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
Phase: PHASE3
Conditions: Postpartum Depression
Sponsor: Biogen

 
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: 
Sage Therapeutics 
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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215 First Street 
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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 
participating subjects.  

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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 
closely as possible.  

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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 
recorded.  

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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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21. 
APPENDICES 

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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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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)