above to form K 
imputed complete datasets. 
 Fit the ANCOVA model including baseline antidepressant use, and baseline HAM-D 
total score, to each imputed dataset, to estimate the treatment effect and its variance at 
Day 15. 
 Combine the results from the K imputed datasets using the SAS procedure 
MIANALYZE, to derive the MI estimator. 
We fit the analysis model (ANCOVA model specified before) to the kth completed dataset, 
denoting the estimate of the treatment difference θ by θk from the kth completed dataset, and 
denoting the corresponding estimate of the variance Vk. The MI estimator of θ, 𝜃̃𝑀𝐼, is the 


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average of the K individual estimators: 
𝜃̃𝑀𝐼= 1
𝐾∑𝜃𝑘
𝐾
𝑘=1
 
The estimated variance of 𝜃̃𝑀𝐼 is a combination of the between- and within-imputation 
variability as follows: 
𝑉𝑀𝐼= 𝑊+ (1 + 1
𝐾) 𝐵
where W =
1
𝐾∑
𝑉𝐾 
𝐾
𝑘=1
is the within-imputation variability and B =
1
𝐾−1 ∑
(𝜃𝑘−𝜃̃𝑀𝐼)
2 
𝐾
𝑘=1
is the 
between-imputation variance. 
It has been shown that the statistic 
T = 𝜃̃𝑀𝐼−𝜃
√𝑉𝑀𝐼
has an approximate tV distribution where V = (K −1) (1 +
𝑊
𝐵)
2
. 
2) The following sensitivity analysis will be performed to account for the possible scenario that
the data is not normally distributed.
Stratified Wilcoxon rank-sum test on change from baseline in the HAM-D total score at Day 15, 
stratified by antidepressant use, will be used as a sensitivity analysis.  If necessary (e.g., serious 
violation of the primary analysis model assumptions on normality, as assessed by using QQ plot 
on the residual values from the primary analysis for HAM-D), this will be considered the 
primary analysis. 
See sample SAS code for stratified Wilcoxon rank-sum test using PROC FREQ in section 12.3. 
9.3.1.7
Subgroup Analysis for Primary Endpoint 
 The MMRM analysis for change from baseline in HAM-D total score analysis will be repeated for the 
following subgroups:  
o
Race category: White, Black or African American, and Other
o
Age category: 18-24, 25-45
o
Baseline antidepressant use: Yes, No
o
BMI category: ≤18.4, 18.5-24.9, 25-29.9, ≥30 kg/m2
o
Onset of PPD: 3rd trimester, within 4 weeks of delivery
o
Family history of PPD: Yes, No
In the MMRM model for subgroup analysis, antidepressant use will be excluded from the model due to 
the small number of subjects in antidepressant use group in each subgroup. 
Observed values and change/percent change from baseline to the Day 15 morning assessment (Day 15 – 
Baseline, and all other time points) in HAM-D total score will be summarized by treatment group and 
subgroup. 
In addition, the LS mean change from baseline (and 95% CI of the mean) in HAM-D total score at Day 
15 based on MMRM results will be plotted by treatment group and subgroup. 


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9.3.2 
  Analysis of Secondary Efficacy Variables 
All secondary analyses will be conducted using the Efficacy Set. 
9.3.2.1
Hamilton Rating Scale for Depression (HAM-D) 
Description of HAM-D Response and Remission 
The HAM-D response is defined as a 50% or greater reduction from baseline in HAM-D total score (ie, 
percent change from baseline ≤-50%); HAM-D remission is defined as a HAM-D total score of ≤7. 
Analysis of HAM-D Response and Remission 
Number and percentage of subjects meeting the criteria for HAM-D response and HAM-D remission will 
be summarized by time point and treatment group.  
The number of subjects meeting HAM-D response and HAM-D remission criteria at each time point will 
be analyzed using GEE for binary response. The model will include terms for treatment, baseline HAM-D 
total score, baseline antidepressant use, assessment time point, and time point-by-treatment interaction. In 
comparing treatments (SAGE-217 minus placebo), model-based point estimates (ie, adjusted odds ratios) 
will be presented along with associated 95% CI and pairwise treatment P value.   
An unstructured covariance structure will be used to model the within-subject errors. In case of 
convergence issues, other covariance structures will be used including Toeplitz, compound symmetry or 
Autoregressive (1) (AR[1]) covariance structure will be used, following this sequence until convergence 
is achieved. If the model still does not converge with AR(1) structure, no results will be reported. 
In addition, as a supportive analysis, a logistic regression model will be used separately for each visit, 
which will include the response variables above as the dependent variable, baseline antidepressant use, 
treatment, and baseline HAM-D total score as explanatory variables.  The Firth penalized likelihood 
method will be used to reduce bias in the parameter estimates and to avoid non-convergence due to 
quasi separation.  
Observed values and derived change/percent change from baseline values in HAM-D subscale and 
individual item scores at each time point will be summarized by treatment group.  The change from 
baseline in HAM-D subscale and individual item scores will be analyzed by MMRM methods similar to 
the primary endpoint, as described in Section 9.3.1.3. 
Bar charts showing the percentage of subjects with HAM-D response and remission by treatment and visit 
will be provided. 
9.3.2.2
Montgomery-Åsberg Depression Rating Scale (MADRS) 
Description of MADRS 
The MADRS is a 10-item diagnostic questionnaire that psychiatrists use to measure the severity of 
depressive episodes in subjects with mood disorders.  It was designed as an adjunct to the HAM-D that 
would be more sensitive to the changes brought on by antidepressants and other forms of treatment than 
the Hamilton Scale. 
The questionnaire includes questions on the following symptoms: apparent sadness; reported sadness; 
inner tension; reduced sleep; reduced appetite; concentration difficulties; lassitude; inability to feel; 
pessimistic thoughts; and suicidal thoughts.  If more than 2 individual items are missing, the MADRS 
total score will not be calculated and will be left as missing.  If less than or equal to 2 individual item 
scores are missing, the missing item scores will be imputed by the mean of all other available item scores. 
Imputed individual scores will be rounded to the nearest integer. 


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Higher MADRS scores indicate more severe depression, and each item yields a score of 0 to 6.  The 
MADRS total score will be calculated as the sum of the 10 individual item scores.  The overall score 
ranges from 0 to 60 (McDowell 2006; Müller-Thomsen 2005).  
The MADRS will be collected in the clinic at Screening; before dosing on Day 1; 12 hours ± 1 hour 
following the evening dose on Days 2 (before PA4 only), 3, 8, and 15; and in the morning on Days 21 and 
45. 
Analysis of MADRS 
Observed values and derived change/percent change from baseline values in MADRS total score and 
individual item scores at each time point will be summarized by treatment group.  The change from 
baseline in MADRS total score will be analyzed by MMRM methods similar to the primary endpoint, as 
described in Section 9.3.1.3. The LS mean change from baseline (and 95% CI of the mean) in MADRS 
total score based on MMRM results will be plotted over time by treatment group.   
The MMRM analysis for change from baseline in MADRS total score analysis will be repeated for the 
following subgroups: subjects on antidepressant medications at treatment start and subjects who are not 
on antidepressant medications at treatment start. 
Description of MADRS Response and Remission 
The MADRS response is defined as a 50% or greater reduction from baseline in MADRS total score (ie, 
percent change from baseline ≤-50%); MADRS remission is defined as a MADRS total score of ≤10. 
Analysis of MADRS Response and Remission 
The MADRS response and remission results will be analyzed by GEE and logistic regression methods 
similar the HAM-D response and remission, as described in Section 9.3.2.1. 
9.3.2.3
Clinical Global Impression (CGI) 
Description of CGI 
The CGI is a validated measure often utilized in clinical trials to allow clinicians to integrate several 
sources of information into a single rating of the subject’s condition.  The CGI scale consists of 3 items. 
Only the first 2 items are being used in this study. Only the first item of the CGI, the CGI-S item, will be 
administered before treatment. 
The CGI-S uses a 7-point Likert scale to rate the severity of the subject’s illness at the time of assessment, 
relative to the clinician’s past experience with subjects who have the same diagnosis.  Considering total 
clinical experience, a subject is assessed on severity of mental illness at the time of rating as 1=normal, 
not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; and 
7=extremely ill. 
The CGI-I employs a 7-point Likert scale to measure the overall improvement in the subject’s condition 
post-treatment.  The Investigator will rate the subject’s total improvement whether or not it is due entirely 
to drug treatment.  Response choices include: 0=not assessed, 1=very much improved, 2=much improved, 
3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, and 7=very much worse. The 
CGI-I is only rated at post-treatment assessments.  By definition, all CGI-I assessments are evaluated 
against baseline conditions. The CGI-I response will be defined as having a CGI-I score of “very much 
improved” (score of 1) or “much improved” (score of 2). 
The CGI-S will be collected in the clinic at Screening; before dosing on Day 1; 12 hours ± 1 hour 
following the evening dose on Days 2 (before PA4 only), 3, 8, and 15; and in the morning on Days 21 and 
45. 
The CGI-I will be collected in the clinic 12 hours ± 1 hour following the evening dose on Days 2 (before 
PA4 only), 3, 8, and 15; and in the morning on Days 21 and 45. 


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Analysis of CGI 
All CGI-S and CGI-I scores will be summarized as both categorical (ie, number and percentages) and 
continuous (ie, descriptive statistics) at each time point (Screening and Days 1, 3, 8, 15, 21, and 45) by 
treatment group.  The mean CGI-I score will be plotted over time by treatment group. 
The CGI-I response will be analyzed using GEE and logistic regression similar to HAM-D response and 
remission as described in Section 9.3.2.1. Baseline CGI-S score will be included in the model. 
The GEE analysis for CGI-I response analysis will be repeated for the following subgroups: subjects on 
antidepressant medications at treatment start and subjects who are not on antidepressant medications at 
treatment start. 
A bar chart showing the percentage of subjects with CGI-I response by treatment and visit will be 
provided. 
9.3.2.4
Hamilton Anxiety Rating Scale (HAM-A) 
Description of HAM-A 
The 14-item HAM-A will be used to rate the severity of symptoms of anxiety (Hamilton 1959).  Each of 
the 14 items is defined by a series of symptoms, and measures both psychic anxiety (mental agitation and 
psychological distress) and somatic anxiety (physical complaints related to anxiety).  Scoring for HAM-A 
is calculated by assigning scores of 0 (not present) to 4 (very severe), with a total score (calculated as the 
sum of the 14 individual scores) ranging from 0 to 56, where ≤17 indicates mild severity, 18 to 24 
indicates mild to moderate severity, 25 to 30 indicates moderate to severe severity, and >30 indicates 
severe severity. If more than 2 individual items are missing, the HAM-A total score will not be calculated 
and will be left as missing. If less than or equal to 2 individual item scores are missing, the missing item 
scores will be imputed by the mean of all other available item scores. 
The HAM-A will be collected in the clinic before dosing on Day 1; 12 hours ± 1 hour following the 
previous evening’s dose on Days 3, 8, and 15; and in the morning on Days 21 and 45. 
Analysis of HAM-A 
Observed values and change/percent change from baseline in HAM-A total score at each time point will 
be summarized by treatment group. The change from baseline in HAM-A total score will be analyzed by 
MMRM methods similar to the primary endpoint, as described in Section 9.3.1.3.  Additionally, number 
and percentage of subjects in each HAM-A total score category at each time point will be presented by 
treatment group. The LS mean change from baseline (and 95% CI of the mean) in HAM-A total score 
based on MMRM results will be plotted over time by treatment group.   
The MMRM analysis for change from baseline in HAM-A total score analysis will be repeated for the 
following subgroups: subjects on antidepressant medications at treatment start and subjects who are not 
on antidepressant medications at treatment start. 
9.3.2.5
Beck Anxiety Inventory (BAI) 
Description of BAI 
The BAI is a subject-rated measure of anxiety with 21 items. Scoring for BAI is calculated by assigning 
scores of 0, 1, 2, and 3 to the response categories of “not at all,” “mildly,” “moderately,” and “severely”, 
respectively.  The BAI total score (calculated as the sum of the 21 individual item scores) ranging from 0 
to 48, where a score of 0 to 21 indicates low anxiety, 22 to 35 indicates moderate anxiety, and 36 and 
above indicates potentially concerning levels of anxiety (Beck 1988).  
The BAI will be collected in the clinic at Screening; before dosing on Day 1; 12 hours ± 1 hour following 
the evening dose on Days 8 and 15; and in the morning on Days 21 and 45.  All assessments are to be 


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completed within ±30 minutes of the scheduled time point. The BAI was only collected for subjects 
enrolled before PA 4.  
Anxiety data collected on the BAI will be listed. 


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9.3.4 
Visit Windows
Any 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 and time, which will be mapped to 
the intended visit.  Once analysis visit windows are 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.  The analysis visit windows are as follows: 


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Analysis Visit 
Window Name 
Target Day of 
Visit 
Lower Bound of 
Window (day) 
Upper Bound of 
Window (day)
Baseline 
1 
-- 
1 
Day 3 (± 1 ) 
3 
2 
4 
Day 8 (± 1 ) 
8 
7 
9 
Day 15 (± 1 ) 
15 
14 
16 
Day 21 (± 1 ) 
21 
20 
22 
Day 45 (± 3 ) 
45 
42 
48 
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 for the analysis visit window, the scheduled visit data will be used.

If there is no scheduled visit for the analysis visit window (eg, a subject missed the visit or the
assessment was not collected), the visit closest to the scheduled study day will be used.

If there is no scheduled visit for the analysis visit window and there are visits equally close to the
day of the scheduled visit, the latest visit will be used.
All visits, including visit not flagged as the “analyzed record,” will be included in the subject listings. 
9.3.5 
Pooling of Centers 
For supporting primary efficacy analysis purposes, centers with fewer than 15 subjects per center will be 
pooled, first centers with fewer than 15 subjects will be ranked by size. Starting with the largest site, 
centers will be pooled until 15 or more subjects are reached to create a unique regional center. Continuing 
this process of creating unique regional centers until there are less than 15 subjects remaining. The 
remaining centers will then be added to the last unique regional center created.  
Unless the combined number of subjects from all centers with fewer than 15 subjects in a region is fewer 
than 15 subjects, all pooled centers should have at least 15 subjects. 
9.3.6 
Protocol Deviations 
Prior to database lock, major protocol deviations are defined as those deviations from the study protocol 
that may have the ability to impact the efficacy results.  As such, subjects with one or more major 
deviation will be excluded from the per-protocol set (as defined in Section 8.3).  
Major protocol deviations include (but are not limited to):  
-
Deviation from inclusion/exclusion criteria
-
Withdrawal criteria met during the study but subject was not withdrawn
-
Prohibited concomitant medications
-
Substantial deviations from the dosing schedule
-
Had overall treatment compliance rate < 80% or > 120%
-
Other
Where possible, major deviations will be programmatically verified. Listings of concomitant medications 
in Excel format will be reviewed and to be identified for prohibited medications prior to unblinding. In 


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addition, listings of protocol deviations will be provided to the sponsor for review and classification of 
each protocol deviation as major/minor. These classifications will then be merged with the protocol 
deviations data for inclusion in tables and listings.  
9.4 
Safety Analysis 
Safety will be evaluated through frequency and severity of AEs, as well as observed values and changes 
from baseline in vital signs, clinical laboratory measures, ECG parameters, suicidal ideation using the 
C-SSRS, and SSS. 
All safety data will be presented in individual subject data listings. Safety analysis described below will 
be conducted using the Safety Set and treatment received (SAGE-217 if any dose of SAGE-217 is 
received, or placebo if all doses received are placebo) as the treatment group. 
Safety 
Evaluation 
Incidence 
Observed 
Value 
Change 
from 
Baseline 
Abnormality/
Clinical 
Significance 
Potentially 
Clinical 
Significance 
(PCS) 
AEs 
X 
CMs 1 
X 
Labs 
X 
X 
* 
x 
ECG 
X 
X 
* 
x 
Vital Signs 
X 
X 
x 
C-SSRS 
X 
X 
X = Safety Assessment will be summarized in tables 
* = Safety Assessment will be presented in individual subject data listings; abnormal
clinically significant lab, ECG, and vital  findings will only be noted on AE CRFs
1 Including antidepressant medication usage 
9.4.1 
Adverse Events 
Adverse events (AEs) will be coded using the MedDRA coding system (version 19.1 or higher).  The 
analysis of AEs will be based on the concept of treatment emergent AEs (TEAEs).  A TEAE is defined as 
an AE with onset after the start of study drug, or any worsening of a pre-existing medical condition/AE 
with onset after the start of study drug. 
A summary of TEAEs will be provided.  Frequencies and percentages of the following will be included: 

Any TEAE

Severe TEAEs

TEAEs which are possibly or probably related to study drug

TEAEs Leading to Study Drug Discontinuation

TEAEs Leading to Study Discontinuation


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
SAEs

AEs Leading to Death
The incidence of all TEAEs, TEAEs by maximum severity, TEAEs by greatest relationship (related>non-
related, related = probably or possibly related or missing) to study drug, and all SAEs (if ≥10 subjects 
experience an SAE) will be summarized by MedDRA System Organ Class (SOC), PT, and treatment 
received.  Additionally, the incidence of all TEAEs will be summarized by PT and treatment received.  
Incidences will be presented in order of decreasing frequency and then alphabetically, first SAGE-217 
then placebo. 
All AEs, SAEs, AEs leading to study drug discontinuation, and AEs leading to death through Day 45 
follow-up visit will be presented as separate listings. 
9.4.2 
Clinical Laboratory 
All summaries of laboratory values will be presented using SI units.  Observed hematology, chemistry, 
and urinalysis values and changes from baseline at each time point will be summarized by treatment 
received.  Shifts from baseline regarding out-of-normal range values will also be summarized by 
treatment received. The shift from baseline status of low/normal/high to low or high at any time during 
treatment, any time during the study and at the end of the study will be presented.  All clinical laboratory 
results will be listed by subject and timing of collection.  This listing will include data from scheduled and 
unscheduled time points.  Clinically significant abnormal findings will be reported as AEs in the clinical 
database, hence will be reported as part of AE reporting. Pregnancy test results will be listed only. 
Potentially clinically significant (PCS) values for selected hematology and clinical chemistry parameters 
have been identified in the following table. The number and percentage of subjects with PCS values at 
each post-baseline visit, any time during treatment, any time during the study, and at the end of the study 
will be summarized by treatment received. 
 Hematology Potentially Clinically Significant Values 
Hematology parameter 
Potentially clinically significant values 
  Hemoglobin 
<125 g/L or >185 g/L (males) 
<110 g/L or >165 g/L (females) 
Hematocrit (HCT) 
<0.415 or >0.504 (males) 
<0.359 or >0.446 (females) 
Platelet count 
<125 10^9/L or >600 10^9/L 
Leukocytes 
<2.5 10^9/L or >15 10^9/L 
Basophils 
>0.5 10^9/L
Eosinophils 
>1.5 10^9/L
Lympocytes 
<0.5 10^9/L or >6.0 10^9/L 
Monocytes 
>1.4 10^9/L
Neutrophils 
<1.5 10^9/L 
Chemistry Potentially Clinically Significant Values 
Chemistry parameter 
Potentially clinically significant values 
Alanine aminotransferase (ALT) 
>3 x ULN
Albumin 
<28 g/L or >70 g/L 
Aspartate aminotransferase (AST) 
>3 x ULN
Alkaline Phosphatase (ALP) 
>1.5 x ULN
Bilirubin 
>2 x ULN
Blood urea nitrogen (BUN) 
>10.71 mmol/L


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Calcium 
<2.0 mmol/L or >2.75 mmol/L 
Chloride 
<90 mmol/L or >120 mmol/L 
Creatinine 
>140 umol/L
Phosphate 
<2 mg/dL or >5 mg/dL 
Potassium 
<3.5 mmol/L or >5.2 mmol/L 
Sodium 
<132 mmol/L or >145 mmol/L 
Protein 
<45 g/L 
Glucose 
<2.8 mmol/L or >13.9 mmol/L 
Summaries of abnormal liver enzymes and liver function tests post-baseline will be presented 
for ALT, AST, Total Bilirubin, and ALP.  Shifts in ALT and AST baseline values to 
maximum post-baseline values will be summarized using the categories ≤1x ULN, >1x to 
3x ULN, >3x to 5x ULN, >5x to 10x ULN, and >10x ULN. 
All scheduled and unscheduled results will be included in the laboratory PCS analyses. 
9.4.3 
Vital Signs 
Vital sign results (body temperature, heart rate, respiratory rate, supine and standing diastolic blood 
pressure, and supine and standing systolic blood pressure) will be listed by subject and timing of 
collection.  Change from baseline for diastolic blood pressure and systolic blood pressure will be 
calculated separately for supine and standing position.  Observed values and change from baseline at each 
time point will be summarized by treatment received. 
Additionally, the change in blood pressure from supine to standing position (standing – supine) will be 
summarized.  A listing will be provided showing the difference between supine and standing blood 
pressures. 
Post-baseline vital signs meeting any of the criteria below for low, high or change from baseline will be 
identified as potentially clinically significant (PCS). These will be summarized and listed by subject: 
Potentially Clinically Significant Vital Sign Values 
 
Parameter 
Low 
High 
Change from Baseline 
Systolic Blood Pressure (mmHg) 
<90 
>180
+ or – change of ≥30
Diastolic Blood Pressure (mmHg) 
<50 
>110
+ or – change of ≥20
Heart Rate (beats/min) 
<40 
>120
Not defined 
In addition, the number of subjects with post-baseline orthostatic hypotension, defined as either a 
decrease in systolic blood pressure of ≥20 mmHg or a decrease in diastolic blood pressure of ≥10 mmHg 
from supine to standing position, will be summarized. 
9.4.4 
Electrocardiogram 
The following 12-lead ECG parameters will be listed for each subject: heart rate, PR interval, QRS 
duration, QT interval, and QT interval using Fridericia’s correction for heart rate (QTcF, derived as QT 
interval / (RR interval)1/3).  Any clinically significant abnormalities or changes in ECGs should be 
recorded as an AE.  Observed values and change from baseline at each time point will be summarized by 
treatment received. Additionally, the number and percentage of subjects with a QTcF value meeting 
following clinical significance criteria will be summarized separately by treatment received. 

Maximum value >450 to 480 msec

Maximum value >480 to 500 msec


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
Maximum value >500 msec

Maximum increase from baseline >30 to 60 msec

Maximum increase from baseline >60 msec
9.4.5 
Physical Examination
Screening physical examination results that are clinically significant will be collected in the medical 
history eCRF page, and hence will be included in medical history listing. Post-screening physical 
examination results that are clinically significant will be reported as AEs in the clinical database, hence 
will be reported as part of AE reporting. A listing will be provided containing information on when 
physical examination occurred and reason it was not done if applicable. 
9.4.6 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011).  This scale consists of a 
baseline evaluation that assesses the lifetime experience of the subject with suicidal ideation and 
behavior, and a post-baseline evaluation that focuses on suicidality since the last study visit.  The C-SSRS 
includes “yes” or “no” responses for assessment of suicidal ideation and behavior as well as numeric 
ratings for severity of ideation, if present (from 1 to 5, with 5 being the most severe).  Assign a score of 0 
if no ideation is present. 
Suicidal Ideation items include: 
Category 1 – Wish to be Dead 
Category 2 – Non-specific Active Suicidal Thoughts 
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Category 5 – Active Suicidal Ideation with Specific Plan and Intent 
Suicidal Behavior items include: 
Category 6 – Preparatory Acts or Behavior 
Category 7 – Aborted Attempt 
Category 8 – Interrupted Attempt 
Category 9 – Actual Attempt (non-fatal) 
Category 10 – Completed Suicide 
Self-injurious behavior without suicidal intent is also a C-SSRS outcome (although not suicide-related) 
and has a binary response (yes/no). 
Endpoints: 
Composite endpoints based on the above categories are defined below: 

Suicidal ideation: A “yes” answer at any time during treatment to any one of the five suicidal
ideation questions (Categories 1-5) on the C-SSRS.

Suicidal behavior: A “yes” answer at any time during treatment to any one of the five suicidal
behavior questions (Categories 6-10) on the C-SSRS.

Suicidal ideation or behavior: A “yes” answer at any time during treatment to any one of the ten
suicidal ideation and behavior questions (Categories 1-10) on the C-SSRS.
Baseline is defined as the most severe ideation and behavior reported in the past 24 months prior to the 
first dose of study drug. Suicidality data collected on the C-SSRS will be listed for all subjects. Tables 
will include results from the Suicidal Ideation and Suicidal Behavior sections of the C-SSRS.  
Frequencies and percentages of subjects with a response of “Yes” at any point as well as by study visit on 
the Suicidal Ideation and Suicidal Behavior items will be summarized by treatment received.   






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12 LIST OF APPENDICES 
12.1 Appendix A: Schedule of Events (subjects enrolled before PA4) 
Screening Period 
Treatment Period 
Follow-up Period 
Visits 
SCREENING 
OUTPATIENT 
OUTPATIENT 
Visit Days 
D-14 to -1
D1* 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
D15 
D21/ET 
(+1d) 
D45 
(+3d) 
Study Procedure 
Informed Consent 
X 
Inclusion/Exclusion 
X 
X 
Demographics 
X 
Medical/Family History a
X 
Physical Examination 
X 
Xb 
XError! 
Reference 
source 
not 
found.
X 
Body Weight/Height 
X 
Xb,c 
Xc 
Clinical Laboratory 
Assessments d
X 
Xb 
Xb 
X 
Drug & Alcohol Screen e 
X 
X 
Pregnancy Test f 
X 
X 
X (ET 
only) 
X 
Hepatitis & HIV Screen 
X 
Hormone Sample g 
O 
Ob 
Ob 
Genetic Sample h 
O 
Vital Signs i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xb 
X 
X 
Pulse Oximetry j
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Screening Period 
Treatment Period 
Follow-up Period 
Visits 
SCREENING 
OUTPATIENT 
OUTPATIENT 
Visit Days 
D-14 to -1
D1* 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
D15 
D21/ET 
(+1d) 
D45 
(+3d) 
Study Procedure 
12-Lead ECG k
X 
X 
X 
X 
X 
X 
C-SSRS l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xb 
X 
X 
CGI-I m 
X 
X 
X 
X 
Xb 
Xb 
CGI-S Error! Reference source not 
found.
X 
X 
X 
X 
X 
X 
Xb 
Xb 
HAM-A Error! Reference source
not found.
X 
X 
X 
X 
Xb 
Xb 
HAM-D Error! Reference source
not found.
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xb 
Xb 
MADRS Error! Reference source
not found.
X 
X 
X 
X 
X 
X 
Xb 
Xb 
BAI Error! Reference source not 
found.
X 
X 
X 
X 
Xb 
Xb 
SSS n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xb 






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12.2 Appendix B: Schedule of Events (subjects enrolled as of PA4) 
Study Procedure 
Study Period / Visit 
Screening 
Period 
Treatment Period a 
Follow-up Period 
D-28 to -1
D1* 
D3 
(+1d) 
D8 
D15 
D21/ET 
(±1d) 
D45 
(±3d) 
Clinic Visit 
X 
X 
X 
X 
X 
X 
X 
Informed Consent 
X 
Inclusion/Exclusion 
X 
X 
Demographics 
X 
Medical/Family History b 
X 
Physical Examination 
X 
Xc 
Xc 
X 
Body Weight/Height 
X 
Xc, d 
Xd 
Clinical Laboratory Assessments e 
X 
Xc 
Xc 
X 
Drug & Alcohol Screen f 
X 
X 
Pregnancy Testg 
X 
X 
X 
(ET only) 
X 
Hepatitis & HIV Screen 
X 
Hormone Sample h 
O 
Oc 
Oc 
Genetic Sample i 
O 
Vital Signs j 
X 
X 
X 
X 
Xc 
X 
X 
12-Lead ECG k
X 
X 
X 
X 
X 
C-SSRS l
X 
X 
X 
X 
Xc 
X 
X 
CGI-I 
X 
X 
X 
Xc 
Xc 
CGI-S 
X 
X 
X 
X 
X 
Xc 
Xc 
HAM-A 
X 
X 
X 
X 
Xc 
Xc 
HAM-D m 
X 
X 
X 
X 
X 
Xc 
Xc 






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12.3 Appendix C: Details of Statistical Methodology 
Sample SAS code for MMRM: 
PROC MIXED DATA = xxx; 
   CLASS  trt avisit usubjid AntiDpUe; 
   MODEL change = base trt avisit avisit*trt AntiDpUe / ddfm=kr; 
   REPEATED avisit/subject = usubjid type= un;  
* if type= un does not converge, use type= TOEP; 
* if type=TOEP does not converge, use type= cs; 
* if type=cs does not converge, use type= ar(1); 
   LSMEANS avisit*trt / diff=all cl alpha=0.05; 
RUN; 
*Note: AntiDpUe represents baseline antidepressant medication use variable 
 
Sample SAS code for GEE: 
PROC GENMOD DATA = xxx; 
   CLASS trt avisit usubjid AntiDpUe; 
   MODEL resp = base trt avisit avisit*trt AntiDpUe/ DIST= bin link=logit; 
   REPEATED subject=usubjid / type = un; 
   LSMEANS avisit*trt / diff exp cl; 
RUN; 
 
 
 
 


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Sample SAS code for Logistic Regression: 
PROC LOGISTIC DATA = xxx; 
  BY avisit; 
   CLASS trt usubjid AntiDpUe /PARAM=GLM; 
   MODEL resp (event=’1’) = base center trt AntiDpUe/firth; Note: for CGI-S, add cgisbase independent variable as well  
   LSMEANS trtan / diff oddsratio cl exp; 
RUN; 
 
Sample SAS code for Stratified Wilcoxon Rank Sum Test: 
PROC FREQ DATA = xxx; 
   WHERE trtan in (1, 2); 
   TABLES AntiDpUe *trtan*chg/cmh2 scores=modridit noprint; 
RUN;