A Phase 3, Randomized, Double-Blind Study Comparing the Efficacy and Safety of SAGE-217 Plus an Antidepressant Versus Placebo Plus an Antidepressant in Adults With Major Depressive Disorder
Phase: PHASE3
Conditions: Depressive Disorder, Major
Sponsor: Biogen



Clinical Study Report 
217-MDD-305
16.1 Study Information 
1 
1.
PROTOCOL AND AMENDMENTS
The original/initial protocol, Version 1.0, dated 13 May 2020, was amended 3 times. 
The title of the study was updated as of Version 2.0. 
Version 
Number 
Date 
Title 
4.0 
10 January 2022 
A Phase 3, Randomized, Double-blind Study Comparing 
the Efficacy and Safety of SAGE-217 plus an 
Antidepressant versus Placebo plus an Antidepressant in 
Adults with Major Depressive Disorder 
3.0 
22 January 2021 
2.0 
11 September 2020 
1.0 
13 May 2020 
A Phase 3, Randomized, Double-blind Study Comparing 
the Efficacy and Safety of SAGE-217 plus Sertraline 
versus Placebo plus Sertraline in Adults with Major 
Depressive Disorder 
Summary of Changes by Version 
Summary of Changes to Version 4.0, 10 January 2022 
Summary of Changes to Version 3.0, 22 January 2021 
Summary of Changes to Version 2.0, 11 September 2020 

Clinical Protocol 
Sage Therapeutics, Inc. 
217-MDD-305 Version 4 
CONFIDENTIAL 
3 
INVESTIGATOR’S AGREEMENT 
I have received and read the Investigator’s Brochure for SAGE-217. I have read the 
217-MDD-305 protocol and agree to conduct the study as outlined. I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
Date (DD/MMM/YYYY) 

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2. 
SYNOPSIS 
Name of Sponsor/Company: Sage Therapeutics, Inc. (hereafter referred to as Sage Therapeutics, or 
Sage) 
Name of Investigational Product: SAGE-217 Capsules 
Name of Active Ingredient: SAGE-217 
Title of Study: A Phase 3, Randomized, Double-Blind Study Comparing the Efficacy and Safety of 
SAGE-217 plus an Antidepressant Versus Placebo plus an Antidepressant in Adults with Major 
Depressive Disorder 
Number of Sites and Study Location: This study will take place at approximately 55 sites in United 
States. 
Phase of Development: 3 
Planned Duration for each Study Participant: Up to 70 days (up to 28-day Screening Period, 14-day 
Double-blind Treatment Period, and a 28-day Antidepressant Therapy (ADT) Continuation Period) 
Objectives: 
Primary: 
• 
To evaluate the efficacy of SAGE-217 plus an antidepressant in the treatment of major 
depressive disorder (MDD) compared to placebo plus an antidepressant 
Secondary: 
• 
To assess patient-reported outcome (PRO) measures as they relate to depressive symptoms 
• 
To evaluate the safety and tolerability of SAGE-217 plus an antidepressant 
 
 
 
 
 
Endpoints: 
Primary: 
• 
Change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D) total 
score at Day 3 
Key Secondary: 
• 
Change from baseline in HAM-D total score over the blinded treatment period (using equal 
weights for the scheduled visits – Day 3, Day 8, Day 12, Day 15) 
Other Secondary: 
• 
Change from baseline in HAM-D total score at Day 15 and Day 42 
• 
Change from baseline in HAM-D total score around end of blinded treatment (using equal 
weights for the scheduled visits –Day 12, Day 15, Day 18) 
• 
HAM-D response at Day 15 and Day 42 
• 
HAM-D remission at Day 15 and Day 42 
• 
Change from baseline in Clinical Global Impression – Severity (CGI-S) at Day 15 
• 
CGI-I response, defined as “much improved” or “very much improved”, at Day 3 and Day 15 
• 
Change from baseline in MADRS total score at Day 15 
• 
MADRS response at Day 15 

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administer ADT in the morning (for twice-daily dosing) as part of a divided dose for the first 7 days. 
Participants will return to the study center as outlined in the Schedule of Assessments (Table 2). 
During the Treatment Period, participants will be able to receive SAGE-217/placebo as long as there 
are no dose-limiting safety/tolerability concerns. Participants who cannot tolerate SAGE-217/placebo 
50 mg will receive 40 mg for the remainder of the Treatment Period. Participants who, in the opinion 
of the investigator, cannot tolerate the SAGE-217/placebo 40-mg dose may be discontinued from 
SAGE-217/placebo at the discretion of the investigator. If blinded IP is discontinued, the ADT may be 
continued at the discretion of the investigator. 
Upon completion of the current study, eligible participants will have the opportunity to enter a long-
term open-label study of SAGE-217.  
Number of Participants (planned): It is estimated that approximately 424 participants will be 
randomized and treated to obtain 382 evaluable participants at Day 3 (assuming a 10% dropout rate). 
Additional participants may be randomized if the dropout rate is greater than 10%. 
Eligibility Criteria: 
Inclusion Criteria 
1. Participant has signed an ICF prior to any study-specific procedures being performed. 
2. Participant is a male or female between 18 and 64 years of age, inclusive. 
3. Participant 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. Participant agrees to adhere to the study requirements. 
5. Participant has a diagnosis of MDD as diagnosed by SCID-5-CT, with symptoms that have 
been present for at least a 4-week period. 
6. Participant has a HAM-D-17 total score of ≥24 at Screening and Day 1 (prior to dosing). 
7. Participant is willing to delay start of any antidepressant (except as per protocol), anxiolytic, 
anti-insomnia, psychostimulant, prescription opioid regimens, or new psychotherapy 
(including Cognitive Behavioral Therapy for Insomnia [CBT-I]) until after study completion. 
Participants receiving psychotherapy must have been receiving therapy on a regular schedule 
for at least 60 days prior to Day 1 and intend to maintain that schedule for the duration of the 
study. 
8. Female participant agrees to use at least one method of highly effective contraception as listed 
in Section 9.2.4 during participation in the study and for 30 days following the last dose of IP, 
unless she is postmenopausal (at least 12 months of spontaneous amenorrhea without an 
alternative medical cause, with confirmatory follicle stimulating hormone >40 mIU/mL), 
and/or surgically sterile (bilateral oophorectomy, hysterectomy, and/or bilateral 
salpingectomy), or does not engage in sexual relations which carry a risk of pregnancy (does 
not include abstinence). 
9. Female participant who is breastfeeding at Screening or on Day 1 (prior to administration of 
IP) must be willing to temporarily cease giving breast milk to her child(ren) from just prior to 
receiving IP on Day 1 until 7 days after the last dose of SAGE-217/placebo. 
10. Male participant agrees to use an acceptable method of effective contraception for the duration 
of the study and for 5 days after receiving IP, unless the participant does not engage in sexual 
relation(s) which carry a risk of pregnancy. Acceptable methods of effective contraception are 
listed in Section 9.2.4. 
11. Male participant is willing to abstain from sperm donation for the treatment period and for 
5 days after receiving the last dose of the IP. 

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12. Participant agrees to refrain from drugs of abuse and alcohol for the duration of the study. 
13. Participant is willing, able, and eligible to take at least 1 of the 5 ADTs specified in the 
protocol (an eligible ADT is an ADT that has not been taken during the current depressive 
episode and for which the participant has no contraindications; further, a participant is not 
eligible for citalopram if escitalopram has been taken during the current depressive episode, 
and vice versa). 
Exclusion Criteria 
1. Participant is currently at significant risk of suicide, as judged by the investigator, or has 
attempted suicide associated with the current episode of MDD. 
2. Participant had onset of the current depressive episode during pregnancy or 4 weeks 
postpartum, or the participant has presented for screening during the 6-month postpartum 
period. 
3. Participant has a recent history or active clinically significant manifestations of metabolic, 
hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, 
dermatological, urogenital, neurological, or eye, ear, nose, and throat disorders, or any other 
acute or chronic condition that, in the investigator's opinion, would limit the participant's 
ability to complete or participate in this clinical study; a BMI ≤18 or ≥45 kg/m2 is 
exclusionary; a BMI of 40 to 44.9 kg/m2, inclusive, at Screening is subject to a broader 
evaluation of medical comorbidities as described above. 
4. Participant has treatment-resistant depression, defined as persistent depressive symptoms 
despite treatment with adequate doses of antidepressants within the current major depressive 
episode (excluding antipsychotics) from 2 different classes for at least 4 weeks of treatment. 
Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH 
ATRQ) will be used for this purpose. 
5. Participant has had vagus nerve stimulation, electroconvulsive therapy, or has taken ketamine 
within the current major depressive episode. 
6. Participant is receiving Cognitive Behavioral Therapy for Insomnia (CBT-I) within 28 days 
prior to Day 1. 
7. Participant has a known allergy to SAGE-217, allopregnanolone, or related compounds. 
8. Participant has taken antidepressants within 30 days prior to Day 1, and/or has taken fluoxetine 
within 60 days prior to Day 1. 
9. Female participant has a positive pregnancy test or confirmed pregnancy. 
10. Participant has a clinically significant abnormal 12-lead ECG at the screening or baseline 
visits. NOTE: mean QT interval calculated using the Fridericia method (QTcF) of >450 msec 
in males or >470 msec in females will be the basis for exclusion from the study. 
11. Participant has active psychosis per investigator assessment. 
12. Participant has a medical history of seizures. 
13. Participant has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder. 
14. Participant has a history of severe substance use disorder (including benzodiazepines) 
diagnosed using DSM-5 criteria in the 12 months prior to Screening or participant has a history 
of mild or moderate substance use disorder not in sustained remission for at least 6 months 
prior to Screening. 
15. Participant has had exposure to another investigational medication or device within 30 days 
prior to Screening. 

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16. Participant has previously received brexanolone or participated in a SAGE-217 or SAGE-547 
(brexanolone) clinical trial. 
17. Participant has used any known strong inhibitors of cytochrome P450 (CYP)3A4 within 
28 days or 5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, or 
Seville oranges, or products containing these, within 14 days prior to Day 1. 
18. Participant has used any strong CYP3A inducer, such as rifampin, carbamazepine, 
enzalutamide, mitotane, phenytoin, or St John’s Wort, within 28 days prior to Day 1. 
19. Participant has a positive drug and/or alcohol screen at screening or on Day 1 prior to dosing. 
20. Participant plans to undergo elective surgery before completion of the Day 42 visit. 
21. Participant is taking benzodiazepines, barbiturates, or GABAA modulators (eg, eszopiclone, 
zopiclone, zaleplon, and zolpidem) within 28 days prior to Day 1, or has been using these 
agents daily or near-daily (≥4 times per week) for more than 1 year. Participant is taking any 
benzodiazepine or GABA modulator with a half-life of ≥48 hours (eg, diazepam) from 60 days 
prior to Day 1. 
22. Participant is taking non-GABA anti-insomnia medications (eg, prescribed therapeutics 
specifically for insomnia and/or over the counter sleep aids), or first or second generation 
(typical/atypical) antipsychotics within 14 days prior to Day 1. Note that nonsedating 
antihistamines are permitted. 
23. Participant has been diagnosed with and/or treated for any type of cancer (excluding basal cell 
carcinoma and melanoma in situ) within the past year prior to Screening. 
24. Participant has a history of sleep apnea. 
25. Participant has had gastric bypass surgery, has a gastric sleeve or lap band, or has had any 
related procedures that interfere with gastrointestinal transit. 
26. Participant is taking psychostimulants (eg, methylphenidate, amphetamine) or opioids, 
regularly or as needed, within 28 days prior to Day 1. 
27. Participant is a dependent of the sponsor, investigator, investigator’s deputy, or study site staff. 
28. Participant expects to perform night shift work during the 14-day Treatment Period. 
29. Participant has detectable hepatitis B surface antigen, anti-hepatitis C virus (HCV) and positive 
HCV viral load, or human immunodeficiency virus (HIV) antibody at Screening. 
Investigational Product Dosage and Mode of Administration: SAGE-217 will be available as hard 
gelatin capsules for oral administration; multiple capsules (in 30-mg or 20-mg dose strengths) will be 
provided to total a 50-mg dose, with option to reduce to 40 mg based on tolerability. 
Blinded placebo will be provided as hard gelatin capsules matched in appearance to SAGE-217, for 
oral administration. 
Sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine will be administered as per labeled 
prescribing information 
Duration of Treatment: Blinded SAGE-217 or placebo will be administered once daily for 14 days; 
open-label ADT will be administered according to labeled prescribing information for 42 days. 

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Table 2: 
Schedule of Assessments 
Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
ADT Continuation Period 
Visit Days 
D-28 to 
D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(+1d) 
D18 
(±1d) 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
/ET  
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
Study Procedure 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Duplicate Participant Check a 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
 
 
Serum FSH test b 
X 
 
 
 
 
 
 
 
 
 
 
SCID-5-CT 
X 
 
 
 
 
 
 
 
 
 
 
MGH ATRQ 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Family Historyc 
X 
 
 
 
 
 
 
 
 
 
 
Participant training d 
 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Physical Examination e 
X 
X 
 
 
 
 
 
 
 
 
X 
Body Weight/Height 
X 
 
 
 
 
X 
(weight 
only) 
 
 
 
 
X 
(weight 
only) 
Clinical Laboratory 
Assessments f 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
Drug & Alcohol Screen g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test h 
X 
X 
 
 
 
X 
 
 
X 
 
X 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 

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Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
ADT Continuation Period 
Visit Days 
D-28 to 
D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(+1d) 
D18 
(±1d) 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
/ET  
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
Study Procedure 
 
Vital Signs k 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
12-Lead ECG l 
X 
X 
 
 
 
X 
 
 
 
 
X 
HAM-D n, o 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MADRS 
 
X 
 
X 
 
X 
 
 
X 
 
X 
HAM-A o 
 
X 
 
X 
 
X 
 
 
X 
 
X 
CGI-S 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
PHQ-9 
 
X 
X 
X 
 
X 
 
 
X 
 
X 
SAGE-217/Placebo 
Dispensation 
 
X 
 
X 
 
 
 
 
 
 
 
SAGE-217/Placebo 
Administration 
 
X (once daily in the evening through Day 14 - inclusive) 
 
 
 
 
 
IP Adherence q 
 
X 

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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............16 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................21 
5. 
INTRODUCTION ......................................................................................................23 
5.1. 
Background of Major Depressive Disorder and Unmet Medical Need ......................23 
5.2. 
Potential Risks and Benefits .......................................................................................24 
5.3. 
Dose Justification ........................................................................................................24 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................26 
6.1. 
Objectives ...................................................................................................................26 
6.1.1. 
Primary Objective .......................................................................................................26 
6.1.2. 
Secondary Objectives .................................................................................................26 
 
26 
6.2. 
Endpoints ....................................................................................................................26 
6.2.1. 
Primary Endpoint ........................................................................................................26 
6.2.2. 
Secondary Endpoints ..................................................................................................26 
6.2.2.1. 
Key Secondary Endpoint ............................................................................................26 
6.2.2.2. 
Other Secondary Endpoints ........................................................................................26 
 
27 
7. 
INVESTIGATIONAL PLAN .....................................................................................28 
7.1. 
Overall Study Design ..................................................................................................28 
7.2. 
Number of Participants ...............................................................................................29 
7.3. 
Treatment Assignment ................................................................................................29 
7.4. 
Dose Adjustment Criteria ...........................................................................................29 
7.5. 
Criteria for Study Termination ...................................................................................29 
8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS .....................................30 
8.1. 
Participant Inclusion Criteria ......................................................................................30 
8.2. 
Participant Exclusion Criteria .....................................................................................31 
8.3. 
Screen Failures ............................................................................................................33 

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8.4. 
Investigational Product Discontinuation and Early Termination from the 
Study ...........................................................................................................................33 
8.4.1. 
Investigational Product Discontinuation .....................................................................33 
8.4.2. 
Early Termination from the Study ..............................................................................33 
8.4.3. 
Loss to Follow-up .......................................................................................................34 
8.4.4. 
Replacement of Participants .......................................................................................34 
9. 
TREATMENT OF PARTICIPANTS .........................................................................35 
9.1. 
Description of Investigational Products ......................................................................35 
9.2. 
Prior Medications, Concomitant Medications, Restrictions, and 
Contraception Requirements ......................................................................................35 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................35 
9.2.2. 
Prohibited Medications ...............................................................................................35 
9.2.3. 
Other Restrictions .......................................................................................................36 
9.2.4. 
Acceptable Forms of Contraception ...........................................................................36 
9.3. 
Intervention after the End of the Study .......................................................................37 
9.4. 
Treatment Adherence ..................................................................................................37 
9.5. 
Randomization and Blinding ......................................................................................38 
9.5.1. 
Emergency Unblinding ...............................................................................................38 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............39 
10.1. 
Investigational Products ..............................................................................................39 
10.1.1. 
Blinded Investigational Products ................................................................................39 
10.1.2. 
Open-label Investigational Product ............................................................................39 
10.2. 
Blinded Investigational Product Packaging and Labeling ..........................................39 
10.3. 
Blinded Investigational Product Storage ....................................................................39 
10.4. 
Blinded Investigational Product Preparation ..............................................................39 
10.5. 
Blinded and Open-label Investigational Product Administration ...............................39 
10.6. 
Blinded Investigational Product Accountability, Handling, and Disposal .................40 
10.7. 
Blinded Investigational Product Complaints ..............................................................40 
11. 
EFFICACY AND CLINICAL PHARMACOLOGY ASSESSMENTS ....................42 
11.1. 
Efficacy Assessments .................................................................................................42 
11.1.1. 
Hamilton Rating Scale for Depression .......................................................................42 
11.1.2. 
Montgomery-Åsberg Depression Rating Scale ..........................................................42 
11.1.3. 
Hamilton Anxiety Rating Scale ..................................................................................42 

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11.1.4. 
Clinical Global Impressions .......................................................................................43 
 
43 
11.1.6. 
Patient Health Questionnaire ......................................................................................43 
 
44 
 
44 
 
44 
 
44 
 
44 
 
44 
 
44 
12. 
SAFETY ASSESSMENTS ........................................................................................46 
12.1. 
Safety Parameters .......................................................................................................46 
12.1.1. 
Demographic/Medical History ...................................................................................46 
12.1.2. 
Weight and Height ......................................................................................................46 
12.1.3. 
Physical Examination .................................................................................................46 
12.1.4. 
COVID-19 Questions .................................................................................................46 
12.1.5. 
Vital Signs ..................................................................................................................47 
12.1.6. 
Electrocardiogram (ECG) ...........................................................................................47 
12.1.7. 
Laboratory Assessments .............................................................................................47 
12.1.7.1. 
Drugs of Abuse and Alcohol ......................................................................................49 
12.1.7.2. 
Pregnancy Screen ........................................................................................................49 
 
49 
 
49 
 
50 
12.2. 
Adverse and Serious Adverse Events .........................................................................50 
12.2.1. 
Adverse Event Definition ...........................................................................................50 
12.2.2. 
Serious Adverse Event Definition ..............................................................................51 
12.2.3. 
Relationship to Investigational Product ......................................................................51 
12.2.4. 
Recording Adverse Events .........................................................................................52 
12.2.5. 
Reporting Serious Adverse Events .............................................................................52 
12.3. 
Pregnancy ...................................................................................................................53 
12.4. 
Overdose .....................................................................................................................53 
13. 
STATISTICS ..............................................................................................................55 

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13.1. 
Data Analysis Sets ......................................................................................................55 
13.2. 
Handling of Missing Data ...........................................................................................55 
13.3. 
General Considerations ...............................................................................................55 
13.4. 
Demographics and Baseline Characteristics ...............................................................56 
13.5. 
Efficacy Analysis ........................................................................................................56 
13.5.1. 
Multiplicity Adjustment for Key Secondary Endpoint ...............................................57 
13.6. 
Safety Analyses ..........................................................................................................57 
13.6.1. 
Adverse Events ...........................................................................................................58 
 
58 
13.6.3. 
Physical Examinations ................................................................................................58 
 
58 
13.6.5. 
12-Lead Electrocardiogram ........................................................................................58 
13.6.6. 
Prior and Concomitant Medications ...........................................................................58 
 
59 
 
59 
13.6.9. 
Other Safety Analysis .................................................................................................59 
 
59 
13.8. 
Sample Size and Power ..............................................................................................59 
13.8.1. 
Interim and Data Monitoring Committee Analyses ....................................................59 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................60 
14.1. 
Study Monitoring ........................................................................................................60 
14.2. 
Audits and Inspections ................................................................................................60 
14.3. 
Institutional Review Board (IRB) or Ethics Committee (EC) ....................................61 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................62 
16. 
ETHICS ......................................................................................................................63 
16.1. 
Ethics Review .............................................................................................................63 
16.2. 
Ethical Conduct of the Study ......................................................................................63 
16.3. 
Written Informed Consent ..........................................................................................63 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................65 
17.1. 
Inspection of Records .................................................................................................65 
17.2. 
Retention of Records ..................................................................................................65 
18. 
PUBLICATION POLICY ..........................................................................................66 
19. 
LIST OF REFERENCES ............................................................................................67 

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LIST OF TABLES 
Table 1: 
Contact Information ......................................................................................................4 
Table 2: 
Schedule of Assessments ............................................................................................12 
Table 3: 
Clinical Laboratory Tests ...........................................................................................48 
 
 

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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Abbreviation 
Definition 
ADT 
Antidepressant therapy 
AE 
adverse event 
ALT 
alanine aminotransferase 
ALP 
alkaline phosphatase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BP 
blood pressure 
CFR 
Code of Federal Regulation 
CRO 
contract research organization 
CSR 
clinical study report 
IEC 
independent ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IND 
investigational new drug  
IP 
investigational product 
MedDRA 
Medical Dictionary for Regulatory Activities 
PD 
pharmacodynamic 
PI 
prescribing information 
PK 
pharmacokinetic 
PV 
pharmacovigilance 
QA 
quality assurance 
QC 
quality control 
QTcF 
QT corrected according to Fridericia’s formula 
SAE 
serious adverse event 
SOP 
Standard Operating Procedure 

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Abbreviation 
Definition 
SNRI 
serotonin-norepinephrine reuptake inhibitor 
SSRI 
selective serotonin reuptake inhibitor 
TEAE 
treatment-emergent adverse event 
WHO 
World Health Organization 

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5. 
INTRODUCTION 
5.1. 
Background of Major Depressive Disorder and Unmet Medical Need 
The World Health Organization (WHO) has identified depression as the leading cause of 
disability worldwide, and as a major contributor to the overall global burden of disease 
(http://www.who.int/mediacentre/factsheets/fs369/en/). Globally, depression has been estimated 
to affect over 300 million people. 
In the United States, the economic burden of depression, including workplace costs, direct costs, 
and suicide-related costs, was estimated to be $210.5 billion in 2010 (Greenberg 2015). As per 
WHO statistics, over 800,000 people die due to suicide every year, and suicide is the second 
leading cause of death in 15- to 29-year-olds. The rate of US adults making a suicide attempt has 
increased (0.62% from 2004 to 2005 to 0.79% from 2012 to 2013), with a shift to more attempts 
among younger adults (42% to 50%, respectively) and among those with a depressive disorder 
(26% to 54%, respectively; Olfson 2017). 
The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5, American 
Psychiatric Association 2013) provides diagnostic criteria for major depressive disorder (MDD). 
These include at least 5 of 9 depressive symptoms (depressed mood and/or loss of interest or 
pleasure, and other changes affecting appetite or weight, sleep, psychomotor activity, energy 
level, feelings of guilt, concentration ability, and suicidality) during the same 2-week period that 
represents a change from previous functioning (DSM-5). 
Antidepressants are a mainstay of pharmacological treatment for depressive disorders. Selective 
serotonin uptake inhibitors (SNRI), serotonin norepinephrine reuptake inhibitors (SSRI), 
tricyclic antidepressants, monoamine oxidase inhibitors (MAOI), and other compounds that 
affect monoaminergic neurotransmission, such as mirtrazapine and bupropion, represent the 
major classes of antidepressants. While antidepressants are widely used, large scale studies have 
demonstrated their limited efficacy, including low remission rates and untreated symptoms 
(Trivedi 2006; Conradi 2011; Romera 2013). Furthermore, these agents can take 4 to 8 weeks to 
demonstrate full clinical efficacy (Rush 2006; Trivedi 2006), and in the case of the most 
commonly prescribed classes—SSRIs and SNRIs—common side effects including weight gain, 
GI symptoms, and sexual dysfunction can prevent titration into an adequate therapeutic range 
(Sadock and Sadock 2007). 
In the largest study to assess the effectiveness of depression treatments in patients with MDD, 
time to patient remission after treatment was 5.4 to 7.4 weeks; approximately one-half of the 
patients who ultimately remitted did so after 6 weeks, and 40% of those who achieved remission 
required 8 or more weeks to do so (Rush 2006; Trivedi 2006). Even following remission, many 
patients report the presence of residual symptoms, often related to decreased positive affect, such 
as loss of interest in activities once considered enjoyable, fatigue, loss of energy, as well as sleep 
and appetite/weight disturbances (Nierenberg 2009; Nierenberg 2015). Thus, patients may 
remain symptomatic for up to 2 months while waiting for current standard-of-care 
pharmacotherapy to take full effect. They may also have to contend with undesirable side effects 
and residual symptoms. These aspects underscore the need for newer, rapid-acting therapies. 
SAGE-217 is a synthetic positive allosteric modulator of GABAA receptors, the major class of 
inhibitory neurotransmitter receptors in the brain. In pharmacokinetic (PK) studies in mice and 

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rats, SAGE-217 demonstrated rapid penetration and equilibrium across the blood brain barrier 
and is generally expected to have good extravascular exposure. In exploratory in vitro receptor 
and ion channel assays and in vivo safety pharmacology studies, SAGE-217 was highly selective 
for GABAA receptors, and, consistent with the actions of other GABAA receptor potentiators 
(Rudolph 2011), exhibits potent anticonvulsant, anxiolytic, and sedative activity when 
administered in vivo. 
SAGE-217 has been generally well tolerated in clinical studies to date. The most common 
treatment-emergent adverse events (TEAEs) associated with SAGE-217 (overall) were sedation, 
somnolence, and dizziness; most adverse events (AEs) were reported as mild or moderate in 
intensity. Refer to the SAGE-217 Investigator’s Brochure for a detailed description of the 
chemistry, pharmacology, efficacy, and safety of SAGE-217. 
This study was designed to target the unmet need of symptom improvement during the latency to 
SSRI and SNRI efficacy in the acute phase of a major depressive episode. This study will assess 
the safety and efficacy of SAGE-217 50 mg plus an antidepressant, examining if SAGE-217 plus 
an antidepressant produces more rapid or more profound reduction in depressive symptoms than 
an antidepressant alone. 
5.2. 
Potential Risks and Benefits 
The apparent risks of SAGE-217 are based on clinical data reports of AEs in completed and 
ongoing studies and the known pharmacology of the drug. Sedation, somnolence, and dizziness 
were identified as adverse drug reactions. Most AEs were reported as mild or moderate in 
intensity and reversible. 
SAGE-217 may present a treatment option for MDD that has more rapid onset of action (days 
instead of weeks/months), when compared to available pharmacotherapies. 
Based on nonclinical findings, embryo-fetal toxicity and withdrawal effects are considered 
important potential risk for SAGE-217. Risk mitigation measures in this study include 
monitoring for adverse effects, monitoring for potential withdrawal effects, requiring highly 
effective contraceptive measures for study participants, and inclusion of dose adjustment criteria 
and guidance for blinded IP discontinuation (Section 8.4). Finally, due to the 
sedation/somnolence observed, SAGE-217 is administered in the evening in this study. 
Given the outcome of the completed studies of SAGE-217 in participants with MDD and PDD, 
the current significant unmet need for well-tolerated and rapid-acting depression treatments, and 
a favorable benefit-risk profile, further investigation of SAGE-217 as a novel rapid response 
treatment in adults with MDD is justified. 
5.3. 
Dose Justification 
Results from a large, multicenter study of SAGE-217 20 and 30 mg in MDD (217-MDD-301) 
support the need for higher steady-state concentrations of SAGE-217 to allow participants to 
experience maximum antidepressant and anti-anxiety benefits. SAGE-217 will be administered 
as a 14-day regimen of an evening dose of 50 mg with reduction to 40 mg as needed based on 
tolerability. The 50-mg dose of SAGE-217 is expected to exhibit a favorable benefit-risk profile 
in the context of results from previous SAGE-217 studies utilizing a 30-mg dose, now identified 
as a minimally effective dose. SAGE-217 is expected to maintain an acceptable tolerability 

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profile, based on a current safety database of over 2000 participants exposed across different 
doses/concentrations. 
Sertraline is a commercially available SSRI indicated for the treatment of MDD and other 
psychiatric disorders. Dosage and administration of sertraline as described in the approved US 
Prescribing Information (PI) recommends a starting dose of 50 mg per day in patients with 
MDD, with an incremental weekly increase in dose of 25-50 mg per day, if there is an 
inadequate response to the starting dose, to a maximum dose of 200 mg per day. . In this study, a 
starting dose of 50 mg per day is recommended for 7 days, with a subsequent increase to 100 mg 
per day. 
Citalopram and escitalopram are commercially available SSRIs that are both indicated for acute 
and maintenance treatment of MDD. Escitalopram is also indicated for treatment of generalized 
anxiety disorder. The starting dosage for MDD in the US PI for citalopram is 20 mg/day and for 
escitalopram is 10 mg/day, with maxima of 40 mg/day and 20 mg/day, respectively. In this 
study, a starting dose of 20 mg/day is recommended for citalopram and of 10 mg/day is 
recommended for escitalopram for the first 14 days; subsequent dose increases may be 
considered, except for participants >60 years old taking citalopram. 
Duloxetine is a commercially available SNRI indicated for the treatment of MDD, generalized 
anxiety disorder, and pain disorders. The starting dosage for MDD in the US PI is 40 to 
60 mg/day. The maximum dosage is 120 mg/day, although there is no evidence that dosages 
greater than 60 mg/day confer any additional benefits. In this study, a starting dose of 40 or 60 
mg/day is recommended (divided as 20 or 30 mg, respectively, twice daily for the first 7 days).  
Desvenlafaxine is a commercially available SNRI indicated for the treatment of MDD. The 
recommended dosage in the US PI is 50 mg/day. In this study, a dose of 50 mg/day is 
recommended. There has been no evidence that doses greater than 50 mg/day confer any 
additional benefit. 

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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Objectives 
6.1.1. 
Primary Objective 
To evaluate the efficacy of SAGE-217 plus an antidepressant in the treatment of MDD compared 
to placebo plus an antidepressant 
6.1.2. 
Secondary Objectives 
• To assess patient-reported outcome (PRO) measures as they relate to depressive 
symptoms 
• To evaluate the safety and tolerability of SAGE-217 plus an antidepressant 
 
 
 
 
 
 
6.2. 
Endpoints 
6.2.1. 
Primary Endpoint 
• Change from baseline in 17-item Hamilton Rating Scale for Depression (HAM-D) 
total score at Day 3 
6.2.2. 
Secondary Endpoints 
6.2.2.1. 
Key Secondary Endpoint 
• Change from baseline in HAM-D total score over the blinded treatment period (using 
equal weights for the scheduled visits – Day 3, Day 8, Day 12, Day 15) 
6.2.2.2. 
Other Secondary Endpoints 
• Change from baseline in HAM-D total score at Day 15 and Day 42 
• Change from baseline in HAM-D total score around end of blinded treatment at 
(using equal weights for the scheduled visits –Day 12, Day 15, Day 18) 
• HAM-D response at Day 15 and Day 42 
• HAM-D remission at Day 15 and Day 42 
• Change from baseline in CGI-S at Day 15 
• CGI-I response, defined as “much improved” or “very much improved”, at Day 3 and 
Day 15 
• Change from baseline in MADRS total score at Day 15 
• MADRS response at Day 15 

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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a randomized, double-blind, parallel-group, placebo-controlled study in adults with 
MDD. The diagnosis of MDD must be made according to Structured Clinical Interview for 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Clinical Trial 
Version (SCID 5-CT) performed by a qualified healthcare professional.  
The study will consist of a Screening Period of up to 28 days, a 14-day double-blind Treatment 
Period, and a 28-day ADT Continuation Period. The Screening Period begins with the signing of 
the informed consent form (ICF) at the Screening Visit. Preliminary screening procedures to 
determine eligibility include completion of the MGH-ATRQ and HAM-D. 
Participants will be randomized to receive blinded SAGE-217 or placebo for administration each 
evening from Day 1 through 14. In addition, all participants will receive 1 of 2 classes of ADTs: 
a selective serotonin reuptake inhibitor (SSRI; sertraline, escitalopram, citalopram) or a 
serotonin-norepinephrine reuptake inhibitor (SNRI; duloxetine, desvenlafaxine) in an open-label 
manner from Day 1 through the end of the study. The investigator will assign 1 of the 5 ADTs 
based on clinical standard of care; the participant must not have been previously treated with the 
assigned ADT within the current depressive episode (and must not have been treated with 
citalopram if escitalopram is assigned, and vice versa) and must not haven taken any ADT within 
30 days prior to Day 1 (or taken fluoxetine within 60 days prior to Day 1). Randomization will 
be stratified by antidepressant class (SSRI or SNRI). 
The open-label ADT will be administered as per labeled prescribing information. 
After the Double-blind Treatment Period, the ADT will be continued each evening for the 
remainder of the study (ADT Continuation Period). During this period (Week 3 to 6), ADT 
dosing may be modified as appropriate per the labeled prescribing information and based on 
individual response. 
Initiation of other antidepressants or any other medications that may potentially have an impact 
on efficacy or safety endpoints will not be allowed between screening and completion of 
assessments at Day 42/end-of-study visit. 
Participants will self-administer blinded investigational product (IP) once daily at approximately 
8 PM with fat-containing food (eg, within 1 hour of an evening meal which contains fat, or with 
a fat-containing snack), on an outpatient basis, for 14 days. The ADT and SAGE-217 or placebo 
will be administered at the same time during the Treatment Period; participants assigned 
duloxetine will also administer ADT in the morning (for twice-daily dosing) as part of a divided 
dose for the first 7 days. Participants will return to the study center as outlined in the Schedule of 
Assessments. 
During the Treatment Period, participants will be able to receive SAGE-217/placebo as long as 
there are no dose-limiting safety/tolerability concerns. Participants who cannot tolerate 
SAGE-217 or placebo 50 mg will receive 40 mg for the remainder of the Treatment Period. 
Participants who cannot tolerate the SAGE-217/placebo 40-mg dose may be discontinued from 
SAGE-217 or placebo at the discretion of the investigator. If blinded IP is discontinued, the ADT 
may be continued at the discretion of the investigator. 

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Upon completion of the current study, eligible participants will have the opportunity to enter a 
long-term open-label study of SAGE-217. Participants that do not enter the open-label study or 
that terminate the current study early may, per the investigator, receive a supply of the ADT with 
instructions on how to taper the drug, if needed, or, if they wish to continue the ADT, a bridge 
supply to permit them to obtain a prescription from another provider. 
7.2. 
Number of Participants 
It is estimated that approximately 424 participants will be randomized and treated to obtain 
382 evaluable participants at Day 3 (assuming 10% dropout rate). Additional participants may be 
randomized if the dropout rate is greater than 10%. 
7.3. 
Treatment Assignment 
Participants will be assigned to blinded IP (SAGE-217 or placebo) in accordance with the 
randomization schedule on Day 1. The investigator will assign 1 of the 5 ADTs based on clinical 
standard of care. The assigned ADT for a participant cannot have been taken previously by the 
participant during the current depressive episode. Further, citalopram cannot be assigned if 
escitalopram has been taken during the current depressive episode, and vice versa.  
Randomization will be stratified by antidepressant class (SSRI or SNRI).Additional details on 
randomization and blinding are provided in Section 9.5. 
Sage will monitor the ratio of SSRIs:SNRIs on an ongoing basis and may restrict assignment of 
any ADT(s) to reflect the ratio expected with standard of care (approximately 3:1; Luo 2020). 
7.4. 
Dose Adjustment Criteria 
During the treatment period, participants will be able to receive SAGE-217/placebo as long as 
there are no dose-limiting safety/tolerability concerns. Participants who cannot tolerate 50 mg (as 
determined by the investigator) will receive 40 mg for the remainder of the treatment period. 
At the discretion of the investigator, participants who cannot tolerate the 40-mg dose at any time 
may be discontinued from dosing. These participants should be followed and complete 
assessments as per the Schedule of Assessments (Table 2). 
During Weeks 3 to 6, the ADT dosing may be modified, based on individual response, per 
investigator discretion and per the labeled prescribing information. 
7.5. 
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 AEs or other findings suggesting unacceptable risk to 
participants, 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 IRB, where required, and initiate withdrawal procedures for participating participants. 

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8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
8.1. 
Participant Inclusion Criteria 
1. Participant has signed an ICF prior to any study-specific procedures being performed. 
2. Participant is a male or female between 18 and 64 years of age, inclusive. 
3. Participant 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. Participant agrees to adhere to the study requirements. 
5. Participant has a diagnosis of MDD as diagnosed by SCID-5-CT, with symptoms that 
have been present for at least a 4-week period. 
6. Participant has a HAM-D-17 total score of ≥24 at Screening and Day 1 (prior to dosing). 
7. Participant is willing to delay start of any antidepressant (except as per protocol), 
anxiolytic, anti-insomnia, psychostimulant, prescription opioid regimens, or new 
psychotherapy (including Cognitive Behavioral Therapy for Insomnia [CBT-I]) until 
after study completion. Participants receiving psychotherapy must have been receiving 
therapy on a regular schedule for at least 60 days prior to Day 1 and intend to maintain 
that schedule for the duration of the study. 
8. Female participant agrees to use at least one method of highly effective contraception as 
listed in Section 9.2.4 during participation in the study and for 30 days following the last 
dose of IP, unless she is postmenopausal (at least 12 months of spontaneous amenorrhea 
without an alternative medical cause, with confirmatory follicle stimulating hormone 
>40 mIU/mL), and/or surgically sterile (bilateral oophorectomy, hysterectomy, and/or 
bilateral salpingectomy), or does not engage in sexual relations which carry a risk of 
pregnancy (does not include abstinence). 
9. Female participant who is breastfeeding at Screening or on Day 1 (prior to administration 
of IP) must be willing to temporarily cease giving breast milk to her child(ren) from just 
prior to receiving IP on Day 1 until 7 days after the last dose of SAGE-217/placebo. 
10. Male participant agrees to use an acceptable method of effective contraception for the 
duration of the study and for 5 days after receiving IP, unless the participant does not 
engage in sexual relation(s) which carry a risk of pregnancy. Acceptable methods of 
effective contraception are listed in Section 9.2.4. 
11. Male participant is willing to abstain from sperm donation for the treatment period and 
for 5 days after receiving the last dose of the IP. 
12. Participant agrees to refrain from drugs of abuse and alcohol for the duration of the study. 
13. Participant is willing, able, and eligible to take at least 1 of the 5 ADTs specified in the 
protocol (an eligible ADT is an ADT that has not been taken during the current 
depressive episode and for which the participant has no contraindications; further, a 
participant is not eligible for citalopram if escitalopram has been taken during the current 
depressive episode, and vice versa). 

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8.2. 
Participant Exclusion Criteria 
Participants who meet any of the following criteria are disqualified from participation in this 
study: 
1. Participant is currently at significant risk of suicide, as judged by the investigator, or has 
attempted suicide associated with the current episode of MDD. 
2. Participant had onset of the current depressive episode during pregnancy or 4 weeks 
postpartum, or the participant has presented for screening during the 6-month postpartum 
period. 
3. Participant 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 participant's ability to complete or participate in this clinical study; a 
BMI ≤18 or ≥45 kg/m2 is exclusionary; a BMI of 40 to 44.9 kg/m2, inclusive, at 
Screening is subject to a broader evaluation of medical comorbidities as described above. 
4. Participant has treatment-resistant depression, defined as persistent depressive symptoms 
despite treatment with adequate doses of antidepressants within the current major 
depressive episode (excluding antipsychotics) from 2 different classes for at least 4 weeks 
of treatment. Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire (MGH ATRQ) will be used for this purpose. 
5. Participant has had vagus nerve stimulation, electroconvulsive therapy, or has taken 
ketamine within the current major depressive episode. 
6. Participant is receiving Cognitive Behavioral Therapy for Insomnia (CBT-I) within 
28 days prior to Day 1. 
7. Participant has a known allergy to SAGE-217, allopregnanolone, or related compounds. 
8. Participant has taken antidepressants within 30 days prior to Day 1, and/or has taken 
fluoxetine within 60 days prior to Day 1. 
9. Female participant has a positive pregnancy test or confirmed pregnancy. 
10. Participant has a clinically significant abnormal 12-lead ECG at the screening or baseline 
visits. NOTE: mean QT interval calculated using the Fridericia method (QTcF) of 
>450 msec in males or >470 msec in females will be the basis for exclusion from the 
study. 
11. Participant has active psychosis per investigator assessment. 
12. Participant has a medical history of seizures. 
13. Participant has a medical history of bipolar disorder, schizophrenia, and/or 
schizoaffective disorder. 

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14. Participant has a history of severe substance use disorder (including benzodiazepines) 
diagnosed using DSM-5 criteria in the 12 months prior to Screening or participant has a 
history of mild or moderate substance use disorder not in sustained remission for at least 
6 months prior to Screening. 
15. Participant has had exposure to another investigational medication or device within 
30 days prior to Screening. 
16. Participant has previously received brexanolone or participated in a SAGE-217 or SAGE-
547 (brexanolone) clinical trial. 
17. Participant has used any known strong inhibitors of cytochrome P450 (CYP)3A4 within 
28 days or five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, 
or Seville oranges, or products containing these within 14 days prior to Day 1. 
18. Participant has used any strong CYP3A inducer, such as rifampin, carbamazepine, 
enzalutamide, mitotane, phenytoin, or St John’s Wort, within 28 days prior to Day 1. 
19. Participant has a positive drug and/or alcohol screen at screening or on Day 1 prior to 
dosing. 
20. Participant plans to undergo elective surgery before completion of the Day 42 visit. 
21. Participant is taking benzodiazepines, barbiturates, or GABAA modulators (eg, 
eszopiclone, zopiclone, zaleplon, and zolpidem) within 28 days prior to Day 1, or has 
been using these agents daily or near-daily (≥4 times per week) for more than 1 year. 
Participant is taking any benzodiazepine or GABA modulator with a half-life of 
≥48 hours (eg, diazepam) from 60 days prior to Day 1. 
22. Participant is taking non-GABA anti-insomnia medications (eg, prescribed therapeutics 
specifically for insomnia and/or over the counter sleep aids), or first generation or second 
generation (typical/atypical) antipsychotics within 14 days prior to Day 1. Note that 
nonsedating antihistamines are permitted. 
23. Participant has been diagnosed with and/or treated for any type of cancer (excluding 
basal cell carcinoma and melanoma in situ) within the past year prior to Screening. 
24. Participant has a history of sleep apnea. 
25. Participant has had gastric bypass surgery, has a gastric sleeve or lap band, or has had any 
related procedures that interfere with gastrointestinal transit. 
26. Participant is taking psychostimulants (eg, methylphenidate, amphetamine) or opioids, 
regularly or as needed, within 28 days prior to Day 1. 
27. Participant is a dependent of the sponsor, investigator, investigator’s deputy, or study site 
staff. 
28. Participant expects to perform night shift work during the 14-day treatment period. 
29. Participant has detectable hepatitis B surface antigen, anti-hepatitis C virus (HCV) and 
positive HCV viral load, or human immunodeficiency virus (HIV) antibody at Screening. 

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8.3. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized to study intervention. A minimal set of screen failure information 
will be collected, including demography, screen failure details, eligibility criteria, and any 
AE/serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once. 
8.4. 
Investigational Product Discontinuation and Early Termination from 
the Study 
A participant may withdraw from the study at any time at his/her own request for any reason. 
The investigator may discontinue a participant from the study and/or from IP for safety, 
behavioral, compliance, or administrative reasons. 
Based on known withdrawal symptoms with other GABAergic drugs and nonclinical findings in 
a 9-month study of SAGE-217 in dogs (Investigator’s Brochure), there is a potential for 
withdrawal-related events, including seizure. The following guidelines for blinded IP 
discontinuation or dose reduction are presented to support participant safety: 
1. Any participant reporting a confirmed or suspected seizure at any time will be 
discontinued from blinded IP but will continue to be followed in the study. 
2. The investigator should monitor the course of CNS-based signs and symptoms suggestive 
of a seizure which are not accounted for by comorbid psychiatric or medical conditions. 
Examples of reported serious or severe events which may reflect an oncoming and/or 
increased risk for seizure may include temporary confusion, tremors, involuntary muscle 
fasciculations or jerking movements of arms or legs, or paresthesia. Should such 
symptoms occur, the investigator should consider decreasing the dose of SAGE-217 or 
placebo to 40 mg, stopping treatment to assess the effect on the symptom(s) 
(eg, resolution, improvement), or discontinuing the participant from treatment. A 
participant who discontinues treatment should remain in the study and continue protocol-
required assessments until the end of the study. 
The investigator must notify the sponsor and/or the medical monitor when a participant stops 
participation in the study for any reason. 
8.4.1. 
Investigational Product Discontinuation 
The primary reason for IP discontinuation must be documented in the participant’s study record 
and recorded in the participant’s electronic case report form (eCRF). 
Participants who discontinue treatment early should complete remaining study visits as 
scheduled through Day 42 (ie, relative to Day 1), unless the participant withdraws consent.  
8.4.2. 
Early Termination from the Study 
If a participant decides to terminate the study, the participant should return for an early 
termination (ET) visit, if possible. The primary reason for early termination from the study must 

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be documented in the participant’s study record and recorded in the participant’s electronic case 
report form (eCRF).  
If the participant withdraws consent for disclosure of future information, the sponsor will retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
Participants who terminate from the study early may, per the investigator, receive a supply of the 
ADT with instructions on how to taper the drug, if needed, or, if they wish to continue the ADT, 
a bridge supply to permit them to obtain a prescription from another provider. 
8.4.3. 
Loss to Follow-up 
A participant will be deemed lost to follow-up after 3 attempts at contacting the participant have 
been unsuccessful. 
8.4.4. 
Replacement of Participants 
Participants will not be replaced. 

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9. 
TREATMENT OF PARTICIPANTS 
9.1. 
Description of Investigational Products 
SAGE-217 will be available as hard gelatin capsules for oral administration; 2 capsules 
(one 30 mg and one 20 mg) will be provided to total a 50-mg dose, with option to reduce to 
40 mg based on tolerability, as per criteria described in Section 7.4. If the dose is reduced to 
40 mg, it will be administered as 2 20-mg capsules. 
Blinded placebo will be provided as hard gelatin capsules matched in appearance to SAGE-217, 
for oral administration. 
All participants will self-administer blinded and open-label IP orally at approximately 8 PM with 
fat-containing food for 14 days. Participants assigned duloxetine will also administer duloxetine 
in the morning (for twice daily dosing) as part of a divided dose for the first 7 days (see below). 
It is recommended that sertraline be administered as per labeled prescribing information, starting 
with 50 mg each evening during Week 1. and It is recommended that the dose be increased to 
100 mg each evening during Week 2.  
It is recommended that citalopram be administered per labeled prescribing information, starting 
with 20 mg/day.  
It is recommended that escitalopram be administered per labeled prescribing information, 
starting with 10 mg/day. 
It is recommended that duloxetine be administered per labeled prescribing information, starting 
with 40 or 60 mg/day (divided as 20 or 30 mg, respectively, twice daily for the first 7 days).  
It is recommended that desvenlafaxine be administered per labeled prescribing information, 
starting with 50 mg/day. 
9.2. 
Prior Medications, Concomitant Medications, Restrictions, and 
Contraception Requirements 
9.2.1. 
Prior and Concomitant Medications and/or Supplements 
The start and end dates, route, dose/units, frequency, and indication for all medications and/or 
supplements taken within 30 days prior to Screening and throughout the duration of the study 
will be recorded. In addition, psychotropic medications taken within 6 months prior to Screening 
will be recorded. 
Any medication and/or supplement determined necessary for the welfare of the participant may 
be given at the discretion of the investigator at any time during the study. 
9.2.2. 
Prohibited Medications 
The following specific classes of medications are prohibited: 
• Initiation of new psychotropic medications through the Day 42 visit 
• Initiation of new antidepressant therapy from 30 days (60 days for fluoxetine) prior to 
Day 1 through the Day 42 visit 

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• Use of any benzodiazepines, barbiturates, GABAA modulators, GABA-containing 
agents from Day -28 through the Day 42 visit (from Day -60 for benzodiazepines or 
GABA modulators with a half-life ≥48 hours) 
• Chronic or as-needed psychostimulants (eg, methylphenidate, amphetamine) or 
opioids from Day -28 through the Day 42 visit 
• First generation (typical) antipsychotics (eg, haloperidol, perphenazine) and second 
generation (atypical) antipsychotics (eg, aripiprazole, quetiapine) from Day -14 
through the Day 42 visit 
• Use of any non-GABA anti-insomnia medications (eg, prescribed therapeutics 
specifically for insomnia and/or over the counter sleep aids) from Day -14 to Day 1. 
Note that nonsedating antihistamines are permitted. 
• Exposure to another investigational medication or device from 30 days prior to 
Screening through the Day 42 visit 
• Any known strong inhibitors of CYP3A4 from Day -28 or 5 half-lives prior to Day 1 
(whichever is longer) through the Treatment Period 
• Use of any strong CYP3A inducer, such as rifampin, carbamazepine, enzalutamide, 
mitotane, phenytoin, or St John’s Wort from Day -28 through the Treatment Period 
• Any contraindications to the assigned SSRI/SNRI per labeled prescribing information 
9.2.3. 
Other Restrictions 
Any specific restrictions for the assigned SSRI/SNRI with concomitant medications per the 
labeled prescribing information should be considered. 
The consumption of grapefruit juice, grapefruit, or Seville oranges, or products containing these 
is prohibited within 14 days prior to Day 1 and throughout the treatment period. 
 Consumption of alcohol or use of drugs of abuse is discouraged throughout the duration of the 
study. 
Female participants who are lactating or actively breastfeeding must stop giving breast milk to 
the baby(ies) starting on Day 1 until 7 days after the last dose of SAGE-217/placebo. 
Elective surgeries or procedures are prohibited through the Day 42 visit. 
Participants must not participate in night shift work during the Treatment Period. 
Participants who are feeling sedated, somnolent, and/or dizzy are to refrain from driving or 
engaging in any activity requiring alertness. 
Participants receiving psychotherapy on a regular schedule for at least 60 days prior to Day 1 are 
permitted if the participant intends to continue that schedule through the Follow-up Period 
(Day 42). Initiation of new psychotherapy is prohibited until after study completion. 
9.2.4. 
Acceptable Forms of Contraception 
Acceptable forms of highly effective contraception for participants of childbearing potential or 
for partners of male participants who are of childbearing potential include: 

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• 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 
• Laparoscopic or abdominal bilateral tubal occlusion procedure (including bilateral 
tubal ligation) 
• Hysteroscopic bilateral tubal occlusion procedure performed at least 3 months prior to 
screening  
• Vasectomized partner (performed at least 3 months prior to screening) 
Acceptable forms of contraception for male participants include: 
• History of vasectomy (performed at least 3 months prior to screening) 
• Condom with spermicide used together with highly effective female contraceptive 
methods if the female partner(s) is of childbearing potential (see above for list of 
acceptable female contraceptive methods) 
9.3. 
Intervention after the End of the Study 
Upon completion of the current study, eligible participants will have the opportunity to enter an 
open-label, long-term study of SAGE-217 in which additional treatment with SAGE-217 will be 
offered. Participants that do not enter the open-label study or that terminate the current study 
early may continue to receive ADT as prescribed by the investigator either to taper the drug 
appropriately or—if the participant wishes to continue ADT—to bridge the participant until he or 
she receives a new prescription. 
9.4. 
Treatment Adherence 
Investigational products will be self-administered by participants (see Section 10.5). 
Administration of blinded and open-label IP will be monitored by a medication adherence 
monitoring platform used on smartphones to confirm IP ingestion. Participants will receive a 
reminder within a predefined time window to take IP while using the application and will follow 
a series of prescribed steps to confirm their ingestion of the medication. For visually confirmed 
IP ingestion, the application will record the date and time of IP administration by dose level, as 
well as missed doses. 
In addition, participants will be instructed to bring their SAGE-217 or placebo dosing kit and 
ADT to the site as outlined in Table 2, at which time the investigator or designee will be 
responsible for ensuring the kit contains sufficient doses for the duration of the treatment period. 
All participants should be reinstructed about the dosing requirements during study contacts. The 
authorized study personnel conducting the reeducation must document the process in the 
participant source records. 

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The investigator(s) will record any reasons for nonadherence in the source documents. 
9.5. 
Randomization and Blinding 
Participants will be randomized in a 1:1 ratio to receive SAGE-217 or matched placebo. 
Participants, site staff, and the sponsor will be blinded to treatment allocation. All participants 
will also receive an open-label ADT. Randomization will be performed centrally via an 
interactive response technology (IRT) system. Randomization schedules will be generated by an 
independent statistician. The allocation to blinded treatment (SAGE-217or 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. The blinding of 
the study will be broken after the database has been locked. 
9.5.1. 
Emergency Unblinding 
During the study, the blind is to be broken by the investigator via the IRT system only when the 
safety of a participant is at risk and the treatment plan is dependent on the study treatment 
received. Unless a participant is at immediate risk, the investigator should make diligent attempts 
to contact Sage prior to unblinding the study treatment administered to a participant. The 
responsibility to break the treatment code resides solely with the investigator. If the unblinding 
occurs without Sage’s knowledge, the investigator must notify Sage within 24 hours of breaking 
the blind. All circumstances surrounding a premature unblinding must be clearly documented in 
the source records. 
In all cases where the IP allocation for a participant is unblinded, pertinent information 
(including the reason for unblinding) must be documented in the participant’s records and on the 
eCRF. 

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10. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
10.1. 
Investigational Products 
10.1.1. 
Blinded Investigational Products 
SAGE-217 is 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, colloidal silicon 
dioxide, and sodium stearyl fumarate as excipients. Capsules will be available in 20-mg and 
30-mg dose strengths. 
Blinded placebo will be provided as hard gelatin capsules matched in appearance to SAGE-217. 
10.1.2. 
Open-label Investigational Product 
Sertraline, escitalopram, citalopram, duloxetine, and desvenlafaxine, packaged and labeled by 
the commercial manufacturer, will be supplied by a third-party vendor. Open-label IP is to be 
stored and administered according to the package insert. Open-label IP during this study is for 
use only as directed in this protocol. 
10.2. 
Blinded Investigational Product Packaging and Labeling 
SAGE-217 and placebo will be provided to the clinic pharmacist and/or designated site staff 
responsible for dispensing the blinded IP in appropriately labeled, participant-specific kits 
containing sealed unit doses. Each unit dose for 40-mg and 50-mg dose levels consists of 
2 capsules. Additional information regarding the packaging and labeling is provided in the 
Pharmacy Manual. 
Labels with all required information and conforming to all applicable FDA Code of Federal 
Regulations and Good Manufacturing Practices/Good Clinical Practices guidelines will be 
prepared by the sponsor for SAGE-217 and placebo. 
10.3. 
Blinded Investigational Product Storage 
SAGE-217 and placebo is to be stored at room temperature (59 to 86°F; 15 to 30°C), safely and 
separately from other drugs. 
10.4. 
Blinded Investigational Product Preparation 
Not applicable. 
10.5. 
Blinded and Open-label Investigational Product Administration 
Blinded IP and open-label ADT are to be administered orally at approximately 8 PM with fat-
containing food (eg, within 1 hour of an evening meal which contains fat, or with a fat-
containing snack). Examples of fat-containing snacks include nuts, peanut butter, avocado, eggs, 
and cheese. Participants assigned duloxetine will also administer duloxetine in the morning (for 
twice-daily divided dosing) for the first 7 days (see Section 9.1). 

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If a participant misses a dose of blinded IP or open-label IP, the participant should skip that dose 
(ie, they should not take the dose in the morning) and take the next scheduled dose. 
10.6. 
Blinded Investigational Product Accountability, Handling, and 
Disposal 
Upon receipt of blinded IP dosing kits, the investigator(s), or the responsible pharmacist or 
designee, will inspect the kits and complete and follow the instructions regarding receipt and 
storage in the SAGE-217 Investigator’s Brochure and (where applicable) in the Pharmacy 
Manual. A copy of the shipping documentation will be kept in the study files. 
The designated site staff will dispense the participant-specific kits to participants at the planned 
dispensation visit intervals outlined in Table 2. Site staff will access the IRT at the Screening 
Visit to obtain a participant identification (ID) number for each participant that has signed an 
informed consent form. On Day 1, site staff will access the IRT and provide the necessary 
participant-identifying information, including the participant ID number assigned at Screening, 
to randomize the eligible participant into the study and obtain the medication ID number for the 
blinded IP to be dispensed to that participant. The medication ID number and the number of 
blinded capsules dispensed must be recorded. 
At the subsequent blinded IP-dispensing visit, the investigator or designee will access the IRT, 
providing the same participant ID number assigned at Screening, to obtain the medication ID 
number for the blinded IP to be dispensed at that visit. The medication ID number, the number of 
capsules dispensed, and the number of capsules returned by the participant at this visit must be 
recorded. 
If dispensing errors or discrepancies are discovered by site staff or sponsor’s designee, the 
sponsor must be notified immediately. 
The blinded IP provided is for use only as directed in this protocol. The investigator or designee 
must keep a record of all blinded IP received, used and returned/discarded. 
Sage Therapeutics will be permitted access to the study supplies at any time and with appropriate 
notice during or after completion of the study to perform drug accountability and reconciliation. 
The investigator, pharmacist, or qualified designee is responsible for drug accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final disposition records). 
At the end of the study, any unused blinded IP will be returned to Sage Therapeutics for 
destruction or destroyed locally per the site’s procedures; disposition of blinded IP will be 
documented. 
10.7. 
Blinded Investigational Product Complaints 
A product complaint is any written, electronic, or verbal expression of dissatisfaction regarding 
the identity, quality, reliability, safety, purity, potency, effectiveness or performance (applicable 
for approved marketed products) of a drug product after it is released for distribution. 
In the course of conduct of the study, study personnel may become aware of a product complaint 
associated with the use of a Sage product. Personnel shall notify Sage within 24 hours by 
forwarding the product complaint information via the contact information provided in Table 1. 

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Where possible, personnel should segregate and retain any product, materials, or packaging 
associated with the product complaint until further instruction is provided by Sage or its 
designated representative(s). 

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11. 
EFFICACY AND CLINICAL PHARMACOLOGY ASSESSMENTS 
11.1. 
Efficacy Assessments 
11.1.1. 
Hamilton Rating Scale for Depression 
The primary outcome measure is the change from baseline in 17-item HAM-D total score at 
Day 3. Every effort should be made for the same rater to perform all HAM-D assessments for an 
individual participant. An assessment timeframe of past 7 days (1 week) will be used at 
Screening, and ‘Since Last Visit’ will be used for all other visits. 
The 17-item HAM-D will be used to rate the severity of depression in participants who are 
already diagnosed as depressed (Williams 2013 a; Williams 2013b). 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 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. 
11.1.2. 
Montgomery-Åsberg Depression Rating Scale 
The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive 
episodes in participants with mood disorders. It was designed as an adjunct to the HAM-D that is 
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 (Williams 2008). 
The MADRS total score will be calculated as the sum of the 10 individual item scores. 
11.1.3. 
Hamilton Anxiety Rating Scale 
The 14-item HAM-A will be used to rate the severity of symptoms of anxiety (Williams 2013c; 
Williams 2013d). Each of the 14 items is defined by a series of symptoms, and measures both 
psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical 
complaints related to anxiety). Scoring for HAM-A is calculated by assigning scores of 0 (not 
present) to 4 (very severe), with a total score range of 0 to 56, where <17 indicates mild severity, 
18 to 24, mild to moderate severity, and 25 to 30, moderate to severe severity. The HAM-A total 
score will be calculated as the sum of the 14 individual item scores. 

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12. 
SAFETY ASSESSMENTS 
12.1. 
Safety Parameters 
All assessments will be conducted according to the Schedule of Assessments (Table 2). 
12.1.1. 
Demographic/Medical History 
Demographic characteristics (age, race, gender, ethnicity, employment status, highest education 
level, marital/civil status) and a full medical history, including: family psychiatric history, 
generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, persistent 
depressive disorder, postpartum depression, substance use disorder, alcohol use disorder, MDD 
with seasonal pattern, MDD with psychotic features, premenstrual dysphoric disorder, MDD 
with atypical features, schizophrenia; or schizoaffective disorder will be documented. The 
diagnosis of MDD will be determined using the SCID-5-CT. If available, the disease code 
associated with the diagnosis of MDD based on the tenth revision of the International Statistical 
Classification of Diseases and Related Health Problems (ICD-10) should be recorded. 
The Massachusetts General Hospital Antidepressant Treatment Response Questionnaire 
(MGH ATRQ) will be used to determine whether the participant has treatment-resistant 
depression, defined as persistent depressive symptoms despite treatment during the current major 
depressive episode with adequate doses of antidepressants from 2 different classes for at least 4 
weeks of treatment. 
12.1.2. 
Weight and Height 
Height (Screening only) and weight will be measured and documented. 
12.1.3. 
Physical Examination 
Physical examinations assessing body systems (eg, head, eyes, ears, nose, and throat; heart; 
lungs; abdomen; and extremities), as well as cognitive and neurological examinations and mental 
status examinations will be conducted and documented. Thereafter, abbreviated physical 
examinations will include brief assessments of general appearance, cardiovascular, respiratory, 
gastrointestinal, and neurological systems, followed by a targeted physical examination as 
needed. Unscheduled, symptom-directed physical examinations may also be conducted at the 
investigator’s discretion. Whenever possible, the same individual is to perform all physical 
examinations for a given participant. Unscheduled brief, symptom-driven physical examinations 
may also be conducted per the investigator’s discretion. 
Any abnormality in physical examinations will be interpreted by the investigator as abnormal, 
not clinically significant (NCS); or abnormal, clinically significant (CS) in source documents. 
New or worsening abnormalities that are judged to be clinically significant will be recorded as 
AEs, assessed according to Section 12.2.1. 
12.1.4. 
COVID-19 Questions 
Information regarding diagnosis, isolation, and/or hospitalization due to COVID-19 will be 
documented as part of Medical History, AE collection, and prior/concomitant 
medication/procedure collection at Screening and throughout the study. 

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assessed according to Section 12.2.1. A clinically significant laboratory abnormality following 
participant randomization will be followed until the abnormality returns to an acceptable level or 
a satisfactory explanation has been obtained. 
The clinical laboratory tests to be performed are listed in Table 3. 
Table 3: 
Clinical Laboratory Tests 
Hematology  
Serum Chemistry 
Urinalysis 
Coagulation 
Red blood cell count 
Hemoglobin 
Hematocrit 
White blood cell count with 
differential 
Platelet count 
Red Blood Cell Indices 
(MCV, MCH, MCHC) 
Reflex to Red blood cell 
morphology if indices are 
abnormal 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
Total protein 
Creatinine 
Blood urea nitrogen 
Creatine kinase 
Gamma-glutamyl transferase 
Potassium 
Sodium 
Lactate dehydrogenase 
Glucose 
Chloride 
Bicarbonate 
Calcium 
Phosphorus 
Triglycerides 
Thyroid stimulating hormone 
(TSH) 
Reflex to free T3/T4 if 
TSH is abnormal  
pH 
Specific gravity 
Protein 
Glucose 
Red blood cell 
Nitrite 
Leukocyte 
esterase 
Ketones 
Bilirubin 
Urobilinogen 
Activated partial 
thromboplastin 
time 
Prothrombin time 
International 
normalized ratio 
Diagnostic  
 
 
 
Serum 
Urine 
Breathalyzer 
 
Hepatitis B 
Hepatitis C 
Reflex HCV RNA 
HIV-1 and -2 
Female participants that are 
not surgically sterile and do 
not meet the protocol-
Drug screen including: 
amphetamines, 
barbiturates, 
benzodiazepines, 
cannabinoids, cocaine, 
opiates, phencyclidine 
Female participants that are 
not surgically sterile and do 
Alcohol 
 

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12.2.2. 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Places the participant at immediate risk of death (a life-threatening event); however, 
this does not include an event that, had it occurred in a more severe form, might have 
caused death 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
An SAE may also be any other medically important event that, in the opinion of the investigator 
may jeopardize the participant or may require medical intervention to prevent 1 of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization). 
All SAEs that occur after any participant has signed the ICF and throughout the duration of the 
study, whether or not they are related to the study, must be recorded on the SAE report form 
provided by Sage Therapeutics. Any SAE that is ongoing when the participant completes their 
final study visit, will be followed by the investigator until the event has resolved, stabilized, 
returned to baseline status, or until the participant dies or is lost to follow up. 
A prescheduled or elective procedure or routinely scheduled treatment will not be considered an 
SAE, even if the participant is hospitalized. The site must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or on a waiting list to be scheduled) prior to obtaining the participant’s 
consent to participate in the study. 
• The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress, in the opinion of an 
investigator, between the participant’s consent to participate in the study and at the 
time of the procedure or treatment. 
12.2.3. 
Relationship to Investigational Product 
The investigator must make the determination of relationship to the IP for each AE (not related, 
related). The following definitions should be considered when evaluating the relationship of AEs 
and SAEs to the IP. 
Not Related 
An AE will be considered “not related” to the use of the IP if there is not a reasonable 
possibility that the event has been caused by the IP. Factors pointing towards this 
assessment include but are not limited to: the lack of temporal relationship between 
administration of the IP and the event, the presence of biologically implausible 
relationship between the product and the AE, or the presence of a more likely 
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Related 
An AE will be considered “related” to the use of the IP if there is a reasonable 
possibility that the event may have been caused by the product under investigation. 
Factors that point towards this assessment include but are not limited to: a positive 
rechallenge, a reasonable temporal sequence between administration of the drug and 
the event, a known response pattern of the suspected drug, improvement following 
discontinuation or dose reduction, a biologically plausible relationship between the 
drug and the AE, or a lack of alternative explanation for the AE 
12.2.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the participant and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. The AE term should be reported in standard medical terminology when 
possible. For each AE, the investigator will evaluate and report the onset (date and time), 
resolution (date and time), intensity, causality, action taken, outcome and seriousness (if 
applicable), and whether or not it caused the participant to discontinue the IP or withdraw early 
from the study. 
Intensity will be assessed according to the following scale: 
• Mild: symptom(s) barely noticeable to participant or does not make participant 
uncomfortable; does not influence performance or functioning; prescription drug not 
ordinarily needed for relief of symptom(s) 
• Moderate: symptom(s) of a sufficient severity to make participant uncomfortable; 
performance of daily activity is influenced; participant is able to continue in study; 
treatment for symptom(s) may be needed 
• Severe: symptom(s) cause severe discomfort; symptoms cause incapacitation or 
significant impact on participant’s daily life; severity may cause cessation of 
treatment with IP; treatment for symptom(s) may be given and/or participant 
hospitalized 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.2.2. An AE of severe intensity 
may not necessarily be considered serious. 
12.2.5. 
Reporting Serious Adverse Events 
In order to adhere to all applicable laws and regulations for reporting an SAE(s), the study site 
must notify Sage or designee within 24 hours of the study site staff becoming aware of the 
SAE(s). The investigator must complete, sign and date the SAE report form, verify the accuracy 
of the information recorded on the SAE report form with the corresponding source documents, 
and send a copy to Sage or designee. 
Additional follow-up information, if required or available, should all be sent to Sage or designee 
within 24 hours of receipt on a follow-up SAE report form and placed with the original SAE 
information and kept with the appropriate section of the eCRF and/or study file. 

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SAEs occurring after the designated follow up time for the study, should be reported to Sage or 
designee according to the timelines noted above only if the investigator considers the SAE 
related to IP. 
Sage, or designee, is responsible for notifying the relevant regulatory authorities of certain 
events. It is the principal investigator’s responsibility to notify the IRB/IEC of all SAEs that 
occur at his or her site. Investigators will also be notified of all suspected unexpected serious 
adverse reactions (SUSARs) that occur during the clinical study. IRBs/IECs will be notified of 
SAEs and/or SUSARs as required by local law. 
In addition, appropriate personnel in Sage Drug Safety and Pharmacovigilance or designee will 
unblind SUSARs for the purpose of regulatory reporting. Sage or designee will submit SUSARs 
(in blinded or unblinded fashion) to regulatory agencies according to local law. Sage, or 
designee, will submit SUSARs to investigators in a blinded fashion. 
12.3. 
Pregnancy 
If a participant becomes pregnant after the first administration of IP, pregnancy information must 
be collected and recorded on the Pregnancy form and submitted to the sponsor within 24 hours of 
learning of the pregnancy. Details will be collected for all pregnancies for which conception was 
likely to have occurred after the start of IP administration until 5 terminal half-lives following 
the last administration of IP or until the completion of the study whichever is longer. Any 
pregnancy occurring in that time frame will be followed until delivery or termination of the 
pregnancy. The investigator will also attempt to collect pregnancy information on any 
participant’s partner who becomes pregnant after the participant has received the first 
administration of IP. After obtaining the necessary signed informed consent from the pregnant 
partner directly, the investigator will follow the same pregnancy reporting procedures specified 
for pregnant participants. 
The participant or participant’s partner will be followed to determine the outcome of the 
pregnancy. The outcome of all pregnancies (eg, spontaneous abortion, elective abortion, normal 
birth) must be followed and documented even if the participant was discontinued from the study. 
The investigator will collect follow-up information on the participant or participant’s partner and 
the neonate, and the information will be forwarded to Sage or designee. Generally, follow-up 
will not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an IP may have 
interfered with the effectiveness of a contraceptive medication. Any complication during 
pregnancy (eg, anemia, infections, pre-eclampsia) should be reported as an AE/SAE. If the 
outcome of the pregnancy meets the criteria for immediate classification as an SAE (ie, 
spontaneous abortion, stillbirth, neonatal death,), the investigator should follow the procedures 
for reporting an SAE. 
12.4. 
Overdose 
Overdoses, regardless of presence of associated clinical manifestation(s) (eg, headache, 
abnormal laboratory value) will be considered an AE and recorded as such on the eCRF. Any 

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clinical manifestation(s) of overdose must also be recorded as an AE on the eCRF. In addition, 
all overdoses must be recorded on an Overdose form and sent to Sage or designee within 
24 hours of the site becoming aware of the overdose. 

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13.4. 
Demographics and Baseline Characteristics 
Demographic data, such as age, race, and ethnicity, and baseline characteristics, such as height, 
weight, and BMI, will be summarized using the safety sets. 
Hepatitis, HIV, drug and alcohol, and pregnancy screening results will be listed, but not 
summarized as they are considered part of the inclusion/exclusion criteria. 
Medical history will be listed by participant. 
13.5. 
Efficacy Analysis 
Efficacy data will be summarized using appropriate descriptive statistics and other data 
presentation methods where applicable; participant listings will be provided for all efficacy data. 
Participants will be analyzed according to randomized treatment. 
The estimand for the primary and key secondary efficacy analysis is defined as follows: 
1) The treatment regimens for participants are: SAGE-217 + ADT and placebo + ADT 
for 14 days. 
2) The target population is adult participants with a diagnosis of major depressive 
disorder and within a current depressive episode of severity HAM-D total score ≥24. 
3) The variable of interest is the change from baseline in HAM-D total score. 
4) The intercurrent events could be: 
a) The premature discontinuation of treatment for any reason. 
b) Certain medications including, but not limited to, new antidepressants (except for 
assigned ADT) or benzodiazepines are prohibited, or ADT discontinuation may 
occur during the study; however, the treatment policy strategy dictates that the 
results following these prohibited medication use will not be manipulated but will 
rather be used ‘as is’ in analysis. Please note that the protocol does not specify 
any rescue process, hence there is no rescue medication. 
5) The population summary level is the model-based estimate of the difference between 
SAGE-217 + ADT and placebo + ADT in change from baseline in HAM-D total 
score. 
a) The population summary level for the primary endpoint is the model-based 
estimate of the difference between SAGE-217 + ADT and placebo + ADT in 
change from baseline in HAM-D total score at Day 3. 
b) The population summary level for the key secondary endpoint is the model-based 
estimate of the difference between SAGE-217 + ADT and placebo + ADT in 
change from baseline in HAM-D total score over the blinded treatment period 
using equal weight to Days 3, 8, 12 and 15. 
Using the FAS, this will be analyzed using a mixed-effects model for repeated measures 
(MMRM); the model will include treatment, baseline HAM-D total score, assessment time point, 
and time point-by-treatment as explanatory variables. All explanatory variables will be treated as 
fixed effects. All postbaseline time points will be included in the model. The main comparison 

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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Before an investigational site can enter a participant into the study, a representative of Sage 
Therapeutics will visit the investigational study site per Sage SOPs to: 
• Determine the adequacy of the facilities 
• Discuss with the investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Sage Therapeutics or its representatives. 
This will be documented in a Clinical Trial Agreement between Sage Therapeutics and 
the investigator. 
During the study, a monitor from Sage Therapeutics or representative 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 case report forms, and that IP accountability checks are being 
performed 
• Perform source data verification. This includes a comparison of the data in the case report 
forms with the participant’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 
participant (eg, clinic charts). 
• Record and report any protocol deviations not previously sent to Sage Therapeutics. 
• Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to Sage Therapeutics and those SAEs that met criteria for 
reporting have been forwarded to the IRB or independent ethics committee. 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
14.2. 
Audits and Inspections 
Sage Therapeutics or authorized representatives of Sage Therapeutics, a regulatory authority, or 
an Independent Ethics Committee or an Institutional Review Board may visit the site to perform 
an audit(s) or inspection(s), including source data verification. The purpose of a Sage 
Therapeutics audit or a regulatory authority 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/ICH GCP guidelines, and any applicable regulatory requirements. The investigator should 
contact Sage Therapeutics immediately if contacted by a regulatory agency or IRB/IEC about an 
inspection. 

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14.3. 
Institutional Review Board (IRB) or Ethics Committee (EC) 
The principal investigator must obtain IRB (or EC) approval for the clinical study prior to 
enrolling a participant. Initial IRB (or EC) approval, and all materials approved by the IRB (or 
EC) for this study including the participant consent form and recruitment materials must be 
maintained by the investigator and made available for inspection. 
 

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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practice and all applicable regulatory requirements, 
Sage Therapeutics may conduct a quality assurance audit(s) at the clinical site. Please see 
Section 14.2 for more details regarding the audit process. 
The investigator must have adequate quality control practices to ensure that the study is 
performed in a manner consistent with the protocol, GCP/ICH GCP guidelines, and applicable 
regulatory requirements. The investigator is responsible for reviewing all identified protocol 
deviations. Significant protocol deviations should be reported to the IRB/IEC per the IRB/IEC’s 
written procedures. 
The investigator is responsible for supervising any individual or party to whom the investigator 
delegates study-related duties and functions conducted at the study site. When the investigator 
retains the services of any individual or party to perform study-related duties and functions, the 
investigator must ensure the individual or party is qualified to perform study-related duties and 
functions and should implement procedures to ensure the integrity of the study-related duties and 
functions performed, and any data generated. 
The investigator must maintain adequate and accurate source documents and study records that 
include all pertinent observations on each of the site’s study participants. Source data must be 
attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data 
should be traceable, should not obscure the original entry, and should be explained, if necessary 
to provide clarification. 
 

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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
given a written and dated approval or favorable opinion by an IRB or IEC as appropriate. The 
investigator must obtain and document approval before he or she can enroll any participant into 
the study. The IRB or IEC must supply to the sponsor a list of the IRB/IEC membership and a 
statement to confirm that the IRB/IEC is organized and operates according to GCP and 
applicable laws and regulations. 
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 participants for the study. The protocol must be re-approved by the 
IRB or IEC upon receipt of amendments and annually, as local regulations require. 
The principal investigator is also responsible for providing the IRB or IEC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. Sage Therapeutics 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. In addition, the principal investigator must 
inform the IRB/IEC and sponsor of any changes significantly affecting the conduct of the study 
and/or increasing the risk to participants (eg, violations to the protocol or urgent safety measures 
taken for participant safety). 
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH and GCP guidelines, as well as all 
applicable regional or national regulatory requirements. 
16.3. 
Written Informed Consent 
Prior to enrolling a study participant, the investigator(s) will ensure that the participant is given 
full and adequate oral and written information about the nature, purpose, possible risk and 
benefit of the study. Participants must also be notified that they are free to discontinue from the 
study at any time. The participant should be given the opportunity to ask questions and allowed 
time to consider the information provided. 
When the participant decides to participate in the study, the participant (or the participant’s, 
parent or legally authorized representative) must provide signed and dated informed consent. The 
written consent must be obtained before conducting any study procedures. The investigator must 
document the consent process in the participant’s source records. The investigator must maintain 
the original, signed ICF. A copy of the signed ICF must be given to the participant or to the 
participant’s parent or legally authorized representative. 
Throughout the study participants should be informed of any changes made to the study and as 
new safety and or risk information becomes known. The provision of this information will be 

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documented in the participant’s source records, and when applicable, an updated ICF will be 
provided. 

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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Inspection of Records 
Sage Therapeutics or its representative(s) will be allowed to conduct site visits at the 
investigation facilities for the purpose of monitoring any aspect of the study. The investigator 
agrees to allow the monitor to inspect the facility, drug storage area, drug accountability records, 
participant charts and study source documents, and other records relative to study conduct. 
Inspection of the study by a Regulatory Authority may occur at any time. The investigator must 
agree to the inspection of study-related records and source documents by the Regulatory 
Authority representative(s). 
17.2. 
Retention of Records 
The principal investigator must maintain all documentation relating to the study for the period 
outlined in the site contract, or for a period of 2 years after the last marketing application 
approval, and until there are no pending or contemplated marketing applications in an ICH 
region or at least 2 years have elapsed since the formal discontinuation of clinical development 
of the investigational product. Sage is responsible to inform the investigator/institution as to 
when study documents no longer need to be retained. 

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18. 
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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INVESTIGATOR’S AGREEMENT 
I have received and read the Investigator’s Brochure for SAGE-217. I have read the 
217-MDD-305 protocol and agree to conduct the study as outlined. I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
Date (DD/MMM/YYYY) 

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2. 
SYNOPSIS 
Name of Sponsor/Company: Sage Therapeutics, Inc. (hereafter referred to as Sage Therapeutics, or 
Sage) 
Name of Investigational Product: SAGE-217 Capsules 
Name of Active Ingredient: SAGE-217 
Title of Study: A Phase 3, Randomized, Double-Blind Study Comparing the Efficacy and Safety of 
SAGE-217 plus an Antidepressant Versus Placebo plus an Antidepressant in Adults with Major 
Depressive Disorder 
Number of Sites and Study Location: This study will take place at approximately 55 sites in United 
States. 
Phase of Development: 3 
Planned Duration for each Study Participant: Up to 70 days (up to 28-day Screening Period, 14-day 
Double-blind Treatment Period, and a 28-day Antidepressant Therapy (ADT) Continuation Period) 
Objectives: 
Primary: 
• 
To evaluate the efficacy of SAGE-217 plus an antidepressant in the treatment of major 
depressive disorder (MDD) compared to placebo plus an antidepressant 
Secondary: 
• 
To assess patient-reported outcome (PRO) measures as they relate to depressive symptoms 
• 
To evaluate the safety and tolerability of SAGE-217 plus an antidepressant 
 
 
 
 
 
Endpoints: 
Primary: 
• 
Change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D) total 
score at Day 15 
Key Secondary: 
• 
Change from baseline in CGI-S at Day 15 
• 
Change from baseline in HAM-D total score at Day 3, Day 8, and Day 42 
Other Secondary: 
• 
HAM-D response at Day 15 and Day 42 
• 
HAM-D remission at Day 15 and Day 42 
• 
CGI-I response, defined as “much improved” or “very much improved”, at Day 15 
• 
Change from baseline in MADRS total score at Day 15 
• 
Change from baseline in HAM-A total score at Day 15 
• 
Time to first HAM-D response 
• 
Change from baseline to Day 15 in depressive symptoms, as assessed by the PHQ-9 
• 
Incidence and severity of treatment-emergent adverse events (TEAEs) 

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continued at the discretion of the investigator. 
Upon completion of the current study, eligible participants will have the opportunity to enter a long-
term open-label study of SAGE-217.  
Number of Participants (planned): It is estimated that approximately 424 participants will be 
randomized and treated to obtain 382 evaluable participants at Day 15 (assuming a 10% dropout rate). 
Additional participants may be randomized if the dropout rate is greater than 10%. 
Eligibility Criteria: 
Inclusion Criteria 
1. Participant has signed an ICF prior to any study-specific procedures being performed. 
2. Participant is a male or female between 18 and 64 years of age, inclusive. 
3. Participant 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. Participant agrees to adhere to the study requirements. 
5. Participant has a diagnosis of MDD as diagnosed by SCID-5-CT, with symptoms that have 
been present for at least a 4-week period. 
6. Participant has a HAM-D-17 total score of ≥24 at Screening and Day 1 (prior to dosing). 
7. Participant is willing to delay start of any antidepressant (except as per protocol), anxiolytic, 
anti-insomnia, psychostimulant, prescription opioid regimens, or new psychotherapy 
(including Cognitive Behavioral Therapy for Insomnia [CBT-I]) until after study completion. 
Participants receiving psychotherapy must have been receiving therapy on a regular schedule 
for at least 60 days prior to Day 1 and intend to maintain that schedule for the duration of the 
study. 
8. Female participant agrees to use at least one method of highly effective contraception as listed 
in Section 9.2.4 during participation in the study and for 30 days following the last dose of IP, 
unless she is postmenopausal (at least 12 months of spontaneous amenorrhea without an 
alternative medical cause, with confirmatory follicle stimulating hormone >40 mIU/mL), 
and/or surgically sterile (bilateral oophorectomy, hysterectomy, and/or bilateral 
salpingectomy), or does not engage in sexual relations which carry a risk of pregnancy (does 
not include abstinence). 
9. Female participant who is breastfeeding at Screening or on Day 1 (prior to administration of 
IP) must be willing to temporarily cease giving breast milk to her child(ren) from just prior to 
receiving IP on Day 1 until 7 days after the last dose of SAGE-217/placebo. 
10. Male participant agrees to use an acceptable method of effective contraception for the duration 
of the study and for 5 days after receiving IP, unless the participant does not engage in sexual 
relation(s) which carry a risk of pregnancy. Acceptable methods of effective contraception are 
listed in Section 9.2.4. 
11. Male participant is willing to abstain from sperm donation for the treatment period and for 
5 days after receiving the last dose of the IP. 
12. Participant agrees to refrain from drugs of abuse and alcohol for the duration of the study. 
13. Participant is willing, able, and eligible to take at least 1 of the 5 ADTs specified in the 
protocol (an eligible ADT is an ADT that has not been taken during the current depressive 
episode and for which the participant has no contraindications; further, a participant is not 
eligible for citalopram if escitalopram has been taken during the current depressive episode, 
and vice versa). 

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Exclusion Criteria 
1. Participant is currently at significant risk of suicide, as judged by the investigator, or has 
attempted suicide associated with the current episode of MDD. 
2. Participant had onset of the current depressive episode during pregnancy or 4 weeks 
postpartum, or the participant has presented for screening during the 6-month postpartum 
period. 
3. Participant has a recent history or active clinically significant manifestations of metabolic, 
hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, 
dermatological, urogenital, neurological, or eye, ear, nose, and throat disorders, or any other 
acute or chronic condition that, in the investigator's opinion, would limit the participant's 
ability to complete or participate in this clinical study; a BMI ≤18 or ≥45 kg/m2 is 
exclusionary; a BMI of 40 to 44.9 kg/m2, inclusive, at Screening is subject to a broader 
evaluation of medical comorbidities as described above. 
4. Participant has treatment-resistant depression, defined as persistent depressive symptoms 
despite treatment with adequate doses of antidepressants within the current major depressive 
episode (excluding antipsychotics) from 2 different classes for at least 4 weeks of treatment. 
Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH 
ATRQ) will be used for this purpose. 
5. Participant has had vagus nerve stimulation, electroconvulsive therapy, or has taken ketamine 
within the current major depressive episode. 
6. Participant is receiving Cognitive Behavioral Therapy for Insomnia (CBT-I) within 28 days 
prior to Day 1. 
7. Participant has a known allergy to SAGE-217, allopregnanolone, or related compounds. 
8. Participant has taken antidepressants within 30 days prior to Day 1, and/or has taken fluoxetine 
within 60 days prior to Day 1. 
9. Female participant has a positive pregnancy test or confirmed pregnancy. 
10. Participant has a clinically significant abnormal 12-lead ECG at the screening or baseline 
visits. NOTE: mean QT interval calculated using the Fridericia method (QTcF) of >450 msec 
in males or >470 msec in females will be the basis for exclusion from the study. 
11. Participant has active psychosis per investigator assessment. 
12. Participant has a medical history of seizures. 
13. Participant has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder. 
14. Participant has a history of severe substance use disorder (including benzodiazepines) 
diagnosed using DSM-5 criteria in the 12 months prior to Screening or participant has a history 
of mild or moderate substance use disorder not in sustained remission for at least 6 months 
prior to Screening. 
15. Participant has had exposure to another investigational medication or device within 30 days 
prior to Screening. 
16. Participant has previously received brexanolone or participated in a SAGE-217 or SAGE-547 
(brexanolone) clinical trial. 
17. Participant has used any known strong inhibitors of cytochrome P450 (CYP)3A4 within 
28 days or 5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, or 
Seville oranges, or products containing these, within 14 days prior to Day 1. 
18. Participant has used any strong CYP3A inducer, such as rifampin, carbamazepine, 

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enzalutamide, mitotane, phenytoin, or St John’s Wort, within 28 days prior to Day 1. 
19. Participant has a positive drug and/or alcohol screen at screening or on Day 1 prior to dosing. 
20. Participant plans to undergo elective surgery before completion of the Day 42 visit. 
21. Participant is taking benzodiazepines, barbiturates, or GABAA modulators (eg, eszopiclone, 
zopiclone, zaleplon, and zolpidem) within 28 days prior to Day 1, or has been using these 
agents daily or near-daily (≥4 times per week) for more than 1 year. Participant is taking any 
benzodiazepine or GABA modulator with a half-life of ≥48 hours (eg, diazepam) from 60 days 
prior to Day 1. 
22. Participant is taking non-GABA anti-insomnia medications (eg, prescribed therapeutics 
specifically for insomnia and/or over the counter sleep aids), or first or second generation 
(typical/atypical) antipsychotics within 14 days prior to Day 1. Note that nonsedating 
antihistamines are permitted. 
23. Participant has been diagnosed with and/or treated for any type of cancer (excluding basal cell 
carcinoma and melanoma in situ) within the past year prior to Screening. 
24. Participant has a history of sleep apnea. 
25. Participant has had gastric bypass surgery, has a gastric sleeve or lap band, or has had any 
related procedures that interfere with gastrointestinal transit. 
26. Participant is taking psychostimulants (eg, methylphenidate, amphetamine) or opioids, 
regularly or as needed, within 28 days prior to Day 1. 
27. Participant is a dependent of the sponsor, investigator, investigator’s deputy, or study site staff. 
28. Participant expects to perform night shift work during the 14-day Treatment Period. 
29. Participant has detectable hepatitis B surface antigen, anti-hepatitis C virus (HCV) and positive 
HCV viral load, or human immunodeficiency virus (HIV) antibody at Screening. 
Investigational Product Dosage and Mode of Administration: SAGE-217 will be available as hard 
gelatin capsules for oral administration; multiple capsules (in 30-mg or 20-mg dose strengths) will be 
provided to total a 50-mg dose, with option to reduce to 40 mg based on tolerability. 
Blinded placebo will be provided as hard gelatin capsules matched in appearance to SAGE-217, for 
oral administration. 
Sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine will be administered as per labeled 
prescribing information 
Duration of Treatment: Blinded SAGE-217 or placebo will be administered once daily for 14 days; 
open-label ADT will be administered according to labeled prescribing information for 42 days. 

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Table 2: 
Schedule of Assessments 
Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
ADT Continuation Period 
Visit Days 
D-28 to 
D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(+1d) 
D18 
(±1d) 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
/ET  
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
Study Procedure 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Duplicate Participant Check a 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
 
 
Serum FSH test b 
X 
 
 
 
 
 
 
 
 
 
 
SCID-5-CT 
X 
 
 
 
 
 
 
 
 
 
 
MGH ATRQ 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Family Historyc 
X 
 
 
 
 
 
 
 
 
 
 
Participant training d 
 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Physical Examination e 
X 
X 
 
 
 
 
 
 
 
 
X 
Body Weight/Height 
X 
 
 
 
 
X 
(weight 
only) 
 
 
 
 
X 
(weight 
only) 
Clinical Laboratory 
Assessments f 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
Drug & Alcohol Screen g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test h 
X 
X 
 
 
 
X 
 
 
X 
 
X 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 

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Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
ADT Continuation Period 
Visit Days 
D-28 to 
D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(+1d) 
D18 
(±1d) 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
/ET  
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
Study Procedure 
 
Vital Signs k 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
12-Lead ECG l 
X 
X 
 
 
 
X 
 
 
 
 
X 
HAM-D n, o 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MADRS 
 
X 
 
X 
 
X 
 
 
X 
 
X 
HAM-A o 
 
X 
 
X 
 
X 
 
 
X 
 
X 
CGI-S 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
PHQ-9 
 
X 
X 
X 
 
X 
 
 
X 
 
X 
SAGE-217/Placebo 
Dispensation 
 
X 
 
X 
 
 
 
 
 
 
 
SAGE-217/Placebo 
Administration 
 
X (once daily in the evening through Day 14 - inclusive) 
 
 
 
 
 
IP Adherence q 
 
X 

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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............16 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................21 
5. 
INTRODUCTION ......................................................................................................23 
5.1. 
Background of Major Depressive Disorder and Unmet Medical Need ......................23 
5.2. 
Potential Risks and Benefits .......................................................................................24 
5.3. 
Dose Justification ........................................................................................................24 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................26 
6.1. 
Objectives ...................................................................................................................26 
6.1.1. 
Primary Objective .......................................................................................................26 
6.1.2. 
Secondary Objectives .................................................................................................26 
 
26 
6.2. 
Endpoints ....................................................................................................................26 
6.2.1. 
Primary Endpoint ........................................................................................................26 
6.2.2. 
Secondary Endpoints ..................................................................................................26 
6.2.2.1. 
Key Secondary Endpoints ...........................................................................................26 
6.2.2.2. 
Other Secondary Endpoints ........................................................................................26 
 
27 
7. 
INVESTIGATIONAL PLAN .....................................................................................28 
7.1. 
Overall Study Design ..................................................................................................28 
7.2. 
Number of Participants ...............................................................................................29 
7.3. 
Treatment Assignment ................................................................................................29 
7.4. 
Dose Adjustment Criteria ...........................................................................................29 
7.5. 
Criteria for Study Termination ...................................................................................29 
8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS.....................................30 
8.1. 
Participant Inclusion Criteria ......................................................................................30 
8.2. 
Participant Exclusion Criteria .....................................................................................31 
8.3. 
Screen Failures ............................................................................................................33 

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8.4. 
Investigational Product Discontinuation and Early Termination from the 
Study ...........................................................................................................................33 
8.4.1. 
Investigational Product Discontinuation .....................................................................33 
8.4.2. 
Early Termination from the Study ..............................................................................33 
8.4.3. 
Loss to Follow-up .......................................................................................................34 
8.4.4. 
Replacement of Participants .......................................................................................34 
9. 
TREATMENT OF PARTICIPANTS .........................................................................35 
9.1. 
Description of Investigational Products ......................................................................35 
9.2. 
Prior Medications, Concomitant Medications, Restrictions, and 
Contraception Requirements ......................................................................................35 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................35 
9.2.2. 
Prohibited Medications ...............................................................................................35 
9.2.3. 
Other Restrictions .......................................................................................................36 
9.2.4. 
Acceptable Forms of Contraception ...........................................................................36 
9.3. 
Intervention after the End of the Study .......................................................................37 
9.4. 
Treatment Adherence ..................................................................................................37 
9.5. 
Randomization and Blinding ......................................................................................38 
9.5.1. 
Emergency Unblinding ...............................................................................................38 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............39 
10.1. 
Investigational Products ..............................................................................................39 
10.1.1. 
Blinded Investigational Products ................................................................................39 
10.1.2. 
Open-label Investigational Product ............................................................................39 
10.2. 
Blinded Investigational Product Packaging and Labeling ..........................................39 
10.3. 
Blinded Investigational Product Storage ....................................................................39 
10.4. 
Blinded Investigational Product Preparation ..............................................................39 
10.5. 
Blinded and Open-label Investigational Product Administration ...............................39 
10.6. 
Blinded Investigational Product Accountability, Handling, and Disposal .................40 
10.7. 
Blinded Investigational Product Complaints ..............................................................40 
11. 
EFFICACY AND CLINICAL PHARMACOLOGY ASSESSMENTS ....................42 
11.1. 
Efficacy Assessments .................................................................................................42 
11.1.1. 
Hamilton Rating Scale for Depression .......................................................................42 
11.1.2. 
Montgomery-Åsberg Depression Rating Scale ..........................................................42 
11.1.3. 
Hamilton Anxiety Rating Scale ..................................................................................42 

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11.1.4. 
Clinical Global Impressions .......................................................................................43 
 
43 
11.1.6. 
Patient Health Questionnaire ......................................................................................43 
 
44 
 
44 
 
44 
 
44 
 
44 
 
44 
 
44 
12. 
SAFETY ASSESSMENTS ........................................................................................46 
12.1. 
Safety Parameters .......................................................................................................46 
12.1.1. 
Demographic/Medical History ...................................................................................46 
12.1.2. 
Weight and Height ......................................................................................................46 
12.1.3. 
Physical Examination .................................................................................................46 
12.1.4. 
COVID-19 Questions .................................................................................................46 
12.1.5. 
Vital Signs ..................................................................................................................47 
12.1.6. 
Electrocardiogram (ECG) ...........................................................................................47 
12.1.7. 
Laboratory Assessments .............................................................................................47 
12.1.7.1. 
Drugs of Abuse and Alcohol ......................................................................................49 
12.1.7.2. 
Pregnancy Screen ........................................................................................................49 
 
49 
 
49 
 
50 
12.2. 
Adverse and Serious Adverse Events .........................................................................50 
12.2.1. 
Adverse Event Definition ...........................................................................................50 
12.2.2. 
Serious Adverse Event Definition ..............................................................................51 
12.2.3. 
Relationship to Investigational Product ......................................................................51 
12.2.4. 
Recording Adverse Events .........................................................................................52 
12.2.5. 
Reporting Serious Adverse Events .............................................................................52 
12.3. 
Pregnancy ...................................................................................................................53 
12.4. 
Overdose .....................................................................................................................53 
13. 
STATISTICS ..............................................................................................................55 

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13.1. 
Data Analysis Sets ......................................................................................................55 
13.2. 
Handling of Missing Data ...........................................................................................55 
13.3. 
General Considerations ...............................................................................................55 
13.4. 
Demographics and Baseline Characteristics ...............................................................56 
13.5. 
Efficacy Analysis ........................................................................................................56 
13.5.1. 
Multiplicity Adjustment for Key Secondary Endpoints .............................................57 
13.6. 
Safety Analyses ..........................................................................................................57 
13.6.1. 
Adverse Events ...........................................................................................................58 
 
58 
13.6.3. 
Physical Examinations ................................................................................................58 
 
58 
13.6.5. 
12-Lead Electrocardiogram ........................................................................................58 
13.6.6. 
Prior and Concomitant Medications ...........................................................................58 
 
59 
 
59 
13.6.9. 
Other Safety Analysis .................................................................................................59 
 
59 
13.8. 
Sample Size and Power ..............................................................................................59 
13.8.1. 
Interim and Data Monitoring Committee Analyses ....................................................59 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................60 
14.1. 
Study Monitoring ........................................................................................................60 
14.2. 
Audits and Inspections ................................................................................................60 
14.3. 
Institutional Review Board (IRB) or Ethics Committee (EC) ....................................61 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................62 
16. 
ETHICS ......................................................................................................................63 
16.1. 
Ethics Review .............................................................................................................63 
16.2. 
Ethical Conduct of the Study ......................................................................................63 
16.3. 
Written Informed Consent ..........................................................................................63 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................65 
17.1. 
Inspection of Records .................................................................................................65 
17.2. 
Retention of Records ..................................................................................................65 
18. 
PUBLICATION POLICY ..........................................................................................66 
19. 
LIST OF REFERENCES ............................................................................................67 

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LIST OF TABLES 
Table 1: 
Contact Information ......................................................................................................4 
Table 2: 
Schedule of Assessments ............................................................................................12 
Table 3: 
Clinical Laboratory Tests ...........................................................................................48 
 
 

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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Abbreviation 
Definition 
ADT 
Antidepressant therapy 
AE 
adverse event 
ALT 
alanine aminotransferase 
ALP 
alkaline phosphatase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BP 
blood pressure 
CFR 
Code of Federal Regulation 
CRO 
contract research organization 
CSR 
clinical study report 
IEC 
independent ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IND 
investigational new drug  
IP 
investigational product 
MedDRA 
Medical Dictionary for Regulatory Activities 
PD 
pharmacodynamic 
PI 
prescribing information 
PK 
pharmacokinetic 
PV 
pharmacovigilance 
QA 
quality assurance 
QC 
quality control 
QTcF 
QT corrected according to Fridericia’s formula 
SAE 
serious adverse event 
SOP 
Standard Operating Procedure 

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Abbreviation 
Definition 
SNRI 
serotonin-norepinephrine reuptake inhibitor 
SSRI 
selective serotonin reuptake inhibitor 
TEAE 
treatment-emergent adverse event 
WHO 
World Health Organization 

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5. 
INTRODUCTION 
5.1. 
Background of Major Depressive Disorder and Unmet Medical Need 
The World Health Organization (WHO) has identified depression as the leading cause of 
disability worldwide, and as a major contributor to the overall global burden of disease 
(http://www.who.int/mediacentre/factsheets/fs369/en/). Globally, depression has been estimated 
to affect over 300 million people. 
In the United States, the economic burden of depression, including workplace costs, direct costs, 
and suicide-related costs, was estimated to be $210.5 billion in 2010 (Greenberg 2015). As per 
WHO statistics, over 800,000 people die due to suicide every year, and suicide is the second 
leading cause of death in 15- to 29-year-olds. The rate of US adults making a suicide attempt has 
increased (0.62% from 2004 to 2005 to 0.79% from 2012 to 2013), with a shift to more attempts 
among younger adults (42% to 50%, respectively) and among those with a depressive disorder 
(26% to 54%, respectively; Olfson 2017). 
The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5, American 
Psychiatric Association 2013) provides diagnostic criteria for major depressive disorder (MDD). 
These include at least 5 of 9 depressive symptoms (depressed mood and/or loss of interest or 
pleasure, and other changes affecting appetite or weight, sleep, psychomotor activity, energy 
level, feelings of guilt, concentration ability, and suicidality) during the same 2-week period that 
represents a change from previous functioning (DSM-5). 
Antidepressants are a mainstay of pharmacological treatment for depressive disorders. Selective 
serotonin uptake inhibitors (SNRI), serotonin norepinephrine reuptake inhibitors (SSRI), 
tricyclic antidepressants, monoamine oxidase inhibitors (MAOI), and other compounds that 
affect monoaminergic neurotransmission, such as mirtrazapine and bupropion, represent the 
major classes of antidepressants. While antidepressants are widely used, large scale studies have 
demonstrated their limited efficacy, including low remission rates and untreated symptoms 
(Trivedi 2006; Conradi 2011; Romera 2013). Furthermore, these agents can take 4 to 8 weeks to 
demonstrate full clinical efficacy (Rush 2006; Trivedi 2006), and in the case of the most 
commonly prescribed classes—SSRIs and SNRIs—common side effects including weight gain, 
GI symptoms, and sexual dysfunction can prevent titration into an adequate therapeutic range 
(Sadock and Sadock 2007). 
In the largest study to assess the effectiveness of depression treatments in patients with MDD, 
time to patient remission after treatment was 5.4 to 7.4 weeks; approximately one-half of the 
patients who ultimately remitted did so after 6 weeks, and 40% of those who achieved remission 
required 8 or more weeks to do so (Rush 2006; Trivedi 2006). Even following remission, many 
patients report the presence of residual symptoms, often related to decreased positive affect, such 
as loss of interest in activities once considered enjoyable, fatigue, loss of energy, as well as sleep 
and appetite/weight disturbances (Nierenberg 2009; Nierenberg 2015). Thus, patients may 
remain symptomatic for up to 2 months while waiting for current standard-of-care 
pharmacotherapy to take full effect. They may also have to contend with undesirable side effects 
and residual symptoms. These aspects underscore the need for newer, rapid-acting therapies. 
SAGE-217 is a synthetic positive allosteric modulator of GABAA receptors, the major class of 
inhibitory neurotransmitter receptors in the brain. In pharmacokinetic (PK) studies in mice and 

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rats, SAGE-217 demonstrated rapid penetration and equilibrium across the blood brain barrier 
and is generally expected to have good extravascular exposure. In exploratory in vitro receptor 
and ion channel assays and in vivo safety pharmacology studies, SAGE-217 was highly selective 
for GABAA receptors, and, consistent with the actions of other GABAA receptor potentiators 
(Rudolph 2011), exhibits potent anticonvulsant, anxiolytic, and sedative activity when 
administered in vivo. 
SAGE-217 has been generally well tolerated in clinical studies to date. The most common 
treatment-emergent adverse events (TEAEs) associated with SAGE-217 (overall) were sedation, 
somnolence, and dizziness; most adverse events (AEs) were reported as mild or moderate in 
intensity. Refer to the SAGE-217 Investigator’s Brochure for a detailed description of the 
chemistry, pharmacology, efficacy, and safety of SAGE-217. 
This study was designed to target the unmet need of symptom improvement during the latency to 
SSRI and SNRI efficacy in the acute phase of a major depressive episode. This study will assess 
the safety and efficacy of SAGE-217 50 mg plus an antidepressant, examining if SAGE-217 plus 
an antidepressant produces more rapid or more profound reduction in depressive symptoms than 
an antidepressant alone. 
5.2. 
Potential Risks and Benefits 
The apparent risks of SAGE-217 are based on clinical data reports of AEs in completed and 
ongoing studies and the known pharmacology of the drug. Sedation, somnolence, and dizziness 
were identified as adverse drug reactions. Most AEs were reported as mild or moderate in 
intensity and reversible. 
SAGE-217 may present a treatment option for MDD that has more rapid onset of action (days 
instead of weeks/months), when compared to available pharmacotherapies. 
Based on nonclinical findings, embryo-fetal toxicity and withdrawal effects are considered 
important potential risk for SAGE-217. Risk mitigation measures in this study include 
monitoring for adverse effects, monitoring for potential withdrawal effects, requiring highly 
effective contraceptive measures for study participants, and inclusion of dose adjustment criteria 
and guidance for blinded IP discontinuation (Section 8.4). Finally, due to the 
sedation/somnolence observed, SAGE-217 is administered in the evening in this study. 
Given the outcome of the completed studies of SAGE-217 in participants with MDD and PDD, 
the current significant unmet need for well-tolerated and rapid-acting depression treatments, and 
a favorable benefit-risk profile, further investigation of SAGE-217 as a novel rapid response 
treatment in adults with MDD is justified. 
5.3. 
Dose Justification 
Results from a large, multicenter study of SAGE-217 20 and 30 mg in MDD (217-MDD-301) 
support the need for higher steady-state concentrations of SAGE-217 to allow participants to 
experience maximum antidepressant and anti-anxiety benefits. SAGE-217 will be administered 
as a 14-day regimen of an evening dose of 50 mg with reduction to 40 mg as needed based on 
tolerability. The 50-mg dose of SAGE-217 is expected to exhibit a favorable benefit-risk profile 
in the context of results from previous SAGE-217 studies utilizing a 30-mg dose, now identified 
as a minimally effective dose. SAGE-217 is expected to maintain an acceptable tolerability 

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profile, based on a current safety database of over 2000 participants exposed across different 
doses/concentrations. 
Sertraline is a commercially available SSRI indicated for the treatment of MDD and other 
psychiatric disorders. Dosage and administration of sertraline as described in the approved US 
Prescribing Information (PI) recommends a starting dose of 50 mg per day in patients with 
MDD, with an incremental weekly increase in dose of 25-50 mg per day, if there is an 
inadequate response to the starting dose, to a maximum dose of 200 mg per day. . In this study, a 
starting dose of 50 mg per day is recommended for 7 days, with a subsequent increase to 100 mg 
per day. 
Citalopram and escitalopram are commercially available SSRIs that are both indicated for acute 
and maintenance treatment of MDD. Escitalopram is also indicated for treatment of generalized 
anxiety disorder. The starting dosage for MDD in the US PI for citalopram is 20 mg/day and for 
escitalopram is 10 mg/day, with maxima of 40 mg/day and 20 mg/day, respectively. In this 
study, a starting dose of 20 mg/day is recommended for citalopram and of 10 mg/day is 
recommended for escitalopram for the first 14 days; subsequent dose increases may be 
considered, except for participants >60 years old taking citalopram. 
Duloxetine is a commercially available SNRI indicated for the treatment of MDD, generalized 
anxiety disorder, and pain disorders. The starting dosage for MDD in the US PI is 40 to 
60 mg/day. The maximum dosage is 120 mg/day, although there is no evidence that dosages 
greater than 60 mg/day confer any additional benefits. In this study, a starting dose of 40 or 60 
mg/day is recommended (divided as 20 or 30 mg, respectively, twice daily for the first 7 days).  
Desvenlafaxine is a commercially available SNRI indicated for the treatment of MDD. The 
recommended dosage in the US PI is 50 mg/day. In this study, a dose of 50 mg/day is 
recommended. There has been no evidence that doses greater than 50 mg/day confer any 
additional benefit. 

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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Objectives 
6.1.1. 
Primary Objective 
To evaluate the efficacy of SAGE-217 plus an antidepressant in the treatment of MDD compared 
to placebo plus an antidepressant 
6.1.2. 
Secondary Objectives 
• To assess patient-reported outcome (PRO) measures as they relate to depressive 
symptoms 
• To evaluate the safety and tolerability of SAGE-217 plus an antidepressant 
 
 
 
 
 
 
6.2. 
Endpoints 
6.2.1. 
Primary Endpoint 
• Change from baseline in 17-item Hamilton Rating Scale for Depression (HAM-D) 
total score at Day 15 
6.2.2. 
Secondary Endpoints 
6.2.2.1. 
Key Secondary Endpoints 
• Change from baseline in CGI-S at Day 15 
• Change from baseline in HAM-D total score at Day 3, Day 8, and Day 42 
6.2.2.2. 
Other Secondary Endpoints 
• HAM-D response at Day 15 and Day 42 
• HAM-D remission at Day 15 and Day 42 
• CGI-I response, defined as “much improved” or “very much improved”, at Day 15 
• Change from baseline in MADRS total score at Day 15 
• Change from baseline in HAM-A total score at Day 15 
• Time to first HAM-D response 
• Change from baseline to Day 15 in depressive symptoms, as assessed by the PHQ-9 
• Incidence and severity of treatment-emergent AEs 

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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a randomized, double-blind, parallel-group, placebo-controlled study in adults with 
MDD. The diagnosis of MDD must be made according to Structured Clinical Interview for 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Clinical Trial 
Version (SCID 5-CT) performed by a qualified healthcare professional.  
The study will consist of a Screening Period of up to 28 days, a 14-day double-blind Treatment 
Period, and a 28-day ADT Continuation Period. The Screening Period begins with the signing of 
the informed consent form (ICF) at the Screening Visit. Preliminary screening procedures to 
determine eligibility include completion of the MGH-ATRQ and HAM-D. 
Participants will be randomized to receive blinded SAGE-217 or placebo for administration each 
evening from Day 1 through 14. In addition, all participants will receive 1 of 2 classes of ADTs: 
a selective serotonin reuptake inhibitor (SSRI; sertraline, escitalopram, citalopram) or a 
serotonin-norepinephrine reuptake inhibitor (SNRI; duloxetine, desvenlafaxine) in an open-label 
manner from Day 1 through the end of the study. The investigator will assign 1 of the 5 ADTs 
based on clinical standard of care; the participant must not have been previously treated with the 
assigned ADT within the current depressive episode (and must not have been treated with 
citalopram if escitalopram is assigned, and vice versa) and must not haven taken any ADT within 
30 days prior to Day 1 (or taken fluoxetine within 60 days prior to Day 1). Randomization will 
be stratified by antidepressant class (SSRI or SNRI). 
The open-label ADT will be administered as per labeled prescribing information. 
After the Double-blind Treatment Period, the ADT will be continued each evening for the 
remainder of the study (ADT Continuation Period). During this period (Week 3 to 6), ADT 
dosing may be modified as appropriate per the labeled prescribing information and based on 
individual response. 
Initiation of other antidepressants or any other medications that may potentially have an impact 
on efficacy or safety endpoints will not be allowed between screening and completion of 
assessments at Day 42/end-of-study visit. 
Participants will self-administer blinded investigational product (IP) once daily at approximately 
8 PM with fat-containing food (eg, within 1 hour of an evening meal which contains fat, or with 
a fat-containing snack), on an outpatient basis, for 14 days. The ADT and SAGE-217 or placebo 
will be administered at the same time during the Treatment Period; participants assigned 
duloxetine will also administer ADT in the morning (for twice-daily dosing) as part of a divided 
dose for the first 7 days. Participants will return to the study center as outlined in the Schedule of 
Assessments. 
During the Treatment Period, participants will be able to receive SAGE-217/placebo as long as 
there are no dose-limiting safety/tolerability concerns. Participants who cannot tolerate 
SAGE-217 or placebo 50 mg will receive 40 mg for the remainder of the Treatment Period. 
Participants who cannot tolerate the SAGE-217/placebo 40-mg dose may be discontinued from 
SAGE-217 or placebo at the discretion of the investigator. If blinded IP is discontinued, the ADT 
may be continued at the discretion of the investigator. 

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Upon completion of the current study, eligible participants will have the opportunity to enter a 
long-term open-label study of SAGE-217. Participants that do not enter the open-label study or 
that terminate the current study early may, per the investigator, receive a supply of the ADT with 
instructions on how to taper the drug, if needed, or, if they wish to continue the ADT, a bridge 
supply to permit them to obtain a prescription from another provider. 
7.2. 
Number of Participants 
It is estimated that approximately 424 participants will be randomized and treated to obtain 
382 evaluable participants at Day 15 (assuming 10% dropout rate). Additional participants may 
be randomized if the dropout rate is greater than 10%. 
7.3. 
Treatment Assignment 
Participants will be assigned to blinded IP (SAGE-217 or placebo) in accordance with the 
randomization schedule on Day 1. The investigator will assign 1 of the 5 ADTs based on clinical 
standard of care. The assigned ADT for a participant cannot have been taken previously by the 
participant during the current depressive episode. Further, citalopram cannot be assigned if 
escitalopram has been taken during the current depressive episode, and vice versa.  
Randomization will be stratified by antidepressant class (SSRI or SNRI).Additional details on 
randomization and blinding are provided in Section 9.5. 
Sage will monitor the ratio of SSRIs:SNRIs on an ongoing basis and may restrict assignment of 
any ADT(s) to reflect the ratio expected with standard of care (approximately 3:1; Luo 2020). 
7.4. 
Dose Adjustment Criteria 
During the treatment period, participants will be able to receive SAGE-217/placebo as long as 
there are no dose-limiting safety/tolerability concerns. Participants who cannot tolerate 50 mg (as 
determined by the investigator) will receive 40 mg for the remainder of the treatment period. 
At the discretion of the investigator, participants who cannot tolerate the 40-mg dose at any time 
may be discontinued from dosing. These participants should be followed and complete 
assessments as per the Schedule of Assessments (Table 2). 
During Weeks 3 to 6, the ADT dosing may be modified, based on individual response, per 
investigator discretion and per the labeled prescribing information. 
7.5. 
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 AEs or other findings suggesting unacceptable risk to 
participants, 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 IRB, where required, and initiate withdrawal procedures for participating participants. 

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8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
8.1. 
Participant Inclusion Criteria 
1. Participant has signed an ICF prior to any study-specific procedures being performed. 
2. Participant is a male or female between 18 and 64 years of age, inclusive. 
3. Participant 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. Participant agrees to adhere to the study requirements. 
5. Participant has a diagnosis of MDD as diagnosed by SCID-5-CT, with symptoms that 
have been present for at least a 4-week period. 
6. Participant has a HAM-D-17 total score of ≥24 at Screening and Day 1 (prior to dosing). 
7. Participant is willing to delay start of any antidepressant (except as per protocol), 
anxiolytic, anti-insomnia, psychostimulant, prescription opioid regimens, or new 
psychotherapy (including Cognitive Behavioral Therapy for Insomnia [CBT-I]) until 
after study completion. Participants receiving psychotherapy must have been receiving 
therapy on a regular schedule for at least 60 days prior to Day 1 and intend to maintain 
that schedule for the duration of the study. 
8. Female participant agrees to use at least one method of highly effective contraception as 
listed in Section 9.2.4 during participation in the study and for 30 days following the last 
dose of IP, unless she is postmenopausal (at least 12 months of spontaneous amenorrhea 
without an alternative medical cause, with confirmatory follicle stimulating hormone 
>40 mIU/mL), and/or surgically sterile (bilateral oophorectomy, hysterectomy, and/or 
bilateral salpingectomy), or does not engage in sexual relations which carry a risk of 
pregnancy (does not include abstinence). 
9. Female participant who is breastfeeding at Screening or on Day 1 (prior to administration 
of IP) must be willing to temporarily cease giving breast milk to her child(ren) from just 
prior to receiving IP on Day 1 until 7 days after the last dose of SAGE-217/placebo. 
10. Male participant agrees to use an acceptable method of effective contraception for the 
duration of the study and for 5 days after receiving IP, unless the participant does not 
engage in sexual relation(s) which carry a risk of pregnancy. Acceptable methods of 
effective contraception are listed in Section 9.2.4. 
11. Male participant is willing to abstain from sperm donation for the treatment period and 
for 5 days after receiving the last dose of the IP. 
12. Participant agrees to refrain from drugs of abuse and alcohol for the duration of the study. 
13. Participant is willing, able, and eligible to take at least 1 of the 5 ADTs specified in the 
protocol (an eligible ADT is an ADT that has not been taken during the current 
depressive episode and for which the participant has no contraindications; further, a 
participant is not eligible for citalopram if escitalopram has been taken during the current 
depressive episode, and vice versa). 

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8.2. 
Participant Exclusion Criteria 
Participants who meet any of the following criteria are disqualified from participation in this 
study: 
1. Participant is currently at significant risk of suicide, as judged by the investigator, or has 
attempted suicide associated with the current episode of MDD. 
2. Participant had onset of the current depressive episode during pregnancy or 4 weeks 
postpartum, or the participant has presented for screening during the 6-month postpartum 
period. 
3. Participant 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 participant's ability to complete or participate in this clinical study; a 
BMI ≤18 or ≥45 kg/m2 is exclusionary; a BMI of 40 to 44.9 kg/m2, inclusive, at 
Screening is subject to a broader evaluation of medical comorbidities as described above. 
4. Participant has treatment-resistant depression, defined as persistent depressive symptoms 
despite treatment with adequate doses of antidepressants within the current major 
depressive episode (excluding antipsychotics) from 2 different classes for at least 4 weeks 
of treatment. Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire (MGH ATRQ) will be used for this purpose. 
5. Participant has had vagus nerve stimulation, electroconvulsive therapy, or has taken 
ketamine within the current major depressive episode. 
6. Participant is receiving Cognitive Behavioral Therapy for Insomnia (CBT-I) within 
28 days prior to Day 1. 
7. Participant has a known allergy to SAGE-217, allopregnanolone, or related compounds. 
8. Participant has taken antidepressants within 30 days prior to Day 1, and/or has taken 
fluoxetine within 60 days prior to Day 1. 
9. Female participant has a positive pregnancy test or confirmed pregnancy. 
10. Participant has a clinically significant abnormal 12-lead ECG at the screening or baseline 
visits. NOTE: mean QT interval calculated using the Fridericia method (QTcF) of 
>450 msec in males or >470 msec in females will be the basis for exclusion from the 
study. 
11. Participant has active psychosis per investigator assessment. 
12. Participant has a medical history of seizures. 
13. Participant has a medical history of bipolar disorder, schizophrenia, and/or 
schizoaffective disorder. 

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14. Participant has a history of severe substance use disorder (including benzodiazepines) 
diagnosed using DSM-5 criteria in the 12 months prior to Screening or participant has a 
history of mild or moderate substance use disorder not in sustained remission for at least 
6 months prior to Screening. 
15. Participant has had exposure to another investigational medication or device within 
30 days prior to Screening. 
16. Participant has previously received brexanolone or participated in a SAGE-217 or SAGE-
547 (brexanolone) clinical trial. 
17. Participant has used any known strong inhibitors of cytochrome P450 (CYP)3A4 within 
28 days or five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, 
or Seville oranges, or products containing these within 14 days prior to Day 1. 
18. Participant has used any strong CYP3A inducer, such as rifampin, carbamazepine, 
enzalutamide, mitotane, phenytoin, or St John’s Wort, within 28 days prior to Day 1. 
19. Participant has a positive drug and/or alcohol screen at screening or on Day 1 prior to 
dosing. 
20. Participant plans to undergo elective surgery before completion of the Day 42 visit. 
21. Participant is taking benzodiazepines, barbiturates, or GABAA modulators (eg, 
eszopiclone, zopiclone, zaleplon, and zolpidem) within 28 days prior to Day 1, or has 
been using these agents daily or near-daily (≥4 times per week) for more than 1 year. 
Participant is taking any benzodiazepine or GABA modulator with a half-life of 
≥48 hours (eg, diazepam) from 60 days prior to Day 1. 
22. Participant is taking non-GABA anti-insomnia medications (eg, prescribed therapeutics 
specifically for insomnia and/or over the counter sleep aids), or first generation or second 
generation (typical/atypical) antipsychotics within 14 days prior to Day 1. Note that 
nonsedating antihistamines are permitted. 
23. Participant has been diagnosed with and/or treated for any type of cancer (excluding 
basal cell carcinoma and melanoma in situ) within the past year prior to Screening. 
24. Participant has a history of sleep apnea. 
25. Participant has had gastric bypass surgery, has a gastric sleeve or lap band, or has had any 
related procedures that interfere with gastrointestinal transit. 
26. Participant is taking psychostimulants (eg, methylphenidate, amphetamine) or opioids, 
regularly or as needed, within 28 days prior to Day 1. 
27. Participant is a dependent of the sponsor, investigator, investigator’s deputy, or study site 
staff. 
28. Participant expects to perform night shift work during the 14-day treatment period. 
29. Participant has detectable hepatitis B surface antigen, anti-hepatitis C virus (HCV) and 
positive HCV viral load, or human immunodeficiency virus (HIV) antibody at Screening. 

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8.3. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized to study intervention. A minimal set of screen failure information 
will be collected, including demography, screen failure details, eligibility criteria, and any 
AE/serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once. 
8.4. 
Investigational Product Discontinuation and Early Termination from 
the Study 
A participant may withdraw from the study at any time at his/her own request for any reason. 
The investigator may discontinue a participant from the study and/or from IP for safety, 
behavioral, compliance, or administrative reasons. 
Based on known withdrawal symptoms with other GABAergic drugs and nonclinical findings in 
a 9-month study of SAGE-217 in dogs (Investigator’s Brochure), there is a potential for 
withdrawal-related events, including seizure. The following guidelines for blinded IP 
discontinuation or dose reduction are presented to support participant safety: 
1. Any participant reporting a confirmed or suspected seizure at any time will be 
discontinued from blinded IP but will continue to be followed in the study. 
2. The investigator should monitor the course of CNS-based signs and symptoms suggestive 
of a seizure which are not accounted for by comorbid psychiatric or medical conditions. 
Examples of reported serious or severe events which may reflect an oncoming and/or 
increased risk for seizure may include temporary confusion, tremors, involuntary muscle 
fasciculations or jerking movements of arms or legs, or paresthesia. Should such 
symptoms occur, the investigator should consider decreasing the dose of SAGE-217 or 
placebo to 40 mg, stopping treatment to assess the effect on the symptom(s) 
(eg, resolution, improvement), or discontinuing the participant from treatment. A 
participant who discontinues treatment should remain in the study and continue protocol-
required assessments until the end of the study. 
The investigator must notify the sponsor and/or the medical monitor when a participant stops 
participation in the study for any reason. 
8.4.1. 
Investigational Product Discontinuation 
The primary reason for IP discontinuation must be documented in the participant’s study record 
and recorded in the participant’s electronic case report form (eCRF). 
Participants who discontinue treatment early should complete remaining study visits as 
scheduled through Day 42 (ie, relative to Day 1), unless the participant withdraws consent.  
8.4.2. 
Early Termination from the Study 
If a participant decides to terminate the study, the participant should return for an early 
termination (ET) visit, if possible. The primary reason for early termination from the study must 

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be documented in the participant’s study record and recorded in the participant’s electronic case 
report form (eCRF).  
If the participant withdraws consent for disclosure of future information, the sponsor will retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
Participants who terminate from the study early may, per the investigator, receive a supply of the 
ADT with instructions on how to taper the drug, if needed, or, if they wish to continue the ADT, 
a bridge supply to permit them to obtain a prescription from another provider. 
8.4.3. 
Loss to Follow-up 
A participant will be deemed lost to follow-up after 3 attempts at contacting the participant have 
been unsuccessful. 
8.4.4. 
Replacement of Participants 
Participants will not be replaced. 

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9. 
TREATMENT OF PARTICIPANTS 
9.1. 
Description of Investigational Products 
SAGE-217 will be available as hard gelatin capsules for oral administration; 2 capsules 
(one 30 mg and one 20 mg) will be provided to total a 50-mg dose, with option to reduce to 
40 mg based on tolerability, as per criteria described in Section 7.4. If the dose is reduced to 
40 mg, it will be administered as 2 20-mg capsules. 
Blinded placebo will be provided as hard gelatin capsules matched in appearance to SAGE-217, 
for oral administration. 
All participants will self-administer blinded and open-label IP orally at approximately 8 PM with 
fat-containing food for 14 days. Participants assigned duloxetine will also administer duloxetine 
in the morning (for twice daily dosing) as part of a divided dose for the first 7 days (see below). 
It is recommended that sertraline be administered as per labeled prescribing information, starting 
with 50 mg each evening during Week 1. and It is recommended that the dose be increased to 
100 mg each evening during Week 2.  
It is recommended that citalopram be administered per labeled prescribing information, starting 
with 20 mg/day.  
It is recommended that escitalopram be administered per labeled prescribing information, 
starting with 10 mg/day. 
It is recommended that duloxetine be administered per labeled prescribing information, starting 
with 40 or 60 mg/day (divided as 20 or 30 mg, respectively, twice daily for the first 7 days).  
It is recommended that desvenlafaxine be administered per labeled prescribing information, 
starting with 50 mg/day. 
9.2. 
Prior Medications, Concomitant Medications, Restrictions, and 
Contraception Requirements 
9.2.1. 
Prior and Concomitant Medications and/or Supplements 
The start and end dates, route, dose/units, frequency, and indication for all medications and/or 
supplements taken within 30 days prior to Screening and throughout the duration of the study 
will be recorded. In addition, psychotropic medications taken within 6 months prior to Screening 
will be recorded. 
Any medication and/or supplement determined necessary for the welfare of the participant may 
be given at the discretion of the investigator at any time during the study. 
9.2.2. 
Prohibited Medications 
The following specific classes of medications are prohibited: 
• Initiation of new psychotropic medications through the Day 42 visit 
• Initiation of new antidepressant therapy from 30 days (60 days for fluoxetine) prior to 
Day 1 through the Day 42 visit 

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• Use of any benzodiazepines, barbiturates, GABAA modulators, GABA-containing 
agents from Day -28 through the Day 42 visit (from Day -60 for benzodiazepines or 
GABA modulators with a half-life ≥48 hours) 
• Chronic or as-needed psychostimulants (eg, methylphenidate, amphetamine) or 
opioids from Day -28 through the Day 42 visit 
• First generation (typical) antipsychotics (eg, haloperidol, perphenazine) and second 
generation (atypical) antipsychotics (eg, aripiprazole, quetiapine) from Day -14 
through the Day 42 visit 
• Use of any non-GABA anti-insomnia medications (eg, prescribed therapeutics 
specifically for insomnia and/or over the counter sleep aids) from Day -14 to Day 1. 
Note that nonsedating antihistamines are permitted. 
• Exposure to another investigational medication or device from 30 days prior to 
Screening through the Day 42 visit 
• Any known strong inhibitors of CYP3A4 from Day -28 or 5 half-lives prior to Day 1 
(whichever is longer) through the Treatment Period 
• Use of any strong CYP3A inducer, such as rifampin, carbamazepine, enzalutamide, 
mitotane, phenytoin, or St John’s Wort from Day -28 through the Treatment Period 
• Any contraindications to the assigned SSRI/SNRI per labeled prescribing information 
9.2.3. 
Other Restrictions 
Any specific restrictions for the assigned SSRI/SNRI with concomitant medications per the 
labeled prescribing information should be considered. 
The consumption of grapefruit juice, grapefruit, or Seville oranges, or products containing these 
is prohibited within 14 days prior to Day 1 and throughout the treatment period. 
 Consumption of alcohol or use of drugs of abuse is discouraged throughout the duration of the 
study. 
Female participants who are lactating or actively breastfeeding must stop giving breast milk to 
the baby(ies) starting on Day 1 until 7 days after the last dose of SAGE-217/placebo. 
Elective surgeries or procedures are prohibited through the Day 42 visit. 
Participants must not participate in night shift work during the Treatment Period. 
Participants who are feeling sedated, somnolent, and/or dizzy are to refrain from driving or 
engaging in any activity requiring alertness. 
Participants receiving psychotherapy on a regular schedule for at least 60 days prior to Day 1 are 
permitted if the participant intends to continue that schedule through the Follow-up Period 
(Day 42). Initiation of new psychotherapy is prohibited until after study completion. 
9.2.4. 
Acceptable Forms of Contraception 
Acceptable forms of highly effective contraception for participants of childbearing potential or 
for partners of male participants who are of childbearing potential include: 

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• 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 
• Laparoscopic or abdominal bilateral tubal occlusion procedure (including bilateral 
tubal ligation) 
• Hysteroscopic bilateral tubal occlusion procedure performed at least 3 months prior to 
screening  
• Vasectomized partner (performed at least 3 months prior to screening) 
Acceptable forms of contraception for male participants include: 
• History of vasectomy (performed at least 3 months prior to screening) 
• Condom with spermicide used together with highly effective female contraceptive 
methods if the female partner(s) is of childbearing potential (see above for list of 
acceptable female contraceptive methods) 
9.3. 
Intervention after the End of the Study 
Upon completion of the current study, eligible participants will have the opportunity to enter an 
open-label, long-term study of SAGE-217 in which additional treatment with SAGE-217 will be 
offered. Participants that do not enter the open-label study or that terminate the current study 
early may continue to receive ADT as prescribed by the investigator either to taper the drug 
appropriately or—if the participant wishes to continue ADT—to bridge the participant until he or 
she receives a new prescription. 
9.4. 
Treatment Adherence 
Investigational products will be self-administered by participants (see Section 10.5). 
Administration of blinded and open-label IP will be monitored by a medication adherence 
monitoring platform used on smartphones to confirm IP ingestion. Participants will receive a 
reminder within a predefined time window to take IP while using the application and will follow 
a series of prescribed steps to confirm their ingestion of the medication. For visually confirmed 
IP ingestion, the application will record the date and time of IP administration by dose level, as 
well as missed doses. 
In addition, participants will be instructed to bring their SAGE-217 or placebo dosing kit and 
ADT to the site as outlined in Table 2, at which time the investigator or designee will be 
responsible for ensuring the kit contains sufficient doses for the duration of the treatment period. 
All participants should be reinstructed about the dosing requirements during study contacts. The 
authorized study personnel conducting the reeducation must document the process in the 
participant source records. 

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The investigator(s) will record any reasons for nonadherence in the source documents. 
9.5. 
Randomization and Blinding 
Participants will be randomized in a 1:1 ratio to receive SAGE-217 or matched placebo. 
Participants, site staff, and the sponsor will be blinded to treatment allocation. All participants 
will also receive an open-label ADT. Randomization will be performed centrally via an 
interactive response technology (IRT) system. Randomization schedules will be generated by an 
independent statistician. The allocation to blinded treatment (SAGE-217or 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. The blinding of 
the study will be broken after the database has been locked. 
9.5.1. 
Emergency Unblinding 
During the study, the blind is to be broken by the investigator via the IRT system only when the 
safety of a participant is at risk and the treatment plan is dependent on the study treatment 
received. Unless a participant is at immediate risk, the investigator should make diligent attempts 
to contact Sage prior to unblinding the study treatment administered to a participant. The 
responsibility to break the treatment code resides solely with the investigator. If the unblinding 
occurs without Sage’s knowledge, the investigator must notify Sage within 24 hours of breaking 
the blind. All circumstances surrounding a premature unblinding must be clearly documented in 
the source records. 
In all cases where the IP allocation for a participant is unblinded, pertinent information 
(including the reason for unblinding) must be documented in the participant’s records and on the 
eCRF. 

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10. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
10.1. 
Investigational Products 
10.1.1. 
Blinded Investigational Products 
SAGE-217 is 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, colloidal silicon 
dioxide, and sodium stearyl fumarate as excipients. Capsules will be available in 20-mg and 
30-mg dose strengths. 
Blinded placebo will be provided as hard gelatin capsules matched in appearance to SAGE-217. 
10.1.2. 
Open-label Investigational Product 
Sertraline, escitalopram, citalopram, duloxetine, and desvenlafaxine, packaged and labeled by 
the commercial manufacturer, will be supplied by a third-party vendor. Open-label IP is to be 
stored and administered according to the package insert. Open-label IP during this study is for 
use only as directed in this protocol. 
10.2. 
Blinded Investigational Product Packaging and Labeling 
SAGE-217 and placebo will be provided to the clinic pharmacist and/or designated site staff 
responsible for dispensing the blinded IP in appropriately labeled, participant-specific kits 
containing sealed unit doses. Each unit dose for 40-mg and 50-mg dose levels consists of 
2 capsules. Additional information regarding the packaging and labeling is provided in the 
Pharmacy Manual. 
Labels with all required information and conforming to all applicable FDA Code of Federal 
Regulations and Good Manufacturing Practices/Good Clinical Practices guidelines will be 
prepared by the sponsor for SAGE-217 and placebo. 
10.3. 
Blinded Investigational Product Storage 
SAGE-217 and placebo is to be stored at room temperature (59 to 86°F; 15 to 30°C), safely and 
separately from other drugs. 
10.4. 
Blinded Investigational Product Preparation 
Not applicable. 
10.5. 
Blinded and Open-label Investigational Product Administration 
Blinded IP and open-label ADT are to be administered orally at approximately 8 PM with fat-
containing food (eg, within 1 hour of an evening meal which contains fat, or with a fat-
containing snack). Examples of fat-containing snacks include nuts, peanut butter, avocado, eggs, 
and cheese. Participants assigned duloxetine will also administer duloxetine in the morning (for 
twice-daily divided dosing) for the first 7 days (see Section 9.1). 

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If a participant misses a dose of blinded IP or open-label IP, the participant should skip that dose 
(ie, they should not take the dose in the morning) and take the next scheduled dose. 
10.6. 
Blinded Investigational Product Accountability, Handling, and 
Disposal 
Upon receipt of blinded IP dosing kits, the investigator(s), or the responsible pharmacist or 
designee, will inspect the kits and complete and follow the instructions regarding receipt and 
storage in the SAGE-217 Investigator’s Brochure and (where applicable) in the Pharmacy 
Manual. A copy of the shipping documentation will be kept in the study files. 
The designated site staff will dispense the participant-specific kits to participants at the planned 
dispensation visit intervals outlined in Table 2. Site staff will access the IRT at the Screening 
Visit to obtain a participant identification (ID) number for each participant that has signed an 
informed consent form. On Day 1, site staff will access the IRT and provide the necessary 
participant-identifying information, including the participant ID number assigned at Screening, 
to randomize the eligible participant into the study and obtain the medication ID number for the 
blinded IP to be dispensed to that participant. The medication ID number and the number of 
blinded capsules dispensed must be recorded. 
At the subsequent blinded IP-dispensing visit, the investigator or designee will access the IRT, 
providing the same participant ID number assigned at Screening, to obtain the medication ID 
number for the blinded IP to be dispensed at that visit. The medication ID number, the number of 
capsules dispensed, and the number of capsules returned by the participant at this visit must be 
recorded. 
If dispensing errors or discrepancies are discovered by site staff or sponsor’s designee, the 
sponsor must be notified immediately. 
The blinded IP provided is for use only as directed in this protocol. The investigator or designee 
must keep a record of all blinded IP received, used and returned/discarded. 
Sage Therapeutics will be permitted access to the study supplies at any time and with appropriate 
notice during or after completion of the study to perform drug accountability and reconciliation. 
The investigator, pharmacist, or qualified designee is responsible for drug accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final disposition records). 
At the end of the study, any unused blinded IP will be returned to Sage Therapeutics for 
destruction or destroyed locally per the site’s procedures; disposition of blinded IP will be 
documented. 
10.7. 
Blinded Investigational Product Complaints 
A product complaint is any written, electronic, or verbal expression of dissatisfaction regarding 
the identity, quality, reliability, safety, purity, potency, effectiveness or performance (applicable 
for approved marketed products) of a drug product after it is released for distribution. 
In the course of conduct of the study, study personnel may become aware of a product complaint 
associated with the use of a Sage product. Personnel shall notify Sage within 24 hours by 
forwarding the product complaint information via the contact information provided in Table 1. 

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Where possible, personnel should segregate and retain any product, materials, or packaging 
associated with the product complaint until further instruction is provided by Sage or its 
designated representative(s). 

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11. 
EFFICACY AND CLINICAL PHARMACOLOGY ASSESSMENTS 
11.1. 
Efficacy Assessments 
11.1.1. 
Hamilton Rating Scale for Depression 
The primary outcome measure is the change from baseline in 17-item HAM-D total score at the 
end of the Treatment Period (Day 15). Every effort should be made for the same rater to perform 
all HAM-D assessments for an individual participant. An assessment timeframe of past 7 days 
(1 week) will be used at Screening, and ‘Since Last Visit’ will be used for all other visits. 
The 17-item HAM-D will be used to rate the severity of depression in participants who are 
already diagnosed as depressed (Williams 2013 a; Williams 2013b). 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 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. 
11.1.2. 
Montgomery-Åsberg Depression Rating Scale 
The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive 
episodes in participants with mood disorders. It was designed as an adjunct to the HAM-D that is 
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 (Williams 2008). 
The MADRS total score will be calculated as the sum of the 10 individual item scores. 
11.1.3. 
Hamilton Anxiety Rating Scale 
The 14-item HAM-A will be used to rate the severity of symptoms of anxiety (Williams 2013c; 
Williams 2013d). Each of the 14 items is defined by a series of symptoms, and measures both 
psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical 
complaints related to anxiety). Scoring for HAM-A is calculated by assigning scores of 0 (not 
present) to 4 (very severe), with a total score range of 0 to 56, where <17 indicates mild severity, 
18 to 24, mild to moderate severity, and 25 to 30, moderate to severe severity. The HAM-A total 
score will be calculated as the sum of the 14 individual item scores. 

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12. 
SAFETY ASSESSMENTS 
12.1. 
Safety Parameters 
All assessments will be conducted according to the Schedule of Assessments (Table 2). 
12.1.1. 
Demographic/Medical History 
Demographic characteristics (age, race, gender, ethnicity, employment status, highest education 
level, marital/civil status) and a full medical history, including: family psychiatric history, 
generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, persistent 
depressive disorder, postpartum depression, substance use disorder, alcohol use disorder, MDD 
with seasonal pattern, MDD with psychotic features, premenstrual dysphoric disorder, MDD 
with atypical features, schizophrenia; or schizoaffective disorder will be documented. The 
diagnosis of MDD will be determined using the SCID-5-CT. If available, the disease code 
associated with the diagnosis of MDD based on the tenth revision of the International Statistical 
Classification of Diseases and Related Health Problems (ICD-10) should be recorded. 
The Massachusetts General Hospital Antidepressant Treatment Response Questionnaire 
(MGH ATRQ) will be used to determine whether the participant has treatment-resistant 
depression, defined as persistent depressive symptoms despite treatment during the current major 
depressive episode with adequate doses of antidepressants from 2 different classes for at least 4 
weeks of treatment. 
12.1.2. 
Weight and Height 
Height (Screening only) and weight will be measured and documented. 
12.1.3. 
Physical Examination 
Physical examinations assessing body systems (eg, head, eyes, ears, nose, and throat; heart; 
lungs; abdomen; and extremities), as well as cognitive and neurological examinations and mental 
status examinations will be conducted and documented. Thereafter, abbreviated physical 
examinations will include brief assessments of general appearance, cardiovascular, respiratory, 
gastrointestinal, and neurological systems, followed by a targeted physical examination as 
needed. Unscheduled, symptom-directed physical examinations may also be conducted at the 
investigator’s discretion. Whenever possible, the same individual is to perform all physical 
examinations for a given participant. Unscheduled brief, symptom-driven physical examinations 
may also be conducted per the investigator’s discretion. 
Any abnormality in physical examinations will be interpreted by the investigator as abnormal, 
not clinically significant (NCS); or abnormal, clinically significant (CS) in source documents. 
New or worsening abnormalities that are judged to be clinically significant will be recorded as 
AEs, assessed according to Section 12.2.1. 
12.1.4. 
COVID-19 Questions 
Information regarding diagnosis, isolation, and/or hospitalization due to COVID-19 will be 
documented as part of Medical History, AE collection, and prior/concomitant 
medication/procedure collection at Screening and throughout the study. 

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assessed according to Section 12.2.1. A clinically significant laboratory abnormality following 
participant randomization will be followed until the abnormality returns to an acceptable level or 
a satisfactory explanation has been obtained. 
The clinical laboratory tests to be performed are listed in Table 3. 
Table 3: 
Clinical Laboratory Tests 
Hematology  
Serum Chemistry 
Urinalysis 
Coagulation 
Red blood cell count 
Hemoglobin 
Hematocrit 
White blood cell count with 
differential 
Platelet count 
Red Blood Cell Indices 
(MCV, MCH, MCHC) 
Reflex to Red blood cell 
morphology if indices are 
abnormal 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
Total protein 
Creatinine 
Blood urea nitrogen 
Creatine kinase 
Gamma-glutamyl transferase 
Potassium 
Sodium 
Lactate dehydrogenase 
Glucose 
Chloride 
Bicarbonate 
Calcium 
Phosphorus 
Triglycerides 
Thyroid stimulating hormone 
(TSH) 
Reflex to free T3/T4 if 
TSH is abnormal  
pH 
Specific gravity 
Protein 
Glucose 
Red blood cell 
Nitrite 
Leukocyte 
esterase 
Ketones 
Bilirubin 
Urobilinogen 
Activated partial 
thromboplastin 
time 
Prothrombin time 
International 
normalized ratio 
Diagnostic  
 
 
 
Serum 
Urine 
Breathalyzer 
 
Hepatitis B 
Hepatitis C 
Reflex HCV RNA 
HIV-1 and -2 
Female participants that are 
not surgically sterile and do 
not meet the protocol-
Drug screen including: 
amphetamines, 
barbiturates, 
benzodiazepines, 
cannabinoids, cocaine, 
opiates, phencyclidine 
Female participants that are 
not surgically sterile and do 
Alcohol 
 

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12.2.2. 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Places the participant at immediate risk of death (a life-threatening event); however, 
this does not include an event that, had it occurred in a more severe form, might have 
caused death 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
An SAE may also be any other medically important event that, in the opinion of the investigator 
may jeopardize the participant or may require medical intervention to prevent 1 of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization). 
All SAEs that occur after any participant has signed the ICF and throughout the duration of the 
study, whether or not they are related to the study, must be recorded on the SAE report form 
provided by Sage Therapeutics. Any SAE that is ongoing when the participant completes their 
final study visit, will be followed by the investigator until the event has resolved, stabilized, 
returned to baseline status, or until the participant dies or is lost to follow up. 
A prescheduled or elective procedure or routinely scheduled treatment will not be considered an 
SAE, even if the participant is hospitalized. The site must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or on a waiting list to be scheduled) prior to obtaining the participant’s 
consent to participate in the study. 
• The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress, in the opinion of an 
investigator, between the participant’s consent to participate in the study and at the 
time of the procedure or treatment. 
12.2.3. 
Relationship to Investigational Product 
The investigator must make the determination of relationship to the IP for each AE (not related, 
related). The following definitions should be considered when evaluating the relationship of AEs 
and SAEs to the IP. 
Not Related 
An AE will be considered “not related” to the use of the IP if there is not a reasonable 
possibility that the event has been caused by the IP. Factors pointing towards this 
assessment include but are not limited to: the lack of temporal relationship between 
administration of the IP and the event, the presence of biologically implausible 
relationship between the product and the AE, or the presence of a more likely 
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Related 
An AE will be considered “related” to the use of the IP if there is a reasonable 
possibility that the event may have been caused by the product under investigation. 
Factors that point towards this assessment include but are not limited to: a positive 
rechallenge, a reasonable temporal sequence between administration of the drug and 
the event, a known response pattern of the suspected drug, improvement following 
discontinuation or dose reduction, a biologically plausible relationship between the 
drug and the AE, or a lack of alternative explanation for the AE 
12.2.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the participant and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. The AE term should be reported in standard medical terminology when 
possible. For each AE, the investigator will evaluate and report the onset (date and time), 
resolution (date and time), intensity, causality, action taken, outcome and seriousness (if 
applicable), and whether or not it caused the participant to discontinue the IP or withdraw early 
from the study. 
Intensity will be assessed according to the following scale: 
• Mild: symptom(s) barely noticeable to participant or does not make participant 
uncomfortable; does not influence performance or functioning; prescription drug not 
ordinarily needed for relief of symptom(s) 
• Moderate: symptom(s) of a sufficient severity to make participant uncomfortable; 
performance of daily activity is influenced; participant is able to continue in study; 
treatment for symptom(s) may be needed 
• Severe: symptom(s) cause severe discomfort; symptoms cause incapacitation or 
significant impact on participant’s daily life; severity may cause cessation of 
treatment with IP; treatment for symptom(s) may be given and/or participant 
hospitalized 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.2.2. An AE of severe intensity 
may not necessarily be considered serious. 
12.2.5. 
Reporting Serious Adverse Events 
In order to adhere to all applicable laws and regulations for reporting an SAE(s), the study site 
must notify Sage or designee within 24 hours of the study site staff becoming aware of the 
SAE(s). The investigator must complete, sign and date the SAE report form, verify the accuracy 
of the information recorded on the SAE report form with the corresponding source documents, 
and send a copy to Sage or designee. 
Additional follow-up information, if required or available, should all be sent to Sage or designee 
within 24 hours of receipt on a follow-up SAE report form and placed with the original SAE 
information and kept with the appropriate section of the eCRF and/or study file. 

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SAEs occurring after the designated follow up time for the study, should be reported to Sage or 
designee according to the timelines noted above only if the investigator considers the SAE 
related to IP. 
Sage, or designee, is responsible for notifying the relevant regulatory authorities of certain 
events. It is the principal investigator’s responsibility to notify the IRB/IEC of all SAEs that 
occur at his or her site. Investigators will also be notified of all suspected unexpected serious 
adverse reactions (SUSARs) that occur during the clinical study. IRBs/IECs will be notified of 
SAEs and/or SUSARs as required by local law. 
In addition, appropriate personnel in Sage Drug Safety and Pharmacovigilance or designee will 
unblind SUSARs for the purpose of regulatory reporting. Sage or designee will submit SUSARs 
(in blinded or unblinded fashion) to regulatory agencies according to local law. Sage, or 
designee, will submit SUSARs to investigators in a blinded fashion. 
12.3. 
Pregnancy 
If a participant becomes pregnant after the first administration of IP, pregnancy information must 
be collected and recorded on the Pregnancy form and submitted to the sponsor within 24 hours of 
learning of the pregnancy. Details will be collected for all pregnancies for which conception was 
likely to have occurred after the start of IP administration until 5 terminal half-lives following 
the last administration of IP or until the completion of the study whichever is longer. Any 
pregnancy occurring in that time frame will be followed until delivery or termination of the 
pregnancy. The investigator will also attempt to collect pregnancy information on any 
participant’s partner who becomes pregnant after the participant has received the first 
administration of IP. After obtaining the necessary signed informed consent from the pregnant 
partner directly, the investigator will follow the same pregnancy reporting procedures specified 
for pregnant participants. 
The participant or participant’s partner will be followed to determine the outcome of the 
pregnancy. The outcome of all pregnancies (eg, spontaneous abortion, elective abortion, normal 
birth) must be followed and documented even if the participant was discontinued from the study. 
The investigator will collect follow-up information on the participant or participant’s partner and 
the neonate, and the information will be forwarded to Sage or designee. Generally, follow-up 
will not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an IP may have 
interfered with the effectiveness of a contraceptive medication. Any complication during 
pregnancy (eg, anemia, infections, pre-eclampsia) should be reported as an AE/SAE. If the 
outcome of the pregnancy meets the criteria for immediate classification as an SAE (ie, 
spontaneous abortion, stillbirth, neonatal death,), the investigator should follow the procedures 
for reporting an SAE. 
12.4. 
Overdose 
Overdoses, regardless of presence of associated clinical manifestation(s) (eg, headache, 
abnormal laboratory value) will be considered an AE and recorded as such on the eCRF. Any 

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clinical manifestation(s) of overdose must also be recorded as an AE on the eCRF. In addition, 
all overdoses must be recorded on an Overdose form and sent to Sage or designee within 
24 hours of the site becoming aware of the overdose. 

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13.4. 
Demographics and Baseline Characteristics 
Demographic data, such as age, race, and ethnicity, and baseline characteristics, such as height, 
weight, and BMI, will be summarized using the safety sets. 
Hepatitis, HIV, drug and alcohol, and pregnancy screening results will be listed, but not 
summarized as they are considered part of the inclusion/exclusion criteria. 
Medical history will be listed by participant. 
13.5. 
Efficacy Analysis 
Efficacy data will be summarized using appropriate descriptive statistics and other data 
presentation methods where applicable; participant listings will be provided for all efficacy data. 
Participants will be analyzed according to randomized treatment. 
The estimand for the primary efficacy analysis is defined as follows: 
1) The treatment regimens for participants are: SAGE-217 + assigned ADT and placebo 
+ assigned ADT for 14 days. 
2) The target population is adult participants with a diagnosis of major depressive 
disorder and within a current depressive episode of severity (HAM-D total score 
>=24). 
3) The variable of interest is the change from baseline in HAM-D total score at Day 15. 
4) The intercurrent events could be: 
a. The premature discontinuation of treatment for any reason, thus not having a Day 15 
HAM-D total score available. This will be dealt with by a sensitivity analysis using 
multiple imputation techniques as described below. 
b. Certain medications including, but not limited to, new antidepressants (except for 
assigned ADT) or benzodiazepines are prohibited during the study; however, the 
treatment policy strategy dictates that the results following these prohibited 
medication use will not be manipulated but will rather be used ‘as is’ in analysis. 
Please note that the protocol does not specify any rescue process, hence there is no 
rescue medication. 
5) The population summary level deals with the difference between SAGE-217 + 
assigned ADT and placebo + assigned ADT treatments in mean change from baseline 
in HAM-D total score at Day 15. 
Using the FAS, this will be analyzed using a mixed-effects model for repeated measures 
(MMRM); the model will include treatment, baseline HAM-D total score, assessment time point, 
and time point-by-treatment as explanatory variables. All explanatory variables will be treated as 
fixed effects. All postbaseline time points will be included in the model. The main comparison 
will be between SAGE-217 + assigned ADT and placebo + assigned ADT at the Day 15 time 
point. Model-based point estimates (ie, least squares means, 95% confidence intervals, and 
p values) will be reported where applicable. An unstructured covariance structure will be used to 
model the within-participant errors. The Toeplitz compound symmetry, Autoregressive (1) 
[AR(1)] covariance structure will be used in that sequence if there is a convergence issue with 

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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Before an investigational site can enter a participant into the study, a representative of Sage 
Therapeutics will visit the investigational study site per Sage SOPs to: 
• Determine the adequacy of the facilities 
• Discuss with the investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Sage Therapeutics or its representatives. 
This will be documented in a Clinical Trial Agreement between Sage Therapeutics and 
the investigator. 
During the study, a monitor from Sage Therapeutics or representative 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 case report forms, and that IP accountability checks are being 
performed 
• Perform source data verification. This includes a comparison of the data in the case report 
forms with the participant’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 
participant (eg, clinic charts). 
• Record and report any protocol deviations not previously sent to Sage Therapeutics. 
• Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to Sage Therapeutics and those SAEs that met criteria for 
reporting have been forwarded to the IRB or independent ethics committee. 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
14.2. 
Audits and Inspections 
Sage Therapeutics or authorized representatives of Sage Therapeutics, a regulatory authority, or 
an Independent Ethics Committee or an Institutional Review Board may visit the site to perform 
an audit(s) or inspection(s), including source data verification. The purpose of a Sage 
Therapeutics audit or a regulatory authority 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/ICH GCP guidelines, and any applicable regulatory requirements. The investigator should 
contact Sage Therapeutics immediately if contacted by a regulatory agency or IRB/IEC about an 
inspection. 

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14.3. 
Institutional Review Board (IRB) or Ethics Committee (EC) 
The principal investigator must obtain IRB (or EC) approval for the clinical study prior to 
enrolling a participant. Initial IRB (or EC) approval, and all materials approved by the IRB (or 
EC) for this study including the participant consent form and recruitment materials must be 
maintained by the investigator and made available for inspection. 
 

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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practice and all applicable regulatory requirements, 
Sage Therapeutics may conduct a quality assurance audit(s) at the clinical site. Please see 
Section 14.2 for more details regarding the audit process. 
The investigator must have adequate quality control practices to ensure that the study is 
performed in a manner consistent with the protocol, GCP/ICH GCP guidelines, and applicable 
regulatory requirements. The investigator is responsible for reviewing all identified protocol 
deviations. Significant protocol deviations should be reported to the IRB/IEC per the IRB/IEC’s 
written procedures. 
The investigator is responsible for supervising any individual or party to whom the investigator 
delegates study-related duties and functions conducted at the study site. When the investigator 
retains the services of any individual or party to perform study-related duties and functions, the 
investigator must ensure the individual or party is qualified to perform study-related duties and 
functions and should implement procedures to ensure the integrity of the study-related duties and 
functions performed, and any data generated. 
The investigator must maintain adequate and accurate source documents and study records that 
include all pertinent observations on each of the site’s study participants. Source data must be 
attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data 
should be traceable, should not obscure the original entry, and should be explained, if necessary 
to provide clarification. 
 

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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
given a written and dated approval or favorable opinion by an IRB or IEC as appropriate. The 
investigator must obtain and document approval before he or she can enroll any participant into 
the study. The IRB or IEC must supply to the sponsor a list of the IRB/IEC membership and a 
statement to confirm that the IRB/IEC is organized and operates according to GCP and 
applicable laws and regulations. 
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 participants for the study. The protocol must be re-approved by the 
IRB or IEC upon receipt of amendments and annually, as local regulations require. 
The principal investigator is also responsible for providing the IRB or IEC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. Sage Therapeutics 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. In addition, the principal investigator must 
inform the IRB/IEC and sponsor of any changes significantly affecting the conduct of the study 
and/or increasing the risk to participants (eg, violations to the protocol or urgent safety measures 
taken for participant safety). 
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH and GCP guidelines, as well as all 
applicable regional or national regulatory requirements. 
16.3. 
Written Informed Consent 
Prior to enrolling a study participant, the investigator(s) will ensure that the participant is given 
full and adequate oral and written information about the nature, purpose, possible risk and 
benefit of the study. Participants must also be notified that they are free to discontinue from the 
study at any time. The participant should be given the opportunity to ask questions and allowed 
time to consider the information provided. 
When the participant decides to participate in the study, the participant (or the participant’s, 
parent or legally authorized representative) must provide signed and dated informed consent. The 
written consent must be obtained before conducting any study procedures. The investigator must 
document the consent process in the participant’s source records. The investigator must maintain 
the original, signed ICF. A copy of the signed ICF must be given to the participant or to the 
participant’s parent or legally authorized representative. 
Throughout the study participants should be informed of any changes made to the study and as 
new safety and or risk information becomes known. The provision of this information will be 

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documented in the participant’s source records, and when applicable, an updated ICF will be 
provided. 

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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Inspection of Records 
Sage Therapeutics or its representative(s) will be allowed to conduct site visits at the 
investigation facilities for the purpose of monitoring any aspect of the study. The investigator 
agrees to allow the monitor to inspect the facility, drug storage area, drug accountability records, 
participant charts and study source documents, and other records relative to study conduct. 
Inspection of the study by a Regulatory Authority may occur at any time. The investigator must 
agree to the inspection of study-related records and source documents by the Regulatory 
Authority representative(s). 
17.2. 
Retention of Records 
The principal investigator must maintain all documentation relating to the study for the period 
outlined in the site contract, or for a period of 2 years after the last marketing application 
approval, and until there are no pending or contemplated marketing applications in an ICH 
region or at least 2 years have elapsed since the formal discontinuation of clinical development 
of the investigational product. Sage is responsible to inform the investigator/institution as to 
when study documents no longer need to be retained. 

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18. 
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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INVESTIGATOR’S AGREEMENT 
I have received and read the Investigator’s Brochure for SAGE-217. I have read the 
217-MDD-305 protocol and agree to conduct the study as outlined. I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
Date (DD/MMM/YYYY) 

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2. 
SYNOPSIS 
Name of Sponsor/Company: Sage Therapeutics, Inc. (hereafter referred to as Sage Therapeutics, or 
Sage) 
Name of Investigational Product: SAGE-217 Capsules 
Name of Active Ingredient: SAGE-217 
Title of Study: A Phase 3, Randomized, Double-Blind Study Comparing the Efficacy and Safety of 
SAGE-217 plus an Antidepressant Versus Placebo plus an Antidepressant in Adults with Major 
Depressive Disorder 
Number of Sites and Study Location: This study will take place at approximately 55 sites in United 
States. 
Phase of Development: 3 
Planned Duration for each Study Participant: Up to 70 days (up to 28-day Screening Period, 14-day 
Double-blind Treatment Period, and a 28-day Antidepressant Therapy (ADT) Continuation Period) 
Objectives: 
Primary: 
• 
To evaluate the efficacy of SAGE-217 plus an antidepressant in the treatment of major 
depressive disorder (MDD) compared to placebo plus an antidepressant 
Secondary: 
• 
To assess patient-reported outcome (PRO) measures as they relate to depressive symptoms 
• 
To evaluate the safety and tolerability of SAGE-217 plus an antidepressant 
 
 
 
 
 
Endpoints: 
Primary: 
• 
Change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D) total 
score at Day 15 
Key Secondary: 
• 
Change from baseline in CGI-S at Day 15 
• 
Change from baseline in HAM-D total score at Day 3, Day 8, and Day 42 
Other Secondary: 
• 
HAM-D response at Day 15 and Day 42 
• 
HAM-D remission at Day 15 and Day 42 
• 
CGI-I response, defined as “much improved” or “very much improved”, at Day 15 
• 
Change from baseline in MADRS total score at Day 15 
• 
Change from baseline in HAM-A total score at Day 15 
• 
Time to first HAM-D response 
• 
Change from baseline to Day 15 in depressive symptoms, as assessed by the PHQ-9 
• 
Incidence and severity of treatment-emergent adverse events (TEAEs) 

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continued at the discretion of the investigator. 
Upon completion of the current study, eligible participants will have the opportunity to enter a long-
term open-label study of SAGE-217.  
Number of Participants (planned): It is estimated that approximately 424 participants will be 
randomized and treated to obtain 382 evaluable participants at Day 15 (assuming a 10% dropout rate). 
Additional participants may be randomized if the dropout rate is greater than 10%. 
Eligibility Criteria: 
Inclusion Criteria 
1. Participant has signed an ICF prior to any study-specific procedures being performed. 
2. Participant is a male or female between 18 and 64 years of age, inclusive. 
3. Participant 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. Participant agrees to adhere to the study requirements. 
5. Participant has a diagnosis of MDD as diagnosed by SCID-5-CT, with symptoms that have 
been present for at least a 4-week period. 
6. Participant has a HAM-D-17 total score of ≥24 at Screening and Day 1 (prior to dosing). 
7. Participant is willing to delay start of any antidepressant (except as per protocol), anxiolytic, 
anti-insomnia, psychostimulant, prescription opioid regimens, or new psychotherapy 
(including Cognitive Behavioral Therapy for Insomnia [CBT-I]) until after study completion. 
Participants receiving psychotherapy must have been receiving therapy on a regular schedule 
for at least 60 days prior to Day 1 and intend to maintain that schedule for the duration of the 
study. 
8. Female participant agrees to use at least one method of highly effective contraception as listed 
in Section 9.2.4 during participation in the study and for 30 days following the last dose of IP, 
unless she is postmenopausal (at least 12 months of spontaneous amenorrhea without an 
alternative medical cause, with confirmatory follicle stimulating hormone >40 mIU/mL), 
and/or surgically sterile (bilateral oophorectomy, hysterectomy, and/or bilateral 
salpingectomy), or does not engage in sexual relations which carry a risk of pregnancy (does 
not include abstinence). 
9. Female participant who is breastfeeding at Screening or on Day 1 (prior to administration of 
IP) must be willing to temporarily cease giving breast milk to her child(ren) from just prior to 
receiving IP on Day 1 until 7 days after the last dose of SAGE-217/placebo. 
10. Male participant agrees to use an acceptable method of effective contraception for the duration 
of the study and for 5 days after receiving IP, unless the participant does not engage in sexual 
relation(s) which carry a risk of pregnancy. Acceptable methods of effective contraception are 
listed in Section 9.2.4. 
11. Male participant is willing to abstain from sperm donation for the treatment period and for 
5 days after receiving the last dose of the IP. 
12. Participant agrees to refrain from drugs of abuse and alcohol for the duration of the study. 
13. Participant is willing, able, and eligible to take at least 1 of the 5 ADTs specified in the 
protocol (an eligible ADT is an ADT that has not been taken during the current depressive 
episode and for which the participant has no contraindications; further, a participant is not 
eligible for citalopram if escitalopram has been taken during the current depressive episode, 
and vice versa). 

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Exclusion Criteria 
1. Participant is currently at significant risk of suicide, as judged by the investigator, or has 
attempted suicide associated with the current episode of MDD. 
2. Participant had onset of the current depressive episode during pregnancy or 4 weeks 
postpartum, or the participant has presented for screening during the 6-month postpartum 
period. 
3. Participant has a recent history or active clinically significant manifestations of metabolic, 
hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, 
dermatological, urogenital, neurological, or eye, ear, nose, and throat disorders, or any other 
acute or chronic condition that, in the investigator's opinion, would limit the participant's 
ability to complete or participate in this clinical study; a BMI ≤18 or ≥45 kg/m2 is 
exclusionary; a BMI of 40 to 44.9 kg/m2, inclusive, at Screening is subject to a broader 
evaluation of medical comorbidities as described above. 
4. Participant has treatment-resistant depression, defined as persistent depressive symptoms 
despite treatment with adequate doses of antidepressants within the current major depressive 
episode (excluding antipsychotics) from 2 different classes for at least 4 weeks of treatment. 
Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH 
ATRQ) will be used for this purpose. 
5. Participant has had vagus nerve stimulation, electroconvulsive therapy, or has taken ketamine 
within the current major depressive episode. 
6. Participant is receiving Cognitive Behavioral Therapy for Insomnia (CBT-I) within 28 days 
prior to Day 1. 
7. Participant has a known allergy to SAGE-217, allopregnanolone, sertraline, or related 
compounds. 
8. Participant has taken antidepressants within 30 days prior to Day 1, and/or has taken fluoxetine 
within 60 days prior to Day 1. 
9. Female participant has a positive pregnancy test or confirmed pregnancy. 
10. Participant has a clinically significant abnormal 12-lead ECG at the screening or baseline 
visits. NOTE: mean QT interval calculated using the Fridericia method (QTcF) of >450 msec 
in males or >470 msec in females will be the basis for exclusion from the study. 
11. Participant has active psychosis per investigator assessment. 
12. Participant has a medical history of seizures. 
13. Participant has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder. 
14. Participant has a history of severe substance use disorder (including benzodiazepines) 
diagnosed using DSM-5 criteria in the 12 months prior to Screening or participant has a history 
of mild or moderate substance use disorder not in sustained remission for at least 6 months 
prior to Screening. 
15. Participant has had exposure to another investigational medication or device within 30 days 
prior to Screening. 
16. Participant has previously received brexanolone or participated in a SAGE-217 or SAGE-547 
(brexanolone) clinical trial. 
17. Participant has used any known strong inhibitors of cytochrome P450 (CYP)3A4 within 
28 days or 5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, or 
Seville oranges, or products containing these, within 14 days prior to Day 1. 

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18. Participant has used any strong CYP3A inducer, such as rifampin, carbamazepine, 
enzalutamide, mitotane, phenytoin, or St John’s Wort, within 28 days prior to Day 1. 
19. Participant has a positive drug and/or alcohol screen at screening or on Day 1 prior to dosing. 
20. Participant plans to undergo elective surgery before completion of the Day 42 visit. 
21. Participant is taking benzodiazepines, barbiturates, or GABAA modulators (eg, eszopiclone, 
zopiclone, zaleplon, and zolpidem) within 28 days prior to Day 1, or has been using these 
agents daily or near-daily (≥4 times per week) for more than 1 year. Participant is taking any 
benzodiazepine or GABA modulator with a half-life of ≥48 hours (eg, diazepam) from 60 days 
prior to Day 1. 
22. Participant is taking non-GABA anti-insomnia medications (eg, prescribed therapeutics 
specifically for insomnia and/or over the counter sleep aids), or first or second generation 
(typical/atypical) antipsychotics within 14 days prior to Day 1. Note that nonsedating 
antihistamines are permitted. 
23. Participant has been diagnosed with and/or treated for any type of cancer (excluding basal cell 
carcinoma and melanoma in situ) within the past year prior to Screening. 
24. Participant has a history of sleep apnea. 
25. Participant has had gastric bypass surgery, has a gastric sleeve or lap band, or has had any 
related procedures that interfere with gastrointestinal transit. 
26. Participant is taking psychostimulants (eg, methylphenidate, amphetamine) or opioids, 
regularly or as needed, within 28 days prior to Day 1. 
27. Participant is a dependent of the sponsor, investigator, investigator’s deputy, or study site staff. 
28. Participant expects to perform night shift work during the 14-day Treatment Period. 
29. Participant has detectable hepatitis B surface antigen, anti-hepatitis C virus (HCV) and positive 
HCV viral load, or human immunodeficiency virus (HIV) antibody at Screening. 
Investigational Product Dosage and Mode of Administration: SAGE-217 will be available as hard 
gelatin capsules for oral administration; multiple capsules (in 30-mg or 20-mg dose strengths) will be 
provided to total a 50-mg dose, with option to reduce to 40 mg based on tolerability. 
Blinded placebo will be provided as hard gelatin capsules matched in appearance to SAGE-217, for 
oral administration. 
Sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine will be administered as per labeled 
prescribing information 
Duration of Treatment: Blinded SAGE-217 or placebo will be administered once daily for 14 days; 
open-label ADT will be administered according to labeled prescribing information for 42 days. 

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Table 2: 
Schedule of Assessments 
Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
ADT Continuation Period 
Visit Days 
D-28 to 
D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(+1d) 
and/or 
EOT a 
D18 
(±1d) 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
/ET  
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
Study Procedure 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Duplicate Participant Check b 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
 
 
Serum FSH test c 
X 
 
 
 
 
 
 
 
 
 
 
SCID-5-CT 
X 
 
 
 
 
 
 
 
 
 
 
MGH ATRQ 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Family Historyd 
X 
 
 
 
 
 
 
 
 
 
 
Participant training e 
 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Physical Examination f 
X 
X 
 
 
 
X 
(EOT 
only) 
 
 
 
 
X 
Body Weight/Height 
X 
 
 
 
 
X 
(weight 
only) 
 
 
 
 
X 
(weight 
only) 
Clinical Laboratory 
Assessments g 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
Drug & Alcohol Screen h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
ADT Continuation Period 
Visit Days 
D-28 to 
D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(+1d) 
and/or 
EOT a 
D18 
(±1d) 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
/ET  
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
Study Procedure 
 
Pregnancy Test i 
X 
X 
 
 
 
X 
 
 
X 
 
X 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs l 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
12-Lead ECG m 
X 
X 
 
 
 
X 
 
 
 
 
X 
HAM-D o, p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MADRS 
 
X 
 
X 
 
X 
 
 
X 
 
X 
HAM-A p 
 
X 
 
X 
 
X 
 
 
X 
 
X 
CGI-S 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
PHQ-9 
 
X 
X 
X 
 
X 
 
 
X 
 
X 
SAGE-217/Placebo 
Dispensation 
 
X 
 
X 
 
 
 
 
 
 
 

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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............16 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................21 
5. 
INTRODUCTION ......................................................................................................23 
5.1. 
Background of Major Depressive Disorder and Unmet Medical Need ......................23 
5.2. 
Potential Risks and Benefits .......................................................................................24 
5.3. 
Dose Justification ........................................................................................................24 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................26 
6.1. 
Objectives ...................................................................................................................26 
6.1.1. 
Primary Objective .......................................................................................................26 
6.1.2. 
Secondary Objectives .................................................................................................26 
 
26 
6.2. 
Endpoints ....................................................................................................................26 
6.2.1. 
Primary Endpoint ........................................................................................................26 
6.2.2. 
Secondary Endpoints ..................................................................................................26 
6.2.2.1. 
Key Secondary Endpoints ...........................................................................................26 
6.2.2.2. 
Other Secondary Endpoints ........................................................................................26 
 
27 
7. 
INVESTIGATIONAL PLAN .....................................................................................28 
7.1. 
Overall Study Design ..................................................................................................28 
7.2. 
Number of Participants ...............................................................................................29 
7.3. 
Treatment Assignment ................................................................................................29 
7.4. 
Dose Adjustment Criteria ...........................................................................................29 
7.5. 
Criteria for Study Termination ...................................................................................29 
8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS .....................................30 
8.1. 
Participant Inclusion Criteria ......................................................................................30 
8.2. 
Participant Exclusion Criteria .....................................................................................31 
8.3. 
Screen Failures ............................................................................................................33 

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8.4. 
Investigational Product Discontinuation and Early Termination from the 
Study ...........................................................................................................................33 
8.4.1. 
Investigational Product Discontinuation .....................................................................33 
8.4.2. 
Early Termination from the Study ..............................................................................34 
8.4.3. 
Loss to Follow-up .......................................................................................................34 
8.4.4. 
Replacement of Participants .......................................................................................34 
9. 
TREATMENT OF PARTICIPANTS .........................................................................35 
9.1. 
Description of Investigational Products ......................................................................35 
9.2. 
Prior Medications, Concomitant Medications, Restrictions, and 
Contraception Requirements ......................................................................................35 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................35 
9.2.2. 
Prohibited Medications ...............................................................................................35 
9.2.3. 
Other Restrictions .......................................................................................................36 
9.2.4. 
Acceptable Forms of Contraception ...........................................................................36 
9.3. 
Intervention after the End of the Study .......................................................................37 
9.4. 
Treatment Adherence ..................................................................................................37 
9.5. 
Randomization and Blinding ......................................................................................38 
9.5.1. 
Emergency Unblinding ...............................................................................................38 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............39 
10.1. 
Investigational Products ..............................................................................................39 
10.1.1. 
Blinded Investigational Products ................................................................................39 
10.1.2. 
Open-label Investigational Product ............................................................................39 
10.2. 
Blinded Investigational Product Packaging and Labeling ..........................................39 
10.3. 
Blinded Investigational Product Storage ....................................................................39 
10.4. 
Blinded Investigational Product Preparation ..............................................................39 
10.5. 
Blinded and Open-label Investigational Product Administration ...............................39 
10.6. 
Blinded Investigational Product Accountability, Handling, and Disposal .................40 
10.7. 
Blinded Investigational Product Complaints ..............................................................40 
11. 
EFFICACY AND CLINICAL PHARMACOLOGY ASSESSMENTS ....................42 
11.1. 
Efficacy Assessments .................................................................................................42 
11.1.1. 
Hamilton Rating Scale for Depression .......................................................................42 
11.1.2. 
Montgomery-Åsberg Depression Rating Scale ..........................................................42 
11.1.3. 
Hamilton Anxiety Rating Scale ..................................................................................42 

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11.1.4. 
Clinical Global Impressions .......................................................................................43 
 
43 
11.1.6. 
Patient Health Questionnaire ......................................................................................43 
 
44 
 
44 
 
44 
 
44 
 
44 
 
44 
 
44 
12. 
SAFETY ASSESSMENTS ........................................................................................46 
12.1. 
Safety Parameters .......................................................................................................46 
12.1.1. 
Demographic/Medical History ...................................................................................46 
12.1.2. 
Weight and Height ......................................................................................................46 
12.1.3. 
Physical Examination .................................................................................................46 
12.1.4. 
COVID-19 Questions .................................................................................................46 
12.1.5. 
Vital Signs ..................................................................................................................47 
12.1.6. 
Electrocardiogram (ECG) ...........................................................................................47 
12.1.7. 
Laboratory Assessments .............................................................................................47 
12.1.7.1. 
Drugs of Abuse and Alcohol ......................................................................................49 
12.1.7.2. 
Pregnancy Screen ........................................................................................................49 
 
49 
 
49 
 
50 
12.2. 
Adverse and Serious Adverse Events .........................................................................50 
12.2.1. 
Adverse Event Definition ...........................................................................................50 
12.2.2. 
Serious Adverse Event Definition ..............................................................................51 
12.2.3. 
Relationship to Investigational Product ......................................................................51 
12.2.4. 
Recording Adverse Events .........................................................................................52 
12.2.5. 
Reporting Serious Adverse Events .............................................................................52 
12.3. 
Pregnancy ...................................................................................................................53 
12.4. 
Overdose .....................................................................................................................53 
13. 
STATISTICS ..............................................................................................................55 

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13.1. 
Data Analysis Sets ......................................................................................................55 
13.2. 
Handling of Missing Data ...........................................................................................55 
13.3. 
General Considerations ...............................................................................................55 
13.4. 
Demographics and Baseline Characteristics ...............................................................55 
13.5. 
Efficacy Analysis ........................................................................................................56 
13.5.1. 
Multiplicity Adjustment for Key Secondary Endpoints .............................................57 
13.6. 
Safety Analyses ..........................................................................................................57 
13.6.1. 
Adverse Events ...........................................................................................................57 
 
58 
13.6.3. 
Physical Examinations ................................................................................................58 
 
58 
13.6.5. 
12-Lead Electrocardiogram ........................................................................................58 
13.6.6. 
Prior and Concomitant Medications ...........................................................................58 
 
59 
 
59 
13.6.9. 
Other Safety Analysis .................................................................................................59 
 
59 
13.8. 
Sample Size and Power ..............................................................................................59 
13.8.1. 
Interim and Data Monitoring Committee Analyses ....................................................59 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................60 
14.1. 
Study Monitoring ........................................................................................................60 
14.2. 
Audits and Inspections ................................................................................................60 
14.3. 
Institutional Review Board (IRB) or Ethics Committee (EC) ....................................61 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................62 
16. 
ETHICS ......................................................................................................................63 
16.1. 
Ethics Review .............................................................................................................63 
16.2. 
Ethical Conduct of the Study ......................................................................................63 
16.3. 
Written Informed Consent ..........................................................................................63 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................65 
17.1. 
Inspection of Records .................................................................................................65 
17.2. 
Retention of Records ..................................................................................................65 
18. 
PUBLICATION POLICY ..........................................................................................66 
19. 
LIST OF REFERENCES ............................................................................................67 

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LIST OF TABLES 
Table 1: 
Contact Information ......................................................................................................4 
Table 2: 
Schedule of Assessments ............................................................................................12 
Table 3: 
Clinical Laboratory Tests ...........................................................................................48 
 
 

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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Abbreviation 
Definition 
ADT 
Antidepressant therapy 
AE 
adverse event 
ALT 
alanine aminotransferase 
ALP 
alkaline phosphatase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BP 
blood pressure 
CFR 
Code of Federal Regulation 
CRO 
contract research organization 
CSR 
clinical study report 
IEC 
independent ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IND 
investigational new drug  
IP 
investigational product 
MedDRA 
Medical Dictionary for Regulatory Activities 
PD 
pharmacodynamic 
PI 
prescribing information 
PK 
pharmacokinetic 
PV 
pharmacovigilance 
QA 
quality assurance 
QC 
quality control 
QTcF 
QT corrected according to Fridericia’s formula 
SAE 
serious adverse event 
SOP 
Standard Operating Procedure 

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Abbreviation 
Definition 
SNRI 
serotonin-norepinephrine reuptake inhibitor 
SSRI 
selective serotonin reuptake inhibitor 
TEAE 
treatment-emergent adverse event 
WHO 
World Health Organization 

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5. 
INTRODUCTION 
5.1. 
Background of Major Depressive Disorder and Unmet Medical Need 
The World Health Organization (WHO) has identified depression as the leading cause of 
disability worldwide, and as a major contributor to the overall global burden of disease 
(http://www.who.int/mediacentre/factsheets/fs369/en/). Globally, depression has been estimated 
to affect over 300 million people. 
In the United States, the economic burden of depression, including workplace costs, direct costs, 
and suicide-related costs, was estimated to be $210.5 billion in 2010 (Greenberg 2015). As per 
WHO statistics, over 800,000 people die due to suicide every year, and suicide is the second 
leading cause of death in 15- to 29-year-olds. The rate of US adults making a suicide attempt has 
increased (0.62% from 2004 to 2005 to 0.79% from 2012 to 2013), with a shift to more attempts 
among younger adults (42% to 50%, respectively) and among those with a depressive disorder 
(26% to 54%, respectively; Olfson 2017). 
The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5, American 
Psychiatric Association 2013) provides diagnostic criteria for major depressive disorder (MDD). 
These include at least 5 of 9 depressive symptoms (depressed mood and/or loss of interest or 
pleasure, and other changes affecting appetite or weight, sleep, psychomotor activity, energy 
level, feelings of guilt, concentration ability, and suicidality) during the same 2-week period that 
represents a change from previous functioning (DSM-5). 
Antidepressants are a mainstay of pharmacological treatment for depressive disorders. Selective 
serotonin uptake inhibitors (SNRI), serotonin norepinephrine reuptake inhibitors (SSRI), 
tricyclic antidepressants, monoamine oxidase inhibitors (MAOI), and other compounds that 
affect monoaminergic neurotransmission, such as mirtrazapine and bupropion, represent the 
major classes of antidepressants. While antidepressants are widely used, large scale studies have 
demonstrated their limited efficacy, including low remission rates and untreated symptoms 
(Trivedi 2006; Conradi 2011; Romera 2013). Furthermore, these agents can take 4 to 8 weeks to 
demonstrate full clinical efficacy (Rush 2006; Trivedi 2006), and in the case of the most 
commonly prescribed classes—SSRIs and SNRIs—common side effects including weight gain, 
GI symptoms, and sexual dysfunction can prevent titration into an adequate therapeutic range 
(Sadock and Sadock 2007). 
In the largest study to assess the effectiveness of depression treatments in patients with MDD, 
time to patient remission after treatment was 5.4 to 7.4 weeks; approximately one-half of the 
patients who ultimately remitted did so after 6 weeks, and 40% of those who achieved remission 
required 8 or more weeks to do so (Rush 2006; Trivedi 2006). Even following remission, many 
patients report the presence of residual symptoms, often related to decreased positive affect, such 
as loss of interest in activities once considered enjoyable, fatigue, loss of energy, as well as sleep 
and appetite/weight disturbances (Nierenberg 2009; Nierenberg 2015). Thus, patients may 
remain symptomatic for up to 2 months while waiting for current standard-of-care 
pharmacotherapy to take full effect. They may also have to contend with undesirable side effects 
and residual symptoms. These aspects underscore the need for newer, rapid-acting therapies. 
SAGE-217 is a synthetic positive allosteric modulator of GABAA receptors, the major class of 
inhibitory neurotransmitter receptors in the brain. In pharmacokinetic (PK) studies in mice and 

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rats, SAGE-217 demonstrated rapid penetration and equilibrium across the blood brain barrier 
and is generally expected to have good extravascular exposure. In exploratory in vitro receptor 
and ion channel assays and in vivo safety pharmacology studies, SAGE-217 was highly selective 
for GABAA receptors, and, consistent with the actions of other GABAA receptor potentiators 
(Rudolph 2011), exhibits potent anticonvulsant, anxiolytic, and sedative activity when 
administered in vivo. 
SAGE-217 has been generally well tolerated in clinical studies to date. The most common 
treatment-emergent adverse events (TEAEs) associated with SAGE-217 (overall) were sedation, 
somnolence, and dizziness; most adverse events (AEs) were reported as mild or moderate in 
intensity. Refer to the SAGE-217 Investigator’s Brochure for a detailed description of the 
chemistry, pharmacology, efficacy, and safety of SAGE-217. 
This study was designed to target the unmet need of symptom improvement during the latency to 
SSRI and SNRI efficacy in the acute phase of a major depressive episode. This study will assess 
the safety and efficacy of SAGE-217 50 mg plus an antidepressant, examining if SAGE-217 plus 
an antidepressant produces more rapid or more profound reduction in depressive symptoms than 
an antidepressant alone. 
5.2. 
Potential Risks and Benefits 
The apparent risks of SAGE-217 are based on clinical data reports of AEs in completed and 
ongoing studies and the known pharmacology of the drug. Sedation, somnolence, and dizziness 
were identified as adverse drug reactions. Most AEs were reported as mild or moderate in 
intensity and reversible. 
SAGE-217 may present a treatment option for MDD that has more rapid onset of action (days 
instead of weeks/months), when compared to available pharmacotherapies. 
Based on nonclinical findings, embryo-fetal toxicity and withdrawal effects are considered 
important potential risk for SAGE-217. Risk mitigation measures in this study include 
monitoring for adverse effects, monitoring for potential withdrawal effects, requiring highly 
effective contraceptive measures for study participants, and inclusion of dose adjustment criteria 
and guidance for blinded IP discontinuation (Section 8.4). Finally, due to the 
sedation/somnolence observed, SAGE-217 is administered in the evening in this study. 
Given the outcome of the completed studies of SAGE-217 in participants with MDD and PDD, 
the current significant unmet need for well-tolerated and rapid-acting depression treatments, and 
a favorable benefit-risk profile, further investigation of SAGE-217 as a novel rapid response 
treatment in adults with MDD is justified. 
5.3. 
Dose Justification 
Results from a large, multicenter study of SAGE-217 20 and 30 mg in MDD (217-MDD-301) 
support the need for higher steady-state concentrations of SAGE-217 to allow participants to 
experience maximum antidepressant and anti-anxiety benefits. SAGE-217 will be administered 
as a 14-day regimen of an evening dose of 50 mg with reduction to 40 mg as needed based on 
tolerability. The 50-mg dose of SAGE-217 is expected to exhibit a favorable benefit-risk profile 
in the context of results from previous SAGE-217 studies utilizing a 30-mg dose, now identified 
as a minimally effective dose. SAGE-217 is expected to maintain an acceptable tolerability 

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profile, based on a current safety database of over 2000 participants exposed across different 
doses/concentrations. 
Sertraline is a commercially available SSRI indicated for the treatment of MDD and other 
psychiatric disorders. Dosage and administration of sertraline as described in the approved US 
Prescribing Information (PI) recommends a starting dose of 50 mg per day in patients with 
MDD, with an incremental weekly increase in dose of 25-50 mg per day, if there is an 
inadequate response to the starting dose, to a maximum dose of 200 mg per day. . In this study, a 
starting dose of 50 mg per day is recommended for 7 days, with a subsequent increase to 100 mg 
per day. 
Citalopram and escitalopram are commercially available SSRIs that are both indicated for acute 
and maintenance treatment of MDD. Escitalopram is also indicated for treatment of generalized 
anxiety disorder. The starting dosage for MDD in the US PI for citalopram is 20 mg/day and for 
escitalopram is 10 mg/day, with maxima of 40 mg/day and 20 mg/day, respectively. In this 
study, a starting dose of 20 mg/day is recommended for citalopram and of 10 mg/day is 
recommended for escitalopram for the first 14 days; subsequent dose increases may be 
considered, except for participants >60 years old taking citalopram. 
Duloxetine is a commercially available SNRI indicated for the treatment of MDD, generalized 
anxiety disorder, and pain disorders. The starting dosage for MDD in the US PI is 40 to 
60 mg/day. The maximum dosage is 120 mg/day, although there is no evidence that dosages 
greater than 60 mg/day confer any additional benefits. In this study, a starting dose of 60 mg/day 
is recommended (divided as 30 mg twice daily for the first 7 days).  
Desvenlafaxine is a commercially available SNRI indicated for the treatment of MDD. The 
recommended dosage in the US PI is 50 mg/day. In this study, a dose of 50 mg/day is 
recommended. There has been no evidence that doses greater than 50 mg/day confer any 
additional benefit. 

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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Objectives 
6.1.1. 
Primary Objective 
To evaluate the efficacy of SAGE-217 plus an antidepressant in the treatment of MDD compared 
to placebo plus an antidepressant 
6.1.2. 
Secondary Objectives 
• To assess patient-reported outcome (PRO) measures as they relate to depressive 
symptoms 
• To evaluate the safety and tolerability of SAGE-217 plus an antidepressant 
 
 
 
 
 
 
6.2. 
Endpoints 
6.2.1. 
Primary Endpoint 
• Change from baseline in 17-item Hamilton Rating Scale for Depression (HAM-D) 
total score at Day 15 
6.2.2. 
Secondary Endpoints 
6.2.2.1. 
Key Secondary Endpoints 
• Change from baseline in CGI-S at Day 15 
• Change from baseline in HAM-D total score at Day 3, Day 8, and Day 42 
6.2.2.2. 
Other Secondary Endpoints 
• HAM-D response at Day 15 and Day 42 
• HAM-D remission at Day 15 and Day 42 
• CGI-I response, defined as “much improved” or “very much improved”, at Day 15 
• Change from baseline in MADRS total score at Day 15 
• Change from baseline in HAM-A total score at Day 15 
• Time to first HAM-D response 
• Change from baseline to Day 15 in depressive symptoms, as assessed by the PHQ-9 
• Incidence and severity of treatment-emergent AEs 

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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a randomized, double-blind, parallel-group, placebo-controlled study in adults with 
MDD. The diagnosis of MDD must be made according to Structured Clinical Interview for 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Clinical Trial 
Version (SCID 5-CT) performed by a qualified healthcare professional.  
The study will consist of a Screening Period of up to 28 days, a 14-day double-blind Treatment 
Period, and a 28-day ADT Continuation Period. The Screening Period begins with the signing of 
the informed consent form (ICF) at the Screening Visit. Preliminary screening procedures to 
determine eligibility include completion of the MGH-ATRQ and HAM-D. 
Participants will be randomized to receive blinded SAGE-217 or placebo for administration each 
evening from Day 1 through 14. In addition, all participants will receive 1 of 2 classes of ADTs: 
a selective serotonin reuptake inhibitor (SSRI; sertraline, escitalopram, citalopram) or a 
serotonin-norepinephrine reuptake inhibitor (SNRI; duloxetine, desvenlafaxine) in an open-label 
manner from Day 1 through the end of the study. The investigator will assign 1 of the 5 ADTs 
based on clinical standard of care; the participant must not have been previously treated with the 
assigned ADT within the current depressive episode (and must not have been treated with 
citalopram if escitalopram is assigned, and vice versa) and must not haven taken any ADT within 
30 days prior to Day 1 (or taken fluoxetine within 60 days prior to Day 1). Randomization will 
be stratified by antidepressant class (SSRI or SNRI). 
The open-label ADT will be administered as per labeled prescribing information. 
After the Double-blind Treatment Period, the ADT will be continued each evening for the 
remainder of the study (ADT Continuation Period). During this period (Week 3 to 6), ADT 
dosing may be modified as appropriate per the labeled prescribing information and based on 
individual response,. 
Initiation of other antidepressants or any other medications that may potentially have an impact 
on efficacy or safety endpoints will not be allowed between screening and completion of 
assessments at Day 42/end-of-study visit. 
Participants will self-administer blinded investigational product (IP) once daily at approximately 
8 PM with fat-containing food (eg, within 1 hour of an evening meal which contains fat, or with 
a fat-containing snack), on an outpatient basis, for 14 days. The ADT and SAGE-217 or placebo 
will be administered at the same time during the Treatment Period; participants assigned 
duloxetine will also administer ADT in the morning (for twice-daily dosing) as part of a divided 
dose for the first 7 days. Participants will return to the study center as outlined in the Schedule of 
Assessments. 
During the Treatment Period, participants will be able to receive SAGE-217/placebo as long as 
there are no dose-limiting safety/tolerability concerns. Participants who cannot tolerate 
SAGE-217 or placebo 50 mg will receive 40 mg for the remainder of the Treatment Period. 
Participants who cannot tolerate the SAGE-217/placebo 40-mg dose may be discontinued from 
SAGE-217 or placebo at the discretion of the investigator. If blinded IP is discontinued, the ADT 
may be continued at the discretion of the investigator. 

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Upon completion of the current study, eligible participants will have the opportunity to enter a 
long-term open-label study of SAGE-217. Participants that do not enter the open-label study or 
that terminate the current study early may, per the investigator, receive a supply of the ADT with 
instructions on how to taper the drug, if needed, or, if they wish to continue the ADT, a bridge 
supply to permit them to obtain a prescription from another provider. 
7.2. 
Number of Participants 
It is estimated that approximately 424 participants will be randomized and treated to obtain 
382 evaluable participants at Day 15 (assuming 10% dropout rate). Additional participants may 
be randomized if the dropout rate is greater than 10%. 
7.3. 
Treatment Assignment 
Participants will be assigned to blinded IP (SAGE-217 or placebo) in accordance with the 
randomization schedule on Day 1. The investigator will assign 1 of the 5 ADTs based on clinical 
standard of care. The assigned ADT for a participant cannot have been taken previously by the 
participant during the current depressive episode. Further, citalopram cannot be assigned if 
escitalopram has been taken during the current depressive episode, and vice versa.  
Randomization will be stratified by antidepressant class (SSRI or SNRI).Additional details on 
randomization and blinding are provided in Section 9.5. 
Sage will monitor the ratio of SSRIs:SNRIs on an ongoing basis and may restrict assignment of 
any ADT(s) to reflect the ratio expected with standard of care (approximately 3:1; Luo 2020). 
7.4. 
Dose Adjustment Criteria 
During the treatment period, participants will be able to receive SAGE-217/placebo as long as 
there are no dose-limiting safety/tolerability concerns. Participants who cannot tolerate 50 mg (as 
determined by the investigator) will receive 40 mg for the remainder of the treatment period. 
At the discretion of the investigator, participants who cannot tolerate the 40-mg dose at any time 
may be discontinued from dosing upon completion of an end of treatment (EOT) visit as soon as 
possible. These participants should be followed and complete assessments as per the Schedule of 
Assessments (Table 2). 
During Weeks 3 to 6, the ADT dosing may be modified, based on individual response, per 
investigator discretion and per the labeled prescribing information. 
7.5. 
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 AEs or other findings suggesting unacceptable risk to 
participants, 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 IRB, where required, and initiate withdrawal procedures for participating participants. 

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8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
8.1. 
Participant Inclusion Criteria 
1. Participant has signed an ICF prior to any study-specific procedures being performed. 
2. Participant is a male or female between 18 and 64 years of age, inclusive. 
3. Participant 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. Participant agrees to adhere to the study requirements. 
5. Participant has a diagnosis of MDD as diagnosed by SCID-5-CT, with symptoms that 
have been present for at least a 4-week period. 
6. Participant has a HAM-D-17 total score of ≥24 at Screening and Day 1 (prior to dosing). 
7. Participant is willing to delay start of any antidepressant (except sertraline as per 
protocol), anxiolytic, anti-insomnia, psychostimulant, prescription opioid regimens, or 
new psychotherapy (including Cognitive Behavioral Therapy for Insomnia [CBT-I]) until 
after study completion. Participants receiving psychotherapy must have been receiving 
therapy on a regular schedule for at least 60 days prior to Day 1 and intend to maintain 
that schedule for the duration of the study. 
8. Female participant agrees to use at least one method of highly effective contraception as 
listed in Section 9.2.4 during participation in the study and for 30 days following the last 
dose of IP, unless she is postmenopausal (at least 12 months of spontaneous amenorrhea 
without an alternative medical cause, with confirmatory follicle stimulating hormone 
>40 mIU/mL), and/or surgically sterile (bilateral oophorectomy, hysterectomy, and/or 
bilateral salpingectomy), or does not engage in sexual relations which carry a risk of 
pregnancy (does not include abstinence). 
9. Female participant who is breastfeeding at Screening or on Day 1 (prior to administration 
of IP) must be willing to temporarily cease giving breast milk to her child(ren) from just 
prior to receiving IP on Day 1 until 7 days after the last dose of SAGE-217/placebo. 
10. Male participant agrees to use an acceptable method of effective contraception for the 
duration of the study and for 5 days after receiving IP, unless the participant does not 
engage in sexual relation(s) which carry a risk of pregnancy. Acceptable methods of 
effective contraception are listed in Section 9.2.4. 
11. Male participant is willing to abstain from sperm donation for the treatment period and 
for 5 days after receiving the last dose of the IP. 
12. Participant agrees to refrain from drugs of abuse and alcohol for the duration of the study. 
13. Participant is willing, able, and eligible to take at least 1 of the 5 ADTs specified in the 
protocol (an eligible ADT is an ADT that has not been taken during the current 
depressive episode and for which the participant has no contraindications; further, a 
participant is not eligible for citalopram if escitalopram has been taken during the current 
depressive episode, and vice versa). 

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8.2. 
Participant Exclusion Criteria 
Participants who meet any of the following criteria are disqualified from participation in this 
study: 
1. Participant is currently at significant risk of suicide, as judged by the investigator, or has 
attempted suicide associated with the current episode of MDD. 
2. Participant had onset of the current depressive episode during pregnancy or 4 weeks 
postpartum, or the participant has presented for screening during the 6-month postpartum 
period. 
3. Participant 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 participant's ability to complete or participate in this clinical study; a 
BMI ≤18 or ≥45 kg/m2 is exclusionary; a BMI of 40 to 44.9 kg/m2, inclusive, at 
Screening is subject to a broader evaluation of medical comorbidities as described above. 
4. Participant has treatment-resistant depression, defined as persistent depressive symptoms 
despite treatment with adequate doses of antidepressants within the current major 
depressive episode (excluding antipsychotics) from 2 different classes for at least 4 weeks 
of treatment. Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire (MGH ATRQ) will be used for this purpose. 
5. Participant has had vagus nerve stimulation, electroconvulsive therapy, or has taken 
ketamine within the current major depressive episode. 
6. Participant is receiving Cognitive Behavioral Therapy for Insomnia (CBT-I) within 
28 days prior to Day 1. 
7. Participant has a known allergy to SAGE-217, allopregnanolone, sertraline, or related 
compounds. 
8. Participant has taken antidepressants within 30 days prior to Day 1, and/or has taken 
fluoxetine within 60 days prior to Day 1. 
9. Female participant has a positive pregnancy test or confirmed pregnancy. 
10. Participant has a clinically significant abnormal 12-lead ECG at the screening or baseline 
visits. NOTE: mean QT interval calculated using the Fridericia method (QTcF) of 
>450 msec in males or >470 msec in females will be the basis for exclusion from the 
study. 
11. Participant has active psychosis per investigator assessment. 
12. Participant has a medical history of seizures. 
13. Participant has a medical history of bipolar disorder, schizophrenia, and/or 
schizoaffective disorder. 

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14. Participant has a history of severe substance use disorder (including benzodiazepines) 
diagnosed using DSM-5 criteria in the 12 months prior to Screening or participant has a 
history of mild or moderate substance use disorder not in sustained remission for at least 
6 months prior to Screening. 
15. Participant has had exposure to another investigational medication or device within 
30 days prior to Screening. 
16. Participant has previously received brexanolone or participated in a SAGE-217 or SAGE-
547 (brexanolone) clinical trial. 
17. Participant has used any known strong inhibitors of cytochrome P450 (CYP)3A4 within 
28 days or five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, 
or Seville oranges, or products containing these within 14 days prior to Day 1. 
18. Participant has used any strong CYP3A inducer, such as rifampin, carbamazepine, 
enzalutamide, mitotane, phenytoin, or St John’s Wort, within 28 days prior to Day 1. 
19. Participant has a positive drug and/or alcohol screen at screening or on Day 1 prior to 
dosing. 
20. Participant plans to undergo elective surgery before completion of the Day 42 visit. 
21. Participant is taking benzodiazepines, barbiturates, or GABAA modulators (eg, 
eszopiclone, zopiclone, zaleplon, and zolpidem) within 28 days prior to Day 1, or has 
been using these agents daily or near-daily (≥4 times per week) for more than 1 year. 
Participant is taking any benzodiazepine or GABA modulator with a half-life of 
≥48 hours (eg, diazepam) from 60 days prior to Day 1. 
22. Participant is taking non-GABA anti-insomnia medications (eg, prescribed therapeutics 
specifically for insomnia and/or over the counter sleep aids), or first generation or second 
generation (typical/atypical) antipsychotics within 14 days prior to Day 1. Note that 
nonsedating antihistamines are permitted. 
23. Participant has been diagnosed with and/or treated for any type of cancer (excluding 
basal cell carcinoma and melanoma in situ) within the past year prior to Screening. 
24. Participant has a history of sleep apnea. 
25. Participant has had gastric bypass surgery, has a gastric sleeve or lap band, or has had any 
related procedures that interfere with gastrointestinal transit. 
26. Participant is taking psychostimulants (eg, methylphenidate, amphetamine) or opioids, 
regularly or as needed, within 28 days prior to Day 1. 
27. Participant is a dependent of the sponsor, investigator, investigator’s deputy, or study site 
staff. 
28. Participant expects to perform night shift work during the 14-day treatment period. 
29. Participant has detectable hepatitis B surface antigen, anti-hepatitis C virus (HCV) and 
positive HCV viral load, or human immunodeficiency virus (HIV) antibody at Screening. 

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8.3. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized to study intervention. A minimal set of screen failure information 
will be collected, including demography, screen failure details, eligibility criteria, and any 
AE/serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once. 
8.4. 
Investigational Product Discontinuation and Early Termination from 
the Study 
A participant may withdraw from the study at any time at his/her own request for any reason. 
The investigator may discontinue a participant from the study and/or from IP for safety, 
behavioral, compliance, or administrative reasons. 
Based on known withdrawal symptoms with other GABAergic drugs and nonclinical findings in 
a 9-month study of SAGE-217 in dogs (Investigator’s Brochure), there is a potential for 
withdrawal-related events, including seizure. The following guidelines for blinded IP 
discontinuation or dose reduction are presented to support participant safety: 
1. Any participant reporting a confirmed or suspected seizure at any time will be 
discontinued from blinded IP but will continue to be followed in the study. 
2. The investigator should monitor the course of CNS-based signs and symptoms suggestive 
of a seizure which are not accounted for by comorbid psychiatric or medical conditions. 
Examples of reported serious or severe events which may reflect an oncoming and/or 
increased risk for seizure may include temporary confusion, tremors, involuntary muscle 
fasciculations or jerking movements of arms or legs, or paresthesia. Should such 
symptoms occur, the investigator should consider decreasing the dose of SAGE-217 or 
placebo to 40 mg, stopping treatment to assess the effect on the symptom(s) 
(eg, resolution, improvement), or discontinuing the participant from treatment. A 
participant who discontinues treatment should remain in the study and continue protocol-
required assessments until the end of the study. 
The investigator must notify the sponsor and/or the medical monitor when a participant stops 
participation in the study for any reason. 
8.4.1. 
Investigational Product Discontinuation 
The primary reason for IP discontinuation must be documented in the participant’s study record 
and recorded in the participant’s electronic case report form (eCRF). 
Participants who discontinue treatment early should return to the site for an end of treatment 
(EOT) visit as soon as possible, preferably the day after treatment is discontinued. Follow-up 
visits should take place as scheduled relative to the last dose of treatment (eg, if a participant’s 
last dose is on Day 13, their first follow-up visit, Visit 7, should occur 4 days later), and will 
continue safety and efficacy assessments as scheduled for 6 weeks following the final dose. 

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Participants that discontinue blinded IP early may, per the investigator, receive a supply of the 
ADT with instructions on how to taper the drug, if needed, or, if they wish to continue the ADT, 
a bridge supply to permit them to obtain a prescription from another provider. 
8.4.2. 
Early Termination from the Study 
If a participant decides to terminate the study, the participant should return for an early 
termination (ET) visit, if possible. The primary reason for early termination from the study must 
be documented in the participant’s study record and recorded in the participant’s electronic case 
report form (eCRF). If a participant discontinues IP and terminates the study on the same day 
during a clinic visit, the EOT and ET visits can be on the same day; in this case, all EOT visit 
assessments should be conducted in addition to an abbreviated physical examination 
If the participant withdraws consent for disclosure of future information, the sponsor will retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
Participants who terminate from the study early may, per the investigator, receive a supply of the 
ADT with instructions on how to taper the drug, if needed, or, if they wish to continue the ADT, 
a bridge supply to permit them to obtain a prescription from another provider. 
8.4.3. 
Loss to Follow-up 
A participant will be deemed lost to follow-up after 3 attempts at contacting the participant have 
been unsuccessful. 
8.4.4. 
Replacement of Participants 
Participants will not be replaced. 

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9. 
TREATMENT OF PARTICIPANTS 
9.1. 
Description of Investigational Products 
SAGE-217 will be available as hard gelatin capsules for oral administration; 2 capsules 
(one 30 mg and one 20 mg) will be provided to total a 50-mg dose, with option to reduce to 
40 mg based on tolerability, as per criteria described in Section 7.4. If the dose is reduced to 
40 mg, it will be administered as 2 20-mg capsules. 
Blinded placebo will be provided as hard gelatin capsules matched in appearance to SAGE-217, 
for oral administration. 
All participants will self-administer blinded and open-label IP orally at approximately 8 PM with 
fat-containing food for 14 days. Participants assigned duloxetine will also administer duloxetine 
in the morning (for twice daily dosing) as part of a divided dose for the first 7 days (see below). 
It is recommended that sertraline be administered as per labeled prescribing information, starting 
with 50 mg each evening during Week 1. and It is recommended that the dose be increased to 
100 mg each evening during Week 2.  
It is recommended that citalopram be administered per labeled prescribing information, starting 
with 20 mg/day.  
It is recommended that escitalopram be administered per labeled prescribing information, 
starting with 10 mg/day. 
It is recommended that duloxetine be administered per labeled prescribing information, starting 
with 60 mg/day (divided as 30 mg twice daily for the first 7 days).  
It is recommended that desvenlafaxine be administered per labeled prescribing information, 
starting with 50 mg/day. 
9.2. 
Prior Medications, Concomitant Medications, Restrictions, and 
Contraception Requirements 
9.2.1. 
Prior and Concomitant Medications and/or Supplements 
The start and end dates, route, dose/units, frequency, and indication for all medications and/or 
supplements taken within 30 days prior to Screening and throughout the duration of the study 
will be recorded. In addition, psychotropic medications taken within 6 months prior to Screening 
will be recorded. 
Any medication and/or supplement determined necessary for the welfare of the participant may 
be given at the discretion of the investigator at any time during the study. 
9.2.2. 
Prohibited Medications 
The following specific classes of medications are prohibited: 
• Initiation of new psychotropic medications through the Day 42 visit 
• Initiation of new antidepressant therapy from 30 days (60 days for fluoxetine) prior to 
Day 1 through the Day 42 visit 

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• Use of any benzodiazepines, barbiturates, GABAA modulators, GABA-containing 
agents from Day -28 through the Day 42 visit (from Day -60 for benzodiazepines or 
GABA modulators with a half-life ≥48 hours) 
• Chronic or as-needed psychostimulants (eg, methylphenidate, amphetamine) or 
opioids from Day -28 through the Day 42 visit 
• First generation (typical) antipsychotics (eg, haloperidol, perphenazine) and second 
generation (atypical) antipsychotics (eg, aripiprazole, quetiapine) from Day -14 
through the Day 42 visit 
• Use of any non-GABA anti-insomnia medications (eg, prescribed therapeutics 
specifically for insomnia and/or over the counter sleep aids) from Day -14 to Day 1. 
Note that nonsedating antihistamines are permitted. 
• Exposure to another investigational medication or device from 30 days prior to 
Screening through the Day 42 visit 
• Any known strong inhibitors of CYP3A4 from Day -28 or 5 half-lives prior to Day 1 
(whichever is longer) through the Treatment Period 
• Use of any strong CYP3A inducer, such as rifampin, carbamazepine, enzalutamide, 
mitotane, phenytoin, or St John’s Wort from Day -28 through the Treatment Period 
• Any contraindications to the assigned SSRI/SNRI per labeled prescribing information 
9.2.3. 
Other Restrictions 
The consumption of grapefruit juice, grapefruit, or Seville oranges, or products containing these 
is prohibited within 14 days prior to Day 1 and throughout the treatment period. 
The concomitant use of sertraline with a CYP2D6 substrate may increase the exposure of the 
CYP2D6 substrate; therefore, decrease the dosage of a CYP2D6 substrate if needed. 
Consumption of alcohol or use of drugs of abuse is discouraged throughout the duration of the 
study. 
Female participants who are lactating or actively breastfeeding must stop giving breast milk to 
the baby(ies) starting on Day 1 until 7 days after the last dose of SAGE-217/placebo. 
Elective surgeries or procedures are prohibited through the Day 42 visit. 
Participants must not participate in night shift work during the Treatment Period. 
Participants who are feeling sedated, somnolent, and/or dizzy are to refrain from driving or 
engaging in any activity requiring alertness. 
Participants receiving psychotherapy on a regular schedule for at least 60 days prior to Day 1 are 
permitted if the participant intends to continue that schedule through the Follow-up Period 
(Day 42). Initiation of new psychotherapy is prohibited until after study completion. 
9.2.4. 
Acceptable Forms of Contraception 
Acceptable forms of highly effective contraception for participants of childbearing potential or 
for partners of male participants who are of childbearing potential include: 

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• 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 ligation or bilateral tubal occlusion (performed at least 3 months prior 
to screening) 
• Vasectomized partner (performed at least 3 months prior to screening) 
Acceptable forms of contraception for male participants include: 
• History of vasectomy (performed at least 3 months prior to screening) 
• Condom with spermicide used together with highly effective female contraceptive 
methods if the female partner(s) is of childbearing potential (see above for list of 
acceptable female contraceptive methods) 
9.3. 
Intervention after the End of the Study 
Upon completion of the current study, eligible participants will have the opportunity to enter an 
open-label, long-term study of SAGE-217 in which additional treatment with SAGE-217 will be 
offered. Participants that do not enter the open-label study or that terminate the current study 
early may continue to receive ADT as prescribed by the investigator either to taper the drug 
appropriately or—if the participant wishes to continue ADT—to bridge the participant until he or 
she receives a new prescription. 
9.4. 
Treatment Adherence 
Investigational products will be self-administered by participants (see Section 10.5). 
Administration of blinded and open-label IP will be monitored by a medication adherence 
monitoring platform used on smartphones to confirm medication ingestion. Participants will 
receive a reminder within a predefined time window to take IP while using the application and 
will follow a series of prescribed steps to confirm their ingestion of the medication. The 
application will record the date and time of IP administration by dose level, as well as missed 
doses. 
In addition, participants will be instructed to bring their SAGE-217 or placebo dosing kit and 
ADT to the site as outlined in Table 2, at which time the investigator or designee will be 
responsible for ensuring the kit contains sufficient doses for the duration of the treatment period. 
All participants should be reinstructed about the dosing requirements during study contacts. The 
authorized study personnel conducting the reeducation must document the process in the 
participant source records. 
The investigator(s) will record any reasons for nonadherence in the source documents. 

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9.5. 
Randomization and Blinding 
Participants will be randomized in a 1:1 ratio to receive SAGE-217 or matched placebo. 
Participants, site staff, and the sponsor will be blinded to treatment allocation. All participants 
will also receive an open-label ADT. Randomization will be performed centrally via an 
interactive response technology (IRT) system. Randomization schedules will be generated by an 
independent statistician. The allocation to blinded treatment (SAGE-217or 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. The blinding of 
the study will be broken after the database has been locked. 
9.5.1. 
Emergency Unblinding 
During the study, the blind is to be broken only when the safety of a participant is at risk and the 
treatment plan is dependent on the study treatment received. Unless a participant is at immediate 
risk, the investigator should make diligent attempts to contact Sage prior to unblinding the study 
treatment administered to a participant. Requests from the investigator about the treatment 
administered to study participants should be discussed with the Sage medical monitor. If the 
unblinding occurs without Sage’s knowledge, the investigator must notify Sage within 24 hours 
of breaking the blind. All circumstances surrounding a premature unblinding must be clearly 
documented in the source records. 
In all cases where the IP allocation for a participant is unblinded, pertinent information 
(including the reason for unblinding) must be documented in the participant’s records and on the 
eCRF. 

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10. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
10.1. 
Investigational Products 
10.1.1. 
Blinded Investigational Products 
SAGE-217 is 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, colloidal silicon 
dioxide, and sodium stearyl fumarate as excipients. Capsules will be available in 20-mg and 
30-mg dose strengths. 
Blinded placebo will be provided as hard gelatin capsules matched in appearance to SAGE-217. 
10.1.2. 
Open-label Investigational Product 
Sertraline, escitalopram, citalopram, duloxetine, and desvenlafaxine, packaged and labeled by 
the commercial manufacturer, will be supplied by a third-party vendor. Open-label IP is to be 
stored and administered according to the package insert. Open-label IP during this study is for 
use only as directed in this protocol. 
10.2. 
Blinded Investigational Product Packaging and Labeling 
SAGE-217 and placebo will be provided to the clinic pharmacist and/or designated site staff 
responsible for dispensing the blinded IP in appropriately labeled, participant-specific kits 
containing sealed unit doses. Each unit dose for 40-mg and 50-mg dose levels consists of 
2 capsules. Additional information regarding the packaging and labeling is provided in the 
Pharmacy Manual. 
Labels with all required information and conforming to all applicable FDA Code of Federal 
Regulations and Good Manufacturing Practices/Good Clinical Practices guidelines will be 
prepared by the sponsor for SAGE-217 and placebo. 
10.3. 
Blinded Investigational Product Storage 
SAGE-217 and placebo is to be stored at room temperature (59 to 86°F; 15 to 30°C), safely and 
separately from other drugs. 
10.4. 
Blinded Investigational Product Preparation 
Not applicable. 
10.5. 
Blinded and Open-label Investigational Product Administration 
Blinded IP and open-label sertraline are to be administered orally at approximately 8 PM with 
fat-containing food (eg, within 1 hour of an evening meal which contains fat, or with a fat-
containing snack). Examples of fat-containing snacks include nuts, peanut butter, avocado, eggs, 
and cheese. Participants assigned duloxetine will also administer duloxetine in the morning (for 
twice-daily divided dosing) for the first 7 days (see Section 9.1). 

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If a participant misses a dose of blinded IP or open-label IP, the participant should skip that dose 
(ie, they should not take the dose in the morning) and take the next scheduled dose. 
10.6. 
Blinded Investigational Product Accountability, Handling, and 
Disposal 
Upon receipt of blinded IP dosing kits, the investigator(s), or the responsible pharmacist or 
designee, will inspect the kits and complete and follow the instructions regarding receipt and 
storage in the SAGE-217 Investigator’s Brochure and (where applicable) in the Pharmacy 
Manual. A copy of the shipping documentation will be kept in the study files. 
The designated site staff will dispense the participant-specific kits to participants at the planned 
dispensation visit intervals outlined in Table 2. Site staff will access the IRT at the Screening 
Visit to obtain a participant identification (ID) number for each participant that has signed an 
informed consent form. On Day 1, site staff will access the IRT and provide the necessary 
participant-identifying information, including the participant ID number assigned at Screening, 
to randomize the eligible participant into the study and obtain the medication ID number for the 
blinded IP to be dispensed to that participant. The medication ID number and the number of 
blinded capsules dispensed must be recorded. 
At the subsequent blinded IP-dispensing visit, the investigator or designee will access the IRT, 
providing the same participant ID number assigned at Screening, to obtain the medication ID 
number for the blinded IP to be dispensed at that visit. The medication ID number, the number of 
capsules dispensed, and the number of capsules returned by the participant at this visit must be 
recorded. 
If dispensing errors or discrepancies are discovered by site staff or sponsor’s designee, the 
sponsor must be notified immediately. 
The blinded IP provided is for use only as directed in this protocol. The investigator or designee 
must keep a record of all blinded IP received, used and returned/discarded. 
Sage Therapeutics will be permitted access to the study supplies at any time and with appropriate 
notice during or after completion of the study to perform drug accountability and reconciliation. 
The investigator, pharmacist, or qualified designee is responsible for drug accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final disposition records). 
At the end of the study, any unused blinded IP will be returned to Sage Therapeutics for 
destruction or destroyed locally per the site’s procedures; disposition of blinded IP will be 
documented. 
10.7. 
Blinded Investigational Product Complaints 
A product complaint is any written, electronic, or verbal expression of dissatisfaction regarding 
the identity, quality, reliability, safety, purity, potency, effectiveness or performance (applicable 
for approved marketed products) of a drug product after it is released for distribution. 
In the course of conduct of the study, study personnel may become aware of a product complaint 
associated with the use of a Sage product. Personnel shall notify Sage within 24 hours by 
forwarding the product complaint information via the contact information provided in Table 1. 

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Where possible, personnel should segregate and retain any product, materials, or packaging 
associated with the product complaint until further instruction is provided by Sage or its 
designated representative(s). 

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11. 
EFFICACY AND CLINICAL PHARMACOLOGY ASSESSMENTS 
11.1. 
Efficacy Assessments 
11.1.1. 
Hamilton Rating Scale for Depression 
The primary outcome measure is the change from baseline in 17-item HAM-D total score at the 
end of the Treatment Period (Day 15). Every effort should be made for the same rater to perform 
all HAM-D assessments for an individual participant. An assessment timeframe of past 7 days 
(1 week) will be used at Screening, and ‘Since Last Visit’ will be used for all other visits. 
The 17-item HAM-D will be used to rate the severity of depression in participants who are 
already diagnosed as depressed (Williams 2013 a; Williams 2013b). 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 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. 
11.1.2. 
Montgomery-Åsberg Depression Rating Scale 
The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive 
episodes in participants with mood disorders. It was designed as an adjunct to the HAM-D that is 
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 (Williams 2008). 
The MADRS total score will be calculated as the sum of the 10 individual item scores. 
11.1.3. 
Hamilton Anxiety Rating Scale 
The 14-item HAM-A will be used to rate the severity of symptoms of anxiety (Williams 2013c; 
Williams 2013d). Each of the 14 items is defined by a series of symptoms, and measures both 
psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical 
complaints related to anxiety). Scoring for HAM-A is calculated by assigning scores of 0 (not 
present) to 4 (very severe), with a total score range of 0 to 56, where <17 indicates mild severity, 
18 to 24, mild to moderate severity, and 25 to 30, moderate to severe severity. The HAM-A total 
score will be calculated as the sum of the 14 individual item scores. 

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12. 
SAFETY ASSESSMENTS 
12.1. 
Safety Parameters 
All assessments will be conducted according to the Schedule of Assessments (Table 2). 
12.1.1. 
Demographic/Medical History 
Demographic characteristics (age, race, gender, ethnicity, employment status, highest education 
level, marital/civil status) and a full medical history, including: family psychiatric history, 
generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, persistent 
depressive disorder, postpartum depression, substance use disorder, alcohol use disorder, MDD 
with seasonal pattern, MDD with psychotic features, premenstrual dysphoric disorder, MDD 
with atypical features, schizophrenia; or schizoaffective disorder will be documented. The 
diagnosis of MDD will be determined using the SCID-5-CT. If available, the disease code 
associated with the diagnosis of MDD based on the tenth revision of the International Statistical 
Classification of Diseases and Related Health Problems (ICD-10) should be recorded. 
The Massachusetts General Hospital Antidepressant Treatment Response Questionnaire 
(MGH ATRQ) will be used to determine whether the participant has treatment-resistant 
depression, defined as persistent depressive symptoms despite treatment during the current major 
depressive episode with adequate doses of antidepressants from 2 different classes for at least 4 
weeks of treatment. 
12.1.2. 
Weight and Height 
Height (Screening only) and weight will be measured and documented. 
12.1.3. 
Physical Examination 
Physical examinations assessing body systems (eg, head, eyes, ears, nose, and throat; heart; 
lungs; abdomen; and extremities), as well as cognitive and neurological examinations and mental 
status examinations will be conducted and documented. Thereafter, abbreviated physical 
examinations will include brief assessments of general appearance, cardiovascular, respiratory, 
gastrointestinal, and neurological systems, followed by a targeted physical examination as 
needed. Unscheduled, symptom-directed physical examinations may also be conducted at the 
investigator’s discretion. Whenever possible, the same individual is to perform all physical 
examinations for a given participant. Unscheduled brief, symptom-driven physical examinations 
may also be conducted per the investigator’s discretion. 
Any abnormality in physical examinations will be interpreted by the investigator as abnormal, 
not clinically significant (NCS); or abnormal, clinically significant (CS) in source documents. 
New or worsening abnormalities that are judged to be clinically significant will be recorded as 
AEs, assessed according to Section 12.2.1. 
12.1.4. 
COVID-19 Questions 
Information regarding diagnosis, isolation, and/or hospitalization due to COVID-19 will be 
documented as part of Medical History, AE collection, and prior/concomitant 
medication/procedure collection at Screening and throughout the study. 

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assessed according to Section 12.2.1. A clinically significant laboratory abnormality following 
participant randomization will be followed until the abnormality returns to an acceptable level or 
a satisfactory explanation has been obtained. 
The clinical laboratory tests to be performed are listed in Table 3. 
Table 3: 
Clinical Laboratory Tests 
Hematology  
Serum Chemistry 
Urinalysis 
Coagulation 
Red blood cell count 
Hemoglobin 
Hematocrit 
White blood cell count with 
differential 
Platelet count 
Red Blood Cell Indices 
(MCV, MCH, MCHC) 
Reflex to Red blood cell 
morphology if indices are 
abnormal 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
Total protein 
Creatinine 
Blood urea nitrogen 
Creatine kinase 
Gamma-glutamyl transferase 
Potassium 
Sodium 
Lactate dehydrogenase 
Glucose 
Chloride 
Bicarbonate 
Calcium 
Phosphorus 
Triglycerides 
Thyroid stimulating hormone 
(TSH) 
Reflex to free T3/T4 if 
TSH is abnormal  
pH 
Specific gravity 
Protein 
Glucose 
Red blood cell 
Nitrite 
Leukocyte 
esterase 
Ketones 
Bilirubin 
Urobilinogen 
Activated partial 
thromboplastin 
time 
Prothrombin time 
International 
normalized ratio 
Diagnostic  
 
 
 
Serum 
Urine 
Breathalyzer 
 
Hepatitis B 
Hepatitis C 
Reflex HCV RNA 
HIV-1 and -2 
Female participants that are 
not surgically sterile and do 
not meet the protocol-
Drug screen including: 
amphetamines, 
barbiturates, 
benzodiazepines, 
cannabinoids, cocaine, 
opiates, phencyclidine 
Female participants that are 
not surgically sterile and do 
Alcohol 
 

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12.2.2. 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Places the participant at immediate risk of death (a life-threatening event); however, 
this does not include an event that, had it occurred in a more severe form, might have 
caused death 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
An SAE may also be any other medically important event that, in the opinion of the investigator 
may jeopardize the participant or may require medical intervention to prevent 1 of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization). 
All SAEs that occur after any participant has signed the ICF and throughout the duration of the 
study, whether or not they are related to the study, must be recorded on the SAE report form 
provided by Sage Therapeutics. Any SAE that is ongoing when the participant completes their 
final study visit, will be followed by the investigator until the event has resolved, stabilized, 
returned to baseline status, or until the participant dies or is lost to follow up. 
A prescheduled or elective procedure or routinely scheduled treatment will not be considered an 
SAE, even if the participant is hospitalized. The site must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or on a waiting list to be scheduled) prior to obtaining the participant’s 
consent to participate in the study. 
• The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress, in the opinion of an 
investigator, between the participant’s consent to participate in the study and at the 
time of the procedure or treatment. 
12.2.3. 
Relationship to Investigational Product 
The investigator must make the determination of relationship to the IP for each AE (not related, 
related). The following definitions should be considered when evaluating the relationship of AEs 
and SAEs to the IP. 
Not Related 
An AE will be considered “not related” to the use of the IP if there is not a reasonable 
possibility that the event has been caused by the IP. Factors pointing towards this 
assessment include but are not limited to: the lack of temporal relationship between 
administration of the IP and the event, the presence of biologically implausible 
relationship between the product and the AE, or the presence of a more likely 
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Related 
An AE will be considered “related” to the use of the IP if there is a reasonable 
possibility that the event may have been caused by the product under investigation. 
Factors that point towards this assessment include but are not limited to: a positive 
rechallenge, a reasonable temporal sequence between administration of the drug and 
the event, a known response pattern of the suspected drug, improvement following 
discontinuation or dose reduction, a biologically plausible relationship between the 
drug and the AE, or a lack of alternative explanation for the AE 
12.2.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the participant and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. The AE term should be reported in standard medical terminology when 
possible. For each AE, the investigator will evaluate and report the onset (date and time), 
resolution (date and time), intensity, causality, action taken, outcome and seriousness (if 
applicable), and whether or not it caused the participant to discontinue the IP or withdraw early 
from the study. 
Intensity will be assessed according to the following scale: 
• Mild: symptom(s) barely noticeable to participant or does not make participant 
uncomfortable; does not influence performance or functioning; prescription drug not 
ordinarily needed for relief of symptom(s) 
• Moderate: symptom(s) of a sufficient severity to make participant uncomfortable; 
performance of daily activity is influenced; participant is able to continue in study; 
treatment for symptom(s) may be needed 
• Severe: symptom(s) cause severe discomfort; symptoms cause incapacitation or 
significant impact on participant’s daily life; severity may cause cessation of 
treatment with IP; treatment for symptom(s) may be given and/or participant 
hospitalized 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.2.2. An AE of severe intensity 
may not necessarily be considered serious. 
12.2.5. 
Reporting Serious Adverse Events 
In order to adhere to all applicable laws and regulations for reporting an SAE(s), the study site 
must notify Sage or designee within 24 hours of the study site staff becoming aware of the 
SAE(s). The investigator must complete, sign and date the SAE report form, verify the accuracy 
of the information recorded on the SAE report form with the corresponding source documents, 
and send a copy to Sage or designee. 
Additional follow-up information, if required or available, should all be sent to Sage or designee 
within 24 hours of receipt on a follow-up SAE report form and placed with the original SAE 
information and kept with the appropriate section of the eCRF and/or study file. 

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SAEs occurring after the designated follow up time for the study, should be reported to Sage or 
designee according to the timelines noted above only if the investigator considers the SAE 
related to IP. 
Sage, or designee, is responsible for notifying the relevant regulatory authorities of certain 
events. It is the principal investigator’s responsibility to notify the IRB/IEC of all SAEs that 
occur at his or her site. Investigators will also be notified of all suspected unexpected serious 
adverse reactions (SUSARs) that occur during the clinical study. IRBs/IECs will be notified of 
SAEs and/or SUSARs as required by local law. 
In addition, appropriate personnel in Sage Drug Safety and Pharmacovigilance or designee will 
unblind SUSARs for the purpose of regulatory reporting. Sage or designee will submit SUSARs 
(in blinded or unblinded fashion) to regulatory agencies according to local law. Sage, or 
designee, will submit SUSARs to investigators in a blinded fashion. 
12.3. 
Pregnancy 
If a participant becomes pregnant after the first administration of IP, pregnancy information must 
be collected and recorded on the Pregnancy form and submitted to the sponsor within 24 hours of 
learning of the pregnancy. Details will be collected for all pregnancies for which conception was 
likely to have occurred after the start of IP administration until 5 terminal half-lives following 
the last administration of IP or until the completion of the study whichever is longer. Any 
pregnancy occurring in that time frame will be followed until delivery or termination of the 
pregnancy. The investigator will also attempt to collect pregnancy information on any 
participant’s partner who becomes pregnant after the participant has received the first 
administration of IP. After obtaining the necessary signed informed consent from the pregnant 
partner directly, the investigator will follow the same pregnancy reporting procedures specified 
for pregnant participants. 
The participant or participant’s partner will be followed to determine the outcome of the 
pregnancy. The outcome of all pregnancies (eg, spontaneous abortion, elective abortion, normal 
birth) must be followed and documented even if the participant was discontinued from the study. 
The investigator will collect follow-up information on the participant or participant’s partner and 
the neonate, and the information will be forwarded to Sage or designee. Generally, follow-up 
will not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an IP may have 
interfered with the effectiveness of a contraceptive medication. Any complication during 
pregnancy (eg, anemia, infections, pre-eclampsia) should be reported as an AE/SAE. If the 
outcome of the pregnancy meets the criteria for immediate classification as an SAE (ie, 
spontaneous abortion, stillbirth, neonatal death,), the investigator should follow the procedures 
for reporting an SAE. 
12.4. 
Overdose 
Overdoses, regardless of presence of associated clinical manifestation(s) (eg, headache, 
abnormal laboratory value) will be considered an AE and recorded as such on the eCRF. Any 

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clinical manifestation(s) of overdose must also be recorded as an AE on the eCRF. In addition, 
all overdoses must be recorded on an Overdose form and sent to Sage or designee within 
24 hours of the site becoming aware of the overdose. 

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Hepatitis, HIV, drug and alcohol, and pregnancy screening results will be listed, but not 
summarized as they are considered part of the inclusion/exclusion criteria. 
Medical history will be listed by participant. 
13.5. 
Efficacy Analysis 
Efficacy data will be summarized using appropriate descriptive statistics and other data 
presentation methods where applicable; participant listings will be provided for all efficacy data. 
Participants will be analyzed according to randomized treatment. 
The estimand for the primary efficacy analysis is the mean change from baseline in HAM-D total 
score at Day 15. The estimand for the primary efficacy analysis is defined as follows: 
• The target population is adults with a diagnosis of MDD and within a current 
depressive episode of severity (HAM-D total score ≥24). 
• The variable of interest is the change from baseline in HAM-D total score at Day 15. 
• The population summary level deals with the difference between the treatments 
(SAGE-217 + an antidepressant and placebo + an antidepressant) in mean change 
from baseline in HAM-D total score at Day 15. 
The intercurrent events could be: 
• The premature discontinuation of treatment for any reason, thus not having a Day 15 
HAM-D total score available. This will be dealt with by a sensitivity analysis using 
multiple imputation techniques as described below. 
• Certain medications including, but not limited to new antidepressants (except as 
described in the protocol) or benzodiazepines are prohibited during the study; 
however, the treatment policy strategy dictates that if any of these prohibited 
medications are used, the results will not be manipulated but will rather be used ‘as 
is’ in analysis. Please note that the protocol does not specify any rescue process, 
hence there is no rescue medication. 
Using the FAS, this will be analyzed using a mixed-effects model for repeated measures 
(MMRM); the model will include treatment, baseline HAM-D total score, assessment time point, 
and time point-by-treatment as explanatory variables. All explanatory variables will be treated as 
fixed effects. All postbaseline time points will be included in the model. The main comparison 
will be between SAGE-217 + an antidepressant and placebo + an antidepressant at the Day 15 
time point. Model-based point estimates (ie, least squares means, 95% confidence intervals, and 
p values) will be reported where applicable. An unstructured covariance structure will be used to 
model the within-participant errors. The Toeplitz compound symmetry, Autoregressive (1) 
[AR(1)] covariance structure will be used in that sequence if there is a convergence issue with 
the unstructured covariance model. If convergence is still not achieved, no results will be 
reported. 
Similar to those methods described above for the primary endpoint, an MMRM will be used for 
the analysis of the change from baseline in other time points in HAM-D total score, MADRS 
total score, HAM-A total score, 
 PHQ-9 total score, and selected individual items 
and/or subscale scores in HAM-D. 

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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Before an investigational site can enter a participant into the study, a representative of Sage 
Therapeutics will visit the investigational study site per Sage SOPs to: 
• Determine the adequacy of the facilities 
• Discuss with the investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Sage Therapeutics or its representatives. 
This will be documented in a Clinical Trial Agreement between Sage Therapeutics and 
the investigator. 
During the study, a monitor from Sage Therapeutics or representative 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 case report forms, and that IP accountability checks are being 
performed 
• Perform source data verification. This includes a comparison of the data in the case report 
forms with the participant’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 
participant (eg, clinic charts). 
• Record and report any protocol deviations not previously sent to Sage Therapeutics. 
• Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to Sage Therapeutics and those SAEs that met criteria for 
reporting have been forwarded to the IRB or independent ethics committee. 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
14.2. 
Audits and Inspections 
Sage Therapeutics or authorized representatives of Sage Therapeutics, a regulatory authority, or 
an Independent Ethics Committee or an Institutional Review Board may visit the site to perform 
an audit(s) or inspection(s), including source data verification. The purpose of a Sage 
Therapeutics audit or a regulatory authority 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/ICH GCP guidelines, and any applicable regulatory requirements. The investigator should 
contact Sage Therapeutics immediately if contacted by a regulatory agency or IRB/IEC about an 
inspection. 

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14.3. 
Institutional Review Board (IRB) or Ethics Committee (EC) 
The principal investigator must obtain IRB (or EC) approval for the clinical study prior to 
enrolling a participant. Initial IRB (or EC) approval, and all materials approved by the IRB (or 
EC) for this study including the participant consent form and recruitment materials must be 
maintained by the investigator and made available for inspection. 
 

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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practice and all applicable regulatory requirements, 
Sage Therapeutics may conduct a quality assurance audit(s) at the clinical site. Please see 
Section 14.2 for more details regarding the audit process. 
The investigator must have adequate quality control practices to ensure that the study is 
performed in a manner consistent with the protocol, GCP/ICH GCP guidelines, and applicable 
regulatory requirements. The investigator is responsible for reviewing all identified protocol 
deviations. Significant protocol deviations should be reported to the IRB/IEC per the IRB/IEC’s 
written procedures. 
The investigator is responsible for supervising any individual or party to whom the investigator 
delegates study-related duties and functions conducted at the study site. When the investigator 
retains the services of any individual or party to perform study-related duties and functions, the 
investigator must ensure the individual or party is qualified to perform study-related duties and 
functions and should implement procedures to ensure the integrity of the study-related duties and 
functions performed, and any data generated. 
The investigator must maintain adequate and accurate source documents and study records that 
include all pertinent observations on each of the site’s study participants. Source data must be 
attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data 
should be traceable, should not obscure the original entry, and should be explained, if necessary 
to provide clarification. 
 

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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
given a written and dated approval or favorable opinion by an IRB or IEC as appropriate. The 
investigator must obtain and document approval before he or she can enroll any participant into 
the study. The IRB or IEC must supply to the sponsor a list of the IRB/IEC membership and a 
statement to confirm that the IRB/IEC is organized and operates according to GCP and 
applicable laws and regulations. 
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 participants for the study. The protocol must be re-approved by the 
IRB or IEC upon receipt of amendments and annually, as local regulations require. 
The principal investigator is also responsible for providing the IRB or IEC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. Sage Therapeutics 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. In addition, the principal investigator must 
inform the IRB/IEC and sponsor of any changes significantly affecting the conduct of the study 
and/or increasing the risk to participants (eg, violations to the protocol or urgent safety measures 
taken for participant safety). 
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH and GCP guidelines, as well as all 
applicable regional or national regulatory requirements. 
16.3. 
Written Informed Consent 
Prior to enrolling a study participant, the investigator(s) will ensure that the participant is given 
full and adequate oral and written information about the nature, purpose, possible risk and 
benefit of the study. Participants must also be notified that they are free to discontinue from the 
study at any time. The participant should be given the opportunity to ask questions and allowed 
time to consider the information provided. 
When the participant decides to participate in the study, the participant (or the participant’s, 
parent or legally authorized representative) must provide signed and dated informed consent. The 
written consent must be obtained before conducting any study procedures. The investigator must 
document the consent process in the participant’s source records. The investigator must maintain 
the original, signed ICF. A copy of the signed ICF must be given to the participant or to the 
participant’s parent or legally authorized representative. 
Throughout the study participants should be informed of any changes made to the study and as 
new safety and or risk information becomes known. The provision of this information will be 

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documented in the participant’s source records, and when applicable, an updated ICF will be 
provided. 

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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Inspection of Records 
Sage Therapeutics or its representative(s) will be allowed to conduct site visits at the 
investigation facilities for the purpose of monitoring any aspect of the study. The investigator 
agrees to allow the monitor to inspect the facility, drug storage area, drug accountability records, 
participant charts and study source documents, and other records relative to study conduct. 
Inspection of the study by a Regulatory Authority may occur at any time. The investigator must 
agree to the inspection of study-related records and source documents by the Regulatory 
Authority representative(s). 
17.2. 
Retention of Records 
The principal investigator must maintain all documentation relating to the study for the period 
outlined in the site contract, or for a period of 2 years after the last marketing application 
approval, and until there are no pending or contemplated marketing applications in an ICH 
region or at least 2 years have elapsed since the formal discontinuation of clinical development 
of the investigational product. Sage is responsible to inform the investigator/institution as to 
when study documents no longer need to be retained. 

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18. 
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. 

 
 
 
 
STUDY TITLE: A PHASE 3, RANDOMIZED, DOUBLE-BLIND 
STUDY COMPARING THE EFFICACY AND SAFETY OF 
SAGE-217 PLUS SERTRALINE VERSUS PLACEBO PLUS 
SERTRALINE IN ADULTS WITH MAJOR DEPRESSIVE 
DISORDER 
 
PROTOCOL NUMBER: 217-MDD-305 
 
Investigational Product 
SAGE-217 
Clinical Phase 
Phase 3 
Sponsor 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 
Sponsor Contact 
 
 
Tel: 
 
e-mail: 
 
Sponsor Medical Monitor 
, MD, PhD, MSc 
 
 
e-mail: 
 
Date of Original Protocol 
13 May 2020 
 
 
 
 
 
 
Confidentiality Statement 
The confidential information in this document is provided to you as an investigator or consultant for 
review by you, your staff, and the applicable Institutional Review Board/Independent Ethics Committee. 
Your acceptance of this document constitutes agreement that you will not disclose the information 
contained herein to others without written authorization from Sage Therapeutics, Inc. 

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INVESTIGATOR’S AGREEMENT 
I have received and read the Investigator’s Brochure for SAGE-217. I have read the 
217-MDD-305 protocol and agree to conduct the study as outlined. I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
Date (DD/MMM/YYYY) 

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CONTACT INFORMATION 
Table 1: 
Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Sage Study Physician 
, MD, PhD, MSc 
 
e-mail: 
 
Tel: 
 
Syneos Medical 
Monitor 
, MD 
 
e-mail: 
 
Tel: 
 
24-Hour Serious 
Adverse Event 
reporting 
IQVIA Lifecycle Safety 
e-mail: Sage.Safety@iqvia.com 
SAE Hotline Tel: 855-564-2229 
Fax: +1-855-638-1674  
Product Complaint 
Reporting 
Sage Therapeutics, Inc. 
e-mail: productcomplaints@sagerx.com 
Phone: +1-833-554-7243 
 

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2. 
SYNOPSIS 
Name of Sponsor/Company: Sage Therapeutics, Inc. (hereafter referred to as Sage Therapeutics, or 
Sage) 
Name of Investigational Product: SAGE-217 Capsules 
Name of Active Ingredient: SAGE-217 
Title of Study: A Phase 3, Randomized, Double-Blind Study Comparing the Efficacy and Safety of 
SAGE-217 plus Sertraline Versus Placebo plus Sertraline in Adults with Major Depressive Disorder 
Number of Sites and Study Location: This study will take place at approximately 55 sites in United 
States. 
Phase of Development: 3 
Planned Duration for each Study Participant: Up to 70 days (up to 28-day Screening Period, 14-day 
Double-blind Treatment Period, and a 28-day Sertraline Continuation Period) 
Objectives: 
Primary: 
• 
To evaluate the efficacy of SAGE-217 plus sertraline in the treatment of major depressive 
disorder (MDD) compared to placebo plus sertraline 
Secondary: 
• 
To assess patient-reported outcome (PRO) measures as they relate to depressive symptoms 
• 
To evaluate the safety and tolerability of SAGE-217 plus sertraline 
 
 
 
 
 
Endpoints: 
Primary: 
• 
Change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D) total 
score at Day 15 
Key Secondary: 
• 
Change from baseline in CGI-S at Day 15 
• 
Change from baseline in HAM-D total score at Day 3, Day 8, and Day 42 
Other Secondary: 
• 
HAM-D response at Day 15 and Day 42 
• 
HAM-D remission at Day 15 and Day 42 
• 
CGI-I response, defined as “much improved” or “very much improved”, at Day 15 
• 
Change from baseline in MADRS total score at Day 15 
• 
Change from baseline in HAM-A total score at Day 15 
• 
Time to first HAM-D response 
• 
Change from baseline to Day 15 in depressive symptoms, as assessed by the PHQ-9 
• 
Incidence and severity of treatment-emergent adverse events (TEAEs) 

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Study Description: 
This is a randomized, double-blind, parallel-group, placebo-controlled study in adults with MDD. The 
diagnosis of MDD must be made according to Structured Clinical Interview for Diagnostic and 
Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Clinical Trial Version (SCID 5-CT) 
performed by a qualified healthcare professional. Participants cannot have been treated with sertraline 
in the current depressive episode. 
The study will consist of a Screening Period of up to 28 days, a 14-day double-blind Treatment Period, 
and a 28-day sertraline Continuation Period. The Screening Period begins with the signing of the 
informed consent form (ICF) at the Screening Visit. Preliminary screening procedures to determine 
eligibility include completion of the MGH-ATRQ and  HAM-D. 
Participants will be randomized to receive blinded SAGE-217 50 mg or placebo for administration 
each evening from Days 1 through 14. In addition, all participants will receive open-label sertraline 
from Day 1 through the end of the study. Sertraline will be administered per labeled prescribing 
information, starting with 50 mg each evening during Week 1 and 100 mg each evening during 
Week 2. 
After the double-blind Treatment Period, sertraline will be continued each evening for the remainder of 
the study (sertraline Continuation Period). During this period (Weeks 3 to 6), sertraline dosing may be 
increased based on individual response, at the discretion of the investigator and per the labeled 
prescribing information in 50-mg increments (up to 200 mg per day). 
Initiation of other antidepressants or any other medications that may potentially have an impact on 
efficacy or safety endpoints will not be allowed between screening and completion of assessments at 
Day 42/end-of-study visit. 
Participants will self-administer investigational product (IP) once daily at approximately 8 PM with 
fat-containing food (eg, within 1 hour of an evening meal which contains fat, or with a fat-containing 
snack), on an outpatient basis, for 14 days. Sertraline and SAGE-217/placebo will be administered at 
the same time during the Treatment Period. Participants will return to the study center as outlined in 
the Schedule of Assessments (Table 2). 
During the Treatment Period, participants will be able to receive SAGE-217/placebo as long as there 
are no dose-limiting safety/tolerability concerns. Participants who cannot tolerate SAGE-217/placebo 
50 mg will receive 40 mg for the remainder of the Treatment Period. Participants who, in the opinion 
of the investigator, cannot tolerate the SAGE-217/placebo 40-mg dose may be discontinued from 
SAGE-217/placebo at the discretion of the investigator. If blinded IP is discontinued, sertraline may be 
continued at the discretion of the investigator. 
Upon completion of the current study, eligible participants will have the opportunity to enter a long-
term open-label study of SAGE-217.  

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Number of Participants (planned): It is estimated that approximately 424 participants will be 
randomized and treated to obtain 382 evaluable participants at Day 15 (assuming a 10% dropout rate). 
Additional participants may be randomized if the dropout rate is greater than 10%. 
Eligibility Criteria: 
Inclusion Criteria 
1. Participant has signed an ICF prior to any study-specific procedures being performed. 
2. Participant is a male or female between 18 and 64 years of age, inclusive. 
3. Participant 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. Participant agrees to adhere to the study requirements. 
5. Participant has a diagnosis of MDD as diagnosed by SCID-5-CT, with symptoms that have 
been present for at least a 4-week period. 
6. Participant has a HAM-D-17 total score of ≥24 at Screening and Day 1 (prior to dosing). 
7. Participant is willing to delay start of any antidepressant (except sertraline as per protocol), 
anxiolytic, anti-insomnia, psychostimulant, prescription opioid regimens, or new 
psychotherapy (including Cognitive Behavioral Therapy for Insomnia [CBT-I]) until after 
study completion. Participants receiving psychotherapy must have been receiving therapy on a 
regular schedule for at least 60 days prior to Day 1 and intend to maintain that schedule for the 
duration of the study. 
8. Female participant agrees to use at least one method of highly effective contraception as listed 
in Section 9.2.4 during participation in the study and for 30 days following the last dose of IP, 
unless she is postmenopausal (at least 12 months of spontaneous amenorrhea without an 
alternative medical cause, with confirmatory follicle stimulating hormone >40 mIU/mL), 
and/or surgically sterile (bilateral oophorectomy, hysterectomy, and/or bilateral 
salpingectomy), or does not engage in sexual relations which carry a risk of pregnancy (does 
not include abstinence). 
9. Female participant who is breastfeeding at Screening or on Day 1 (prior to administration of 
IP) must be willing to temporarily cease giving breast milk to her child(ren) from just prior to 
receiving IP on Day 1 until 7 days after the last dose of SAGE-217/placebo. 
10. Male participant agrees to use an acceptable method of effective contraception for the duration 
of the study and for 5 days after receiving IP, unless the participant does not engage in sexual 
relation(s) which carry a risk of pregnancy. Acceptable methods of effective contraception are 
listed in Section 9.2.4. 
11. Male participant is willing to abstain from sperm donation for the treatment period and for 
5 days after receiving the last dose of the IP. 
12. Participant agrees to refrain from drugs of abuse and alcohol for the duration of the study. 
Exclusion Criteria 
1. Participant is currently at significant risk of suicide, as judged by the investigator, or has 
attempted suicide associated with the current episode of MDD. 
2. Participant had onset of the current depressive episode during pregnancy or 4 weeks 
postpartum, or the participant has presented for screening during the 6-month postpartum 
period. 
3. Participant has a recent history or active clinically significant manifestations of metabolic, 
hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, 
dermatological, urogenital, neurological, or eye, ear, nose, and throat disorders, or any other 

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acute or chronic condition that, in the investigator's opinion, would limit the participant's 
ability to complete or participate in this clinical study; a BMI ≤18 or ≥45 kg/m2 is 
exclusionary; a BMI of 40 to 44.9 kg/m2, inclusive, at Screening is subject to a broader 
evaluation of medical comorbidities as described above. 
4. Participant has treatment-resistant depression, defined as persistent depressive symptoms 
despite treatment with adequate doses of antidepressants within the current major depressive 
episode (excluding antipsychotics) from 2 different classes for at least 4 weeks of treatment. 
Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH 
ATRQ) will be used for this purpose. 
5. Participant has had vagus nerve stimulation, electroconvulsive therapy, or has taken ketamine 
within the current major depressive episode. 
6. Participant is receiving Cognitive Behavioral Therapy for Insomnia (CBT-I) within 28 days 
prior to Day 1. 
7. Participant has a known allergy to SAGE-217, allopregnanolone, sertraline, or related 
compounds. 
8. Participant has been treated with sertraline in the current depressive episode. 
9. Participant has taken antidepressants within 30 days prior to Day 1, and/or has taken fluoxetine 
within 60 days prior to Day 1. 
10. Female participant has a positive pregnancy test or confirmed pregnancy. 
11. Participant has a clinically significant abnormal 12-lead ECG at the screening or baseline 
visits. NOTE: mean QT interval calculated using the Fridericia method (QTcF) of >450 msec 
in males or >470 msec in females will be the basis for exclusion from the study. 
12. Participant has active psychosis per investigator assessment. 
13. Participant has a medical history of seizures. 
14. Participant has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder. 
15. Participant has a history of mild, moderate, or severe substance use disorder (including 
benzodiazepines) diagnosed using DSM-5 criteria in the 12 months prior to Screening. 
16. Participant has had exposure to another investigational medication or device within 30 days 
prior to Screening. 
17. Participant has previously received brexanolone or participated in a SAGE-217 or SAGE-547 
(brexanolone) clinical trial. 
18. Participant has used any known strong inhibitors of cytochrome P450 (CYP)3A4 within 
28 days or 5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, or 
Seville oranges, or products containing these, within 14 days prior to Day 1. 
19. Participant has used any strong CYP3A inducer, such as rifampin, carbamazepine, 
enzalutamide, mitotane, phenytoin, or St John’s Wort, within 28 days prior to Day 1. 
20. Participant has used any monoamine oxidase inhibitor (MAOI) or pimozide within 14 days 
prior to Day 1. 
21. Participant has a positive drug and/or alcohol screen at screening or on Day 1 prior to dosing. 
22. Participant plans to undergo elective surgery before completion of the Day 42 visit. 
23. Participant is taking benzodiazepines, barbiturates, or GABAA modulators (eg, eszopiclone, 
zopiclone, zaleplon, and zolpidem) within 28 days prior to Day 1, or has been using these 
agents daily or near-daily (≥4 times per week) for more than 1 year. Participant is taking any 

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benzodiazepine or GABA modulator with a half-life of ≥48 hours (eg, diazepam) from 60 days 
prior to Day 1. 
24. Participant is taking non-GABA anti-insomnia medications (eg, prescribed therapeutics 
specifically for insomnia and/or over the counter sleep aids), or first or second generation 
(typical/atypical) antipsychotics within 14 days prior to Day 1. Note that nonsedating 
antihistamines are permitted. 
25. Participant has been diagnosed with and/or treated for any type of cancer (excluding basal cell 
carcinoma and melanoma in situ) within the past year prior to Screening. 
26. Participant has a history of sleep apnea. 
27. Participant has had gastric bypass surgery, has a gastric sleeve or lap band, or has had any 
related procedures that interfere with gastrointestinal transit. 
28. Participant is taking psychostimulants (eg, methylphenidate, amphetamine) or opioids, 
regularly or as needed, within 28 days prior to Day 1. 
29. Participant is a dependent of the sponsor, investigator, investigator’s deputy, or study site staff. 
30. Participant expects to perform night shift work during the 14-day Treatment Period. 
Investigational Product Dosage and Mode of Administration: SAGE-217 will be available as hard 
gelatin capsules for oral administration; multiple capsules (in 30-mg or 20-mg dose strengths) will be 
provided to total a 50-mg dose, with option to reduce to 40 mg based on tolerability. 
Blinded placebo will be provided as hard gelatin capsules matched in appearance to SAGE-217, for 
oral administration. 
Sertraline tablets will be administered as per labeled prescribing information, starting with 50 mg each 
evening during Week 1 and 100 mg each evening during Week 2. During Weeks 3 to 6, sertraline 
dosing may be increased in 50-mg increments (up to 200 mg per day), as appropriate per the labeled 
prescribing information and based on individual response. 
Duration of Treatment: Blinded SAGE-217 or placebo will be administered once daily for 14 days; 
open-label sertraline will be administered according to labeled prescribing information for 42 days. 
Statistical Methods: 
Detailed description of the analyses to be performed in the study will be provided in the statistical 
analysis plan (SAP). The SAP will be finalized and approved prior to database lock and treatment 
unblinding. Any deviations from or changes to the SAP following database lock will be detailed in the 
Clinical Study Report. 
General Considerations 
For the purpose of all primary and secondary analyses where applicable, baseline is defined as 
the last measurement prior to start of IP administration. 
Continuous endpoints will be summarized with number (n), mean, standard deviation, median, 
minimum, and maximum. In addition, change from baseline values will be calculated at each 
time point and summarized descriptively. For categorical endpoints, descriptive summaries 
will include counts and percentages. 
Analysis Sets 
The Full Analysis Set (FAS) is defined as all randomized participants who receive at least 1 dose of IP 
and who have a valid baseline as well as at least 1 postbaseline HAM-D evaluation. 
The Safety Set is defined as all participants who receive at least 1 dose of IP. 
The Randomized Set, defined as all participants who are randomized. 
 

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Determination of Sample Size 
Using a two-sided alpha level of 0.05, a sample size of 382 total evaluable participants would provide 
90% power to detect a treatment difference (between SAGE-217 + sertraline and placebo + sertraline) 
of approximately 3 points in the primary endpoint, change from baseline in HAM-D total score at 
Day 15, assuming standard deviation of 9 points. Assuming a 10% dropout rate and a 1:1 
randomization ratio within each treatment group, approximately 424 total randomized participants will 
be required to obtain a total of 382 evaluable participants. Evaluable participants are defined as those 
randomized participants who receive IP and have valid baseline and at least 1 postbaseline HAM-D 
assessment. 
Analysis of Primary Endpoint 
The estimand for the primary analysis is the mean change from baseline in HAM-D total score at Day 
15. Using FAS, this will be analyzed using a mixed-effects model for repeated measures (MMRM); the 
model will include treatment, baseline HAM-D total score, assessment time point, and time point-by-
treatment as explanatory variables. All explanatory variables will be treated as fixed effects. All 
postbaseline time points will be included in the model. The main comparison will be between 
SAGE-217 + sertraline and placebo + sertraline at the 15-day time point. Model-based point estimates 
(ie, least squares means, 95% confidence intervals, and p values) will be reported where applicable. An 
unstructured covariance structure will be used to model the within-participant errors. The Toeplitz 
compound symmetry, Autoregressive (1) [AR(1)] covariance structure will be used in that sequence if 
there is a convergence issue with the unstructured covariance model. If convergence is still not 
achieved, no results will be reported. 
Analysis of Secondary Endpoints 
Similar to those methods described above for the primary endpoint, an MMRM will be used for the 
analysis of the change from baseline in other time points in HAM-D total score, MADRS total score, 
HAM-A total score, CGI-S score, and PHQ-9 total score. 
Generalized estimating equation methods will be used for the analysis of HAM-D response (defined as 
≥50% reduction from baseline in HAM-D total score) and HAM-D remission (defined as HAM-D total 
score of ≤7.0). GEE 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 + sertraline and placebo + sertraline at the 15-day time point. Model-
based point estimates (ie, odds ratios), 95% confidence intervals, and p values will be reported. 
A GEE method will also be used for the analysis of CGI-I response including terms for center, 
treatment, baseline CGI-S score, assessment time point, and time point-by-treatment as explanatory 
variables. 
Safety Analysis 
Safety and tolerability of IP will be evaluated by adverse events (AEs)/serious adverse event (SAEs), 
. 
 
 Safety data will be listed by participant and summarized by treatment group. All safety 
summaries will be performed on the Safety Set. 
 
 
 
 
 

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Table 2: 
Schedule of Assessments 
Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
Sertraline Continuation Period 
Visit Days 
D-28 to 
D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(+1d) 
and/or 
EOT a 
D18 
(±1d) 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
/ET  
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
Study Procedure 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Duplicate Participant Check b 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
 
 
Serum FSH test c 
X 
 
 
 
 
 
 
 
 
 
 
SCID-5-CT 
X 
 
 
 
 
 
 
 
 
 
 
MGH ATRQ 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Family History 
X 
 
 
 
 
 
 
 
 
 
 
Participant training d 
 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Physical Examination e 
X 
X 
 
 
 
X 
(EOT 
only) 
 
 
 
 
X 
Body Weight/Height 
X 
 
 
 
 
X 
(weight 
only) 
 
 
 
 
X 
(weight 
only) 
Clinical Laboratory 
Assessments f 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
Drug & Alcohol Screen g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
Sertraline Continuation Period 
Visit Days 
D-28 to 
D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(+1d) 
and/or 
EOT a 
D18 
(±1d) 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
/ET  
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
Study Procedure 
 
Pregnancy Test h 
X 
X 
 
 
 
X 
 
 
X 
 
X 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs k 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
12-Lead ECG l 
X 
X 
 
 
 
X 
 
 
 
 
X 
HAM-D n, o 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
MADRS 
 
X 
 
X 
 
X 
 
 
X 
 
X 
HAM-A o 
 
X 
 
X 
 
X 
 
 
X 
 
X 
CGI-S 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
PHQ-9 
 
X 
X 
X 
 
X 
 
 
X 
 
X 
SAGE-217/Placebo 
Dispensation 
 
X 
 
X 
 
 
 
 
 
 
 

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Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
Sertraline Continuation Period 
Visit Days 
D-28 to 
D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(+1d) 
and/or 
EOT a 
D18 
(±1d) 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
/ET  
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
Study Procedure 
 
SAGE-217/Placebo 
Administration 
 
X (once daily in the evening through Day 14 - inclusive) 
 
 
 
 
 
IP Adherence r 
 
X 
Sertraline Administration s 
 
X 
IP Accountability/Return 
 
 
X 
X 
 
X 
 
X 
X 
X 
X q 
AEs/SAEs t 
X 
Prior/Concomitant 
Medications/Procedures u 
X 
Abbreviations: AE = adverse event; CGI-I = Clinical Global Impression – Improvement; CGI-S – Clinical Global Impression – Severity; 
 
 D = day; EOT = end of treatment; ET = early termination; ECG = electrocardiogram; FSH = follicle stimulating hormone; HAM-A = Hamilton Anxiety Rating 
Scale; HAM-D = Hamilton Rating Scale for Depression, 17-item; HIV = human immunodeficiency virus; IP = investigational product; MADRS = Montgomery-Åsberg 
Depression Rating Scale; MGH ATRQ = Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; PHQ-9 = 9-item Patient Health Questionnaire; 
 O = Optional; 
 SCID-5-CT = Structured Clinical Interview for Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition Clinical Trials Version; 
 V = visit. 
a Participants who discontinue treatment early should return to the site for an end of treatment (EOT) visit as soon as possible, preferably the day after treatment is discontinued. If 
necessary, the EOT and ET visits can be on the same day if a participant discontinues IP and terminates the study on the same day during a clinic visit; in this case, all EOT visit 
assessments should be conducted. 
b Participants will be asked to authorize that their unique participant identifiers be entered into a registry (www.subjectregistry.com) with the intent of identifying participants who 
may meet exclusion criteria for participation in another clinical study. 
c A serum FSH test will be conducted at Screening for female participants that are not surgically sterile to confirm whether a female participant with ≥12 months of spontaneous 
amenorrhea meets the protocol-defined criteria for being postmenopausal. 
d Participants will be trained on use of software applications and devices necessary for the conduct of the study by site personnel. 
e A full physical examination will be conducted at Screening and abbreviated physical examinations will be conducted thereafter. A full physical examination includes assessment 
of body systems (eg, head, eye, ear, nose, and throat; heart; lungs; abdomen; and extremities). An abbreviated physical examination includes a brief medical history followed by 
targeted physical examination 
f Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. 
g Urine toxicology for selected drugs of abuse (Table 3) and breath test for alcohol. 

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h Serum pregnancy test at screening and urine pregnancy test thereafter for female participants who are not surgically sterile and do not meet the protocol-defined criteria for being 
postmenopausal. 
 
 
 
 
k When vital signs are scheduled at the same time as blood draws, vital signs will be obtained first. Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood 
pressure (supine and standing). Heart rate and blood pressure to be collected in supine position at all scheduled time points after the participant has been resting for 5 minutes and 
then after approximately 3 minutes in the standing position. Vital signs may be repeated at the discretion of the investigator as clinically indicated. 
l Triplicate ECGs will be collected. 
 
 
 
n The HAM-D is to be completed as early during the visit as possible. 
o The assessment timeframe for HAM-D scales will refer to the past 7 days (1 week) at Screening and “Since Last Visit” for all other visits. The assessment timeframe for HAM-A 
scales will refer to the past 7 days (1 week) at all visits. 
 
 
 
 
q To be performed at the ET visit only. 
r IP administration will be monitored via a medication adherence monitoring platform used on smartphones to visually confirm IP ingestion. 
s Sertraline 50 mg each evening during Week 1, and 100 mg each evening during Week 2. May be increased in 50 mg increments up to 200 mg total daily dose, from Weeks 3 
to 6, per investigator judgement 
t AEs will be collected starting at the time of informed consent and throughout the duration of the participant’s participation in the study. 
u Prior medications will be collected at Screening and concomitant medications and/or procedures will be collected at each subsequent visit. 
 

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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
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 MDD and Unmet Medical Need ........................................................22 
5.2. 
Potential Risks and Benefits .......................................................................................23 
5.3. 
Dose Justification ........................................................................................................23 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................25 
6.1. 
Objectives ...................................................................................................................25 
6.1.1. 
Primary Objective .......................................................................................................25 
6.1.2. 
Secondary Objectives .................................................................................................25 
 
25 
6.2. 
Endpoints ....................................................................................................................25 
6.2.1. 
Primary Endpoint ........................................................................................................25 
6.2.2. 
Secondary Endpoints ..................................................................................................25 
6.2.2.1. 
Key Secondary Endpoints ...........................................................................................25 
6.2.2.2. 
Other Secondary Endpoints ........................................................................................25 
 
26 
7. 
INVESTIGATIONAL PLAN .....................................................................................27 
7.1. 
Overall Study Design ..................................................................................................27 
7.2. 
Number of Participants ...............................................................................................28 
7.3. 
Treatment Assignment ................................................................................................28 
7.4. 
Dose Adjustment Criteria ...........................................................................................28 
7.5. 
Criteria for Study Termination ...................................................................................29 
8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS .....................................30 
8.1. 
Participant Inclusion Criteria ......................................................................................30 
8.2. 
Participant Exclusion Criteria .....................................................................................31 
8.3. 
Screen Failures ............................................................................................................32 

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8.4. 
Investigational Product Discontinuation and Early Termination from the 
Study ...........................................................................................................................33 
8.4.1. 
Investigational Product Discontinuation .....................................................................33 
8.4.2. 
Early Termination from the Study ..............................................................................34 
8.4.3. 
Loss to Follow-up .......................................................................................................34 
8.4.4. 
Replacement of Participants .......................................................................................34 
9. 
TREATMENT OF PARTICIPANTS .........................................................................35 
9.1. 
Description of Investigational Products ......................................................................35 
9.2. 
Prior Medications, Concomitant Medications, Restrictions, and 
Contraception Requirements ......................................................................................35 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................35 
9.2.2. 
Prohibited Medications ...............................................................................................35 
9.2.3. 
Other Restrictions .......................................................................................................36 
9.2.4. 
Acceptable Forms of Contraception ...........................................................................36 
9.3. 
Intervention after the End of the Study .......................................................................37 
9.4. 
Treatment Adherence ..................................................................................................37 
9.5. 
Randomization and Blinding ......................................................................................37 
9.5.1. 
Emergency Unblinding ...............................................................................................38 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............39 
10.1. 
Investigational Products ..............................................................................................39 
10.1.1. 
Blinded Investigational Products ................................................................................39 
10.1.2. 
Open-label Investigational Product ............................................................................39 
10.2. 
Blinded Investigational Product Packaging and Labeling ..........................................39 
10.3. 
Blinded Investigational Product Storage ....................................................................39 
10.4. 
Blinded Investigational Product Preparation ..............................................................39 
10.5. 
Blinded and Open-label Investigational Product Administration ...............................39 
10.6. 
Blinded Investigational Product Accountability, Handling, and Disposal .................40 
10.7. 
Blinded Investigational Product Complaints ..............................................................40 
11. 
EFFICACY AND CLINICAL PHARMACOLOGY ASSESSMENTS ....................42 
11.1. 
Efficacy Assessments .................................................................................................42 
11.1.1. 
Hamilton Rating Scale for Depression .......................................................................42 
11.1.2. 
Montgomery-Åsberg Depression Rating Scale ..........................................................42 
11.1.3. 
Hamilton Anxiety Rating Scale ..................................................................................42 

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11.1.4. 
Clinical Global Impressions .......................................................................................43 
 
43 
11.1.6. 
Patient Health Questionnaire ......................................................................................43 
 
44 
 
44 
 
44 
 
44 
 
44 
 
44 
 
44 
12. 
SAFETY ASSESSMENTS ........................................................................................46 
12.1. 
Safety Parameters .......................................................................................................46 
12.1.1. 
Demographic/Medical History ...................................................................................46 
12.1.2. 
Weight and Height ......................................................................................................46 
12.1.3. 
Physical Examination .................................................................................................46 
12.1.4. 
Vital Signs ..................................................................................................................46 
12.1.5. 
Electrocardiogram (ECG) ...........................................................................................47 
12.1.6. 
Laboratory Assessments .............................................................................................47 
12.1.6.1. 
Drugs of Abuse and Alcohol ......................................................................................48 
12.1.6.2. 
Pregnancy Screen ........................................................................................................49 
 
49 
 
49 
 
49 
12.2. 
Adverse and Serious Adverse Events .........................................................................50 
12.2.1. 
Adverse Event Definition ...........................................................................................50 
12.2.2. 
Serious Adverse Event Definition ..............................................................................50 
12.2.3. 
Relationship to Investigational Product ......................................................................51 
12.2.4. 
Recording Adverse Events .........................................................................................51 
12.2.5. 
Reporting Serious Adverse Events .............................................................................52 
12.3. 
Pregnancy ...................................................................................................................53 
12.4. 
Overdose .....................................................................................................................53 
13. 
STATISTICS ..............................................................................................................54 
13.1. 
Data Analysis Sets ......................................................................................................54 

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13.2. 
Handling of Missing Data ...........................................................................................54 
13.3. 
General Considerations ...............................................................................................54 
13.4. 
Demographics and Baseline Characteristics ...............................................................54 
13.5. 
Efficacy Analysis ........................................................................................................55 
13.6. 
Safety Analyses ..........................................................................................................55 
13.6.1. 
Adverse Events ...........................................................................................................56 
 
56 
13.6.3. 
Physical Examinations ................................................................................................56 
 
56 
13.6.5. 
12-Lead Electrocardiogram ........................................................................................56 
13.6.6. 
Prior and Concomitant Medications ...........................................................................56 
 
57 
 
57 
13.6.9. 
Other Safety Analysis .................................................................................................57 
 
57 
13.8. 
Sample Size and Power ..............................................................................................57 
13.8.1. 
Interim and Data Monitoring Committee Analyses ....................................................57 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................58 
14.1. 
Study Monitoring ........................................................................................................58 
14.2. 
Audits and Inspections ................................................................................................58 
14.3. 
Institutional Review Board (IRB) or Ethics Committee (EC) ....................................59 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................60 
16. 
ETHICS ......................................................................................................................61 
16.1. 
Ethics Review .............................................................................................................61 
16.2. 
Ethical Conduct of the Study ......................................................................................61 
16.3. 
Written Informed Consent ..........................................................................................61 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................63 
17.1. 
Inspection of Records .................................................................................................63 
17.2. 
Retention of Records ..................................................................................................63 
18. 
PUBLICATION POLICY ..........................................................................................64 
19. 
LIST OF REFERENCES ............................................................................................65 
 

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LIST OF TABLES 
Table 1: 
Contact Information ......................................................................................................4 
Table 2: 
Schedule of Assessments ............................................................................................11 
Table 3: 
Clinical Laboratory Tests ...........................................................................................47 
 
LIST OF FIGURES 
Figure 1: 
Study Design (Screening and Day 1 through 42) .......................................................27 
 
 

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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
ALP 
alkaline phosphatase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BP 
blood pressure 
CFR 
Code of Federal Regulation 
CRO 
contract research organization 
CSR 
clinical study report 
IEC 
independent ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IND 
investigational new drug  
IP 
investigational product 
MedDRA 
Medical Dictionary for Regulatory Activities 
PD 
pharmacodynamic 
PI 
principal investigator; the investigator who leads the study conduct at an 
individual study center. Every study center has a principal investigator. 
PK 
pharmacokinetic 
PV 
pharmacovigilance 
QA 
quality assurance 
QC 
quality control 
QTcF 
QT corrected according to Fridericia’s formula 
SAE 
serious adverse event 
SOP 
Standard Operating Procedure 

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Abbreviation 
Definition 
TEAE 
treatment-emergent adverse event 
WHO 
World Health Organization 

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5. 
INTRODUCTION 
5.1. 
Background of Major Depressive Disorder and Unmet Medical Need 
The World Health Organization (WHO) has identified depression as the leading cause of 
disability worldwide, and as a major contributor to the overall global burden of disease 
(http://www.who.int/mediacentre/factsheets/fs369/en/). Globally, depression has been estimated 
to affect over 300 million people. 
In the United States, the economic burden of depression, including workplace costs, direct costs, 
and suicide-related costs, was estimated to be $210.5 billion in 2010 (Greenberg 2015). As per 
WHO statistics, over 800,000 people die due to suicide every year, and suicide is the second 
leading cause of death in 15- to 29-year-olds. The rate of US adults making a suicide attempt has 
increased (0.62% from 2004 to 2005 to 0.79% from 2012 to 2013), with a shift to more attempts 
among younger adults (42% to 50%, respectively) and among those with a depressive disorder 
(26% to 54%, respectively; Olfson 2017). 
The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5, American 
Psychiatric Association 2013) provides diagnostic criteria for major depressive disorder (MDD). 
These include at least 5 of 9 depressive symptoms (depressed mood and/or loss of interest or 
pleasure, and other changes affecting appetite or weight, sleep, psychomotor activity, energy 
level, feelings of guilt, concentration ability, and suicidality) during the same 2-week period that 
represents a change from previous functioning (DSM-5). 
Antidepressants are a mainstay of pharmacological treatment for depressive disorders. Selective 
serotonin uptake inhibitors (SNRI), serotonin norepinephrine reuptake inhibitors (SSRI), 
tricyclic antidepressants, monoamine oxidase inhibitors (MAOI), and other compounds that 
affect monoaminergic neurotransmission, such as mirtrazapine and bupropion, represent the 
major classes of antidepressants. While antidepressants are widely used, large scale studies have 
demonstrated their limited efficacy, including low remission rates and untreated symptoms 
(Trivedi 2006; Conradi 2011; Romera 2013). Furthermore, these agents can take 4 to 8 weeks to 
demonstrate full clinical efficacy (Rush 2006; Trivedi 2006), and in the case of the most 
commonly prescribed classes—SSRIs and SNRIs—common side effects including weight gain, 
GI symptoms, and sexual dysfunction can prevent titration into an adequate therapeutic range 
(Sadock and Sadock 2007). 
In the largest study to assess the effectiveness of depression treatments in patients with MDD, 
time to patient remission after treatment was 5.4 to 7.4 weeks; approximately one-half of the 
patients who ultimately remitted did so after 6 weeks, and 40% of those who achieved remission 
required 8 or more weeks to do so (Rush 2006; Trivedi 2006). Even following remission, many 
patients report the presence of residual symptoms, often related to decreased positive affect, such 
as loss of interest in activities once considered enjoyable, fatigue, loss of energy, as well as sleep 
and appetite/weight disturbances (Nierenberg 2009; Nierenberg 2015). Thus, patients may 
remain symptomatic for up to 2 months while waiting for current standard-of-care 
pharmacotherapy to take full effect. They may also have to contend with undesirable side effects 
and residual symptoms. These aspects underscore the need for newer, rapid-acting therapies. 
SAGE-217 is a synthetic positive allosteric modulator of GABAA receptors, the major class of 
inhibitory neurotransmitter receptors in the brain. In pharmacokinetic (PK) studies in mice and 

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rats, SAGE-217 demonstrated rapid penetration and equilibrium across the blood brain barrier 
and is generally expected to have good extravascular exposure. In exploratory in vitro receptor 
and ion channel assays and in vivo safety pharmacology studies, SAGE-217 was highly selective 
for GABAA receptors, and, consistent with the actions of other GABAA receptor potentiators 
(Rudolph 2011), exhibits potent anticonvulsant, anxiolytic, and sedative activity when 
administered in vivo. 
SAGE-217 has been generally well tolerated in clinical studies to date. The most common 
treatment-emergent adverse events (TEAEs) associated with SAGE-217 (overall) were sedation, 
somnolence, and dizziness; most adverse events (AEs) were reported as mild or moderate in 
intensity. Refer to the SAGE-217 Investigator’s Brochure for a detailed description of the 
chemistry, pharmacology, efficacy, and safety of SAGE-217. 
This study was designed to target the unmet need of symptom improvement during the latency to 
SSRI efficacy in the acute phase of a major depressive episode. This study will assess the safety 
and efficacy of SAGE-217 50 mg plus sertraline, examining if SAGE-217 plus sertraline 
produces more rapid or more profound reduction in depressive symptoms than sertraline alone. 
5.2. 
Potential Risks and Benefits 
The apparent risks of SAGE-217 are based on clinical data reports of AEs in completed and 
ongoing studies and the known pharmacology of the drug. Sedation, somnolence, and dizziness 
were identified as adverse drug reactions. Most AEs were reported as mild or moderate in 
intensity and reversible. 
SAGE-217 may present a treatment option for MDD that has more rapid onset of action (days 
instead of weeks/months), when compared to available pharmacotherapies. 
Based on nonclinical findings, embryo-fetal toxicity and withdrawal effects are considered 
important potential risk for SAGE-217. Risk mitigation measures in this study include 
monitoring for adverse effects, monitoring for potential withdrawal effects, requiring highly 
effective contraceptive measures for study participants, and inclusion of dose adjustment criteria 
and guidance for blinded IP discontinuation (Section 8.4). Finally, due to the 
sedation/somnolence observed, SAGE-217 is administered in the evening in this study. 
Given the outcome of the completed studies of SAGE-217 in participants with MDD and PDD, 
the current significant unmet need for well-tolerated and rapid-acting depression treatments, and 
a favorable benefit-risk profile, further investigation of SAGE-217 as a novel rapid response 
treatment in adults with MDD is justified. 
5.3. 
Dose Justification 
Results from a large, multicenter study of SAGE-217 20 and 30 mg in MDD (217-MDD-301) 
support the need for higher steady-state concentrations of SAGE-217 to allow participants to 
experience maximum antidepressant and anti-anxiety benefits. SAGE-217 will be administered 
as a 14-day regimen of an evening dose of 50 mg with reduction to 40 mg as needed based on 
tolerability. The 50-mg dose of SAGE-217 is expected to exhibit a favorable benefit-risk profile 
in the context of results from previous SAGE-217 studies utilizing a 30-mg dose, now identified 
as a minimally effective dose. SAGE-217 is expected to maintain an acceptable tolerability 

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profile, based on a current safety database of over 2000 participants exposed across different 
doses/concentrations. 
Sertraline is a commercially available SSRI indicated for the treatment of MDD and other 
psychiatric disorders. Dosage and administration of sertraline as described in the approved US 
Prescribing Information (PI) recommends a starting dose of 50 mg per day in patients with 
MDD, with an incremental weekly increase in dose of 25-50 mg per day, if there is an 
inadequate response to the starting dose, to a maximum dose of 200 mg per day. The dose of 
sertraline used in this study aligns with the recommended dosing as defined in the PI. 

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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Objectives 
6.1.1. 
Primary Objective 
To evaluate the efficacy of SAGE-217 plus sertraline in the treatment of MDD compared to 
placebo plus sertraline 
6.1.2. 
Secondary Objectives 
• To assess patient-reported outcome (PRO) measures as they relate to depressive 
symptoms 
• To evaluate the safety and tolerability of SAGE-217 plus sertraline 
 
 
 
 
 
 
6.2. 
Endpoints 
6.2.1. 
Primary Endpoint 
• Change from baseline in 17-item Hamilton Rating Scale for Depression (HAM-D) 
total score at Day 15 
6.2.2. 
Secondary Endpoints 
6.2.2.1. 
Key Secondary Endpoints 
• Change from baseline in CGI-S at Day 15 
• Change from baseline in HAM-D total score at Day 3, Day 8, and Day 42 
6.2.2.2. 
Other Secondary Endpoints 
• HAM-D response at Day 15 and Day 42 
• HAM-D remission at Day 15 and Day 42 
• CGI-I response, defined as “much improved” or “very much improved”, at Day 15 
• Change from baseline in MADRS total score at Day 15 
• Change from baseline in HAM-A total score at Day 15 
• Time to first HAM-D response 
• Change from baseline to Day 15 in depressive symptoms, as assessed by the PHQ-9 
• Incidence and severity of treatment-emergent AEs 

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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a randomized, double-blind, parallel-group, placebo-controlled study in adults with 
MDD. The diagnosis of MDD must be made according to Structured Clinical Interview for 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Clinical Trial 
Version (SCID 5-CT) performed by a qualified healthcare professional. Participants cannot have 
been treated with sertraline in the current depressive episode. 
The study will consist of a Screening Period of up to 28 days, a 14-day double-blind Treatment 
Period, and a 28-day sertraline Continuation Period. The Screening Period begins with the 
signing of the informed consent form (ICF) at the Screening Visit. Preliminary screening 
procedures to determine eligibility include completion of the MGH-ATRQ and HAM-D. 
Participants will be randomized to receive blinded SAGE-217 or placebo for administration each 
evening from Day 1 through 14. In addition, all participants will receive open-label sertraline 
from Day 1 through the end of the study. 
The study design is diagrammed in Figure 1. 
Figure 1: 
Study Schematic 
 
Doses are presented as daily doses. All participants will receive open-label sertraline in addition to blinded IP 
(SAGE-217/placebo) from Week 1 to Week 2 then continue to receive sertraline alone from Weeks 3 to 6. During 
Weeks 1 and 2, the blinded IP dose may be reduced to 40 mg, as needed. During Weeks 3 to 6, the sertraline dose 
may be increased in 50-mg increments each week, as needed, up to a total daily dose of sertraline 200 mg. 
Open-label sertraline will be administered as per labeled prescribing information, starting with 
50 mg each evening during Week 1 and 100 mg each evening during Week 2. 
After the Double-blind Treatment Period, sertraline will be continued each evening for the 
remainder of the study (sertraline Continuation Period). During this period (Week 3 to 6), 

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sertraline dosing may be increased in 50-mg increments (up to 200 mg)as appropriate per the 
labeled prescribing information and based on individual response,. 
Initiation of other antidepressants or any other medications that may potentially have an impact 
on efficacy or safety endpoints will not be allowed between screening and completion of 
assessments at Day 42/end-of-study visit. 
Participants will self-administer investigational product (IP) once daily at approximately 8 PM 
with fat-containing food (eg, within 1 hour of an evening meal which contains fat, or with a fat-
containing snack), on an outpatient basis, for 14 days. Sertraline and SAGE-217 or placebo will 
be administered at the same time during the Treatment Period. Participants will return to the 
study center as outlined in the Schedule of Assessments. 
During the Treatment Period, participants will be able to receive SAGE-217/placebo as long as 
there are no dose-limiting safety/tolerability concerns. Participants who cannot tolerate 
SAGE-217 or placebo 50 mg will receive 40 mg for the remainder of the Treatment Period. 
Participants who cannot tolerate the SAGE-217/placebo 40-mg dose may be discontinued from 
SAGE-217 or placebo at the discretion of the investigator. If blinded IP is discontinued, 
sertraline may be continued at the discretion of the investigator. 
Upon completion of the current study, eligible participants will have the opportunity to enter a 
long-term open-label study of SAGE-217. Participants that do not enter the open-label study or 
that terminate the current study early may, per the investigator, receive a supply of sertraline 
with instructions on how to taper the drug or, if they wish to continue sertraline, a bridge supply 
to permit them to obtain a prescription from another provider. 
7.2. 
Number of Participants 
It is estimated that approximately 424 participants will be randomized and treated to obtain 
382 evaluable participants at Day 15 (assuming 10% dropout rate). Additional participants may 
be randomized if the dropout rate is greater than 10%. 
7.3. 
Treatment Assignment 
Participants will be assigned to blinded IP (SAGE-217 or placebo) in accordance with the 
randomization schedule on Day 1. All participants will also receive open-label sertraline for the 
study duration; as detailed in Section 9.1 and as per the Schedule of Assessments (Table 2). 
Additional details on randomization and blinding are provided in Section 9.5. 
7.4. 
Dose Adjustment Criteria 
During the treatment period, participants will be able to receive SAGE-217/placebo as long as 
there are no dose-limiting safety/tolerability concerns. Participants who cannot tolerate 50 mg (as 
determined by the investigator) will receive 40 mg for the remainder of the treatment period. 
At the discretion of the investigator, participants who cannot tolerate the 40-mg dose at any time 
may be discontinued from dosing upon completion of an end of treatment (EOT) visit as soon as 
possible. These participants should be followed and complete assessments as per the Schedule of 
Assessments (Table 2). 

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During Weeks 3 to 6, sertraline dosing may be increased, based on individual response, per 
investigator discretion and per the labeled prescribing information, in 50-mg increments (up to 
200 mg). 
7.5. 
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 AEs or other findings suggesting unacceptable risk to 
participants, 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 IRB, where required, and initiate withdrawal procedures for participating participants. 

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8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
8.1. 
Participant Inclusion Criteria 
1. Participant has signed an ICF prior to any study-specific procedures being performed. 
2. Participant is a male or female between 18 and 64 years of age, inclusive. 
3. Participant 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. Participant agrees to adhere to the study requirements. 
5. Participant has a diagnosis of MDD as diagnosed by SCID-5-CT, with symptoms that 
have been present for at least a 4-week period. 
6. Participant has a HAM-D-17 total score of ≥24 at Screening and Day 1 (prior to dosing). 
7. Participant is willing to delay start of any antidepressant (except sertraline as per 
protocol), anxiolytic, anti-insomnia, psychostimulant, prescription opioid regimens, or 
new psychotherapy (including Cognitive Behavioral Therapy for Insomnia [CBT-I]) until 
after study completion. Participants receiving psychotherapy must have been receiving 
therapy on a regular schedule for at least 60 days prior to Day 1 and intend to maintain 
that schedule for the duration of the study. 
8. Female participant agrees to use at least one method of highly effective contraception as 
listed in Section 9.2.4 during participation in the study and for 30 days following the last 
dose of IP, unless she is postmenopausal (at least 12 months of spontaneous amenorrhea 
without an alternative medical cause, with confirmatory follicle stimulating hormone 
>40 mIU/mL), and/or surgically sterile (bilateral oophorectomy, hysterectomy, and/or 
bilateral salpingectomy), or does not engage in sexual relations which carry a risk of 
pregnancy (does not include abstinence). 
9. Female participant who is breastfeeding at Screening or on Day 1 (prior to administration 
of IP) must be willing to temporarily cease giving breast milk to her child(ren) from just 
prior to receiving IP on Day 1 until 7 days after the last dose of SAGE-217/placebo. 
10. Male participant agrees to use an acceptable method of effective contraception for the 
duration of the study and for 5 days after receiving IP, unless the participant does not 
engage in sexual relation(s) which carry a risk of pregnancy. Acceptable methods of 
effective contraception are listed in Section 9.2.4. 
11. Male participant is willing to abstain from sperm donation for the treatment period and 
for 5 days after receiving the last dose of the IP. 
12. Participant agrees to refrain from drugs of abuse and alcohol for the duration of the study. 

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8.2. 
Participant Exclusion Criteria 
Participants who meet any of the following criteria are disqualified from participation in this 
study: 
1. Participant is currently at significant risk of suicide, as judged by the investigator, or has 
attempted suicide associated with the current episode of MDD. 
2. Participant had onset of the current depressive episode during pregnancy or 4 weeks 
postpartum, or the participant has presented for screening during the 6-month postpartum 
period. 
3. Participant 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 participant's ability to complete or participate in this clinical study; a 
BMI ≤18 or ≥45 kg/m2 is exclusionary; a BMI of 40 to 44.9 kg/m2, inclusive, at 
Screening is subject to a broader evaluation of medical comorbidities as described above. 
4. Participant has treatment-resistant depression, defined as persistent depressive symptoms 
despite treatment with adequate doses of antidepressants within the current major 
depressive episode (excluding antipsychotics) from 2 different classes for at least 4 weeks 
of treatment. Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire (MGH ATRQ) will be used for this purpose. 
5. Participant has had vagus nerve stimulation, electroconvulsive therapy, or has taken 
ketamine within the current major depressive episode. 
6. Participant is receiving Cognitive Behavioral Therapy for Insomnia (CBT-I) within 
28 days prior to Day 1. 
7. Participant has a known allergy to SAGE-217, allopregnanolone, sertraline, or related 
compounds. 
8. Participant has been treated with sertraline in the current depressive episode. 
9. Participant has taken antidepressants within 30 days prior to Day 1, and/or has taken 
fluoxetine within 60 days prior to Day 1. 
10. Female participant has a positive pregnancy test or confirmed pregnancy. 
11. Participant has a clinically significant abnormal 12-lead ECG at the screening or baseline 
visits. NOTE: mean QT interval calculated using the Fridericia method (QTcF) of 
>450 msec in males or >470 msec in females will be the basis for exclusion from the 
study. 
12. Participant has active psychosis per investigator assessment. 
13. Participant has a medical history of seizures. 
14. Participant has a medical history of bipolar disorder, schizophrenia, and/or 
schizoaffective disorder. 

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15. Participant has a history of mild, moderate, or severe substance use disorder (including 
benzodiazepines) diagnosed using DSM-5 criteria in the 12 months prior to Screening. 
16. Participant has had exposure to another investigational medication or device within 
30 days prior to Screening. 
17. Participant has previously received brexanolone or participated in a SAGE-217 or SAGE-
547 (brexanolone) clinical trial. 
18. Participant has used any known strong inhibitors of cytochrome P450 (CYP)3A4 within 
28 days or five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, 
or Seville oranges, or products containing these within 14 days prior to Day 1. 
19. Participant has used any strong CYP3A inducer, such as rifampin, carbamazepine, 
enzalutamide, mitotane, phenytoin, or St John’s Wort, within 28 days prior to Day 1. 
20. Participant has a positive drug and/or alcohol screen at screening or on Day 1 prior to 
dosing. 
21. Participant has used any monoamine oxidase inhibitor (MAOI) or pimozide within 
14 days prior to Day 1. 
22. Participant plans to undergo elective surgery before completion of the Day 42 visit. 
23. Participant is taking benzodiazepines, barbiturates, or GABAA modulators (eg, 
eszopiclone, zopiclone, zaleplon, and zolpidem) within 28 days prior to Day 1, or has 
been using these agents daily or near-daily (≥4 times per week) for more than 1 year. 
Participant is taking any benzodiazepine or GABA modulator with a half-life of 
≥48 hours (eg, diazepam) from 60 days prior to Day 1. 
24. Participant is taking non-GABA anti-insomnia medications (eg, prescribed therapeutics 
specifically for insomnia and/or over the counter sleep aids), or first generation or second 
generation (typical/atypical) antipsychotics within 14 days prior to Day 1. Note that 
nonsedating antihistamines are permitted. 
25. Participant has been diagnosed with and/or treated for any type of cancer (excluding 
basal cell carcinoma and melanoma in situ) within the past year prior to Screening. 
26. Participant has a history of sleep apnea. 
27. Participant has had gastric bypass surgery, has a gastric sleeve or lap band, or has had any 
related procedures that interfere with gastrointestinal transit. 
28. Participant is taking psychostimulants (eg, methylphenidate, amphetamine) or opioids, 
regularly or as needed, within 28 days prior to Day 1. 
29. Participant is a dependent of the sponsor, investigator, investigator’s deputy, or study site 
staff. 
30. Participant expects to perform night shift work during the 14-day treatment period. 
8.3. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized to study intervention. A minimal set of screen failure information 

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will be collected, including demography, screen failure details, eligibility criteria, and any 
AE/serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once. 
8.4. 
Investigational Product Discontinuation and Early Termination from 
the Study 
A participant may withdraw from the study at any time at his/her own request for any reason. 
The investigator may discontinue a participant from the study and/or from IP for safety, 
behavioral, compliance, or administrative reasons. 
Based on known withdrawal symptoms with other GABAergic drugs and nonclinical findings in 
a 9-month study of SAGE-217 in dogs (Investigator’s Brochure), there is a potential for 
withdrawal-related events, including seizure. The following guidelines for blinded IP 
discontinuation or dose reduction are presented to support participant safety: 
1. Any participant reporting a confirmed or suspected seizure at any time will be 
discontinued from blinded IP but will continue to be followed in the study. 
2. The investigator should monitor the course of CNS-based signs and symptoms suggestive 
of a seizure which are not accounted for by comorbid psychiatric or medical conditions. 
Examples of reported serious or severe events which may reflect an oncoming and/or 
increased risk for seizure may include temporary confusion, tremors, involuntary muscle 
fasciculations or jerking movements of arms or legs, or paresthesia. Should such 
symptoms occur, the investigator should consider decreasing the dose of SAGE-217 or 
placebo to 40 mg, stopping treatment to assess the effect on the symptom(s) 
(eg, resolution, improvement), or discontinuing the participant from treatment. A 
participant who discontinues treatment should remain in the study and continue protocol-
required assessments until the end of the study. 
The investigator must notify the sponsor and/or the medical monitor when a participant stops 
participation in the study for any reason. 
8.4.1. 
Investigational Product Discontinuation 
The primary reason for IP discontinuation must be documented in the participant’s study record 
and recorded in the participant’s electronic case report form (eCRF). 
Participants who discontinue treatment early should return to the site for an end of treatment 
(EOT) visit as soon as possible, preferably the day after treatment is discontinued. Follow-up 
visits should take place as scheduled relative to the last dose of treatment (eg, if a participant’s 
last dose is on Day 13, their first follow-up visit, Visit 7, should occur 4 days later), and will 
continue safety and efficacy assessments as scheduled for 6 weeks following the final dose. 
Participants that discontinue blinded IP early may, per the investigator, receive a supply of 
sertraline with instructions on how to taper the drug or, if they wish to continue sertraline, a 
bridge supply to permit them to obtain a prescription from another provider. 

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8.4.2. 
Early Termination from the Study 
If a participant decides to terminate the study, the participant should return for an early 
termination (ET) visit, if possible. The primary reason for early termination from the study must 
be documented in the participant’s study record and recorded in the participant’s electronic case 
report form (eCRF). If a participant discontinues IP and terminates the study on the same day 
during a clinic visit, the EOT and ET visits can be on the same day; in this case, all EOT visit 
assessments should be conducted in addition to an abbreviated physical examination 
If the participant withdraws consent for disclosure of future information, the sponsor will retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
Participants who terminate from the study early may, per the investigator, receive a supply of 
sertraline with instructions on how to taper the drug or, if they wish to continue sertraline, a 
bridge supply to permit them to obtain a prescription from another provider. 
8.4.3. 
Loss to Follow-up 
A participant will be deemed lost to follow-up after 3 attempts at contacting the participant have 
been unsuccessful. 
8.4.4. 
Replacement of Participants 
Participants will not be replaced. 

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9. 
TREATMENT OF PARTICIPANTS 
9.1. 
Description of Investigational Products 
SAGE-217 will be available as hard gelatin capsules for oral administration; 2 capsules 
(one 30 mg and one 20 mg) will be provided to total a 50-mg dose, with option to reduce to 
40 mg based on tolerability, as per criteria described in Section 7.4. If the dose is reduced to 
40 mg, it will be administered as 2 20-mg capsules. 
Blinded placebo will be provided as hard gelatin capsules matched in appearance to SAGE-217, 
for oral administration. 
All participants will self-administer blinded and open-label IP orally once daily at approximately 
8 PM with fat-containing food for 14 days. 
Sertraline tablets will be administered as per labeled prescribing information, starting with 50 mg 
each evening during Week 1 and 100 mg each evening during Week 2. During Weeks 3 to 6, 
sertraline dosing may be increased in 50-mg increments (up to 200 mg per day), based on 
individual response per Investigator discretion and the labeled prescribing information. 
9.2. 
Prior Medications, Concomitant Medications, Restrictions, and 
Contraception Requirements 
9.2.1. 
Prior and Concomitant Medications and/or Supplements 
The start and end dates, route, dose/units, frequency, and indication for all medications and/or 
supplements taken within 30 days prior to Screening and throughout the duration of the study 
will be recorded. In addition, psychotropic medications taken within 6 months prior to Screening 
will be recorded. 
Any medication and/or supplement determined necessary for the welfare of the participant may 
be given at the discretion of the investigator at any time during the study. 
9.2.2. 
Prohibited Medications 
The following specific classes of medications are prohibited: 
• Initiation of new psychotropic medications through the Day 42 visit 
• Initiation of new antidepressant therapy from 30 days (60 days for fluoxetine) prior to 
Day 1 through the Day 42 visit 
• Use of any benzodiazepines, barbiturates, GABAA modulators, GABA-containing 
agents from Day -28 through the Day 42 visit (from Day -60 for benzodiazepines or 
GABA modulators with a half-life ≥48 hours) 
• Chronic or as-needed psychostimulants (eg, methylphenidate, amphetamine) or 
opioids from Day -28 through the Day 42 visit 
• First generation (typical) antipsychotics (eg, haloperidol, perphenazine) and second 
generation (atypical) antipsychotics (eg, aripiprazole, quetiapine) from Day -14 
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• Use of any non-GABA anti-insomnia medications (eg, prescribed therapeutics 
specifically for insomnia and/or over the counter sleep aids) from Day -14 to Day 1. 
Note that nonsedating antihistamines are permitted. 
• Exposure to another investigational medication or device from 30 days prior to 
Screening through the Day 42 visit 
• Any known strong inhibitors of CYP3A4 from Day -28 or 5 half-lives prior to Day 1 
(whichever is longer) through the Treatment Period 
• Use of any strong CYP3A inducer, such as rifampin, carbamazepine, enzalutamide, 
mitotane, phenytoin, or St John’s Wort from Day -28 through the Treatment Period 
• Use of any monoamine oxidase inhibitor from Day -14 to Day 1 
• Use of pimozide from Day -14 through the Day 42 visit 
9.2.3. 
Other Restrictions 
The consumption of grapefruit juice, grapefruit, or Seville oranges, or products containing these 
is prohibited throughout the treatment period. 
The concomitant use of sertraline with a CYP2D6 substrate may increase the exposure of the 
CYP2D6 substrate; therefore, decrease the dosage of a CYP2D6 substrate if needed. 
Consumption of alcohol or use of drugs of abuse is discouraged throughout the duration of the 
study. 
Female participants who are lactating or actively breastfeeding must stop giving breast milk to 
the baby(ies) starting on Day 1 until 7 days after the last dose of SAGE-217/placebo. 
Elective surgeries or procedures are prohibited through the Day 42 visit. 
Participants must not participate in night shift work during the Treatment Period. 
Participants who are feeling sedated, somnolent, and/or dizzy are to refrain from driving or 
engaging in any activity requiring alertness. 
Participants receiving psychotherapy on a regular schedule for at least 60 days prior to Day 1 are 
permitted if the participant intends to continue that schedule through the Follow-up Period 
(Day 42). Initiation of new psychotherapy is prohibited until after study completion. 
9.2.4. 
Acceptable Forms of Contraception 
Acceptable forms of highly effective contraception for participants of childbearing potential or 
for partners of male participants who are of childbearing potential include: 
• 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 

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• Bilateral tubal ligation or bilateral tubal occlusion (performed at least 3 months prior 
to screening) 
• Vasectomized partner (performed at least 3 months prior to screening) 
Acceptable forms of contraception for male participants include: 
• History of vasectomy (performed at least 3 months prior to screening) 
• Condom with spermicide used together with highly effective female contraceptive 
methods if the female partner(s) is of childbearing potential (see above for list of 
acceptable female contraceptive methods) 
9.3. 
Intervention after the End of the Study 
Upon completion of the current study, eligible participants will have the opportunity to enter an 
open-label, long-term study of SAGE-217 in which additional treatment with SAGE-217 will be 
offered. Participants that do not enter the open-label study or that terminate the current study 
early may continue to receive sertraline as prescribed by the investigator either to taper the drug 
appropriately or—if the participant wishes to continue sertraline—to bridge the participant until 
he or she receives a new prescription. 
9.4. 
Treatment Adherence 
Investigational products will be self-administered by participants (see Section 10.5). 
Administration of blinded and open-label IP will be monitored by a medication adherence 
monitoring platform used on smartphones to visually confirm medication ingestion. Participants 
will receive a reminder within a predefined time window to take IP while using the application. 
Participants will follow a series of prescribed steps in front of the front-facing webcam to 
visually confirm their ingestion of the medication. The application will record the date and time 
of IP administration by dose level, as well as missed doses. 
In addition, participants will be instructed to bring their SAGE-217 or placebo dosing kit and 
sertraline to the site as outlined in Table 2, at which time the investigator or designee will be 
responsible for ensuring the kit contains sufficient doses for the duration of the treatment period. 
All participants should be reinstructed about the dosing requirements during study contacts. The 
authorized study personnel conducting the reeducation must document the process in the 
participant source records. 
The investigator(s) will record any reasons for nonadherence in the source documents. 
9.5. 
Randomization and Blinding 
Participants will be randomized in a 1:1 ratio to receive SAGE-217 or matched placebo. 
Participants, site staff, and the sponsor will be blinded to treatment allocation. All participants 
will also receive open-label sertraline. Randomization will be performed centrally via an 
interactive response technology (IRT) system. Randomization schedules will be generated by an 
independent statistician. The allocation to blinded treatment (SAGE-217or placebo) will be 
based on the randomization schedule. The randomization schedules will be kept strictly 

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confidential, accessible only to authorized personnel until the time of unblinding. The blinding of 
the study will be broken after the database has been locked. 
9.5.1. 
Emergency Unblinding 
During the study, the blind is to be broken only when the safety of a participant is at risk and the 
treatment plan is dependent on the study treatment received. Unless a participant is at immediate 
risk, the investigator should make diligent attempts to contact Sage prior to unblinding the study 
treatment administered to a participant. Requests from the investigator about the treatment 
administered to study participants should be discussed with the Sage medical monitor. If the 
unblinding occurs without Sage’s knowledge, the investigator must notify Sage within 24 hours 
of breaking the blind. All circumstances surrounding a premature unblinding must be clearly 
documented in the source records. 
In all cases where the IP allocation for a participant is unblinded, pertinent information 
(including the reason for unblinding) must be documented in the participant’s records and on the 
eCRF. 

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10. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
10.1. 
Investigational Products 
10.1.1. 
Blinded Investigational Products 
SAGE-217 is 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, colloidal silicon 
dioxide, and sodium stearyl fumarate as excipients. Capsules will be available in 20-mg and 
30-mg dose strengths. 
Blinded placebo will be provided as hard gelatin capsules matched in appearance to SAGE-217. 
10.1.2. 
Open-label Investigational Product 
Sertraline tablets, packaged and labeled by the commercial manufacturer, will be supplied by a 
third-party vendor. Sertraline is to be stored and administered according to the package insert. 
Sertraline during this study is for use only as directed in this protocol. 
10.2. 
Blinded Investigational Product Packaging and Labeling 
SAGE-217 and placebo will be provided to the clinic pharmacist and/or designated site staff 
responsible for dispensing the blinded IP in appropriately labeled, participant-specific kits 
containing sealed unit doses. Each unit dose for 40-mg and 50-mg dose levels consists of 
2 capsules. Additional information regarding the packaging and labeling is provided in the 
Pharmacy Manual. 
Labels with all required information and conforming to all applicable FDA Code of Federal 
Regulations and Good Manufacturing Practices/Good Clinical Practices guidelines will be 
prepared by the sponsor for SAGE-217 and placebo. 
10.3. 
Blinded Investigational Product Storage 
SAGE-217 and placebo is to be stored at room temperature (59 to 86°F; 15 to 30°C), safely and 
separately from other drugs. 
10.4. 
Blinded Investigational Product Preparation 
Not applicable. 
10.5. 
Blinded and Open-label Investigational Product Administration 
Blinded IP and open-label sertraline are to be administered orally once daily at approximately 
8 PM with fat-containing food (eg, within 1 hour of an evening meal which contains fat, or with 
a fat-containing snack). Examples of fat-containing snacks include nuts, peanut butter, avocado, 
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If a participant misses a dose of blinded IP or open-label sertraline, the participant should skip 
that dose (ie, they should not take the dose in the morning) and take the next scheduled dose the 
next evening. 
10.6. 
Blinded Investigational Product Accountability, Handling, and 
Disposal 
Upon receipt of blinded IP dosing kits, the investigator(s), or the responsible pharmacist or 
designee, will inspect the kits and complete and follow the instructions regarding receipt and 
storage in the SAGE-217 Investigator’s Brochure and (where applicable) in the Pharmacy 
Manual. A copy of the shipping documentation will be kept in the study files. 
The designated site staff will dispense the participant-specific kits to participants at the planned 
dispensation visit intervals outlined in Table 2. Site staff will access the IRT at the Screening 
Visit to obtain a participant identification (ID) number for each participant that has signed an 
informed consent form. On Day 1, site staff will access the IRT and provide the necessary 
participant-identifying information, including the participant ID number assigned at Screening, 
to randomize the eligible participant into the study and obtain the medication ID number for the 
blinded IP to be dispensed to that participant. The medication ID number and the number of 
blinded capsules dispensed must be recorded. 
At the subsequent blinded IP-dispensing visit, the investigator or designee will access the IRT, 
providing the same participant ID number assigned at Screening, to obtain the medication ID 
number for the blinded IP to be dispensed at that visit. The medication ID number, the number of 
capsules dispensed, and the number of capsules returned by the participant at this visit must be 
recorded. 
If dispensing errors or discrepancies are discovered by site staff or sponsor’s designee, the 
sponsor must be notified immediately. 
The blinded IP provided is for use only as directed in this protocol. The investigator or designee 
must keep a record of all blinded IP received, used and returned/discarded. 
Sage Therapeutics will be permitted access to the study supplies at any time and with appropriate 
notice during or after completion of the study to perform drug accountability and reconciliation. 
The investigator, pharmacist, or qualified designee is responsible for drug accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final disposition records). 
At the end of the study, any unused blinded IP will be returned to Sage Therapeutics for 
destruction or destroyed locally per the site’s procedures; disposition of blinded IP will be 
documented. 
10.7. 
Blinded Investigational Product Complaints 
A product complaint is any written, electronic, or verbal expression of dissatisfaction regarding 
the identity, quality, reliability, safety, purity, potency, effectiveness or performance (applicable 
for approved marketed products) of a drug product after it is released for distribution. 
In the course of conduct of the study, study personnel may become aware of a product complaint 
associated with the use of a Sage product. Personnel shall notify Sage within 24 hours by 

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forwarding the product complaint information via the contact information provided in Table 1. 
Where possible, personnel should segregate and retain any product, materials, or packaging 
associated with the product complaint until further instruction is provided by Sage or its 
designated representative(s). 

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11. 
EFFICACY AND CLINICAL PHARMACOLOGY ASSESSMENTS 
11.1. 
Efficacy Assessments 
11.1.1. 
Hamilton Rating Scale for Depression 
The primary outcome measure is the change from baseline in 17-item HAM-D total score at the 
end of the Treatment Period (Day 15). Every effort should be made for the same rater to perform 
all HAM-D assessments for an individual participant. An assessment timeframe of past 7 days 
(1 week) will be used at Screening, and ‘Since Last Visit’ will be used for all other visits. 
The 17-item HAM-D will be used to rate the severity of depression in participants who are 
already diagnosed as depressed (Williams 2013 a; Williams 2013b). 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 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. 
11.1.2. 
Montgomery-Åsberg Depression Rating Scale 
The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive 
episodes in participants with mood disorders. It was designed as an adjunct to the HAM-D that is 
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 (Williams 2008). 
The MADRS total score will be calculated as the sum of the 10 individual item scores. 
11.1.3. 
Hamilton Anxiety Rating Scale 
The 14-item HAM-A will be used to rate the severity of symptoms of anxiety (Williams 2013c; 
Williams 2013d). Each of the 14 items is defined by a series of symptoms, and measures both 
psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical 
complaints related to anxiety). Scoring for HAM-A is calculated by assigning scores of 0 (not 
present) to 4 (very severe), with a total score range of 0 to 56, where <17 indicates mild severity, 
18 to 24, mild to moderate severity, and 25 to 30, moderate to severe severity. The HAM-A total 
score will be calculated as the sum of the 14 individual item scores. 

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11.1.4. 
Clinical Global Impressions 
The CGI is a validated measure often utilized in clinical studies to allow clinicians to integrate 
several sources of information into a single rating of the participant’s condition. The CGI scale 
consists of 3 items. Only the first 2 items are being used in this study. 
The CGI-S uses a 7-point Likert scale to rate the severity of the participant’s illness at the time of 
assessment, relative to the clinician’s past experience with participants who have the same 
diagnosis. Considering total clinical experience, a participant is assessed on severity of mental 
illness at the time of rating as 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 
4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = extremely ill (Busner 2007a). 
The CGI-I employs a 7-point Likert scale to measure the overall improvement in the 
participant’s condition posttreatment. The investigator will rate the participant’s total 
improvement whether or not it is due entirely to drug treatment. Response choices include: 
0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no 
change, 5 = minimally worse, 6 = much worse, and 7 = very much worse (Busner 2007b). The 
CGI-I is only rated at posttreatment assessments. By definition, all CGI-I assessments are 
evaluated against baseline conditions. CGI-I response will be defined as having a CGI-I score of 
“very much improved” or “much improved.” 
 
 
 
 
 
 
 
 
 
 
 
 
11.1.6. 
Patient Health Questionnaire 
The PHQ-9 is a participant-rated depressive symptom severity scale. To monitor severity over 
time for newly diagnosed participants or participants in current treatment for depression, 
participants may complete questionnaires at baseline and at regular intervals thereafter. Scoring 
is based on responses to specific questions, as follows: 0 = not at all; 1 = several days; 2 = more 
than half the days; and 3 = nearly every day. 
The PHQ-9 total score will be calculated as the sum of the 9 individual item scores. The PHQ-9 
total score will be categorized as follows: 1 to 4 = minimal depression, 5 to 9 = mild depression, 
10 to 14 = moderate depression, 15 to 19 = moderately severe depression; and 20 to 27 = severe 
depression. 

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12. 
SAFETY ASSESSMENTS 
12.1. 
Safety Parameters 
All assessments will be conducted according to the Schedule of Assessments (Table 2). 
12.1.1. 
Demographic/Medical History 
Demographic characteristics (age, race, gender, ethnicity, employment status, highest education 
level, marital/civil status) and a full medical history, including: family psychiatric history, 
generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, persistent 
depressive disorder, postpartum depression, substance use disorder, alcohol use disorder, MDD 
with seasonal pattern, MDD with psychotic features, premenstrual dysphoric disorder, MDD 
with atypical features, schizophrenia; or schizoaffective disorder will be documented. The 
diagnosis of MDD will be determined using the SCID-5-CT. If available, the disease code 
associated with the diagnosis of MDD based on the tenth revision of the International Statistical 
Classification of Diseases and Related Health Problems (ICD-10) should be recorded. 
The Massachusetts General Hospital Antidepressant Treatment Response Questionnaire 
(MGH ATRQ) will be used to determine whether the participant has treatment-resistant 
depression, defined as persistent depressive symptoms despite treatment during the current major 
depressive episode with adequate doses of antidepressants from 2 different classes for at least 4 
weeks of treatment. 
12.1.2. 
Weight and Height 
Height (Screening only) and weight will be measured and documented. 
12.1.3. 
Physical Examination 
Physical examinations assessing body systems (eg, head, eyes, ears, nose, and throat; heart; 
lungs; abdomen; and extremities), as well as cognitive and neurological examinations and mental 
status examinations will be conducted and documented. Thereafter, abbreviated physical 
examinations will include brief assessments of general appearance, cardiovascular, respiratory, 
gastrointestinal, and neurological systems, followed by a targeted physical examination as 
needed. Unscheduled, symptom-directed physical examinations may also be conducted at the 
investigator’s discretion. Whenever possible, the same individual is to perform all physical 
examinations for a given participant. Unscheduled brief, symptom-driven physical examinations 
may also be conducted per the investigator’s discretion. 
Any abnormality in physical examinations will be interpreted by the investigator as abnormal, 
not clinically significant (NCS); or abnormal, clinically significant (CS) in source documents. 
New or worsening abnormalities that are judged to be clinically significant will be recorded as 
AEs, assessed according to Section 12.2.1. 
12.1.4. 
Vital Signs 
Vital signs comprise both supine and standing for systolic and diastolic blood pressure and heart 
rate measurements. Heart rate and blood pressure are to be collected in supine position after the 
participant has been resting for 5 minutes and then after approximately 3 minutes in the standing 

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position. Respiratory rate and temperature are collected once, in either position. Vital signs will 
be documented. When vital signs are scheduled at the same time as blood draws, vital signs will 
be obtained first. 
Any abnormality in vital signs will be interpreted by the investigator as abnormal, NCS or 
abnormal, CS in source documents. New or worsening abnormalities that are judged to be 
clinically significant will be recorded as AEs, assessed according to Section 12.2.1. 
12.1.5. 
Electrocardiogram (ECG) 
Supine 12-lead ECGs will be performed in triplicate at all scheduled time points. The standard 
intervals (heart rate, PR, QRS, QT, and QTcF) as well as any rhythm abnormalities will be 
recorded. 
 
 
12.1.6. 
Laboratory Assessments 
Samples will be collected in accordance with acceptable laboratory procedures detailed in the 
laboratory manual. 
The central laboratory will perform laboratory tests for hematology, serum chemistry, urinalysis, 
and coagulation. The results of laboratory tests will be returned to the investigator, who is 
responsible for reviewing and filing these results. All laboratory safety data will be transferred 
electronically to Sage Therapeutics or designee in the format requested by Sage Therapeutics. 
Laboratory reports must be signed and dated by the investigator or subinvestigator indicating that 
the report has been reviewed and any abnormalities have been assessed for clinical significance. 
Any abnormalities identified prior to first dose will require clear and complete documentation in 
the source documents as to the investigator’s assessment of not clinically significant before 
proceeding with randomization. 
All clinical laboratory test results outside the central laboratory’s reference range will be 
interpreted by the investigator as abnormal, NCS; or abnormal, CS in source documents. New or 
worsening abnormalities that are judged to be clinically significant will be recorded as AEs, 
assessed according to Section 12.2.1. A clinically significant laboratory abnormality following 
participant randomization will be followed until the abnormality returns to an acceptable level or 
a satisfactory explanation has been obtained. 
The clinical laboratory tests to be performed are listed in Table 3. 
Table 3: 
Clinical Laboratory Tests 
Hematology  
Serum Chemistry 
Urinalysis 
Coagulation 
Red blood cell count 
Hemoglobin 
Hematocrit 
White blood cell count with 
differential 
Platelet count 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
pH 
Specific gravity 
Protein 
Glucose 
Red blood cell 
Nitrite 
Activated partial 
thromboplastin 
time 
Prothrombin time 
International 
normalized ratio 

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Red Blood Cell Indices 
(MCV, MCH, MCHC) 
Reflex to Red blood cell 
morphology if indices are 
abnormal 
Total protein 
Creatinine 
Blood urea nitrogen 
Creatine kinase 
Gamma-glutamyl transferase 
Potassium 
Sodium 
Lactate dehydrogenase 
Glucose 
Chloride 
Bicarbonate 
Calcium 
Phosphorus 
Triglycerides 
Thyroid stimulating hormone 
(TSH) 
Reflex to free T3/T4 if 
TSH is abnormal  
Leukocyte 
esterase 
Ketones 
Bilirubin 
Urobilinogen 
Diagnostic  
 
 
 
Serum 
Urine 
Breathalyzer 
 
Hepatitis B 
Hepatitis C 
Reflex HCV RNA 
HIV-1 and -2 
Female participants that are 
not surgically sterile and do 
not meet the protocol-
defined criteria for being 
postmenopausal: serum 
hCG 
Female participants, if 
menopause is suspected 
and not surgically sterile: 
FSH 
Drug screen including: 
amphetamines, 
barbiturates, 
benzodiazepines, 
cannabinoids, cocaine, 
opiates, phencyclidine 
Female participants that are 
not surgically sterile and do 
not meet the protocol-
defined criteria for being 
postmenopausal: urine 
hCG  
Alcohol 
 
Abbreviations: FSH = follicle stimulating hormone; hCG = human chorionic gonadotropin; HCV = hepatitis C 
virus; HIV = human immunodeficiency virus 
A serum follicle stimulating hormone test will be conducted at Screening to confirm whether a 
female participant with ≥12 months of spontaneous amenorrhea meets the protocol-defined 
criteria for being postmenopausal (Section 8.1). 
12.1.6.1. Drugs of Abuse and Alcohol 
Urine toxicology tests will be performed for selected drugs of abuse (see Table 3). A breath test 
for alcohol will be performed. 

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12.1.6.2. Pregnancy Screen 
For female participants that are not surgically sterile, a serum pregnancy test will be performed at 
Screening and a urine pregnancy test will be performed at all other scheduled time points 
thereafter, including the ET visit for participants who prematurely discontinue. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Adverse Event Definition 
An AE is any untoward medical occurrence in a patient or clinical investigation participant 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the use of a 
medicinal (investigational) product whether or not related to the medicinal (investigational) 
product. In clinical studies, an AE can include an undesirable medical condition occurring at any 
time, including baseline or washout periods, even if no study treatment has been administered. 
A TEAE is defined as an AE with onset after the start of IP, or any worsening of a pre-existing 
medical condition/AE with onset after the start of IP and throughout the study. The term IP 
includes any Sage IP, a comparator, or a placebo administered in a clinical study. 
 are considered AEs 
if they result in discontinuation or interruption of study treatment, require therapeutic medical 
intervention, meet protocol specific criteria (if applicable) or if the investigator considers them to 
be clinically significant. Any abnormalities that meet the criteria for an SAE should be reported 
in an expedited manner. 
 
 that are clearly attributable to another AE do not require discrete reporting (eg, electrolyte 
disturbances in the context of dehydration, chemistry and hematologic disturbances in the 
context of sepsis). 
All AEs that occur after any participant has signed the informed consent and throughout the 
duration of the study, whether or not they are related to the study, must be reported to Sage 
Therapeutics. 
Participants who discontinue the IP due to an AE, regardless of investigator-determined 
causality, should be followed until the event is resolved, considered stable, or the investigator 
determines the event is no longer clinically significant. Any AEs that are unresolved at the 
participant’s last AE assessment in the study are followed up by the investigator for as long as 
medically indicated, but without further recording in the eCRF. The sponsor or its representative 
retains the right to request additional information for any patient with ongoing AE(s)/SAE(s) at 
the end of the study, if judged necessary. 
12.2.2. 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Places the participant at immediate risk of death (a life-threatening event); however, 
this does not include an event that, had it occurred in a more severe form, might have 
caused death 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 

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An SAE may also be any other medically important event that, in the opinion of the investigator 
may jeopardize the participant or may require medical intervention to prevent 1 of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization). 
All SAEs that occur after any participant has signed the ICF and throughout the duration of the 
study, whether or not they are related to the study, must be recorded on the SAE report form 
provided by Sage Therapeutics. Any SAE that is ongoing when the participant completes their 
final study visit, will be followed by the investigator until the event has resolved, stabilized, 
returned to baseline status, or until the participant dies or is lost to follow up. 
A prescheduled or elective procedure or routinely scheduled treatment will not be considered an 
SAE, even if the participant is hospitalized. The site must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or on a waiting list to be scheduled) prior to obtaining the participant’s 
consent to participate in the study. 
• The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress, in the opinion of an 
investigator, between the participant’s consent to participate in the study and at the 
time of the procedure or treatment. 
12.2.3. 
Relationship to Investigational Product 
The investigator must make the determination of relationship to the IP for each AE (not related, 
related). The following definitions should be considered when evaluating the relationship of AEs 
and SAEs to the IP. 
Not Related 
An AE will be considered “not related” to the use of the IP if there is not a reasonable 
possibility that the event has been caused by the IP. Factors pointing towards this 
assessment include but are not limited to: the lack of temporal relationship between 
administration of the IP and the event, the presence of biologically implausible 
relationship between the product and the AE, or the presence of a more likely 
alternative explanation for the AE 
Related 
An AE will be considered “related” to the use of the IP if there is a reasonable 
possibility that the event may have been caused by the product under investigation. 
Factors that point towards this assessment include but are not limited to: a positive 
rechallenge, a reasonable temporal sequence between administration of the drug and 
the event, a known response pattern of the suspected drug, improvement following 
discontinuation or dose reduction, a biologically plausible relationship between the 
drug and the AE, or a lack of alternative explanation for the AE 
12.2.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the participant and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 

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investigational site. The AE term should be reported in standard medical terminology when 
possible. For each AE, the investigator will evaluate and report the onset (date and time), 
resolution (date and time), intensity, causality, action taken, outcome and seriousness (if 
applicable), and whether or not it caused the participant to discontinue the IP or withdraw early 
from the study. 
Intensity will be assessed according to the following scale: 
• Mild: symptom(s) barely noticeable to participant or does not make participant 
uncomfortable; does not influence performance or functioning; prescription drug not 
ordinarily needed for relief of symptom(s) 
• Moderate: symptom(s) of a sufficient severity to make participant uncomfortable; 
performance of daily activity is influenced; participant is able to continue in study; 
treatment for symptom(s) may be needed 
• Severe: symptom(s) cause severe discomfort; symptoms cause incapacitation or 
significant impact on participant’s daily life; severity may cause cessation of 
treatment with IP; treatment for symptom(s) may be given and/or participant 
hospitalized 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.2.2. An AE of severe intensity 
may not necessarily be considered serious. 
12.2.5. 
Reporting Serious Adverse Events 
In order to adhere to all applicable laws and regulations for reporting an SAE(s), the study site 
must notify Sage or designee within 24 hours of the study site staff becoming aware of the 
SAE(s). The investigator must complete, sign and date the SAE report form, verify the accuracy 
of the information recorded on the SAE report form with the corresponding source documents, 
and send a copy to Sage or designee. 
Additional follow-up information, if required or available, should all be sent to Sage or designee 
within 24 hours of receipt on a follow-up SAE report form and placed with the original SAE 
information and kept with the appropriate section of the eCRF and/or study file. 
SAEs occurring after the designated follow up time for the study, should be reported to Sage or 
designee according to the timelines noted above only if the investigator considers the SAE 
related to IP. 
Sage, or designee, is responsible for notifying the relevant regulatory authorities of certain 
events. It is the principal investigator’s responsibility to notify the IRB/IEC of all SAEs that 
occur at his or her site. Investigators will also be notified of all suspected unexpected serious 
adverse reactions (SUSARs) that occur during the clinical study. IRBs/IECs will be notified of 
SAEs and/or SUSARs as required by local law. 
In addition, appropriate personnel in Sage Drug Safety and Pharmacovigilance or designee will 
unblind SUSARs for the purpose of regulatory reporting. Sage or designee will submit SUSARs 
(in blinded or unblinded fashion) to regulatory agencies according to local law. Sage, or 
designee, will submit SUSARs to investigators in a blinded fashion. 

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12.3. 
Pregnancy 
If a participant becomes pregnant after the first administration of IP, pregnancy information must 
be collected and recorded on the Pregnancy form and submitted to the sponsor within 24 hours of 
learning of the pregnancy. Details will be collected for all pregnancies for which conception was 
likely to have occurred after the start of IP administration until 5 terminal half-lives following 
the last administration of IP or until the completion of the study whichever is longer. Any 
pregnancy occurring in that time frame will be followed until delivery or termination of the 
pregnancy. The investigator will also attempt to collect pregnancy information on any 
participant’s partner who becomes pregnant after the participant has received the first 
administration of IP. After obtaining the necessary signed informed consent from the pregnant 
partner directly, the investigator will follow the same pregnancy reporting procedures specified 
for pregnant participants. 
The participant or participant’s partner will be followed to determine the outcome of the 
pregnancy. The outcome of all pregnancies (eg, spontaneous abortion, elective abortion, normal 
birth) must be followed and documented even if the participant was discontinued from the study. 
The investigator will collect follow-up information on the participant or participant’s partner and 
the neonate, and the information will be forwarded to Sage or designee. Generally, follow-up 
will not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an IP may have 
interfered with the effectiveness of a contraceptive medication. Any complication during 
pregnancy (eg, anemia, infections, pre-eclampsia) should be reported as an AE/SAE. If the 
outcome of the pregnancy meets the criteria for immediate classification as an SAE (ie, 
spontaneous abortion, stillbirth, neonatal death,), the investigator should follow the procedures 
for reporting an SAE. 
12.4. 
Overdose 
Overdoses, regardless of presence of associated clinical manifestation(s) (eg, headache, 
abnormal laboratory value) will be considered an AE and recorded as such on the eCRF. Any 
clinical manifestation(s) of overdose must also be recorded as an AE on the eCRF. In addition, 
all overdoses must be recorded on an Overdose form and sent to Sage or designee within 
24 hours of the site becoming aware of the overdose. 

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13. 
STATISTICS 
Detailed description of the analyses to be performed in the study will be provided in the 
statistical analysis plan (SAP). The SAP will be finalized and approved prior to database lock. 
Any changes/additions to the SAP following database lock will be described in detail in the 
clinical study report. 
13.1. 
Data Analysis Sets 
The Full Analysis Set (FAS) is defined as all randomized participants in the Safety Set who have 
a valid baseline as well as at least 1 postbaseline HAM-D evaluation. 
The Randomized Set is defined as all participants who are randomized. 
The Safety Set is defined as all participants who receive at least 1 dose of IP. 
 
 
13.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data. All participants will be used in the analyses, 
as per the analysis populations, using all nonmissing data available. No imputation process will 
be used to estimate missing data. A sensitivity analysis will be used to investigate the impact of 
missing data if ≥5% of participants in any treatment group have missing data. 
13.3. 
General Considerations 
All participant data, including those that are derived, that support the tables and figures will be 
presented in the participant data listings. Some data may be presented only in a participant data 
listing, some may be presented with a corresponding table or figure; these will be indicated in 
relevant sections below. All summaries will be provided by treatment – either by randomized 
treatment or actual treatment received. Actual treatment is defined as SAGE-217 if the 
participant received any SAGE-217 (50 mg or 40 mg) at any time; otherwise, it is placebo. 
If a participant takes any dose of SAGE-217, the participant’s actual treatment is considered as 
SAGE-217 regardless of the treatment to which the participant has been randomized. 
For the purpose of all primary and secondary analyses where applicable, baseline is defined as 
the last measurement prior to start of IP administration. 
Continuous endpoints will be summarized with number (n), mean, standard deviation, median, 
minimum, and maximum. In addition, change from baseline values will be calculated at each 
time point and summarized descriptively. For categorical endpoints, descriptive summaries will 
include counts and percentages. 
13.4. 
Demographics and Baseline Characteristics 
Demographic data, such as age, race, and ethnicity, and baseline characteristics, such as height, 
weight, and BMI, will be summarized using the Safety Set. 

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Hepatitis, HIV, drug and alcohol, and pregnancy screening results will be listed, but not 
summarized as they are considered part of the inclusion/exclusion criteria. 
Medical history will be listed by participant. 
13.5. 
Efficacy Analysis 
Efficacy data will be summarized using appropriate descriptive statistics and other data 
presentation methods where applicable; participant listings will be provided for all efficacy data. 
Participants will be analyzed according to randomized treatment. 
The estimand for the primary efficacy analysis is the mean change from baseline in HAM-D total 
score at Day 15. Using the FAS, this will be analyzed using a mixed-effects model for repeated 
measures (MMRM); the model will include treatment, baseline HAM-D total score, assessment 
time point, and time point-by-treatment as explanatory variables. All explanatory variables will 
be treated as fixed effects. All postbaseline time points will be included in the model. The main 
comparison will be between SAGE-217 + sertraline and placebo + sertraline at the Day 15 time 
point. Model-based point estimates (ie, least squares means, 95% confidence intervals, and 
p values) will be reported where applicable. An unstructured covariance structure will be used to 
model the within-participant errors. The Toeplitz compound symmetry, Autoregressive (1) 
[AR(1)] covariance structure will be used in that sequence if there is a convergence issue with 
the unstructured covariance model. If convergence is still not achieved, no results will be 
reported. 
Similar to those methods described above for the primary endpoint, an MMRM will be used for 
the analysis of the change from baseline in other time points in HAM-D total score, MADRS 
total score, HAM-A total score, 
 PHQ-9 total score, and selected individual items 
and/or subscale scores in HAM-D. 
Generalized estimating equation (GEE) methods will be used for the analysis of HAM-D 
response (defined as ≥50% reduction from baseline in HAM-D total score) and HAM-D 
remission (defined as HAM-D total score ≤7.0). GEE models will include terms for 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 + sertraline and 
placebo + sertraline at the Day 15 time point. Model-based point estimates (ie, odds ratios), 95% 
confidence intervals, and p values will be reported. 
A GEE method will also be used for the analysis of CGI-I response, including terms for 
treatment, baseline CGI-S score, assessment time point, and time point-by-treatment as 
explanatory variables. 
13.6. 
Safety Analyses 
Safety and tolerability of SAGE-217 will be evaluated by TEAEs, changes from baseline in 
 
. 
 
 Safety data will be listed by participant and summarized by treatment group. All 
safety summaries will be presented for the Safety Set using actual treatment received. Where 
applicable, ranges of potentially clinically significant values will be provided in the SAP. 

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13.6.1. 
Adverse Events 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
Version 18.1 or higher. A TEAE is defined as an AE with onset after the first dose of IP. The 
analysis of AEs will be based on the concept of TEAEs. The incidence of TEAEs will be 
summarized by System Organ Class and preferred term. In addition, summaries will be provided 
by intensity (mild, moderate, severe) and by causality (related, not related) to IP. 
Any TEAEs leading to discontinuation of treatment or withdrawal from the study and any 
treatment-emergent SAEs will be summarized. 
All AEs and SAEs (including those with onset or worsening before the start of IP) through the 
end of the study will be listed. 
 
 
 
 
 
 
 
13.6.3. 
Physical Examinations 
The occurrence of a physical examination (yes/no) and the date performed will be listed by 
participant. 
 
 
 
 
 
13.6.5. 
12-Lead Electrocardiogram 
The following ECG parameters will be listed for each of the triplicate ECGs for each participant: 
heart rate, PR, QRS, QT, and QTcF. The derived mean of each parameter will also be listed. 
Mean ECG data will be summarized by visit. Potentially clinically significant values of QTcF 
will be summarized by treatment. Electrocardiogram findings will be listed by participant and 
visit. 
13.6.6. 
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 2015, or later. 
All medications taken within 30 days prior to informed consent through the duration of the study 
will be recorded. In addition, all psychotropic medications taken in the 6 months prior to 
Screening will be recorded on the eCRF. Those medications taken prior to the initiation of the 
start of IP will be denoted “Prior”. Those medications taken prior to the initiation of the IP and 
continuing beyond the initiation of the IP or those medications started at the same time or after 
the initiation of the IP will be denoted “Concomitant”. 

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Medications will be presented according to whether they are “Prior” or “Concomitant” as 
defined above. 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 participant, start date, and 
verbatim term. 
 
 
 
 
 
 
 
 
 
13.6.9. 
Other Safety Analysis 
 
 
 
 
 
13.8. 
Sample Size and Power 
Using a 2-sided alpha level of 0.05, a sample size of 382 total evaluable participants would 
provide 90% power to detect a treatment difference (between SAGE-217 + sertraline and 
placebo + sertraline) of approximately 3 points in the primary endpoint, change from baseline in 
HAM-D total score at Day 15, assuming standard deviation of 9 points. Assuming a 
10% dropout rate and a 1:1 randomization ratio within each treatment group, approximately 
424 total randomized participants will be required to obtain a total of 382 evaluable participants. 
Evaluable participants are defined as those randomized participants who receive IP and have 
valid baseline and at least 1 postbaseline HAM-D assessment. 
13.8.1. 
Interim and Data Monitoring Committee Analyses 
No interim analyses or data monitoring committee analyses will be conducted. 

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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Before an investigational site can enter a participant into the study, a representative of Sage 
Therapeutics will visit the investigational study site per Sage SOPs to: 
• Determine the adequacy of the facilities 
• Discuss with the investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Sage Therapeutics or its representatives. 
This will be documented in a Clinical Trial Agreement between Sage Therapeutics and 
the investigator. 
During the study, a monitor from Sage Therapeutics or representative 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 case report forms, and that IP accountability checks are being 
performed 
• Perform source data verification. This includes a comparison of the data in the case report 
forms with the participant’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 
participant (eg, clinic charts). 
• Record and report any protocol deviations not previously sent to Sage Therapeutics. 
• Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to Sage Therapeutics and those SAEs that met criteria for 
reporting have been forwarded to the IRB or independent ethics committee. 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
14.2. 
Audits and Inspections 
Sage Therapeutics or authorized representatives of Sage Therapeutics, a regulatory authority, or 
an Independent Ethics Committee or an Institutional Review Board may visit the site to perform 
an audit(s) or inspection(s), including source data verification. The purpose of a Sage 
Therapeutics audit or a regulatory authority 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/ICH GCP guidelines, and any applicable regulatory requirements. The investigator should 
contact Sage Therapeutics immediately if contacted by a regulatory agency or IRB/IEC about an 
inspection. 

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14.3. 
Institutional Review Board (IRB) or Ethics Committee (EC) 
The principal investigator must obtain IRB (or EC) approval for the clinical study prior to 
enrolling a participant. Initial IRB (or EC) approval, and all materials approved by the IRB (or 
EC) for this study including the participant consent form and recruitment materials must be 
maintained by the investigator and made available for inspection. 
 

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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practice and all applicable regulatory requirements, 
Sage Therapeutics may conduct a quality assurance audit(s) at the clinical site. Please see 
Section 14.2 for more details regarding the audit process. 
The investigator must have adequate quality control practices to ensure that the study is 
performed in a manner consistent with the protocol, GCP/ICH GCP guidelines, and applicable 
regulatory requirements. The investigator is responsible for reviewing all identified protocol 
deviations. Significant protocol deviations should be reported to the IRB/IEC per the IRB/IEC’s 
written procedures. 
The investigator is responsible for supervising any individual or party to whom the investigator 
delegates study-related duties and functions conducted at the study site. When the investigator 
retains the services of any individual or party to perform study-related duties and functions, the 
investigator must ensure the individual or party is qualified to perform study-related duties and 
functions and should implement procedures to ensure the integrity of the study-related duties and 
functions performed, and any data generated. 
The investigator must maintain adequate and accurate source documents and study records that 
include all pertinent observations on each of the site’s study participants. Source data must be 
attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data 
should be traceable, should not obscure the original entry, and should be explained, if necessary 
to provide clarification. 
 

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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
given a written and dated approval or favorable opinion by an IRB or IEC as appropriate. The 
investigator must obtain and document approval before he or she can enroll any participant into 
the study. The IRB or IEC must supply to the sponsor a list of the IRB/IEC membership and a 
statement to confirm that the IRB/IEC is organized and operates according to GCP and 
applicable laws and regulations. 
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 participants for the study. The protocol must be re-approved by the 
IRB or IEC upon receipt of amendments and annually, as local regulations require. 
The principal investigator is also responsible for providing the IRB or IEC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. Sage Therapeutics 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. In addition, the principal investigator must 
inform the IRB/IEC and sponsor of any changes significantly affecting the conduct of the study 
and/or increasing the risk to participants (eg, violations to the protocol or urgent safety measures 
taken for participant safety). 
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH and GCP guidelines, as well as all 
applicable regional or national regulatory requirements. 
16.3. 
Written Informed Consent 
Prior to enrolling a study participant, the investigator(s) will ensure that the participant is given 
full and adequate oral and written information about the nature, purpose, possible risk and 
benefit of the study. Participants must also be notified that they are free to discontinue from the 
study at any time. The participant should be given the opportunity to ask questions and allowed 
time to consider the information provided. 
When the participant decides to participate in the study, the participant (or the participant’s, 
parent or legally authorized representative) must provide signed and dated informed consent. The 
written consent must be obtained before conducting any study procedures. The investigator must 
document the consent process in the participant’s source records. The investigator must maintain 
the original, signed ICF. A copy of the signed ICF must be given to the participant or to the 
participant’s parent or legally authorized representative. 
Throughout the study participants should be informed of any changes made to the study and as 
new safety and or risk information becomes known. The provision of this information will be 

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documented in the participant’s source records, and when applicable, an updated ICF will be 
provided. 

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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Inspection of Records 
Sage Therapeutics or its representative(s) will be allowed to conduct site visits at the 
investigation facilities for the purpose of monitoring any aspect of the study. The investigator 
agrees to allow the monitor to inspect the facility, drug storage area, drug accountability records, 
participant charts and study source documents, and other records relative to study conduct. 
Inspection of the study by a Regulatory Authority may occur at any time. The investigator must 
agree to the inspection of study-related records and source documents by the Regulatory 
Authority representative(s). 
17.2. 
Retention of Records 
The principal investigator must maintain all documentation relating to the study for the period 
outlined in the site contract, or for a period of 2 years after the last marketing application 
approval, and until there are no pending or contemplated marketing applications in an ICH 
region or at least 2 years have elapsed since the formal discontinuation of clinical development 
of the investigational product. Sage is responsible to inform the investigator/institution as to 
when study documents no longer need to be retained. 

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18. 
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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19. 
LIST OF REFERENCES 
Busner J, Targum S. CGI-S. (2007a), as adapted from Kay, Stanley R, Positive and Negative 
Symptoms in Schizophrenia:Assessment and Research. Clinical and Experimental Psychiatry, 
Monograph No. 5. Brunner/Mazel, 1991. Modified from Guy W. Clinical Global Impressions: In 
ECDEU Assessment Manual for Psychopharmacology. 1976; 218-22. Revised DHEW Pub. 
(ADM) Rockville, MD: National Institute for Mental Health. 
Busner J, Targum S. CGI-I. (2007b), as adapted from Spearing, et al. Psychiatry Research, 
1997;73:159-71. Modified from Guy W. Clinical Global Impressions: In ECDEU Assessment 
Manual for Psychopharmacology. 1976; 218-22. Revised DHEW Pub. (ADM) Rockville, MD: 
National Institute for Mental Health. 
Conradi HJ, Ormel J, de Jonge P. Presence of individual (residual) symptoms during depressive 
episodes and periods of remission: a 3-year prospective study. Psychol Med. 2011 
Jun;41(6):1165-74. 
DSM-5. Diagnostic and statistical manual of mental disorders (5th ed.). American Psychiatric 
Association 2013. Arlington, VA: American Psychiatric Publishing. 
Greenberg PE, Fournier AA, Sisitsky T, Pike CT, Kessler RC. The economic burden of adults 
with major depressive disorder in the United States (2005 and 2010). J Clin Psychiatry. 2015 
Feb;76(2):155-62. 
Nierenberg AA, Husain MM, Trivedi MH, et al. Residual symptoms after remission of major 
depressive disorder with citalopram and risk of relapse: a STAR*D report. Psychol Med. 
2009;40(1):41-50. 
Nierenberg AA. Residual symptoms in depression: prevalence and impact. J Clin Psychiatry. 
2015;76(11):e1480. 
Olfson M, Marcus SC, Shaffer D. Antidepressant drug therapy and suicide in severely depressed 
children and adults: A case-control study. Archives of general psychiatry. 2006:63(8);865-872. 
 
 
 
 
Romera I, Pérez V, Ciudad A, et al. Residual symptoms and functioning in depression, does the 
type of residual symptom matter? A post-hoc analysis. BMC Psychiatry. 2013 Feb 11;13:51. 
Rudolph U, Knoflach F. Beyond classical benzodiazepines: novel therapeutic potential of 
GABAA receptor subtypes. Nat Rev Drug Discov. 2011 Jul 29;10(9):685-97. 
Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed 
outpatients requiring one or several treatment steps: a STAR* D report. Am J Psychiatry. 
2006;163(11):1905-1917. 
Sadock J, Sadock VA. Kaplan and Sadock’s Synopsis of Psychiatry, Tenth Edition. Philadelphia, 
PA: Lippincott Williams and Wilkins; 2007, pp 557-560, 1080-1091. 

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Trivedi MH, Rush AJ, Wisniewski SR, et al. (STAR*D Study Team). Evaluation of outcomes 
with citalopram for depression using measurement-based care in STAR*D: implications for 
clinical practice. Am J Psychiatry. 2006 Jan;163(1):28-40. 
 
 
Williams JBW, Kobak KA. Development and reliability of a structured interview guide for the 
Montgomery-Asberg Depression Rating Scale (SIGMA). Br J Psychiatry. 2008;192:52-8. 
Williams JBW. SIGH-D 24hr: V1.3 – 24 HR Version. 2013a. 
Williams JBW. SIGH-D Past week: Past Week Version. 2013b. 
Williams JBW. SIGH-A 24hr: V1.3 – 24 HR Version. 2013c. 
Williams JBW. SIGH-A Past week: Past Week Version. 2013d. 

217-MDD-305 Summary of Changes 
Sage Therapeutics 
Version 4, Amendment 3 
 
 
1 
Protocol 217-MDD-305, Amendment 3 
Date of Draft Amendment: 10 January 2022 
A PHASE 3, RANDOMIZED, DOUBLE-BLIND STUDY COMPARING THE EFFICACY 
AND SAFETY OF SAGE-217 PLUS AN ANTIDEPRESSANT VERSUS PLACEBO PLUS 
AN ANTIDEPRESSANT IN ADULTS WITH MAJOR DEPRESSIVE DISORDER 
Rationale for Protocol Amendment 
The primary purpose for this protocol amendment is to revise the primary endpoint to change 
from baseline in HAM-D total score at Day 3 (instead of Day 15). In line with the objectives of 
this study as a rapid response therapy in the treatment paradigm of co-initiation, an earlier time 
point in the treatment period will characterize the rapid onset of effect while awaiting the 
efficacy of a standard antidepressant. Additional changes are outlined below: 
 
Study Endpoints 
• The change from baseline in HAM-D total score over the blinded treatment period (using 
equal weights for the scheduled visits – Day 3, Day 8, Day 12, Day 15) has been added as 
the key secondary endpoint 
• The change from baseline in CGI-S at Day 15 has been designated as an ‘other 
secondary’ endpoint (previously key secondary endpoint) 
• The change from baseline in HAM-D total score at Day 3, Day 8, and Day 42 (previously 
key secondary endpoint) has been removed 
• The change from baseline in HAM-D total score at Day 15 and Day 42 has been 
designated as an ‘other secondary’ endpoint 
• Added the following as new ‘other secondary’ endpoints: 
o CGI-I response at Day 3 
o The change from baseline in the HAM-D total score around end of blinded 
treatment (using equal weights for the scheduled visits – Day 12, Day 15, Day 18) 
o MADRS response at Day 15  
o MADRS remission at Day 15 
Statistics 
• Expanded the Full Analysis Set definition to include participants who have data from 
other efficacy endpoints in addition to HAM-D total score 
• Modified the condition of the sensitivity analyses to assess the impact of missing data to 
be performed regardless of missing data rate 
• Clarified the estimand for the primary and key secondary endpoints  
Confidential Information

217-MDD-305 Summary of Changes 
Sage Therapeutics 
Version 4, Amendment 3 
 
 
2 
• Updated methods of the covariance structure for the MMRM model for the primary and 
key secondary endpoints to be consistent with recent FDA feedback for a Phase 1 
SAGE-217 study 
• Updated the method of the multiplicity adjustment to align with the change in key 
secondary endpoint 
Other 
• Removed score of ‘0 (not assessed)’ as a choice for the Clinical Global Impression Scale 
• Corrected the PHQ-9 category of “minimal depression” to start at ‘0’ instead of ‘1’ 
Confidential Information

217-MDD-305 Summary of Changes 
Sage Therapeutics 
Version 3, Amendment 2 
 
 
1 
Protocol 217-MDD-305, Amendment 2 
Date of Amendment: 22 January 2021 
A PHASE 3, RANDOMIZED, DOUBLE-BLIND STUDY COMPARING THE EFFICACY 
AND SAFETY OF SAGE-217 PLUS AN ANTIDEPRESSANT VERSUS PLACEBO PLUS 
AN ANTIDEPRESSANT IN ADULTS WITH MAJOR DEPRESSIVE DISORDER 
Rationale for Protocol Amendment 
The primary purpose for this protocol amendment in response to FDA feedback is to update the 
visit schedule for participants that discontinue any treatment early: these participants will now 
complete remaining study visits as scheduled through Day 42 (ie, relative to Day 1), unless the 
participant withdraws consent. Additional changes to incorporate FDA feedback or clarify the 
study design are outlined below: 
 
Schedule of Assessments 
• Subsequent to the primary purpose for this amendment, the End of Treatment (EOT) visit 
is no longer needed and has been removed 
Investigational Products 
• Updated the recommended starting dose options for duloxetine to better align with its 
labeled prescribing information 
Inclusion/Exclusion Criteria 
• Corrected Exclusion Criterion #7, which incorrectly specified sertraline  
• Specified the types of bilateral tubal occlusion procedures that are considered to be 
acceptable forms of contraception, including a minimum time for which hysteroscopic 
bilateral tubal occlusion procedures may have been performed prior to Screening 
Statistical Analysis: 
• Specified separate Safety Sets for those participants that administered blinded IP and 
those that administered open-label antidepressant therapy only; subsequently updated the 
Full Analysis Set definition to specify this set includes participants who administered 
blinded IP 
• Removed the statement that no imputation process will be used to estimate missing data 
and replaced with a statement that missing data for particular visits may be imputed using 
the visit window and available data, as described in the statistical analysis plan (SAP) 
• Specified the 2 treatment regimens as part of the estimand definition and re-formatted the 
estimand definition 
• Added a reference to the SAP for the definition and details of the Per Protocol Set 
Other 
• Updated the study medical monitors 

217-MDD-305 Summary of Changes 
Sage Therapeutics 
Version 3, Amendment 2 
 
 
2 
• Specified that any restriction(s) for the assigned SSRI/SNRI with concomitant 
medications per the labeled prescribing information should be considered; subsequently 
removed a restriction specific only to sertraline 
• Specified that the treatment adherence monitoring application will only record details of 
IP ingestion that has been visually confirmed 
• Updated the emergency unblinding procedure to specify that if the blind is to be broken, 
it should be done by the investigator via the IRT system, removed the statement that the 
investigator should discuss requests about treatment with the Sage medical monitor, and 
specified that the responsibility to break treatment code resides solely with the 
investigator