Conditions: Depressive Disorder, Major
Keywords: Major Depressive Disorder MDD SAGE-217
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 440
Healthy volunteers: no

Brief summary:
The primary purpose of this study is to evaluate the efficacy of SAGE-217 plus an ADT in the treatment of major depressive disorder (MDD) compared to placebo plus an ADT.

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

Arms:
arm 1: Participants received SAGE-217-matching placebo capsules, orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily, from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42. arm 2: Participants received SAGE-217, 50 milligrams (mg), orally, once daily along with an assigned ADT (sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine administered per labeled prescribing information), daily from Day 1 through 14, followed by the same ADT, per labeled prescribing information, daily, up to Day 42.

Interventions: intervention 1: SAGE-217 intervention 2: Matching Placebo intervention 3: Sertraline intervention 4: Escitalopram intervention 5: Citalopram intervention 6: Duloxetine intervention 7: Desvenlafaxine
Intervention descriptions: intervention 1: Oral capsules intervention 2: Oral capsules intervention 3: Oral tablets intervention 4: Oral tablets intervention 5: Oral tablets intervention 6: Oral capsules intervention 7: Oral tablets

Protocol document:
Prot_000.pdf: 


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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217-MDD-305 Version 4 
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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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Sage Therapeutics, Inc. 
217-MDD-305 Version 4 
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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 
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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 
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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 
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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 
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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 
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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 
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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 
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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 
 



SAP_001.pdf: 
Official Title: 
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
NCT Number: 
NCT04476030
Document Date:
SAP Version 1.0 : 11 January 2022 


Clinical Study Report 
217-MDD-305
16.1 Study Information 
1 
9.
DOCUMENTATION OF STATISTICAL METHODS
The following statistical analysis plan is provided: 
Statistical analysis plan Version 1.0, 11 January 2022 


Statistical Analysis Plan Methods Version 1.0 
               Page 1 
Protocol Number: 217-MDD-305 
 
 
 
STATISTICAL ANALYSIS PLAN 
METHODS 
Protocol Number 217-MDD-305 
 
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 
 
Author of SAP: 
 and 
 
Version: 1.0 
Version Date of SAP: 11 Jan 2022 
 
Sponsor: 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, Massachusetts 02142 
 
 
 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure 
without the prior written consent of Sage Therapeutics, Inc. is strictly prohibited except to the 
extent required under applicable laws or regulations.  Persons to whom the information is 
disclosed must be informed that the information is confidential and may not be further 
disclosed by them. 
 


Statistical Analysis Plan Methods Version 1.0 
Page 2 
Protocol Number: 217-MDD-305 
 
Authorization Signature Page 
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  
 
Author: 
 
 
 
 
 
, 
 
Syneos Health 
 
 
 
 
Date 
, PhD, 
 
Sage Therapeutics, Inc. 
 
 
Date 
Approved by: 
 
 
 
 
__________________________________________ 
, MD, MBA, 
 
Sage Therapeutics, Inc. 
 
 
_________________ 
Date 
 
 
_______________________________________________ 
  
Sage Therapeutics, Inc. 
 
 
_______________________________________________ 
, PhD, 
 
Sage Therapeutics, Inc. 
 
 
_________________ 
Date 
 
 
 
_______________ 
Date 
DocuSign Envelope ID: E6201D7B-5202-44BE-99A7-2A0268585B9C
11-Jan-2022 | 12:08 EST
11-Jan-2022 | 11:11 EST
11-Jan-2022 | 08:44 PST
11-Jan-2022 | 11:28 EST
11-Jan-2022 | 13:32 EST


Statistical Analysis Plan Methods Version 1.0 
Page 3 
Protocol Number: 217-MDD-305 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................. 3 
LIST OF TABLES ....................................................................................................... 5 
1. 
LIST OF ABBREVIATIONS................................................................... 7 
2. 
INTRODUCTION .................................................................................... 9 
3. 
STUDY OBJECTIVES ............................................................................ 9 
3.1. 
Primary Objective ..................................................................................... 9 
3.2. 
Secondary Objective ................................................................................. 9 
 
 9 
4. 
STUDY ENDPOINTS .............................................................................. 9 
4.1. 
Efficacy Endpoints .................................................................................... 9 
4.1.1. 
Primary Efficacy Endpoint ....................................................................... 9 
4.1.2. 
Secondary Efficacy Endpoints ................................................................ 10 
4.1.2.1. 
Key Secondary Efficacy Endpoint .......................................................... 10 
4.1.2.2. 
Other Secondary Efficacy Endpoints ...................................................... 10 
4.2. 
Other Endpoints ...................................................................................... 10 
5. 
STUDY DESIGN ................................................................................... 11 
5.1. 
Overall Design ........................................................................................ 11 
5.2. 
Sample Size and Power .......................................................................... 12 
5.3. 
Randomization ........................................................................................ 12 
5.4. 
Blinding and Unblinding ........................................................................ 12 
6. 
MODIFICATIONS ................................................................................. 13 
6.1. 
Modifications to the Approved Clinical Study Protocol ........................ 13 
6.2. 
Modifications to the Approved Statistical Analysis Plan ....................... 13 
6.3. 
Modifications to the Approved DMC Charter ........................................ 13 
7. 
ANALYSIS SETS .................................................................................. 13 
7.1. 
Full Analysis Set ..................................................................................... 13 
7.2. 
Randomized Set ...................................................................................... 13 
7.3. 
Safety Set ................................................................................................ 13 
7.3.1. 
Safety Set –ADT Only ............................................................................ 13 
 
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7.5. 
Per Protocol Set ...................................................................................... 13 
8. 
STATISTICAL ANALYSIS .................................................................. 14 
8.1. 
General Considerations ........................................................................... 14 
8.1.1. 
Study Day Definition .............................................................................. 15 
8.1.2. 
Missing Data ........................................................................................... 15 
8.2. 
Background Characteristics .................................................................... 15 
8.2.1. 
Participant Disposition ............................................................................ 16 
8.2.2. 
Protocol Deviations ................................................................................ 16 
8.2.3. 
Demographics and Baseline Characteristics ........................................... 17 
8.2.4. 
Medical/Surgical History ........................................................................ 18 
8.2.5. 
Prior and Concomitant Medications ....................................................... 19 
8.2.6. 
Concomitant Procedures ......................................................................... 20 
8.2.7. 
Investigational Product Exposure ........................................................... 20 
8.2.8. 
Investigational Product Adherence ......................................................... 22 
8.3. 
Efficacy Analysis .................................................................................... 22 
8.3.1. 
Definition of Efficacy Variables ............................................................. 22 
8.3.1.1. 
Hamilton Rating Scale for Depression (HAM-D) .................................. 22 
8.3.1.2. 
Clinical Global Impression – Improvement (CGI-I) .............................. 24 
8.3.1.3. 
Clinical Global Impression – Severity (CGI-S) ...................................... 24 
8.3.1.4. 
Hamilton Anxiety Rating Scale (HAM-A) ............................................. 24 
8.3.1.5. 
Montgomery-Åsberg Depression Rating Scale (MADRS) .................... 25 
8.3.1.6. 
Patient Health Questionnaire (PHQ-9) ................................................... 25 
8.3.2. 
Visit Windows ........................................................................................ 25 
8.3.3. 
Analysis of Efficacy Variable(s) ............................................................ 27 
8.3.3.1. 
Mixed Effects Model for Repeated Measures ........................................ 28 
8.3.3.2. 
Generalized Estimating Equation (GEE) Models ................................... 31 
8.3.3.3. 
Sensitivity Analysis ................................................................................ 32 
8.3.3.4. 
Analysis of Time to First HAM-D Response/Remission ....................... 34 
8.3.3.5. 
Multiplicity Adjustment for Key Secondary Endpoint ........................... 35 
8.3.4. 
Characterization of Durability of SAGE-217 Treatment Effect ............. 35 
8.3.4.1. 
Durability of Clinically Meaningful Treatment Effect for SAGE-217 .. 35 


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8.3.4.2. 
Durability of Treatment Effect at Day 42 via Statistical Comparison of 
SAGE-217 Versus Placebo ..................................................................... 36 
8.4. 
Safety Analysis ....................................................................................... 37 
8.4.1. 
Adverse Events ....................................................................................... 38 
8.4.2. 
Clinical Laboratory ................................................................................. 40 
8.4.3. 
Vital Signs .............................................................................................. 43 
8.4.4. 
Electrocardiogram ................................................................................... 44 
8.4.5. 
Physical Examination ............................................................................. 45 
 
 45 
 
 46 
 
 47 
 
 47 
 
 47 
 
 48 
9. 
SUMMARY OF INTERIM AND DMC ANALYSES .......................... 48 
10. 
REFERENCES ....................................................................................... 48 
11. 
LIST OF APPENDICES......................................................................... 49 
11.1. 
Appendix A: Schedule of Assessments .................................................. 49 
11.2. 
Appendix B: Details of Statistical Methodology .................................... 53 
11.3. 
Appendix C: Handling of Missing Dates ................................................ 55 
11.4. 
Appendix D: Daily Trends in Number of COVID-19 Cases in The 
United States Reported to Centers for Disease Control and Prevention 
(CDC) ..................................................................................................... 57 
11.5. 
Appendix E: List of Displays ................................................................. 59 
 
LIST OF TABLES 
Table 1: 
Diagnostic Screening Tests..................................................................... 18 
Table 2: 
HAM-D Subscale Calculation ................................................................ 23 
Table 3: 
Visit Windows for Efficacy Analysis ..................................................... 26 
Table 4: 
Safety Endpoints and Variables in the Summary Tables ........................ 37 
Table 5: 
Clinical Laboratory Tests ....................................................................... 40 
Table 6: 
Potentially Clinically Significant Values for Specific Laboratory 
Parameters ............................................................................................... 42 


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1. 
LIST OF ABBREVIATIONS 
Abbreviation or specialist term 
Explanation 
AE 
adverse event 
AR 
autoregressive 
ATC 
anatomical therapeutic chemical 
ADT 
Antidepressant therapy 
BMI 
body mass index 
CGI-I 
Clinical Global Impression scale for improvement 
CGI-S 
Clinical Global Impression scale for severity 
 
 
ECG 
electrocardiogram 
eCRF  
electronic case report form  
ET 
early termination 
FAS 
Full Analysis Set 
GEE  
generalized estimating equation  
HAM-A  
Hamilton Rating Scale for Anxiety  
HAM-D 
Hamilton Depression Rating Scale 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
ICF 
informed consent form 
IP 
Investigational product 
IRT 
interactive response technology  
LFT 
Liver Function Tests 
LLOQ 
Lower limit of quantification 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MDD 
major depressive disorder 
MMRM  
mixed effects model for repeated measures  
MedDRA 
Medical Dictionary for Regulatory Activities 
PCS 
potentially clinically significant  
PCSC 
potentially clinically significant change 
PHQ-9 
Patient Health Questionnaire 
 
 


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Abbreviation or specialist term 
Explanation 
PRO 
patient-reported outcome 
PT 
preferred term 
 
  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
 
 
SI 
International System of Units 
SNRI 
serotonin-norepinephrine reuptake inhibitor 
SOC 
System Organ Class 
SSRI 
selective serotonin reuptake inhibitor 
TEAE 
treatment-emergent adverse event 
UN 
unstructured 
 


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2. 
INTRODUCTION 
This statistical analysis plan (SAP) is for the final analysis of data from 217-MDD-305 study, 
and is based on clinical study protocol, version 4.0, dated 10 Jan 2022.  
The purpose of the SAP is to describe in detail the statistical methodology and analyses to be 
conducted for 217-MDD-305 protocol. The SAP will be finalized and approved before the 
database lock.  
Any changes made to this SAP after the clinical database lock has occurred will be 
documented and discussed in the clinical study report for this study. 
3. 
STUDY OBJECTIVES  
3.1. 
Primary Objective 
The primary objective of Study 217-MDD-305 is to evaluate the efficacy of SAGE-217 plus 
an antidepressant in the treatment of major depressive disorder (MDD) compared to placebo 
plus an antidepressant. 
3.2. 
Secondary Objective 
The secondary objectives of Study 217-MDD-305 are:  
 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 
 
 
 
 
 
 
 
 
4. 
STUDY ENDPOINTS 
4.1. 
Efficacy Endpoints 
4.1.1. 
Primary Efficacy Endpoint  
The primary efficacy endpoint is the change from baseline in the 17-item Hamilton Rating 
Scale for Depression (HAM-D) total score at Day 3.  


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4.1.2. 
Secondary Efficacy Endpoints 
4.1.2.1. 
Key Secondary Efficacy 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) 
4.1.2.2. 
Other Secondary Efficacy 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 
(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 at Day 15 
 CGI-I response, defined as “much improved” or “very much improved”, at Day 3 
and Day 15 
 Change from baseline in Montgomery-Åsberg Depression Rating Scale 
(MADRS) total score at Day 15 
 MADRS response at Day 15  
 MADRS remission at Day 15  
 Change from baseline Hamilton Rating Scale for Anxiety (HAM-A) total score at 
Day 15 
 Time to first HAM-D response 
 Change from baseline in depressive symptoms at Day 15, as assessed by the 
PHQ-9  
4.2. 
Other Endpoints 
 Incidence and severity of treatment-emergent adverse events (TEAEs) 
 
 
 
 
 
 
 
 
 
 
 
 


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5. 
STUDY DESIGN 
5.1. 
Overall 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 Antidepressant (ADT) Continuation Period. Upon meeting 
the eligibility criteria (including, but not limited to, not having taken any antidepressant 
within 30 days prior to Day 1 or taken fluoxetine within 60 days prior to Day 1), participants 
will be randomized to receive blinded investigation product (IP; 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 
or desvenlafaxine) in an open-label manner from Day 1 through the end of the study. The 
ADT will be administered per labeled prescribing information. 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. 
Randomization will be stratified by ADT class (SSRI or SNRI). Blinded IP (SAGE-217 or 
placebo) dosing starts with 50 mg on Day 1; the dose may be reduced for safety/tolerability 
concerns (at the discretion of the investigator) to 40 mg any time during the 14-day 
Treatment Period.  
After the Double-blind Treatment Period, the assigned ADT will be continued each evening 
for the remainder of the study (ADT Continuation Period; Week 3 to 6). During this period, 
ADT dosing may be modified based on individual response, at the discretion of the 
investigator and per the labeled prescribing information. 
Participants will self-administer 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. 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. Blinded IP will be administered as 2 capsules per dose each evening. 
Participants who cannot tolerate the 40-mg blinded IP dose may be discontinued from 


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blinded IP at the discretion of the investigator. If blinded IP is discontinued, 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. Participants who do not enter the open-label 
study or who terminate the current study early may, per the investigator, receive a supply of 
ADT with instructions on how to taper the drug or, if they wish to continue ADT, a bridge 
supply will be provided to permit them to obtain a prescription from another provider.  
5.2. 
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 + assigned ADT 
and placebo + assigned ADT) of approximately 3 points in the primary endpoint, change 
from baseline in HAM-D total score at Day 3, 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 blinded IP and have a valid baseline and at least 1 postbaseline HAM-D 
assessment. 
5.3. 
Randomization 
This is a randomized, double-blind, placebo-controlled study. Participants who meet the 
eligibility criteria will be randomized in a 1:1 ratio to receive SAGE-217 50 mg plus 
assigned ADT or matched placebo plus assigned ADT. The randomization is stratified by the 
class of ADT use – SSRI or SNRI. 
Randomization schedules will be generated by an independent statistician. The allocation to 
treatment group (SAGE-217 50 mg, or placebo) will be based on the randomization schedule. 
Randomization will be performed centrally via an interactive response technology (IRT) 
system. 
5.4. 
Blinding and Unblinding 
This is a randomized, double-blind, placebo-controlled study. The Sponsor, site personnel 
and participants will remain blinded until the database lock, after all participants complete 
the Day 42 visit. 
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 blinded IP 
received. In all cases where the blinded 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 electronic case report form (eCRF).  
If a participant or site personnel become unblinded to an individual participant’s treatment 
before database lock, the participant will be excluded from the Per Protocol Set (See 
Section 0 ), but will be included in the Full Analysis Set (See Section 7.1).  


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6. 
MODIFICATIONS 
6.1. 
Modifications to the Approved Clinical Study Protocol 
Not applicable 
6.2. 
Modifications to the Approved Statistical Analysis Plan 
Not applicable 
6.3. 
Modifications to the Approved DMC Charter 
Not applicable 
7. 
ANALYSIS SETS 
7.1. 
Full Analysis Set 
The Full Analysis Set (FAS) is defined as all randomized participants who administered 
blinded IP and have a valid baseline total score and at least 1 valid post-baseline total score 
in at least one of HAM-D, HAM-A, MADRS, PHQ-9 or have a valid baseline and at least 1 
valid post-baseline value in at least one of CGI-S or CGI-I score. 
7.2. 
Randomized Set 
The Randomized Set is defined as all participants who are randomized. 
7.3. 
Safety Set 
The Safety Set is defined as all participants who administered blinded IP. 
7.3.1. 
Safety Set –ADT Only 
The Safety Set – ADT Only is defined as all participants who administered assigned ADT at 
baseline but did not administer any dose of blinded IP. 
 
 
 
 
7.5. 
Per Protocol Set 
The Per Protocol Set is defined as all participants in the FAS without any major protocol 
deviations related to efficacy. For further details, see Section 8.2.2.  
In addition, Per Protocol Set will also exclude FAS participants with any of the following 
conditions: 
 Participants who consumed <22 blinded IP capsules  


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 Participants who consumed less than 11 days of assigned ADT 
 Participants who consumed incorrect blinded IP (i.e., IP other than which a 
participant was randomized to receive) at any time during the study 
 Participant whose treatment blind has been broken before the study database has 
been unblinded 
8. 
STATISTICAL ANALYSIS 
8.1. 
General Considerations 
Unless otherwise specified, continuous endpoints will be summarized with n, mean standard 
deviation (SD), median, minimum (min) and maximum (max). If the measurements in the 
source (raw) data are integers, then the corresponding mean and median will be presented to 
1 decimal place and the SD to 2 decimal places; if the measurements are obtained to 
1 decimal place, then the mean and median will be presented to 2 decimal places and the SD 
to 3 decimal places; and so forth. Minimum and maximum will be displayed with the 
precision as reported in the source (raw) data. In addition, change from baseline values (visit 
value – baseline value) will be calculated at each time point and summarized descriptively.  
For categorical endpoints, descriptive summaries will include counts and percentages. 
Percentages will be presented to 1 decimal place unless otherwise specified; the denominator 
of percentages will be the number of participants in the analysis set used unless specified 
otherwise.  
All analyses and summary outputs will be generated using SAS® 9.4 or higher. 
All summaries and figures will be provided by treatment group: “placebo + assigned ADT’ 
or “SAGE-217 + assigned ADT”.  Assigned ADT is the ADT that is assigned to each 
participant at baseline by the investigator as the concomitant, open label ADT; this will be 
taken from the ADT administration eCRF page irrespective of how the participant was 
stratified at randomization.  Assigned ADT use is derived from the first record of ADT 
administration available in eCRF.  The SAGE-217+ assigned ADT treatment group does not 
differentiate 50mg or 40mg dose of SAGE-217. These treatment groups do not distinguish 
between different doses of ADT after the 14-day blinded Treatment Period. Efficacy data are 
analyzed by the treatment group that the participant is randomized to. Safety data are 
analyzed by the actual blinded IP treatment received, determined as follows: if a participant 
received any dose of SAGE-217 at any time, the participant is assigned to actual treatment of 
SAGE-217 + assigned ADT (irrespective of whether the participant took the ADT); the 
participant is assigned to actual treatment of Placebo + assigned ADT (irrespective of 
whether the participant took the ADT) if the participant has taken Placebo and has never 
taken any dose of SAGE-217. 
All participant data, including those derived, to support tables and figures will be presented 
in the participant data listings. In general, the participant data listings will be sorted by 


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participant ID and assessment visit and date (and time, if applicable). The treatment will be 
identified for each participant – either planned or actual – according to the analysis set used. 
Adverse event data for participants in Safety Set – ADT Only will be provided in a listing; 
other data from this analysis set will reside in the database but will not be used in analysis. 
For the purpose of all safety and efficacy analyses, baseline is defined as the last non-missing 
measurement, including unscheduled visits, prior to the first dose of blinded IP, unless stated 
otherwise. If the time of an assessment is collected, baseline will be the latest assessment 
prior to first dose of blinded IP administration time; if the time of an assessment is not 
collected, the assessment on Day 1 is assumed to be prior to dosing if the protocol mentions 
that this assessment needs to be before dosing or it is collected as “predose”. 
8.1.1. 
Study Day Definition 
First dose of IP is administered in the evening; assessments at the clinic on Day 1 are hence 
assumed to be before the first dose of blinded IP. 
Study day will be defined as follows:  
The day of participant receiving the first dose of blinded IP is designated as Day 1. 
For visit/assessment days after Day 1, study day = visit/assessment date – Day 1 date + 1. 
For visit/assessment days prior to Day 1, study day = visit/assessment date – Day 1 date.  
Thus, study days for screening visit are negative numbers. There is no “Day 0”. 
8.1.2. 
Missing Data 
All participants will be used in the analyses, as per the analysis populations, using all non-
missing data available. Missing scheduled visit values may be replaced by windowing 
unscheduled visit values (see Section 8.3.2). Efficacy analyses will use sensitivity analyses to 
assess the impact of missing data. Imputation of missing data in scoring of questionnaires is 
discussed in respective sections below. Handling of missing or incomplete dates have been 
discussed in Section 11.3 Appendix C.  
8.2. 
Background Characteristics 
All summary tables in this section will be presented under treatment columns of ‘placebo + 
ADT’, ‘SAGE-217 + ADT’, and ‘Overall’. 
The subgroup (SSRI or SNRI) of assigned ADT will be determined as follows: 
 SSRI: the generic term contains “sertraline”, “escitalopram”, “citalopram” and has a 
start date on or after the first dose of blinded IP. 
 SNRI: the generic term contains “duloxetine”, “desvenlafaxine” and has a start date 
on or after the first dose of blinded IP. 


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8.2.1. 
Participant Disposition 
The summary of participant disposition will use all participants who provided written 
informed consent to the study. The disposition summary will also be provided using FAS. 
The summary of participant disposition will include the number of participants who were 
screened, who screen failed, who were randomized, who received IP – either ADT or 
SAGE-217/Placebo, reasons for not being dosed, the number and percentage of participants 
who completed the study, who consented to continue in another SAGE-217 follow-up study, 
who prematurely withdrew from the study, and primary reasons for not completing the study, 
who completed blinded IP, who completed ADT, who discontinued blinded IP prematurely,  
who discontinued ADT prematurely, primary reasons for discontinuing blinded IP, and 
primary reasons for discontinuing ADT. All percentages will be calculated based on the 
participants who were randomized and received blinded IP; treatment group assignment will 
use planned treatment.  
If a participant was rescreened (because the participant was a screen failure the first time), 
the status of the participant will be determined from the second screening. In the count of 
screened participants, this participant will be counted only once.  
A completer for the study is defined as one who completed the last follow-up visit (Day 42) 
based on the study completion CRF page with the completion question answered Yes.  
A participant is marked as completing the blinded treatment if the blinded IP completion 
CRF page indicates treatment completion. 
A participant is marked as completing the assigned ADT treatment if the assigned ADT 
completion CRF page indicates treatment completion. 
The number of participants in each analysis set will be provided. Using Randomized Set, the 
reason for not being included in other analysis sets will be summarized. 
A separate data listing will be provided for all participants who prematurely discontinued 
blinded IP or prematurely withdrew from the study with reasons, number of days on blinded 
IP, date of withdrawal from the study, using Safety Set. A similar listing will be provided for 
premature discontinuation from assigned ADT. 
8.2.2. 
Protocol Deviations 
Protocol deviations identified during the study will be captured and categorized by the study 
team review as major or minor deviations in blinded fashion on an ongoing basis until 
database lock.   
The study team will identify the major protocol deviations related to efficacy or which may 
have an impact on efficacy to determine the participants in FAS to be excluded from the Per 
Protocol Set prior to database lock in a blinded fashion (ie, it is possible for a participant to 
have a major protocol deviation and be included in the Per Protocol Set).  
In addition, COVID-19 related protocol deviations such as remote telephone/video 
visit/assessment, home healthcare visit, missed visit/assessment, out of window 
visit/assessment, safety reporting, IP administration, and others will be documented.  


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All protocol deviations – major and minor – will be included in a data listing using 
Randomized set and randomized treatment. Any protocol deviation related to COVID-19 will 
be provided in a separate data listing using randomized set and randomized treatment. Major 
protocol deviations will be summarized using randomized treatment and FAS. 
Any violation of inclusion/exclusion criteria will be presented by randomized treatment in a 
separate data listing using Randomized Set. 
If a participant received any incorrected blinded IP other than what he/she was randomized 
to, the details of such inappropriate blinded IP consumption will be provided in a separate 
listing. 
8.2.3. 
Demographics and Baseline Characteristics 
The following analyses will be provided separately for the below sets: 
 Safety Set (using actual treatment received),  
 FAS (using randomized treatment),  
 FAS by the subgroup of Assigned ADT use,  
 FAS by US COVID-19 status at time of enrollment. 
Demographic data (age at informed consent date, race, sex, ethnicity, employment status, 
highest education level, marital/civil status) and baseline characteristics, such as height, 
weight, and body mass index (BMI), will be summarized.  
Baseline subgroups will be summarized for the following categories whenever appropriate: 
 Assigned Antidepressant Use: SSRI, SNRI 
 Age:18-24, 25-50, 51-64 years 
 Sex: Female, Male 
 Race: Black or African American, White, Other 
 BMI at baseline: ≤18.4, 18.5-24.9, 25-29.9, ≥30 kg/m2 
 COVID-19 History: this will be summarized by COVID-19 related preferred term (PT) 
coded by Medical Dictionary for Regulatory Activities (MedDRA) in medical history 
data. For participants without COVID-19 related PT, the participants are categorized as 
‘Not Impacted’. If a participant had multiple PTs related to COVID-19, then the 
participant will be counted once under the worst case in the following order: 
Hospitalization > SARS-CoV-2 test positive > Patient isolation > Suspected COVID-
19 > COVID-19.  
 Depression with elevated anxiety by HAM-D subscale:  
      Baseline HAM-D Anxiety subscale score >=7 (equivalent to normalized score of  
     >=39), Baseline HAM-D Anxiety subscale score <7 (equivalent to normalized  
     score of  <39) 
 
Depression with elevated anxiety by HAM-A total score:  


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      Baseline HAM-A total score >=20, Baseline HAM-A total score <20 
 US COVID-19 status at time of enrollment: First informed consent sign date: 
<=18Mar2021, > 18Mar2021: a new subgroup is defined by the COVID-19 status in 
the US at the time of a participant's enrolment in the study. This is to investigate any 
potential impact of COVID-19 on study results using a date of the first informed 
consent; i.e. pre and during peak vs. post-peak has been determined from CDC report 
on COVID-19 (see Section 11.4).  
Any deviation from the antidepressant stratum recorded at IRT system will be included as a 
protocol deviation and will be included in the protocol deviation listing. 
Diagnostic labs are part of screening. The results of the diagnostic screening tests in Table 1 
will be provided in a data listing using the Safety Set. 
Table 1: 
Diagnostic Screening Tests 
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 
 virus; HIV = human immunodeficiency virus 
Child-bearing potential data will be collected at screening and will be listed in a data listing 
using the Safety Set. 
8.2.4. 
Medical/Surgical History 
The following analyses will use the Safety Set.  
Years since initial diagnosis of MDD, antidepressant usage, and information about 
depressive episodes will be summarized. Years since initial diagnosis of MDD, days since 
start of current episode and years since start of first episode will be calculated using: First 
dose date of the blinded IP – date of interest. For imputation of incomplete dates in medical 
history, please see Section 11.3.  
Medical/surgical history collected at screening will be coded using the MedDRA, Version 
23.0 or higher. Medical/surgical history data will be summarized by system organ class 


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(SOC) and preferred term (PT). A summary of medical/surgical history that are ongoing at 
the time of screening will be provided separately.   
Participant history of psychiatric disorders and family psychiatric history will be 
summarized.   
8.2.5. 
Prior and Concomitant Medications  
The following analyses will use the Safety Set and will exclude the assigned ADT 
medication use. 
All medications taken during the study will be recorded; in addition, psychotropic 
medications taken within 6 months prior to screening, and non-psychotropic medications 
taken within 30 days prior to screening will also be collected.  All medications will be coded 
using World Health Organization-Drug (WHO) Global B3 March 2020 or later. 
Medications will be presented according to whether they are being taken prior to and/or 
during the study (concomitant).  Prior medications are defined as those taken prior to the 
initiation of the start of blinded IP.  Concomitant medications are defined as those with a start 
date on or after the first dose of blinded IP or those with a start date before the first dose of 
blinded IP that are ongoing or with a stop date on or after the first dose of blinded IP. If 
medication dates are incomplete and it is not clear whether the medication was concomitant, 
it will be assumed concomitant.  For imputation of missing concomitant medication dates, 
please refer to Section 11.3 , Appendix C. Note that it is possible for a medication to be both 
‘prior’ and ‘concomitant’ when a medication has start date before first dose of blinded IP and 
end date either missing or after the first dose of blinded IP. 
Concomitant medications will be further divided by usage period as follows:  
 On-treatment concomitant medications are those that have been used any time 
from start of first dose to the last dose of blinded IP. 
 Post-treatment concomitant medications are those that have been started after the 
last dose of blinded IP. 
Prior and concomitant non-psychotropic medication use will be summarized by anatomical 
therapeutic chemical (ATC) level 1 and Standard Medication Name. Similar summary tables 
will be provided for psychotropic medications. Separate but similar summaries will be 
provided for concomitant medication use for on-treatment and post-treatment periods as 
defined above. 
In addition, for prior and concomitant psychotropic medication separate summaries will be 
provided by ATC level 1 and ATC level 4. 
Prohibited medications are reviewed by the medical monitor in the study team on an ongoing 
basis in blinded fashion; any medication identified as prohibited medication intake is 
captured in the protocol deviations list.   


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8.2.6. 
Concomitant Procedures 
Concomitant procedures are recorded on a separate eCRF page; this will be presented in a 
listing by participant. The study day for the end date of the procedure will be provided when 
a complete end date is available.  
8.2.7. 
Investigational Product Exposure 
The following analyses will use the Safety Set.  Exposure to blinded IP and assigned ADT 
will be determined separately. 
Blinded IP Exposure: 
Total drug exposure (in mg) is defined as the total mg for SAGE-217 that was taken during 
the study. Total drug exposure for participants randomized to placebo is zero, unless the 
participant has taken SAGE-217 in error, in which case the total exposure comes from 
SAGE-217 exposure. If the participant missed the dose on any day, the dose taken for that 
day is 0 mg.  
The kit for the 50-mg dose contains two capsules – one for 30 mg, the other for 20 mg. For a 
participant who took only 1 capsule for a dosing day of 50 mg, it is assumed that the 
participant took the higher dose (ie, 30 mg) for the day and will be calculated as such for the 
total drug exposure and percent of the planned exposure received.  If a participant takes more 
than 2 capsules for a planned dosing day of 50 mg, it is assumed that the participant took all 
capsules for 30 mg. 
The kit for the 40-mg dose contains two capsules, 20 mg each; therefore, taking one capsule 
will unambiguously be assigned to 20 mg.  Taking more than 2 capsules is also determined 
unambiguously counting each capsule as 20 mg. 
Total exposure duration to blinded IP (in days) is defined as: date of last dose – date of first 
dose + 1. Note that this does not exclude days when the dose has been missed. 
Percent of the planned exposure received for blinded IP is defined as the total drug exposure, 
divided by planned exposure, times 100, where planned exposure is defined as follows: 
 For participants who complete the blinded treatment period without dose reduction, 
planned exposure is 14 days of treatment planned, × 50 mg for participants 
randomized to SAGE-217.  
 For participants who discontinue the blinded treatment early without dose reduction, 
the planned exposure is the number of days (last date of 50 mg – first dose date + 1) 
× 50 mg. For participants who reduce dose to 40 mg, the planned exposure is the 
number of days (first date of 40 mg – first dose date) × 50 mg + the number of days 
(minimum of (end date of 40 mg, 14) – first date of 40 mg + 1) × 40 mg for 
participants randomized to SAGE-217. The maximum planned exposure is 14 days 
For participants randomized to placebo, planned exposure is not applicable. 


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Total drug exposure, total exposure duration and percent of the planned exposure received 
will be summarized descriptively. Participants will also be summarized by number of blinded 
IP capsules administered (<22 capsules, ≥22 capsules).  
The number and percent of participants who had a dose adjustment per Investigator (reduced, 
interrupted, withdrawn) and who had a dose modification (missed dose, took an extra day of 
dosing, took more than the planned dose for dosing day, took partial dose, other) will also be 
summarized descriptively.  
Total drug exposure, total exposure duration, planned exposure, and percent of the planned 
exposure received will be listed with details of dates of first and last dose and details of any 
dose reduction. 
Blinded IP administration for each study day will be listed, including the date and time of 
administration, the number of capsules taken and details of any planned or unplanned dose 
adjustments. Whether the participant ate fat-containing food within 1 hour of the blinded IP 
administration will also be included in the blinded IP administration data listing. 
Assigned ADT Exposure: 
Total drug exposure (in mg) is defined as the total mg for ADT that was taken. Total 
exposure duration to ADT (in days) is defined as: date of last dose of ADT – date of first 
dose of ADT + 1. Note that this does not exclude days when the dose was missed. These two 
measures will be summarized for blinded Treatment Period (the end of period is defined as 
the last dose of blinded IP), and for the entire study separately, and total drug exposure will 
be presented separately by each assigned ADT. 
Sertraline: 50 mg per day for Week 1 and 100 mg per day for Week 2  
Citalopram: 20 mg per day 
Escitalopram: 10 mg per day 
Duloxetine: 40 or 60 mg per day (divided in two 20 or 30 mg doses for Week 1) 
Desvenlafaxine: 50 mg per day 
During the assigned ADT Continuation Period, planned exposure may vary for each 
participant depending on their dose regimen; therefore, planned exposure will not be 
calculated during the ADT Continuation Period.   
For participants who complete the blinded treatment period, without discontinuing from the 
study, the planned exposure of assigned ADT is planned daily dose (in mg) times 14, for 
ADTs other than sertraline; for sertraline it is 50mg times 7, plus 100 mg times 7. For 
duloxetine, the first dose taken will be used to determine if the planned dose is 40 mg or 60 
mg per day. 
For participants who discontinue the study during the blinded Treatment Period, the planned 
exposure of assigned ADT is: 
 For assigned ADTs except sertraline: (minimum of (14, last dose date of blinded 
IP) – first dose date of ADT +1) × (planned daily dose in mg) 
 For sertraline as assigned ADT: 


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 If last dose date of blinded IP is <= Day 7 then (last dose date of blinded IP) – 
first dose date of ADT + 1) × 50 mg 
 If last dose date of blinded IP > Day 7 then (minimum of (14, last dose date of 
blinded IP) – 7) × 100 mg + 7 × 50 mg 
Percent of the planned exposure received for assigned ADT is defined as the total drug 
exposure, divided by the planned exposure, times 100.  
8.2.8. 
Investigational Product Adherence 
The following analyses will use the FAS. Blinded IP adherence (%) is defined as the number 
of blinded capsules taken, divided by the number of blinded capsules planned to be taken, 
times 100.   
The schedule of blinded IP is two capsules per day. The number of capsules planned to be 
taken is defined as follows: 
 If the participant discontinues blinded IP within Day 1 and Day 14 (both 
inclusive), the number of capsules planned to be taken is the last dose day of 
blinded IP, times 2.  
 If the participant does not discontinue blinded IP, the number of capsules planned 
to be taken is 28.  
Blinded IP adherence will be summarized descriptively. Number and percentage of 
participants with blinded IP adherence in categories - <80%, 80-100%, >100% - will be 
provided.   
For assigned ADT adherence, the number of tablets taken for the same dose may be different 
for different participants. Without a planned number of tablets to be taken for each dose, 
ADT adherence based on number of tablets cannot be derived. Percent of planned exposure 
for the blinded Treatment Period will be used as a measure of ADT adherence. 
8.3. 
Efficacy Analysis 
8.3.1. 
Definition of Efficacy Variables 
The efficacy variables are defined as follows: 
8.3.1.1. 
Hamilton Rating Scale for Depression (HAM-D) 
The 17-item HAM-D will be used to rate the severity of depression in participants already 
diagnosed as depressed.  HAM-D is collected during the clinic visit on Screening, Days 1, 3, 
8, 12, 15, 18, 21, 28, 35, and 42. The 17-item HAM-D comprises of 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.  Each item is scored in a range of 0 


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to 2 or 0 to 4, with higher scores indicating a greater degree of depression.  The score for 
each item will be summed to compute a total score, which ranges from 0 to 52.  
If more than 3 individual items are missing a response, the HAM-D total score will not be 
calculated and will be left as missing.  If less than or equal to 3 individual item scores are 
missing, the missing item scores will be imputed by the mean of all other available item 
scores, or the maximum possible values for the missing responses, whichever is smaller, to 
calculate the HAM-D total score.   
Four HAM-D subscale scores will be calculated as the sum of the individual rating scores 
related to each subscale, divided by the total possible score within the subscale, multiplied by 
100, and rounded to a whole number.  If more than one item is missing or HAM-D total score 
is missing, the subscale score is left as missing; if one item on a particular subscale is missing 
but has been imputed for the calculation of total score, the imputed value from total score 
calculation will be used in subscale score calculation for that item. Table 2 describes the 
subscale score calculation. 
HAM-D response will be defined as having a 50% or greater reduction from baseline in 
HAM-D total score; only participants who have a non-missing total score of HAM-D at 
baseline as well as the visit will be considered in HAM-D response evaluations.  HAM-D 
remission will be defined as having a HAM-D total score of ≤7; if HAM-D total score is 
missing, remission will not be defined. For a sensitivity analysis the worst-case scenario 
imputation will be used, i.e., missing values for HAM-D response (remission) will be 
considered as “No response” (“No remission”). 
Table 2: 
HAM-D Subscale Calculation 
HAM-D Subscales 
Items 
Calculation 
Core 
Depressed mood 
Feeling of guilt 
Suicide 
Work and activities 
Retardation 
Sum of the 5-item responses/20 x 100.   
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale.  
Anxiety 
Anxiety psychic 
Anxiety somatic 
Somatic symptoms gastrointestinal 
Somatic symptoms general 
Hypochondriasis 
Insight 
Sum of the 6-item responses/18 x 100.   
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale.  
Bech-6 
Depressed mood 
Feeling of guilt 
Work and activities 
Retardation 
Sum of the 6-item responses/22 x 100.   
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 


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HAM-D Subscales 
Items 
Calculation 
Anxiety psychic 
Somatic symptoms general 
calculate HAM-D total score to 
calculate the subscale.  
Maier 
Depressed mood 
Feeling of guilt 
Work and activities 
Retardation 
Agitation 
Anxiety psychic 
Sum of the 6-item responses/24 x 100.   
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale.  
8.3.1.2. 
Clinical Global Impression – Improvement (CGI-I) 
The Clinical Global Impression – Improvement (CGI-I) employs a 7-point Likert scale to 
measure the overall improvement in the participant’s condition post-treatment. The 
Investigator will rate the participant’s total improvement. Response choices include:  1=very 
much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally 
worse, 6=much worse, and 7=very much worse. The CGI-I is only rated at post-treatment 
assessments on Days 3, 8, 12, 15, 21, 28, 35, and 42. By definition, all CGI-I assessments are 
evaluated against baseline conditions. Missing CGI-I score at the visit will not be imputed. 
CGI-I response will be defined as having a CGI-I score of “very much improved” or “much 
improved.”  For a sensitivity analysis the worst-case scenario imputation will be used, i.e. 
missing values for CHI-I response will be considered as “No response”. 
8.3.1.3. 
Clinical Global Impression – Severity (CGI-S) 
The Clinical Global Impression – Severity (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.  CGI-S is collected at Screening, Days 1, 3, 8, 12, 15, 
21, 28, 35, and 42. 
8.3.1.4. 
Hamilton Anxiety Rating Scale (HAM-A) 
The 14-item HAM-A will be used to rate the severity of symptoms of anxiety. HAM-A is 
collected during the clinic visit at Days 1, 8, 15, 28, and 42.  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. If more than 3 individual items are missing a 
response, the HAM-A total score will not be calculated and will be left as missing.  If less 


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than or equal to 3 individual item scores are missing, the missing item scores will be imputed 
by the mean of all other available item scores.   
8.3.1.5. 
Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive 
episodes in participants with mood disorders.  MADRS is collected at Screening, during the 
clinic visit on Days 1, 8, 15, 28, and 42. 
Each MADRS item ranges from 0 to 6; higher MADRS scores indicate more severe 
depression.  The MADRS total score will be calculated as the sum of the 10 individual item 
scores, which ranges from 0 to 60.  If more than two individual items are missing, the 
MADRS total score will not be calculated and will be left as missing.  If less than or equal to 
two individual item scores are missing, the missing item scores will be imputed by the mean 
of all other available item scores. 
MADRS response will be defined as having a 50% or greater reduction from baseline in 
MADRS total score; only participants who have a non-missing total score of MADRS at 
baseline as well as the visit will be considered in MADRS response evaluations.  MADRS 
remission will be defined as having a MADRS total score of ≤10; if MADRS total score is 
missing, remission will not be defined. For a sensitivity analysis the worst-case scenario 
imputation will be used, i.e., missing values for MADRS response (remission) will be 
considered as “No response” (“No remission”). 
8.3.1.6. 
Patient Health Questionnaire (PHQ-9)  
The PHQ-9 is a 9-item participant-rated depressive symptom severity scale. It is collected 
during the clinic visit on Days 1, 3, 8, 15, 28, and 42. 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. If more 
than 1 individual item is missing, the PHQ-9 total score will not be calculated and will be left 
as missing.  If 1 individual item score is missing, the missing item score will be imputed by 
the mean of all other available item scores to calculate the PHQ-9 total score. The PHQ-9 
total score will be categorized as follows: 0 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. Improvement since baseline is defined as having a lower category 
from baseline. 
8.3.2. 
Visit Windows 
The blinded treatment period scheduled visits (Day 3, Day 8, Day 12, and Day 15) will not 
be windowed and will be used at nominal visit value for analysis purposes. However, 
unscheduled, end-of-double blind treatment, and early termination (ET) visits will be 
included for the analyses by mapping to a blinded treatment period scheduled visit only if 
there is no measurement available from the scheduled visit. For ADT Continuation period 
visits (Day 21, Day 28, Day 35, and Day 42), including unscheduled, end-of-double blind 


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treatment, and ET visits will be mapped to a scheduled visit for analysis. Day 18 visit will 
not use a window visit but nominal visit, so no window is identified for Day 18. The 
windows outlined in Table 3 for each scheduled visit have been widened compared to 
protocol-specified operational window, to have no gap between them; these windows are 
used for analysis purposes only.  Once analysis visit windows are assigned, all visits, 
including scheduled visits and windowed visits will be eligible for being flagged as the 
“analyzed record” within the analysis window; a participant’s individual analysis visit 
window could potentially contain more than 1 visit. In the event of multiple visits falling 
within an analysis window or in case of a tie, the following rules will be used in sequence to 
determine the “analyzed record” for the analysis visit window: 
 If the data from the scheduled visit within the blinded treatment period is 
available, then the scheduled visit data will be used.  
 If there is no data from the scheduled visit within the blinded treatment period 
is available, the data closest to the target day for that window will be used.  
 For ADT Continuation period the windowed visit will be used. 
o In case there is more than one windowed visit within a window, the data 
closest to the target day for that window will be used. 
 If there is a tie between the data in the number of days before and after the target 
day, the later data will be used.  
 If there is a tie on the same day with different times, the later time data will be 
used. 
The summary by visit will use the “analyzed records” only – at most one per participant. The 
data not flagged as the “analyzed record” will be included in listings. An unscheduled visit 
that does not fall under any analysis window will remain in the database and will be included 
in the listings. 
Table 3  displays windows for efficacy analysis. 
Table 3: 
Visit Windows for Efficacy Analysis 
Scheduled Visit  
(+/1 window days) in protocol 
Target Study Day  
Study Day Window for Visit 
in Analysisa 
Day 1 
Day 1 (pre-dose) 
Day 1 (pre-dose) or last non-
missing assessment before first 
dose of blinded IP 
Day 3 (±1 day) 
Day 3 
Day 2 – Day 5  
Day 8 (+1 day) 
Day 8 
Day 6 – Day 9  
Day 12 (±1 day) 
Day 12 
Day 10 – Day 13 
Day 15 (+1 day) 
Day 15 
Day 14 – Day 17 
Day 21 (±3 day) 
Day 21  
Day 18 – Day 23  


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Scheduled Visit  
(+/1 window days) in protocol 
Target Study Day  
Study Day Window for Visit 
in Analysisa 
Day 28 (±3 day) 
Day 28  
Day 24 – Day 31  
Day 35 (±3 day) 
Day 35  
Day 32 – Day 38  
Day 42 (±3 day) 
Day 42  
>=Day 39  
a. For blinded treatment period (Day 3, Day 8, Day 12, and Day 15), the study day window will be 
used for unscheduled, end-of- double blind treatment, and ET visit only if there is no 
measurement available from the scheduled visit. 
8.3.3. 
Analysis of Efficacy Variable(s) 
The FAS will be used for efficacy analyses. Participants will be analyzed according to 
randomized treatment.   
The following efficacy endpoints will be summarized descriptively by scheduled assessment 
time point:  
 HAM-D total score – observed, change from baseline, percent change from 
baseline  
 HAM-D subscale scores – observed, change from baseline, percent change from 
baseline 
 HAM-D individual item score – observed, change from baseline  
 HAM-D response  
 HAM-D response – missing response counted as No response 
 HAM-D remission  
 HAM-D remission – missing remission counted as No remission 
 CGI-S score – observed and change from baseline 
 CGI-I score - observed  
 CGI-I response  
 CGI-I response – missing response counted as No response 
 HAM-A total score – observed, change from baseline, percent change from 
baseline 
 HAM-A individual item score – observed, change from baseline  
 MADRS total score – observed, change from baseline, percent change from 
baseline 
 MADRS individual item score – observed, change from baseline 
 MADRS response 


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 MADRS response – missing response counted as No response 
 MADRS remission 
 MADRS remission – missing remission counted as No response 
 PHQ-9 score – observed (including categories), change from baseline  
The summaries of HAM-D change from baseline in total score will also be presented by the 
following subgroups: 
 Assigned Antidepressant Use: SSRI, SNRI 
 Age group: 18-24, 25-50, 51-64 years 
 Sex: Male, Female  
 Race: White, Black, or African American, Other 
 BMI at baseline: ≤18.4, 18.5-24.9, 25-29.9, ≥30 kg/m2 
 COVID-19 History: this will be summarized by worst case COVID-19 related 
preferred term (PT) coded by MedDRA in medical history data. For participants 
without COVID-19 related PT, the participants are categorized as ‘Not Impacted’.  
 Depression with elevated anxiety by HAM-D subscale:  
Baseline HAM-D Anxiety subscale score >=7 (equivalent to normalized score of 
>=39), Baseline HAM-D Anxiety subscale score <7(equivalent to normalized 
score of <39) 
 Depression with elevated anxiety by HAM-A total score:  
      Baseline HAM-A total score >=20, Baseline HAM-A total score <20 
 US COVID-19 status at time of enrollment: First informed consent sign date:  
<= 18Mar2021, > 18Mar2021  
In addition, post-baseline percentage improvement in HAM-D total score will be presented in 
histogram over scheduled visits by treatment group under the following categories: < 0% 
(worsened), ≥0% but < 25%, ≥25% but < 50%, ≥ 50% but <75%, ≥75%. Post baseline HAM-
D total score will also be presented in histogram over scheduled visits: ≤7, >7 but ≤15, >15 
but ≤ 23, ≥ 24 but <26, >=26.  Corresponding data will be presented in summary tables. 
As part of supportive analyses, the summaries (observed, change from baseline, percent 
 change from baseline) and model-based estimates on HAM-D total scores and CGI-S scores  
will be summarized for Per Protocol Set.  
8.3.3.1. 
Mixed Effects Model for Repeated Measures 
The estimand for the primary and the key secondary efficacy analysis is defined as follows: 
1) The treatment regimens for participants are: SAGE-217 + ADT and placebo + 
ADT for 14 days. 


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2) The target population is adult participants with a diagnosis of major depressive 
disorder and within a current depressive episode of severity (baseline 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 uses 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 treatments 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. 
Data from SAGE-217 + ADT group versus Placebo + ADT group will be analyzed using a 
mixed effects model for repeated measures (MMRM); the model will include randomized 
treatment (SAGE-217 + ADT or placebo + ADT), baseline HAM-D total score, assigned 
ADT based on ADT use in ADT administration page of CRF (SSRI/SNRI), assessment time 
point, and time point-by-treatment as explanatory variables. All explanatory variables will be 
treated as fixed effects. All post-baseline time points will be included in the model. The 
primary comparison will be between SAGE-217 + ADT and Placebo + ADT.at Day 3. 
Model-based point estimates (i.e., treatment difference in least squares [LS] mean is the 
estimate of the effect) will be reported along with 95% confidence intervals, and p-values. 
An unstructured (UN) covariance structure (with the default Newton-Raphson algorithm used 
by SAS PROC MIXED) will be used to model the within-participant errors. If there is a 
convergence issue with the unstructured covariance model, the Fisher Scoring algorithm (via 
the SCORING option of the PROC MIXED statement), the no-diagonal factor analytic 
structure (via the TYPE=FA0(T) option of the REPEATED statement, where T is the total 
number of time points), Toeplitz, or Autoregressive (1) [AR (1)] covariance structure will be 
used, following this sequence until convergence is achieved. If the model still does not 
converge with AR (1) structure, no results will be reported. When the covariance structure is 
not UN, the sandwich estimator for the variance covariance matrix will be derived, using the 
EMPIRICAL option in the PROC MIXED statement in SAS. Observed Margins (OM) 


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option will be used in SAS with LSMEAN statement.  The p-value will be interpreted at two-
sided 5% level of significance. 
Within the MMRM model of HAM-D total score over time, change from baseline in HAM-D 
total scores over the blinded treatment period using equal weights for (Day 3, Day 8, Day 12, 
Day 15), as well as over the time around end of blinded treatment, using equal weights for 
(Day 12, Day 15, Day 18) will be tested. LSMESTIMATE statement in SAS code will be 
used to estimate the difference in LS mean between treatment groups, 95% confidence 
intervals, and p-values. 
If the comparison of SAGE-217 + ADT versus Placebo + ADT at Day 3 is significant at a 
two-sided 0.05 level, the hypothesis testing for the key secondary endpoint will be followed 
with multiplicity adjustment, as described in Section 8.3.3.5. Similar to those methods 
described above for the primary endpoint, a MMRM will be used for the analysis of the 
change from baseline in other time points in HAM-D total score, all time points in HAM-D 
subscale scores (Core Subscale score, Anxiety Subscale score, Bech-6 Subscale score and 
Maier Subscale score), HAM-D individual item scores, CGI-S score, HAM-A total score, 
HAM-A individual item score, MADRS total score, MADRS individual item scores, and 
PHQ-9 total score.  
For each model, the comparison of interest will be between SAGE-217 + ADT and Placebo + 
ADT; model-based point estimates (i.e., LS means), 95% confidence intervals, and p-values 
will be reported for all assessment time points. 
The MMRM analyses will also be provided for change from baseline in HAM-D total score 
within each baseline subgroup level (see Section 8.2.3 and 8.3.3) separately; if any treatment 
group for any level of subgroup has <=15 participants, the subgroup level will not be used in 
the analysis. The model for subgroup analysis of assigned ADT will not use assigned ADT as 
explanatory variable.  
Line plot of model-based LS Mean and standard error (SE) over time will be prepared for 
change from baseline in HAM-D total score, CGI-S score, HAM-A total score, and MADRS 
total score. Forest plot for baseline subgroup analysis for change from baseline in HAM-D 
total score at Day 3, Day 8, Day 15, and Day 42 – LS mean, 95% confidence interval, and p-
value – will be provided. 
The estimate of change from baseline in HAM-D total scores over the treatment period will 
be tested for the following subgroups:  
1. Assigned ADT use (the term for assigned ADT will be skipped in the model) 
2. US COVID-19 status at time of enrollment: First informed consent date: <= 
18Mar2021, > 18Mar2021   
In addition, the MMRM analyses will be provided for change from baseline in HAM-D 
subscale scores, HAM-D individual item scores, CGI-S score, HAM-A total score and 
MADRS total score for the above two subgroups. 


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A Forest plot for individual items in HAM-D, and for subscales of HAM-D will also be 
provided. These plots along with supporting tables will also be produced for the above two 
subgroups.   
Summary of the model-based estimates for HAM-D total score and CGI-S score will be 
provided separately for Per Protocol Set. Line plot of model-based LS Mean and standard 
error (SE) over time will be prepared for change from baseline in HAM-D total score, and 
CGI-S score will be provided separately for Per Protocol Set.   
8.3.3.2. 
Generalized Estimating Equation (GEE) Models 
Generalized estimating equation (GEE) methods will be used for the analysis of HAM-D 
response and HAM-D remission. GEE models will include terms for randomized treatment 
(SAGE-217 + ADT, or Placebo + ADT), baseline HAM-D score, assigned ADT 
(SSRI/SNRI), assessment time point, and time point-by-treatment as explanatory variables.  
An unstructured (UN) covariance structure will be used to model. If there is a convergence 
issue with the unstructured covariance model, then exchangeable covariance structure will be 
used. If the model still does not converge with exchangeable structure, no results will be 
reported. 
Model-based point estimates (i.e., odds ratios), 95% confidence intervals, and p-values will 
be reported.  
Similar GEE method will be used for the analysis of MADRS response and remission.  
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.  
For a sensitivity analysis the worst-case scenario imputation will be used, GEE methods will 
be repeated for the analysis of HAM-D response with missing values considered as “No 
response”. This sensitivity analysis will be performed similarly for HAM-D remission with 
missing values considered as “No remission”. This sensitivity analysis will be also performed 
for MADRS response, MADRS remission, and CGI-I response. 
Model diagnostics to access the goodness of fit for the GEE models will be examined. In the 
event of poor goodness of fit, logistic regression will be performed separately for each visit, 
including baseline score, and assigned ADT (SSRI/SNRI) as explanatory variables. 
Similar GEE method will be used for the analysis of HAM-D response/remission and 
MADRS response/remission for the following subgroups: 
          1. Assigned ADT use (the term for assigned ADT will be skipped in the model) 
          2. US COVID-19 status at time of enrollment at time of enrollment: First informed                
              consent date: <= 18Mar2021, > 18Mar2021   
If the model does not converge due to 0 frequency at certain visits, a new model will be run 
without these visits and the results will be reported. 
This analysis will also be provided for the above two subgroups for CGI-I response.  


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Bar charts over scheduled visits by treatment for HAM-D response/remission, MADRS 
response/remission, and CGI-I response will be provided. In addition, theses bar charts will 
be also provided above sensitivity analyses, as well as for the above subgroups, separately. A 
GEE method will also be used for the analysis of HAM-D response, HAM-D remission, 
CGI-I response by scheduled assessment time point for anxious subgroup 1 and 2 in Section 
8.3.3, respectively.   
8.3.3.3. 
Sensitivity Analysis 
8.3.3.3.1.  Imputation Based on Study Withdrawal Reasons 
A sensitivity analysis will be used to investigate the impact of missing data in HAM-D total 
score at each study visit.  
Imputation based on study withdrawal reason will be used.  The missing  HAM-D total 
scores will be imputed using multiple imputation (MI) methods. The MMRM model will use 
the dataset (all observed and imputed values included) to estimate the treatment difference in 
change from baseline in HAM-D total score. The FAS will be used for sensitivity analyses. 
Sample SAS code for MI is provided in Section 11.2 Appendix B. 
Imputation distribution: 
All randomized participants will be classified as missing category 1, or missing category 2, 
based on the following rules: 
 Missing category 1: Participant discontinued due to adverse events, physician 
decision, protocol deviation, non-compliance with IP, lost to follow-up, participant 
decision, withdrawal by subject, sponsor request, or other. 
 Missing category 2: Participant discontinued due to pregnancy, or due to COVID-19 
Imputation algorithm: 
Missing values of HAM-D total score at all visits will be imputed using the fully conditional 
specification (FCS) models. Two different imputation models will be used based on reasons 
of missing:  
 Missing category 1: simulate missing values of HAM-D total score using an 
imputation model based on the non-missing HAM-D total scores for placebo group 
(“Jump to Reference”).  This represents a conservative approach as it tends to reduce 
the difference between treatment and placebo group.  
 Missing category 2: simulate missing values of HAM-D total score using an 
imputation model based on the non-missing HAM-D total scores within the same 
treatment group. 
Analysis model: 
The complete multiple imputation method is described below: 
 Repeat the process K (K=100) times, using the procedure described above to form K 
imputed complete datasets with the same variance structure. 


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 Fit the MMRM model including treatment, baseline antidepressant use, baseline 
HAM-D total score, assessment time point, and time point-by-treatment to each 
imputed dataset, to estimate the treatment effect and its variance. 
 Combine the results from the K imputed datasets using the SAS procedure 
MIANALYZE, to derive the MI estimator. 
We fit the analysis model (MMRM model specified before) to the kth completed dataset, 
denoting the estimate of the treatment difference θ by θk from the kth completed dataset and 
denoting the corresponding estimate of the variance Vk. The MI estimator of θ, θ̃MI, is the 
average of the K individual estimators: 
𝜃̃𝑀𝐼= 1
𝐾∑𝜃𝑘
𝐾
𝑘=1
 
The estimated variance of θ̃MI is a combination of the between- and within-imputation 
variability as follows: 
𝑉𝑀𝐼= 𝑊+ (1 + 1
𝐾) 𝐵 
where W =
1
K ∑
VK
K
k=1
is the within-imputation variability and B =
1
K-1 ∑
(θk-θ̃MI)
2
K
k=1
is the 
between-imputation variance. 
It has been shown that the statistic 
T = 𝜃̃𝑀𝐼−𝜃
√𝑉𝑀𝐼
 
has an approximate t distribution where V = (K-1) (1 +
W
B)
2
. 
8.3.3.3.2. Tipping Point Analysis 
The purpose of a tipping point analysis is to evaluate the sensitivity of results in missing data 
assumed missing at random (MAR) by finding out the size of the change assumed missing 
not a random (MNAR) that tips a statistically significant treatment effect on HAM-D to 
become not statistically significant. This analysis will use FAS. 
In the tipping point analysis, missing HAM-D total score from each study visit will be 
imputed using multiple imputation in the following steps:  
1. For treatment group (i.e., SAGE-217 + ADT) a positive constant shift from 0 will be 
added to the imputed HAM-D total score values at each study visit.  
Assumed arbitrary missing pattern, a multiple imputation step with SAS MI FCS method will 
be used to impute the missing values of HAM-D total score with “mnar” procedure to make 
the shift. One hundred datasets will be generated for each study visit. 


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2.  For each of the 100 complete datasets after imputation, the change from baseline will be 
calculated so that the MMRM model will be fitted to estimate treatment differences and 
corresponding p-values.  
3. The 100 sets of MMRM results will be combined with SAS PROC MIANALYZE, which 
combines estimates as specified in step 2.  
4. Steps 1 to 3 will be repeated with different values of the shift parameter until the tipping 
point will be reached at each study visit.  
The tipping point will be provided by study visit along with the main estimates in change 
from baseline by study visit from MMRM in Section 8.3.3.1 . Sample SAS code for MI is 
provided in Section 11.2 Appendix B. 
8.3.3.3.3. Weighted Generalized Estimating Equation 
The standard GEE method in Section 8.3.3.2 is valid if the data are missing completely at 
random (MCAR), but it can lead to biased results if the data are missing at random (MAR). 
The weighted GEE implements the inverse probability-weighted method to account for 
dropouts under the MAR assumption. This analysis will be performed using the binary 
secondary endpoints - HAM-D response, HAM-D remission, CGI-I response, MADRS 
response and MADRS remission. This analysis will use FAS. 
A weighted GEE method does not apply for the data with intermittent missing from any of 
the participants and the procedure does not converge in SAS. A SAS procedure with MI 
Markov Chain Monte Carlo (MCMC) with 100 imputations will be used to fill out  
intermittent missing values so that  the data will have monotone missing pattern. Therefore, a 
weighted GEE on each binary endpoint will be run as a sensitivity analysis. Since the 
endpoints are a binary outcome, the imputation to fill out intermittent missing will be 
performed using the raw scores. The imputed values will be rounded and dichotomized to 
obtain each binary endpoint as defined in Section 8.3.1.1 and Section 8.3.1.2. 
Therefore, a weighted GEE model including baseline HAM-D score, assigned ADT, 
assessment time point, and time point-by-treatment as explanatory variables will be used to 
estimate point estimates (i.e., odds ratios), 95% confidence intervals, and p-values. The 
results from the 100 imputed datasets will be combined using the SAS procedure 
MIANALYZE. 
Sample SAS code for weighted GEE is provided in Section 11.2 Appendix B. 
8.3.3.4. 
Analysis of Time to First HAM-D Response/Remission 
Using the FAS, Kaplan-Meier (KM) method will be used to analyze time to first HAM-D 
response; the median time, first quartile (Q1), third quartile (Q3) , min and max to first 
response will be estimated. The number and percent of participants who had a response or 
was censored will be provided. A participant will be censored at the participant’s last study 
day of HAM-D evaluation in the database if the participant did not have a response. Similar 
analysis will be done for first HAM-D remission.  


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8.3.3.5. 
Multiplicity Adjustment for Key Secondary Endpoint 
Multiplicity adjustment to statistical testing of the hypothesis of the key secondary endpoint 
is conducted by using fixed sequence strategy (Dmitrienko et al 2013)1. Only if the primary 
endpoint is statistically significant at a two-sided 0.05 level, the key secondary endpoint will 
be tested  at 5% level of significance.  
All other secondary efficacy endpoints are not adjusted for multiplicity, and hence all p-
values are considered as nominal. 
8.3.4. 
Characterization of Durability of SAGE-217 Treatment Effect  
After completion of 14 days of treatment, the study participant is followed during the ADT 
continuation period, without any further treatment with blinded IP.  During this period, clinic 
visits are scheduled for Days 18, 21, 28, 35 and 42.   
Demonstration of SAGE-217 + ADT durable effect will be characterized via 2 
complementary approaches:  
1) clinically meaningful durable SAGE-217 + ADT treatment effect at Day 42 (see 
Section 8.3.4.1 below), and  
2) statistically significant change from baseline at Day 42 in SAGE-217 + ADT versus 
placebo + ADT (for statistical demonstration of durable SAGE-217 treatment effect, 
see Section 8.3.4.2 below).  
8.3.4.1. 
Durability of Clinically Meaningful Treatment Effect for SAGE-217 
Durability of treatment effect is assessed over the post-treatment period in the SAGE-217 + 
ADT group, based on the efficacy observed at Day 15.  The endpoint for clinically durable 
effect will be examined by the percent retention of the Day 15 reduction from baseline in 
HAM-D total score among SAGE-217 + ADT participants (referred to as “percent retention 
of D15 change from baseline (CFB)” going forward).   
Percent retention of D15 CFB is defined as follows: Let Xb be the baseline HAM-D total 
score, X15 be Day 15 HAM-D total score, Xy be Day Y (Y>15) HAM-D total score.  Then 
percent retention (%) for Day Y is defined as  
𝑋𝑦−𝑋𝑏
𝑋15−𝑋𝑏× 100.  It will be calculated for the 
scheduled visits after Day 15, for the participants who had improvement in HAM-D total 
score at Day 15 since baseline (i.e . X15 < Xb ). For example, for a participant with a baseline 
HAM-D of 27 (Xb) and a HAM-D score of 13 (X15) at Day 15, percent retention at Day 42 
with HAM-D of 16 (Xy) would be 79%. If D42 HAM-D score is 18, percent retention would 
be 64%.   
A summary of percent retention of D15 CFB will be presented for participants who improved 
at Day 15 for post-Day 15 visits by treatment group, based on FAS.  This will serve as the 
approach for assessing clinically durable effect for SAGE-217+ADT; mean percent retention 
of D15 CFB at Day 42 is considered clinically meaningful durability if it is >=65%. The 
mean (±SE) percent retention over time by treatment group will be presented in a line plot.  
In addition, the number, and percent of participants with at least 65% retention of D15 CFB 
at each of post-Day 15 scheduled visit will also be provided by treatment group.  


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This analysis will also be presented using the subgroup of assigned ADT use and the US 
COVID-19 status at time of enrollment. 
 
Following analysis will be presented by treatment group for supportive purposes to assist 
with further understanding of clinical durability of effect of SAGE-217 + ADT.  These 
analyses will be conducted using both FAS and using the subgroup of assigned ADT use and 
the US COVID-19 status at time of enrollment. 
A. A summary of percent retention of D15 CFB will be presented for HAM-D 
responders at Day 15 for scheduled post-Day 15 visits. The mean (±SE) percent 
retention over time will be presented in a line plot.  In addition, the number and 
percent of HAM-D responders at Day 15 with at least 65% retention of D15 CFB at 
each of post-Day 15 visit will also be provided. 
B. The number and percent of HAM-D responders at scheduled post-Day 15 visits 
among HAM-D responders at Day 15 will be provided. A bar chart will be provided. 
C. The number and percent of HAM-D remitters (HAM-D total score <=7) at post-Day 
15 visits among HAM-D remitters at Day 15 will be provided. A bar chart will be 
provided. 
D. Relapse: A relapse is defined for HAM-D responders at Day 15.  A relapse is defined 
as having at least 2 consecutive HAM-D total score >=20 after Day 15, including the 
last value.  The number and percent of participants with relapse will be provided.    
E. Rebound: A rebound is defined for HAM-D responders at Day 15.  A rebound is any 
HAM-D total score (after Day 15) >= Baseline HAM-D total score.  The number and 
percent of participants with rebound will be provided.  
F. The number and percent of CGI-I responders (CGI-IR) at post-Day 15 visits among 
CGI-I responders at Day 15 will be provided. A bar chart will be provided base. 
A summary of percent retention of D15 CFB will be presented by treatment group for 
MADRS responders at Day 15 for scheduled post-Day 15 visits for FAS and the subgroup of 
assigned ADT use and the US COVID-19 status at time of enrollment. The mean (±SE)  
percent retention over time by treatment group will be presented in a line plot for FAS and 
the subgroup of assigned ADT use and US COVID-19 status at time of enrollment at time of 
enrollment.   
Post Day 15 HAM-D and MADRS results supporting the above analyses will be listed 
separately. 
8.3.4.2. 
Durability of Treatment Effect at Day 42 via Statistical Comparison of 
SAGE-217 Versus Placebo 
These analyses have been discussed in Section  8.3.3.1  and Section 8.3.3.2 as part of the 
efficacy analyses with Day 42 using FAS. 
A. MMRM analysis of change from baseline in HAM-D total score at Day 42 comparing 
SAGE-217+ADT versus placebo + ADT (LS mean, p-value and 95% CI) will be 
provided. 


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B. GEE analysis of HAM-D response/remission rates comparing SAGE-217 + ADT 
versus placebo + ADT at Day 42 (Odds Ratio, p-value and 95% CI) will be provided.   
8.4. 
Safety Analysis 
A secondary objective of this study is to evaluate the safety and tolerability of SAGE-217 as 
assessed by the incidence and severity of adverse events. 
 
 
 
 Safety analyses will be 
conducted using the Safety Set, unless specified otherwise. The data will be presented by the 
actual treatment received rather than the treatment to which the participant was randomized; 
for definition of actual treatment assignment, see Section 7.1 .The safety endpoints evaluated 
at scheduled visits within the blinded treatment period are taken as done in nominal visit, 
without any windowing. If a value is available for a nominal scheduled visit within the 
blinded treatment period, that value will be used in summary by visit. If scheduled visit value 
is not available within the blinded treatment period and for all visits in ADT Continuation 
period, a value from the specific visit window will be included in summary, the choice of the 
record following the same rule as described in Section 8.3.2 . 
“Any time during treatment” values are defined as any value on or after first blinded IP 
intake but on or before the last dose of blinded IP + 1 day. “Within 14 days after last dose” is 
defined as any value after last dose of blinded IP but on or before last dose of blinded IP + 14 
days.  “Last value on treatment” and “Last value on study" will be included in the summaries 
whenever indicated in the relevant sections below.  “Last value on treatment” is defined as 
the last post-baseline value between first dose of blinded IP (exclusive) and up to last dose of 
blinded IP + 1 days (inclusive).  “Last value on study” is defined as the last post-baseline 
value after the first dose of blinded IP.  
The safety endpoints and variables considered in the summary tables for this study are 
summarized in Table 4 . 
Table 4: 
Safety Endpoints and Variables in the Summary Tables 
Safety 
Evaluation 
Incidence 
Observed 
Value 
Change 
from 
Baseline 
Abnormality (Out of 
Normal Range) / 
Clinical Significance 
(CS) 
Potentially 
Clinically 
Significant (PCS) 
AEs 
X 
 
 
 
 
Note: PCS criteria are outlined in sections 8.4.2-8.4.4  
X = to be summarized in tables  


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Z = to be presented in listings only 
8.4.1. 
Adverse Events 
Adverse events (AEs) are collected starting at the time of informed consent and throughout 
the duration of participation in the study.  A treatment-emergent adverse event (TEAE) is 
defined as an adverse event with onset on or after the start of blinded IP. The TEAEs will be 
further categorized by the phase of occurrence as follows: 
Adverse events are assigned an AE period based on the onset date/time.  AE periods are 
defined as follows: 
Pre-treatment AE: AE onset date before first blinded IP dosing date/time 
TEAE: AE onset date/time on or after first blinded IP dose date/time (If an AE start date 
same as blinded IP first dose date, but no time either in AE start or treatment start, then 
consider this AE to be a TEAE.)   
On-Treatment TEAE: AE onset date/time on or after first blinded IP dose date/time and on or 
before blinded IP last dose date + 1 day (Note that time does not matter for the end of this 
period.) 
Post-Treatment TEAE: AE onset date after blinded IP last dose date +1 day (Typically, Day 
16 through Day 42 – time does not matter) 
If the date of an adverse event is incomplete and an unambiguous determination could not be 
made with respect to its onset time versus the first dose of blinded IP and/or last dose of 
blinded IP, the adverse event will be assumed to be a TEAE and a treatment period TEAE.  
For imputation of missing AE dates, please refer to Section 11.3 , Appendix C.  
All adverse events will be coded using MedDRA version 23.0 or higher.  
An overview summary table of TEAEs will present the number and percentage of 
participants as well as the number of events for the following: 
 TEAE  
 On-Treatment TEAE 
 Post-Treatment TEAE 
 TEAEs by maximum severity (severe>moderate>mild) 
 TEAE leading to discontinuation of blinded IP 
 TEAE leading to discontinuation of assigned ADT 
 TEAE leading to dose reduction of blinded IP 
 TEAE leading to withdrawal from the study 
 Treatment-emergent Serious Adverse Event (TESAE) 
 Death 


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 Incidence of TEAEs in the following categories will be provided by SOC and PT.  
A participant is counted only once under each SOC and PT in case of multiple 
occurrences of the same AE. In these tables, the display will be sorted by 
decreasing frequency of SOC in SAGE-217 + ADT group, then of SOC in the 
placebo + ADT group; if 2 or more SOCs have the same frequency, the order will 
be alphabetical. Within each SOC, preferred terms will be sorted by the same 
algorithm as in SOC. TEAE 
 
On-Treatment TEAE 
 
Post-Treatment TEAE 
 TEAEs by maximum Severity 
 TEAEs by relationship to blinded IP  
 TEAEs by relationship to assigned ADT 
 Serious TEAEs 
 TEAEs leading to discontinuation of blinded IP 
 On-treatment TEAEs leading to discontinuation of assigned ADT 
 Post-treatment TEAEs leading to discontinuation of assigned ADT 
 TEAE leading to dose reduction of blinded IP 
 TEAEs leading to withdrawal from the study  
Listing of AEs with onset prior to first dose of blinded IP will be provided.  A separate  
listing of the TEAEs for participants who underwent dose reduction will be provided.  
A summary of most common TEAEs by preferred term where the incidence is more than 2% 
in any treatment group will be provided, sorted by decreasing frequency of PT in SAGE-217 
+ ADT group, then of PT in the placebo + ADT group; if 2 or more PTs have the same 
frequency, the order will be alphabetical.  
For maximum severity, participants will be counted only once within each SOC and PT at the 
maximum severity in the following order: severe> moderate> mild; an AE with missing 
severity will be omitted from severity presentation.  A participant will be counted only once 
within each SOC and PT at the strongest relationship to blinded IP in the following order: 
related > not related. Adverse events with onset before the first dose of blinded IP will be 
provided in a separate listing.  Separate data listing for deaths, SAEs, and participants who 
had AEs leading dose reduction will be provided. 
In addition, TEAE summary by SOC/PT will also be presented by the following subgroups: 
 Assigned Antidepressant Use: SSRI, SNRI 
 Age group: 18-24, 25-50, 51-64 years 
 Sex: Male, Female  
 Race: White, Black or African American, Other 


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 BMI at baseline:≤18.4, 18.5-24.9, 25-29.9, ≥30 kg/m2 
 COVID-19 History: this will be summarized by worst case COVID-19 related 
preferred term(PT) coded by MedDRA in medical history data. For participants 
without COVID-19 related PT, the participants are categorized as ‘Not Impacted’ 
 US COVID-19 status at time of enrollment: First informed consent sign date:  
<= 18Mar2021, > 18Mar2021 
8.4.2. 
Clinical Laboratory 
The clinical laboratory tests to be performed for monitoring of safety are listed in Table 5 .  
They are collected on Screening, days 1, 8, 15, 21, 28, and 42. 
Table 5: 
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/and freeT4 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  
All parameters will be converted to the International System of Units (SI) before analysis. 


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For laboratory results that are “≤ x”, where x is a number as collected in the data, the numeric 
part of the result will be used in the calculation in the summary tables. The same is true if the 
result is presented as below limit of quantification (BLQ) and a lower limit of quantification 
(LLOQ) value is provided – LLOQ value will be used for calculation in the summary tables. 
The actual results as collected will be displayed in the listings. 
Summary tables on lab parameters will include descriptive statistics for the observed values 
 by scheduled assessment timepoint in hematology, serum 
chemistry, coagulation, and quantitative urinalysis test results.  
 
 
 
 
If a normal range is provided for the parameter, out-of-range values will be flagged as low or 
high, where applicable, in the data listings.  
 
 
 Qualitative urinalysis parameters will be summarized 
descriptively.  
The number and percentage of participants with PCS values will be provided in separate 
displays in hematology, serum chemistry, liver function tests and urinalysis tests provided for 
such occurrence at any time during treatment, last value on treatment, within 14 days after 
the last dose. Potentially clinically significant values will be identified for specific laboratory 
parameters as outlined in Table 6 .  
Liver function tests will be monitored closely for PCS values, and will be summarized for 
occurrence for the following parameters for these PCS threshold (for condition involving 
more than one parameter, the results need to be from the same timepoint): 
Alanine Aminotransferase: >3xULN, >5xULN, >10xULN 
Aspartate Aminotransferase: >3xULN, >5xULN, >10xULN 
Alanine Aminotransferase or Aspartate Aminotransferase: >3xULN, >5xULN, >10xULN 
Alkaline Phosphatase: >1.5xULN, >2xULN 
Total Bilirubin: >1.5xULN, >2xULN 
Total Bilirubin > 2xULN AND (Alanine Aminotransferase or Aspartate Aminotransferase 
>3xULN) 
Total Bilirubin >2xULN AND Alkaline Phosphatase >2xULN AND (Alanine 
Aminotransferase or Aspartate Aminotransferase >3xULN) 
Total Bilirubin >2xULN AND Alkaline Phosphatase < 2xULN AND (Alanine 
Aminotransferase or Aspartate Aminotransferase >3xULN) 
Any lab results considered clinically significant by the investigator will be captured as 
adverse events, hence will be included in AE displays. 
Pregnancy test results will be listed but not summarized.  


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Table 6: 
Potentially Clinically Significant Values for Specific Laboratory 
Parameters 
Laboratory  
Parameter 
Units 
Criteria for PCS Values (Observed 
values) 
 
 
High  
Low  
Hematology 
 
 
 
Hemoglobin -male 
g/L  
>185  
<115 
Hemoglobin -female 
g/L  
>170 
<100 
Hematocrit-male 
Fraction of 1 
>0.55  
<0.385  
Hematocrit-female 
Fraction of 1 
>0.49 
<0.345 
Platelet count  
10^9/L  
>600 
<125 
White blood cell 
10^9/L  
>15  
<2.5  
Basophils  
10^9/L  
>0.5 
NA 
Eosinophils 
10^9/L  
>1.5 
NA 
Neutrophils  
10^9/L  
NA  
<1.5  
Lymphocytes  
10^9/L  
>6.0  
<0.5  
Monocytes  
10^9/L  
>1.4 
NA 
 
 
 
 
Serum Chemistry 
 
 
 
Albumin  
g/L  
>70  
<28  
Blood urea nitrogen  
mmol/L 
>10.71 
NA 
Calcium 
mmol/L 
>2.75 
<2.0 
Chloride 
mmol/L 
>120 
<90 
Creatinine 
mmol/L 
>3xULN or >3x 
Baseline 
 
Gamma Glutamyl Transferase  
 
>3xULN 
 
Glucose 
mmol/L 
>13.9 
<2.8 
Sodium  
mmol/L  
>150 
<132  
Potassium  
mmol/L  
>5.4  
<3.3  
Protein  
g/L 
 
<45 
Bicarbonate  
mmol/L  
>34  
<18  
Chloride  
mmol/L  
>120  
<90  
Phosphorus  
mmol/L 
>1.94 
<0.61 


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Laboratory  
Parameter 
Units 
Criteria for PCS Values (Observed 
values) 
Liver Function Tests (LFT) 
 
 
 
Bilirubin  
μmol/L  
>2xULN  
NA  
Aspartate Aminotransferase  
U/L  
>3xULN  
NA  
Alanine Aminotransferase  
U/L  
>3xULN  
NA  
Alkaline Phosphatase  
U/L  
>1.5xULN  
NA  
8.4.3. 
Vital Signs 
Vitals for the following parameters – respiratory rate (breaths/minute), oral temperature 
(degrees C), supine heart rate (beats/minute), supine systolic blood pressure (mmHg), supine 
diastolic blood pressure (mmHg), standing heart rate (beats/minute), standing systolic blood 
pressure (mmHg), standing diastolic blood pressure (mmHg), – are collected at screening, 
days 1, 3, 8, 12, 15, 18, 28,  and 42. Descriptive summaries of observed values 
 
 will be provided for vital sign parameters – by scheduled assessment time 
point.  It will also include the summary of last values on treatment and on study assessments.  
Additionally, 
 
 will be summarized for such occurrence any time during 
treatment, last value on treatment, within 14 days after the last dose. Potentially clinically 
significant values will be identified for vital sign parameters as outlined in Table 7 . 


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8.4.4. 
Electrocardiogram 
Supine 12-lead ECGs will be performed in triplicate, and are collected on screening, days 1, 
15, and 42. The following ECG parameters will be listed for each participant: heart rate 
(beats per minute), PR (msec), RR (bmp), QRS (msec), QT (msec), and QTcF (msec).     
The average of the triplicate values will be used in the summary, including baseline ECG 
values.  The observed value at each time point 
This summary will also include the last 
values on treatment and on study.   
 
 
 
 
 
 will be summarized 
for such occurrence any time during treatment, last value on treatment, and within 14 days 
after the last dose.  Potentially clinically significant values will be identified for ECG 
parameters as outlined in Table 8 . This analysis includes triplicate values individually and is 
not based on average value. In addition, the maximum value of QTcF if within any of the 
PCS criteria will be summarized. 
 
 


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8.4.5. 
Physical Examination  
Physical examination is scheduled on screening, day 1 and 42 (and EOT if applicable). Only 
clinically significant abnormalities are captured in the database – for post-baseline 
observations, these will be reported as adverse events, hence these will be included in AE 
displays; for pre-baseline observations, these will be reported as medical history, hence these 
will be included in Medical History displays.  The dates of physical examination will be 
listed to confirm that the examination was done.  
 
 
 
 
 
   
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 


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9. 
SUMMARY OF INTERIM AND DMC ANALYSES 
Not applicable 
10. 
REFERENCES 
1. Dmitrienko A., D’Agostino, Sr. R.B., and Huque, M.F (2013). Key multiplicity issues 
in clinical drug development. Statistics in Medicine. 32(7); 1079-1111 
 
 


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11. 
LIST OF APPENDICES 
11.1. 
Appendix A: 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 


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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 
 
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 
 
 
 
 
 
 
 
 
 
 
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 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 


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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 
 
SAGE-217/Placebo 
Dispensation 
 
X 
 
X 
 
 
 
 
 
 
 
SAGE-217/Placebo 
Administration 
 
X (once daily in the evening through Day 14 - inclusive) 
 
 
 
 
 
IP Adherence s 
 
X 
ADT Administration t 
 
X 
IP Accountability/Return 
 
 
X 
X 
 
X 
 
X 
X 
X 
X  
AEs/SAEs d, u 
X 
Prior/Concomitant 
Medications/Procedures d, v 
X 
Abbreviations: ADT = Antidepressant therapy; AE = adverse event; CGI-I = Clinical Global Impression – Improvement; CGI-S – Clinical Global Impression – Severity; 
 D = day; 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. 
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 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. 
e Participants will be trained on use of software applications and devices necessary for the conduct of the study by site personnel. 
f 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 


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g Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. 
h Urine toxicology for selected drugs of abuse and breath test for alcohol. 
i 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. 
 
 
 
 
l 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. 
m Triplicate ECGs will be collected. 
 
 
 
o The HAM-D is to be completed as early during the visit as possible. 
p 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. 
 
 
 
 
s IP administration will be monitored via a medication adherence monitoring platform used on smartphones to visually confirm IP ingestion. 
t ADT will be administered as per labeled prescribing information  
u AEs will be collected starting at the time of informed consent and throughout the duration of the participant’s participation in the study. 
v Prior medications will be collected at Screening and concomitant medications and/or procedures will be collected at each subsequent visit. 
 
 


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11.2. 
Appendix B: Details of Statistical Methodology 
Sample SAS code for Mixed Effects Model for Repeated Measures (MMRM): 
 If type=un: 
ods output lsmeans=estimates diffs=diffs; 
proc mixed data=&data; 
class trtpn avisitn usubjid antidep; 
model chg=base trtpn avisitn trtpn*avisitn antidep / ddfm=kr s; 
repeated avisitn / subject=usubjid type=un;  
lsmeans trtpn*avisitn /diff=all cl alpha=0.05 OM; 
** assuming trtpn=1 for the placebo, trtpn=2 for SAGE-217 
lsmestimate trtpn*avisitn ' Placebo Over Treatment Period (Equal Weights)' 1 1 1 1 0 0    
                                                                  0 0 0  0 0 0 0 0 0 0 0 0 / divisor=4 OM;  
lsmestimate trtpn*avisitn ' Sage Over Treatment Period (Equal Weights)' 0 0 0 0 0 0                      
                                                                  0 0 0 1 1 1 1 0 0 0 0 0/ divisor=4 OM;  
lsmestimate trtpn*avisitn 'Sage vs Placebo Over Treatment Period (Equal Weights)'   
                                                     -1  -1 -1  -1 0 0 0 0 0 1 1 1 1 0 0 0 0 0 / divisor=4 OM;  
 
lsmestimate trtpn*avisitn 'Placebo Over Day 12, Day 15, and Day 18 (Equal Weights)' 0 0 1   
                                                          1 1 0 0 0 0  0 0 0 0 0 0 0 0 0 / divisor=3 OM;     
                                                                  
lsmestimate trtpn*avisitn 'Sage Over Day 12, Day 15, and Day 18 (Equal Weights)' 0 0 0 0 0  
                                                          0  0 0 0 0 0 1 1 1 0 0 0 0/ divisor=3 OM;                                                   
lsmestimate trtpn*avisitn 'Sage vs Placebo Over Day 12, Day 15, and Day 18 (Equal 
Weights)'  0  0  -1  -1 -1 0 0 0 0 0 0 1 1 1 0 0 0 0 / divisor=3 OM;  
run;  
Sample SAS code for Generalized Estimating Equation (GEE): 
proc genmod data=&data; 
class usubjid trtpn antidep avisitn; 
model aval=base trtpn avisitn trtpn*avisitn antidep /dist=bin link=logit; 
repeated participant=usubjid / type=un; * if convergence not met, use type=exch; 
lsmeans trtpn*avisitn / diff exp cl; 
run;  
 
Sample SAS code for Multiple Imputation (MI): 
** Missing category 1, trtp=A represent the PLACEBO group 


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proc mi data=in seed=xxxx nimpute=100 round=. . . . 1 1 1 1 1 1 1 1 1 1 1 1 1 1 out= 
fcs_reg1; 
class trtp ADT; 
FCS reg; 
mnar model (base day3 day8 day12 day15 day18 day21 day28 day35 day42/ modelobs= 
(trtp=’A’)); 
var strata base day3 day8 day12 day15 day18 day21 day28 day35 day42; 
run; 
** Missing category 2 
proc mi data=&data seed=xxxx nimpute=100 round=. . . . 1 1 1 1 1 1 1 1 1 1 1 1 1 
1out=fcs_reg2; 
class trtp ADT; 
fcs nbiter=20 reg (base day3 day8 day12 day15 day18 day21 day28 day35 day42/details); 
var trtp ADT base day3 day8 day12 day15 day18 day21 day28 day35 day42; 
run;  
 
Sample SAS code for Tipping Point Analysis: 
proc mi data=&data out=temp seed=xxxxxx nimpute=100; 
class trtpn adt;  
var trtpn adt base day3 day8 day12 day15 day18  day21 day28 day35 day42 ; 
fcs reg;  
mnar adjust(day_xx/shift=xx adjustobs=(trtpn='2'))  
     adjust(day_xx/shift=xx adjustobs=(trtpn='2'))  
     adjust(day_xx/shift=xx adjustobs=(trtpn='2'))  
     adjust(day_xx/shift=xx adjustobs=(trtpn='2'))  
     adjust(day_xx/shift=xx adjustobs=(trtpn='2')) 
     adjust(day_xx/shift=xx adjustobs=(trtpn='2')) ; 
run; 
 
Sample SAS code for Weighted GEE analysis: 
 Change the missing pattern from arbitrary to monotone; 
proc mi data=&data out==&data1 seed= xxxxxx nimpute=100;  
mcmc chain=multiple impute= monotone ;  
var base adt day3 day8 day12 day15 day18 day21 day28 day35 day42 ;  
run; 
 
proc gee data==&data ; 
by _imputation_; 


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class usubjid trtpn adttype avisitn ; 
missmodel base trtpn avisitn trtpn*avisitn adttype / type=obslevel; 
model dep = base trtpn avisitn trtpn*avisitn adttype  /dist=bin link=logit ; 
repeated subject=usubjid / type=un ; * if convergence not met, use type=exch; 
lsmeans trtpn*avisitn / diff exp cl; 
run; 
11.3. 
Appendix C: Handling of Missing Dates 
Dates missing the day, or both the day and month of the year will adhere to the following 
conventions in order to classify TEAEs and to classify prior and concomitant medications.  
In general, listings will present the actual partial or missing values rather than the imputed 
values that may be used in derivation. In instances where imputed values will be presented, 
imputed values will be flagged.  
Adverse Events 
If the AE start date is completely missing, do not impute a date but consider it as TEAE, 
unless the AE end date is before the initiation of treatment, in which case the AE will be 
considered prior. 
For partial AE start dates: 
a. When the year is known, but the month and day is unknown, then: 
o If the year matches the year of first dose date and the end date (if present) is 
after first dose date, or AE is ongoing, then impute as the month and day of 
min (first dose date + 1 day, last dose date). 
o If the year of AE onset < year of initiation of the treatment, then the month 
and day will be set to December 31st.  
o If the year of AE onset > the year of initiation of treatment, then the month 
and day will be set to January 1st. 
b. If the year and month are known, but the day is unknown, then: 
o If the year of AE onset = the year of initiation of the treatment and: 
 the month of AE onset = the month of initiation of the treatment, then the 
day will be set to the day of initiation of the treatment. 
 the month of AE onset < the month of initiation of the treatment, then the 
day will be set to the last day of month of the particular year. 
 if the month of AE onset > the month of initiation of the treatment, then 
the day will be set to the 1
st day of month. 
o If the year of AE onset < the year of initiation of the treatment, then the day 
will be set to the last day of month of the particular year. 


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o If the year of AE onset > the year of initiation of the treatment, then the day 
will be set to the 1
st day of month. 
If the imputed AE onset date is after the AE stop date, then the onset date will be set 
to the stop date. When the year and day are present and the month is missing, treat it 
as if the day is missing, and only year is present.  Follow the imputation rules for 
“year is known, but the month and day is unknown”. 
c. When the year is missing, but the month and/or day is known, treat this date as 
missing; do not impute. 
 
Dates in Disease History (Dates of diagnosis, current episode, first episode) 
If the year is present and the month and day are missing, then the month and day will be set 
to January 1. 
If the year and day are present and the month is missing, then the month will be set to 
January. 
If the year and month are present and the day is missing, then the day will be set to the 1st day 
of month 
 
Prior and Concomitant Medications 
For the partial start date of medication: 
a. If the year is present and the month and day are missing, then the month and day 
will be set to January 1. 
b. If the year and day are present and the month is missing, then the month will be 
set to January. 
c. If the year and month are present and the day is missing, then the day will be set 
to the 1st day of month. 
d. If the imputed start date of medication is after the end date (imputed date if 
applicable) of medication, then the start date will be set to the end date of 
medication. 
For the partial end date of medication: 
a. If the year is present and the month and day are missing, then the month and day will 
be set to min (December 31, date of death). 
b. If the year and day are present and the month is missing, then the month will be set to 
min (December, month of death). If the year and month are present and the day is 
missing, then the day will be set to min (last day of the month, month of death). 
c. If the year and day are present and the month is missing, then treat it as if the day is 
also missing.  Set the month and day to be min (December 31, date of death).   


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11.4. 
Appendix D: Daily Trends in Number of COVID-19 Cases in The United States Reported to 
Centers for Disease Control and Prevention (CDC)  
The date of 18March2021 has been determined as the cutoff pre and during peak vs. post-peak.  
SOURCE: CDC COVID Data Tracker. https://covid.cdc.gov/covid-data-tracker/#trends_dailycases. 
As the context of COVID-19 has substantially increased the numbers of individuals experiencing MDD, it is reasonable to 
examine if enrollment during different periods of the US pandemic had an impact on treatment outcomes.  


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Rather than assessing the impact of COVID on the treatment outcome, the analyses ask if it is possible that the experience of 
prolonged quarantine influenced treatment outcomes, particularly during the wave of COVID in the US over the 2020-2021 winter 
period.  
As such, the sponsor has chosen a timepoint which allows for a balanced sample but helps elucidate any potential effects on the 
placebo response during this period, which may influence the study outcome.  
 
 


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11.5. 
Appendix E: List of Displays 
Tables 
Table Number 
Title 
Analysis Set 
Table 14.1.1.1 
Summary of Participant Disposition 
All Participants 
Table 14.1.1.2 
Summary of Analysis Sets 
All Participants 
Table 14.1.1.3 
Summary of Participant Disposition 
Full Analysis Set 
Table 14.1.2.1 
Summary of Major Protocol Deviations 
Full Analysis Set 
Table 14.1.2.2 
Reasons for Exclusion from Analysis Sets 
Randomized Set 
Table 14.1.3.1.1 
Summary of Demographics and Baseline Characteristics 
Safety Set 
Table 14.1.3.1.2 
Summary of Demographics and Baseline Characteristics 
Full Analysis Set 
Table 14.1.3.1.3 
Summary of Baseline Subgroups 
Safety Set 
Table 14.1.3.1.4 
Summary of Baseline Subgroups 
Full Analysis Set 
Table 14.1.3.1.5 
Summary of Demographics and Baseline Characteristics  by the Assigned 
Antidepressant Use 
Full Analysis Set 
Table 14.1.3.1.6 
Summary of Baseline Subgroups by the Assigned Antidepressant Use 
Full Analysis Set 
Table 14.1.3.1.7 
Summary of Demographics and Baseline Characteristics by the US COVID-19 status 
at time of enrollment  
Full Analysis Set 
Table 14.1.3.1.8 
Summary of Baseline Subgroups by the US COVID-19 status at time of enrollment  
Full Analysis Set 
Table 14.1.3.2.1 
Summary of Disease History 
Safety Set 
Table 14.1.3.2.2 
Summary of Medical and Surgical History 
Safety Set 
Table 14.1.3.2.3 
Summary of Interim Medical and Surgical History  
Safety Set 
Table 14.1.3.2.4 
Summary of Participant History of Psychiatric Disorder 
Safety Set 
Table 14.1.3.2.5 
Summary of Family History of Psychiatric Disorder 
Safety Set 


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Table Number 
Title 
Analysis Set 
Table 14.1.4.1.1 
Summary of Prior Non-Psychotropic Medications 
Safety Set 
Table 14.1.4.1.2 
Summary of Concomitant Non-Psychotropic Medications 
Safety Set 
Table 14.1.4.1.3 
Summary of On-treatment Non-Psychotropic Medications  
Safety Set 
Table 14.1.4.1.4 
Summary of Post-treatment Non-Psychotropic Medications 
Safety Set 
Table 14.1.4.2.1 
Summary of Prior Psychotropic Medications 
Safety Set 
Table 14.1.4.2.2 
Summary of Prior Psychotropic Medications by ATC Level 4 
Safety Set 
Table 14.1.4.2.3 
Summary of Concomitant Psychotropic Medications 
Safety Set 
Table 14.1.4.2.4 
Summary of Concomitant Psychotropic Medications by ATC Level 4 
Safety Set 
Table 14.1.4.2.5 
Summary of On-treatment Psychotropic Medications 
Safety Set 
Table 14.1.4.2.6 
Summary of Post-treatment Psychotropic Medications 
Safety Set 
Table 14.1.5.1 
Summary of Investigational Product Exposure  
Safety Set 
Table 14.1.5.2 
Summary of Blinded Investigational Product Adherence 
Full Analysis Set 
Table 14.2.1.1.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Study 
Visit 
Full Analysis Set 
Table 14.2.1.1.2 
Model-based Results on Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score by Study Visit 
Full Analysis Set 
Table 14.2.1.1.3 
Model-based Sensitivity Analysis on Change from Baseline in Hamilton Rating Scale 
for Depression (HAM-D) Total Score at Day 15 
Full Analysis Set 
Table 14.2.1.1.4 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Study 
Visit 
Per Protocol Set 
Table 14.2.1.1.5 
Model-based Results on Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score by Study Visit 
Per Protocol Set 
Table 14.2.1.1.6 
Results from Tipping Point Analysis on Changed from Baseline in in Hamilton 
Rating Scale for Depression (HAM-D) Total Score by Study Visit 
Full Analysis Set 


Statistical Analysis Plan Methods Version 1.0 
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Table Number 
Title 
Analysis Set 
Table 14.2.1.2.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Subscale Scores by 
Study Visit 
Full Analysis Set 
Table 14.2.1.2.2 
Model-based Results on Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Subscale Score by Study Visit 
Full Analysis Set 
Table 14.2.1.2.3 
Summary of Hamilton Rating Scale for Depression (HAM-D) Subscale Scores by 
Study Visit and Assigned Antidepressant Use 
 Full Analysis Set 
Table 14.2.1.2.4 
Model-based Results on Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Subscale Score by Study Visit and Assigned Antidepressant 
Use 
 Full Analysis Set 
Table 14.2.1.2.5 
Summary of Hamilton Rating Scale for Depression (HAM-D) Subscale Scores by 
Study Visit and Enrollment based on US COVID-19 
 Full Analysis Set 
Table 14.2.1.2.6 
Model-based Results on Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Subscale Score by Study Visit and US COVID-19 status at 
time of enrollment 
 Full Analysis Set 
Table 14.2.1.3.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Individual Item Score 
by Study Visit 
Full Analysis Set 
Table 14.2.1.3.2 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Individual 
Item Score, Change from Baseline by Study Visit 
Full Analysis Set 
Table 14.2.1.3.3 
Summary of Hamilton Rating Scale for Depression (HAM-D) Individual Item Score 
by Study Visit and Assigned Antidepressant Use 
Full Analysis Set 
Table 14.2.1.3.4 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Individual 
Item Score, Change from Baseline by Study Visit and Assigned Antidepressant Use  
 Full Analysis Set 
Table 14.2.1.3.5 
Summary of Hamilton Rating Scale for Depression (HAM-D) Individual Item Score 
by Study Visit and US COVID-19 status at time of enrollment 
Full Analysis Set 
Table 14.2.1.3.6 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Individual 
Item Score, Change from Baseline by Study Visit and US COVID-19 status at time of 
enrollment 
 Full Analysis Set 


Statistical Analysis Plan Methods Version 1.0 
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Table Number 
Title 
Analysis Set 
Table 14.2.1.4.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Response by Study 
Visit 
Full Analysis Set 
Table 14.2.1.4.2 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Response 
by Study Visit 
Full Analysis Set 
Table 14.2.1.4.3 
Sensitivity Analysis: Summary of Hamilton Rating Scale for Depression (HAM-D) 
Response by Study Visit  
Full Analysis Set 
Table 14.2.1.4.4 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score – Percent 
Improvement – by Study Visit 
Full Analysis Set 
Table 14.2.1.4.5 
Summary of Time to First Hamilton Rating Scale for Depression (HAM-D) Response 
– Kaplan-Meier Analysis 
Full Analysis Set 
Table 14.2.1.4.6 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Response 
by Study Visit and Assigned Antidepressant use 
 Full Analysis Set 
Table 14.2.1.4.7 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Response 
by Study Visit and US COVID-19 status at time of enrollment 
 Full Analysis Set 
Table 14.2.1.4.8 
Weighted GEE Model-Based Results on Hamilton Rating Scale for Depression 
(HAM-D) Response by Study Visit 
Full Analysis Set 
Table 14.2.1.4.9 
Sensitivity Analysis: Model-based Results on Hamilton Rating Scale for Depression 
(HAM-D) Response by Study Visit 
Full Analysis Set 
Table 14.2.1.4.10 
Sensitivity Analysis: Model-based Results on Hamilton Rating Scale for Depression 
(HAM-D) Response by Study Visit and Assigned Antidepressant use 
Full Analysis Set 
Table 14.2.1.5.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Remission by Study 
Visit 
Full Analysis Set 
Table 14.2.1.5.2 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Remission 
by Study Visit 
Full Analysis Set 
Table 14.2.1.5.3 
Sensitivity Analysis: Summary of Hamilton Rating Scale for Depression (HAM-D) 
Remission by Study Visit 
Full Analysis Set 


Statistical Analysis Plan Methods Version 1.0 
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Table Number 
Title 
Analysis Set 
Table 14.2.1.5.4 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score in 
Categories, by Study Visit 
Full Analysis Set 
Table 14.2.1.5.5 
Summary of Time to First Hamilton Rating Scale for Depression (HAM-D) 
Remission – Kaplan-Meier Analysis 
Full Analysis Set 
Table 14.2.1.5.6 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Remission 
by Study Visit and Assigned Antidepressant Use 
 Full Analysis Set 
Table 14.2.1.5.7 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Remission 
by Study Visit and US COVID-19 status at time of enrollment 
 Full Analysis Set 
Table 14.2.1.5.8 
Weighted GEE Model-Based Results on Hamilton Rating Scale for Depression 
(HAM-D) Remission by Study Visit 
Full Analysis Set 
Table 14.2.1.5.9 
Sensitivity Analysis: Model-based Results on Hamilton Rating Scale for Depression 
(HAM-D) Remission by Study Visit 
Full Analysis Set 
Table 14.2.1.5.10 
Sensitivity Analysis: Model-based Results on Hamilton Rating Scale for Depression 
(HAM-D) Remission by Study Visit and Assigned Antidepressant use 
Full Analysis Set 
Table 14.2.1.6.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Study 
Visit and Assigned Antidepressant Use 
Full Analysis Set 
Table 14.2.1.6.2 
Model-based Results on Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score by Study Visit and Assigned Antidepressant Use 
Full Analysis Set 
Table 14.2.1.7.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Study 
Visit and Age Group 
Full Analysis Set 
Table 14.2.1.7.2 
Model-based Results on Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score by Study Visit and Age Group  
Full Analysis Set 
Table 14.2.1.8.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Study 
Visit and Sex 
Full Analysis Set 
Table 14.2.1.8.2 
Model-based Results on Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score by Study Visit and Sex 
Full Analysis Set 


Statistical Analysis Plan Methods Version 1.0 
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Table Number 
Title 
Analysis Set 
Table 14.2.1.9.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Study 
Visit and Race Group 
Full Analysis Set 
Table 14.2.1.9.2 
Model-based Results on Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score by Study Visit and Race Group 
Full Analysis Set 
Table 14.2.1.10.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Study 
Visit and BMI at Baseline 
Full Analysis Set 
Table 14.2.1.10.2 
Model-based Results on Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score by Study Visit and BMI at Baseline 
Full Analysis Set 
Table 14.2.1.11.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Study 
Visit and COVID-19 History 
Full Analysis Set 
Table 14.2.1.11.2 
Model-based Results on Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score by Study Visit and COVID-19 History 
Full Analysis Set 
Table 14.2.1.12.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Study 
Visit and US COVID-19 status at time of enrollment 
Full Analysis Set 
Table 14.2.1.12.2 
Model-based Results on Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score by Study Visit and US COVID-19 status at time of 
enrollment 
Full Analysis Set 
Table 14.2.2.1.1 
Summary of Clinical Global Impression – Improvement (CGI-I) by Study Visit 
Full Analysis Set 
Table 14.2.2.1.2 
Summary of Clinical Global Impression – Improvement (CGI-I) Response by Study 
Visit 
Full Analysis Set 
Table 14.2.2.1.3 
Model-based Results on Clinical Global Impression – Improvement (CGI-I) 
Response by Study Visit 
Full Analysis Set 
Table 14.2.2.1.4 
Summary of Clinical Global Impression – Improvement (CGI-I) by Study Visit and 
Assigned Antidepressant Use  
 Full Analysis Set 
Table 14.2.2.1.5 
Model-based Results on Clinical Global Impression – Improvement (CGI-I) 
Response by Study Visit and Assigned Antidepressant Use 
 Full Analysis Set 


Statistical Analysis Plan Methods Version 1.0 
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Table Number 
Title 
Analysis Set 
Table 14.2.2.1.6 
Summary of Clinical Global Impression – Improvement (CGI-I) by Study Visit and 
US COVID-19 status at time of enrollment 
 Full Analysis Set 
Table 14.2.2.1.7 
Model-based Results on Clinical Global Impression – Improvement (CGI-I) 
Response by Study Visit and US COVID-19 status at time of enrollment 
 Full Analysis Set 
Table 14.2.2.1.8 
Weighted GEE Model-Based Results on Clinical Global Impression - Improvement 
(CGI-I) Response by Study Visit 
Full Analysis Set 
Table 14.2.2.1.9 
Sensitivity Analysis: Model-based Results on Clinical Global Impression - 
Improvement (CGI-I) Response by Study Visit 
Full Analysis Set 
Table 14.2.3.1.1 
Summary of Clinical Global Impression – Severity (CGI-S) by Study Visit 
Full Analysis Set 
Table 14.2.3.1.2 
Model-based Results on Change from Baseline in Clinical Global Impression – 
Severity (CGI-S) by Study Visit 
Full Analysis Set 
Table 14.2.3.1.3 
Summary of Clinical Global Impression – Severity (CGI-S) by Study Visit and 
Assigned Antidepressant Use 
Full Analysis Set 
Table 14.2.3.1.4 
Model-based Results on Change from Baseline in Clinical Global Impression – 
Severity (CGI-S) by Study Visit and Assigned Antidepressant Use 
Full Analysis Set 
Table 14.2.3.1.5 
Summary of Clinical Global Impression – Severity (CGI-S) by Study Visit  
 Per Protocol Set 
Table 14.2.3.1.6 
Model-based Results on Change from Baseline in Clinical Global Impression – 
Severity (CGI-S) by Study Visit  
 Per Protocol Set 
Table 14.2.3.1.7 
Summary of Clinical Global Impression – Severity (CGI-S) by Study Visit and US 
COVID-19 status at time of enrollment 
 Full Analysis Set 
Table 14.2.3.1.8 
Model-based Results on Change from Baseline in Clinical Global Impression – 
Severity (CGI-S) by Study Visit and US COVID-19 status at time of enrollment 
 Full Analysis Set 
Table 14.2.4.1.1 
Summary of Hamilton Rating Scale for Anxiety (HAM-A) Total Score by Visit 
Full Analysis Set 
Table 14.2.4.1.2 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Anxiety 
(HAM-A) Total Score by Study Visit 
Full Analysis Set 


Statistical Analysis Plan Methods Version 1.0 
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Table Number 
Title 
Analysis Set 
Table 14.2.4.1.3 
Summary of Hamilton Rating Scale for Anxiety (HAM-A) Total Score by Visit and 
Assigned Antidepressant Use 
Full Analysis Set 
Table 14.2.4.1.4 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Anxiety 
(HAM-A) Total Score by Study Visit and Assigned Antidepressant Use 
Full Analysis Set 
Table 14.2.4.1.5 
Summary of Hamilton Rating Scale for Anxiety (HAM-A) Total Score by Visit and 
US COVID-19 status at time of enrollment 
Full Analysis Set 
Table 14.2.4.1.6 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Anxiety 
(HAM-A) Total Score by Study Visit and US COVID-19 status at time of enrollment 
Full Analysis Set 
Table 14.2.4.2.1 
Summary of Hamilton Rating Scale for Anxiety (HAM-A) Individual Item Score by 
Study Visit 
Full Analysis Set 
Table 14.2.4.2.2 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Anxiety 
(HAM-A) Individual Item Score by Study Visit 
Full Analysis Set 
Table 14.2.5.1.1 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Total Score by 
Study Visit 
Full Analysis Set 
Table 14.2.5.1.2 
Model-based Results on Change from Baseline in Montgomery-Asberg Depression 
Rating Scale (MADRS) Total Score by Study Visit 
Full Analysis Set 
Table 14.2.5.1.3 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Total Score by 
Study Visit and Assigned Antidepressant Use 
Full Analysis Set 
Table 14.2.5.1.4 
Model-based Results on Change from Baseline in Montgomery-Asberg Depression 
Rating Scale (MADRS) Total Score by Study Visit and Assigned Antidepressant Use 
Full Analysis Set 
Table 14.2.5.1.5 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Total Score by 
Study Visit and US COVID-19 status at time of enrollment 
Full Analysis Set 
Table 14.2.5.1.6 
Model-based Results on Change from Baseline in Montgomery-Asberg Depression 
Rating Scale (MADRS) Total Score by Study Visit and US COVID-19 status at time 
of enrollment 
Full Analysis Set 
Table 14.2.5.2.1 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Individual 
Item Score by Study Visit 
Full Analysis Set 


Statistical Analysis Plan Methods Version 1.0 
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Table Number 
Title 
Analysis Set 
Table 14.2.5.2.2 
Model-based Results on Change from Baseline in Montgomery-Asberg Depression 
Rating Scale (MADRS) Individual Item Score 
Full Analysis Set 
Table 14.2.5.3.1 
Summary of Montgomery-Åsberg Depression Rating Scale (MADRS) Response by 
Study Visit 
Full Analysis Set 
Table 14.2.5.3.2 
Model-based Results on Montgomery-Asberg Depression Rating Scale (MADRS) 
Response by Study Visit  
Full Analysis Set 
Table 14.2.5.3.3 
Model-based Results on Montgomery-Asberg Depression Rating Scale (MADRS) 
Response by Study Visit and Assigned Antidepressant Use 
Full Analysis Set 
Table 14.2.5.3.4 
Model-based Results on Montgomery-Asberg Depression Rating Scale (MADRS) 
Response by Study Visit and US COVID-19 status at time of enrollment 
Full Analysis Set 
Table 14.2.5.3.5 
Weighted GEE Model-Based Results on Montgomery-Asberg Depression Rating 
Scale (MADRS) Response by Study Visit 
Full Analysis Set 
Table 14.2.5.3.6 
Sensitivity Analysis: Model-based Results on Montgomery-Asberg Depression 
Rating Scale (MADRS) Response by Study Visit 
Full Analysis Set 
Table 14.2.5.4.1 
Summary of Montgomery-Åsberg Depression Rating Scale (MADRS) Remission by 
Study Visit 
Full Analysis Set 
Table 14.2.5.4.2 
Model-based Results on Montgomery-Asberg Depression Rating Scale (MADRS) 
Remission by Study Visit 
Full Analysis Set 
Table 14.2.5.4.3 
Model-based Results on Montgomery-Asberg Depression Rating Scale (MADRS) 
Remission by Study Visit and Assigned Antidepressant Use 
Full Analysis Set 
Table 14.2.5.4.4 
Model-based Results on Montgomery-Asberg Depression Rating Scale (MADRS) 
Remission by Study Visit and US COVID-19 status at time of enrollment 
Full Analysis Set 
Table 14.2.5.4.5 
Weighted GEE Model-Based Results on Montgomery-Asberg Depression Rating 
Scale (MADRS) Remission by Study Visit 
Full Analysis Set 
Table 14.2.5.4.6 
Sensitivity Analysis: Model-based Results on Montgomery-Asberg Depression 
Rating Scale (MADRS) Remission by Study Visit 
Full Analysis Set 


Statistical Analysis Plan Methods Version 1.0 
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Table Number 
Title 
Analysis Set 
Table 14.2.6.1.1 
Summary of Patient Health Questionnaire (PHQ-9) Total Score by Study Visit 
Full Analysis Set 
Table 14.2.6.1.2 
Summary of Patient Health Questionnaire (PHQ-9) Total Score Category by Study 
Visit 
Full Analysis Set 
Table 14.2.6.1.3 
Model-based Results on Change from Baseline in Patient Health Questionnaire 
(PHQ-9) Total Score by Study Visit 
Full Analysis Set 
Table 14.2.6.1.4 
Summary of Patient Health Questionnaire (PHQ-9) Total Score by Study Visit and 
Assigned Antidepressant Use 
 Full Analysis Set 
Table 14.2.6.1.5 
Summary of Patient Health Questionnaire (PHQ-9) Total Score Category by Study 
Visit and Assigned Antidepressant Use 
 Full Analysis Set 
Table 14.2.6.1.6 
Model-based Results on Change from Baseline in Patient Health Questionnaire 
(PHQ-9) Total Score by Study Visit and Assigned Antidepressant Use 
 Full Analysis Set 
Table 14.2.6.1.7 
Summary of Patient Health Questionnaire (PHQ-9) Total Score by Study Visit and 
US COVID-19 status at time of enrollment 
 Full Analysis Set 
Table 14.2.6.1.8 
Summary of Patient Health Questionnaire (PHQ-9) Total Score Category by Study 
Visit and US COVID-19 status at time of enrollment  
 Full Analysis Set 
Table 14.2.6.1.9 
Model-based Results on Change from Baseline in Patient Health Questionnaire 
(PHQ-9) Total Score by Study Visit and US COVID-19 status at time of enrollment  
 Full Analysis Set 
Table 14.2.7.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Percent Retention (%) 
of Day 15 Change from Baseline at Post-Day15 Visits 
Full Analysis Set – 
Participants who Had HAM-
D Improvement at Day 15  
Table 14.2.7.2 
Summary of Hamilton Rating Scale for Depression (HAM-D) Percent Retention (%) 
of Day 15 Change from Baseline at Post-D15 Visits, for HAM-D Responders at Day 
15 
Full Analysis Set – HAM-D 
Responders at Day 15 
Table 14.2.7.3 
Summary of Hamilton Rating Scale for Depression (HAM-D) Response at Post-Day 
15 Visits, for HAM-D Responders at Day 15 
Full Analysis Set – HAM-D 
Responders at Day 15 
Table 14.2.7.4 
Summary of Hamilton Rating Scale for Depression (HAM-D) Remission at Post-Day 
15 Visits, for HAM-D Remitters at Day 15 
Full Analysis Set – HAM-D 
Remitters at Day 15 


Statistical Analysis Plan Methods Version 1.0 
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Table Number 
Title 
Analysis Set 
Table 14.2.7.5 
Summary of Hamilton Rating Scale for Depression (HAM-D) Relapse and Rebound 
Post-Day 15, for HAM-D Responders at Day 15 
Full Analysis Set – HAM-D 
Responders at Day 15 
Table 14.2.7.6 
Summary of Clinical Global Impression – Improvement (CGI-I) Response at Post-
Day 15 Visits, for CGI-I Responders at Day 15 
Full Analysis Set – CGI-I 
Responders at Day 15 
Table 14.2.7.7 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Percent 
Retention at Post-Day 15 Visits, for MADRS Responders at Day 15  
Full Analysis Set – MADRS 
Responders at Day 15 
Table 14.2.7.8 
Summary of Hamilton Rating Scale for Depression (HAM-D) Percent Retention (%) 
of Day 15 Change from Baseline at Post-Day15 Visits and Assigned Antidepressant 
Use 
Full Analysis Set – 
Participants who Had HAM-
D Improvement at Day 15  
Table 14.2.7.9 
Summary of Hamilton Rating Scale for Depression (HAM-D) Percent Retention (%) 
of Day 15 Change from Baseline at Post-D15 Visits, for HAM-D Responders at Day 
15 and Assigned Antidepressant Use 
 Full Analysis Set – HAM-D 
Responders at Day 15 
Table 14.2.7.10 
Summary of Hamilton Rating Scale for Depression (HAM-D) Response at Post-Day 
15 Visits, for HAM-D Responders at Day 15 and Assigned Antidepressant Use 
 Full Analysis Set – HAM-D 
Responders at Day 15 
Table 14.2.7.11 
Summary of Hamilton Rating Scale for Depression (HAM-D) Remission at Post-Day 
15 Visits, for HAM-D Remitters at Day 15 and Assigned Antidepressant Use 
 Full Analysis Set – HAM-D 
Remitters at Day 15 
Table 14.2.7.12 
Summary of Hamilton Rating Scale for Depression (HAM-D) Relapse and Rebound 
Post-Day 15, for HAM-D Responders at Day 15 and Assigned Antidepressant Use 
 Full Analysis Set – HAM-D 
Responders at Day 15 
Table 14.2.7.13 
Summary of Clinical Global Impression – Improvement (CGI-I) Response at Post-
Day 15 Visits, for CGI-I Responders at Day 15 and Assigned Antidepressant Use 
 Full Analysis Set – CGI-I 
Responders at Day 15 
Table 14.2.7.14 
Summary of Hamilton Rating Scale for Depression (HAM-D) Percent Retention (%) 
of Day 15 Change from Baseline at Post-Day15 Visits and US COVID-19 status at 
time of enrollment 
Full Analysis Set – 
Participants who Had HAM-
D Improvement at Day 15  
Table 14.2.7.15 
Summary of Hamilton Rating Scale for Depression (HAM-D) Percent Retention (%) 
of Day 15 Change from Baseline at Post-D15 Visits, for HAM-D Responders at Day 
15 and US COVID-19 status at time of enrollment 
 Full Analysis Set – HAM-D 
Responders at Day 15 


Statistical Analysis Plan Methods Version 1.0 
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Table Number 
Title 
Analysis Set 
Table 14.2.7.16 
Summary of Hamilton Rating Scale for Depression (HAM-D) Response at Post-Day 
15 Visits, for HAM-D Responders at Day 15 and US COVID-19 status at time of 
enrollment  
 Full Analysis Set – HAM-D 
Responders at Day 15 
Table 14.2.7.17 
Summary of Hamilton Rating Scale for Depression (HAM-D) Remission at Post-Day 
15 Visits, for HAM-D Remitters at Day 15 and US COVID-19 status at time of 
enrollment 
Full Analysis Set – HAM-D 
Remitters at Day 15 
Table 14.2.7.18 
Summary of Hamilton Rating Scale for Depression (HAM-D) Relapse and Rebound 
Post-Day 15, for HAM-D Responders at Day 15 and US COVID-19 status at time of 
enrollment  
 Full Analysis Set – HAM-D 
Responders at Day 15 
Table 14.2.7.19 
Summary of Clinical Global Impression – Improvement (CGI-I) Response at Post-
Day 15 Visits, for CGI-I Responders at Day 15 and US COVID-19 status at time of 
enrollment  
 Full Analysis Set – CGI-I 
Responders at Day 15 
Table 14.2.7.20 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Percent 
Retention at Post-Day 15 Visits, for MADRS Responders at Day 15 and Assigned 
Antidepressant Use 
Full Analysis Set – MADRS 
Responders at Day 15 
Table 14.2.7.21 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Percent 
Retention at Post-Day 15 Visits, for MADRS Responders at Day 15 and US COVID-
19 status at time of enrollment  
Full Analysis Set – MADRS 
Responders at Day 15 
Table 14.2.9.1.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Study 
visit and Elevated Anxiety by HAM-D Subscale 
Full Analysis Set 
Table 14.2.9.1.2 
Model-based Results on Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score by Study Visit and Depression with Elevated 
Anxiety by HAM-D Subscale 
Full Analysis Set 
Table 14.2.9.1.3 
Model-Based Results on Hamilton Rating Scale for Depression (HAM-D) Response 
by Study Visit and Elevated Anxiety by HAM-D Subscale 
Full Analysis Set 
Table 14.2.9.1.4 
Model-Based Results on Hamilton Rating Scale for Depression (HAM-D) Remission 
by Study Visit and Depression with Elevated Anxiety by HAM-D Subscale 
Full Analysis Set 


Statistical Analysis Plan Methods Version 1.0 
Page 71 
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Table Number 
Title 
Analysis Set 
Table 14.2.9.1.5 
Summary of Hamilton Rating Scale for Anxiety (HAM-A) Total Score by Study visit 
and Depression with Elevated Anxiety by HAM-D Subscale 
Full Analysis Set 
Table 14.2.9.1.6 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Anxiety 
(HAM-A) Total Score by Study Visit and Depression with Elevated Anxiety by 
HAM-D Subscale 
Full Analysis Set 
Table 14.2.9.1.7 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Total Score by 
Study visit and Depression with Elevated Anxiety by HAM-D Subscale 
Full Analysis Set 
Table 14.2.9.1.8 
Model-based Results on Change from Baseline in Montgomery-Asberg Depression 
Rating Scale (MADRS) by Study Visit and Depression with Elevated Anxiety by 
HAM-D Subscale 
Full Analysis Set 
Table 14.2.9.1.9 
Summary of Clinical Global Impression-Severity (CGI-S) Score by Study visit and 
Depression with Elevated Anxiety by HAM-D Subscale 
Full Analysis Set 
Table 14.2.9.1.10 
Model-based Results on Change from Baseline in Clinical Global Impression-
Severity (CGI-S) by Study Visit and Depression with Elevated Anxiety by HAM-D 
Subscale 
Full Analysis Set 
Table 14.2.9.1.11 
Model-Based Results on Clinical Global Impression-Impression (CGI-I) Response by 
Study Visit and Depression with Elevated Anxiety by HAM-D Subscale 
Full Analysis Set 
Table 14.2.10.1.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Study 
visit and Depression with Elevated Anxiety by HAM-A Total Score 
Full Analysis Set 
Table 14.2.10.1.2 
Model-based Results on Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score by Study Visit and Depression with Elevated 
Anxiety by HAM-A Total Score 
Full Analysis Set 
Table 14.2.10.1.3 
Model-Based Results on Hamilton Rating Scale for Depression (HAM-D) Response 
by Study Visit and Depression with Elevated Anxiety by HAM-A Total Score 
Full Analysis Set 
Table 14.2.10.1.4 
Model-Based Results on Hamilton Rating Scale for Depression (HAM-D) Remission 
by Study Visit and Depression with Elevated Anxiety by HAM-A Total Score 
Full Analysis Set 


Statistical Analysis Plan Methods Version 1.0 
Page 72 
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Table Number 
Title 
Analysis Set 
Table 14.2.10.1.5 
Summary of Hamilton Rating Scale for Anxiety (HAM-A) Total Score by Study visit 
and Depression with Elevated Anxiety by HAM-A Total Score 
Full Analysis Set 
Table 14.2.10.1.6 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Anxiety 
(HAM-A) Total Score by Study Visit and Depression with Elevated Anxiety by 
HAM-A Total Score 
Full Analysis Set 
Table 14.2.10.1.7 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Total Score by 
Study visit and Depression with Elevated Anxiety by HAM-A Total Score 
Full Analysis Set 
Table 14.2.10.1.8 
Model-based Results on Change from Baseline in Montgomery-Asberg Depression 
Rating Scale (MADRS) by Study Visit and Depression with Elevated Anxiety by 
HAM-A Total Score 
Full Analysis Set 
Table 14.2.10.1.9 
Summary of Clinical Global Impression-Severity (CGI-S) Score by Study visit and 
Depression with Elevated Anxiety by HAM-A Total Score 
Full Analysis Set 
Table 14.2.10.1.10 
Model-based Results on Change from Baseline in Clinical Global Impression-
Severity (CGI-S) by Study Visit and Depression with Elevated Anxiety by HAM-A 
Total Score 
Full Analysis Set 
Table 14.2.10.1.11 
Model-Based Results on Clinical Global Impression-Impression (CGI-I) Response by 
Study Visit and Depression with Elevated Anxiety by HAM-A Total Score 
Full Analysis Set 
Table 14.3.1.1 
Overview of Treatment-Emergent Adverse Events 
Safety Set 
Table 14.3.1.2 
Summary of Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
Safety Set 
Table 14.3.1.2.1 
Summary of On-Treatment Emergent Adverse Events by System Organ Class and 
Preferred Term 
Safety Set 
Table 14.3.1.2.2 
Summary of Post- Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
Safety Set 
Table 14.3.1.3.1 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term, and Assigned  Antidepressant Use 
Safety Set  


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Table Number 
Title 
Analysis Set 
Table 14.3.1.3.2 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term, and Age Group 
Safety Set 
Table 14.3.1.3.3 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term, and Sex 
Safety Set 
Table 14.3.1.3.4 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term, and Race Group 
Safety Set 
Table 14.3.1.3.5 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term, and BMI at Baseline 
Safety Set 
Table 14.3.1.3.6 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term, and Baseline HAM-D Total Score 
Safety Set 
Table 14.3.1.3.7 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term, and COVID-19 History 
Safety Set 
Table 14.3.1.3.8 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term, and US COVID-19 status at time of enrollment  
Safety Set 
Table 14.3.1.4 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term, and Maximum Severity 
Safety Set 
Table 14.3.1.5.1 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term, and Relationship to Blinded Investigational Product  
Safety Set 
Table 14.3.1.5.2 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term, and Relationship to Assigned Antidepressant 
Safety Set 
Table 14.3.1.6.1 
Summary of Treatment-Emergent Adverse Events Leading to Discontinuation of 
Blinded Investigational Product, by System Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.6.2 
Summary of Treatment Period Treatment-Emergent Adverse Events Leading to 
Discontinuation of Assigned Antidepressant, by System Organ Class and Preferred 
Term 
Safety Set 


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Table Number 
Title 
Analysis Set 
Table 14.3.1.6.3 
Summary of Post-Treatment Period Treatment-Emergent Adverse Events Leading to 
Discontinuation of Assigned Antidepressant, by System Organ Class and Preferred 
Term 
Safety Set 
Table 14.3.1.7 
Summary of Treatment-Emergent Adverse Events Leading to Dose Reduction of 
Blinded Investigational Product, by System Organ Class, Preferred Term, and 
Safety Set 
Table 14.3.1.8 
Summary of Treatment-Emergent Adverse Events Leading to Withdrawal from the 
Study by System Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.9 
Summary of Treatment-Emergent Serious Adverse Events by System Organ Class 
and Preferred Term 
Safety Set 
Table 14.3.1.10 
Summary of Most Common (>2%) Treatment-Emergent Adverse Events by Preferred 
Term 
Safety Set 
Table 14.3.4.1.1 
Summary of Serum Chemistry Results by Study Visit 
Safety Set 
Table 14.3.4.1.3 
Summary of Potentially Clinically Significant Liver Function Tests  
Safety Set 
Table 14.3.4.1.4 
Summary of Potentially Clinically Significant Serum Chemistry (excluding LFT)  
Safety Set 
Table 14.3.4. 2.1 
Summary of Hematology Results by Study Visit 
Safety Set 
Table 14.3.4.2.3 
Summary of Potentially Clinically Significant Hematology Results  
Safety Set 
Table 14.3.4. 3.1 
Summary of Urinalysis Results by Study Visit – Quantitative Results 
Safety Set 
Table 14.3.4. 3.2 
Summary of Urinalysis by Study Visit – Qualitative Results 
Safety Set 
Table 14.3.4.4.1 
Summary of Coagulation Results by Study Visit  
Safety Set 
Table 14.3.4.5.1 
Summary of Vital Signs by Study Visit 
Safety Set 
Table 14.3.4.5.2 
Summary of Potentially Clinically Significant Vital Signs  
Safety Set 


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Table Number 
Title 
Analysis Set 
Table 14.3.4.6.1 
Summary of ECG data by Study Visit 
Safety Set 
Table 14.3.4.6.2 
Summary of Abnormal ECG by Study Visit 
Safety Set 
Table 14.3.4.6.3 
Summary of Potentially Clinically Significant Average QTcF in ECG Data  
Safety Set 


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Figures 
Figure Number 
Title 
Analysis Set 
Figure 14.2.1.1.1 
 
Line Plot of LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score Over Time by Treatment Group 
Full Analysis Set 
Figure 14.2.1.1.2 
 
Line Plot of LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score Over Time by Treatment Group 
Per Protocol Set 
Figure 14.2.1.2.1 
 
Line Plot of LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score Over Time by Treatment Group and by Assigned 
Antidepressant Use 
Full Analysis Set 
Figure 14.2.1.2.2 
 
Line Plot of LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score Over Time by Treatment Group and US COVID-19 
status at time of enrollment 
Full Analysis Set 
Figure 14.2.1.3.1 
 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Response over Time 
Full Analysis Set 
Figure 14.2.1.3.2 
 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Response over Time by 
Assigned Antidepressant Use 
Full Analysis Set 
Figure 14.2.1.3.3 
 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Response over Time by 
US COVID-19 status at time of enrollment  
 Full Analysis Set 
Figure 14.2.1.3.4 
Sensitivity Analysis: Bar Chart of Hamilton Rating Scale for Depression (HAM-D) 
Response over Time  
Full Analysis Set 


Statistical Analysis Plan Methods Version 1.0 
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Figure Number 
Title 
Analysis Set 
Figure 14.2.1.3.5 
Sensitivity Analysis: Bar Chart of Hamilton Rating Scale for Depression (HAM-D) 
Response over Time by Assigned Antidepressant Use 
Full Analysis Set 
Figure 14.2.1.4.1 
 
Histogram of Hamilton Rating Scale for Depression (HAM-D) Percentage Improvement 
over Time 
Full Analysis Set 
Figure 14.2.1.5.1 
 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Remission over Time 
Full Analysis Set 
Figure 14.2.1.5.2 
 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Remission over Time by 
Assigned Antidepressant Use 
Full Analysis Set 
Figure 14.2.1.5.3 
 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Remission over Time by 
US COVID-19 status at time of enrollment 
 Full Analysis Set 
Figure 14.2.1.5.4 
Sensitivity Analysis: Bar Chart of Hamilton Rating Scale for Depression (HAM-D) 
Remission over Time  
Full Analysis Set 
Figure 14.2.1.5.5 
Sensitivity Analysis: Bar Chart of Hamilton Rating Scale for Depression (HAM-D) 
Remission over Time by Assigned Antidepressant Use 
Full Analysis Set 
Figure 14.2.1.6.1 
 
Histogram of Hamilton Rating Scale for Depression (HAM-D) Total Score in Categories 
over Time 
Full Analysis Set 
Figure 14.2.1.7.1 
 
Forest Plot of LS Mean (95% CI) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score by Treatment Group and Baseline Subgroups  
Full Analysis Set 
Figure 14.2.1.8.1 
 
Forest Plot of LS Mean (95% CI) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Subscale Scores by Treatment Group  
Full Analysis Set 


Statistical Analysis Plan Methods Version 1.0 
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Protocol Number: 217-MDD-305 
 
Figure Number 
Title 
Analysis Set 
Figure 14.2.1.8.2 
 
Forest Plot of LS Mean (95% CI) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Subscale Scores by Treatment Group and Assigned 
Antidepressant Use 
 Full Analysis Set 
Figure 14.2.1.8.3 
 
Forest Plot of LS Mean (95% CI) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Subscale Scores by Treatment Group and US COVID-19 status at 
time of enrollment  
 Full Analysis Set 
Figure 14.2.1.9.1 
 
Forest Plot of LS Mean (95% CI) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Individual Item Scores by Treatment Group  
Full Analysis Set 
Figure 14.2.1.9.2 
 
Forest Plot of LS Mean (95% CI) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Individual Item Scores by Treatment Group and Assigned 
Antidepressant Use 
 Full Analysis Set 
Figure 14.2.1.9.3 
 
Forest Plot of LS Mean (95% CI) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Individual Item Scores by Treatment Group and US COVID-19 
status at time of enrollment  
 Full Analysis Set 
Figure 14.2.2.1 
Bar Chart of CGI-I Response over Time by Treatment Group 
 Full Analysis Set 
Figure 14.2.2.2 
Bar Chart of CGI-I Response over Time by Treatment Group and Assigned 
Antidepressant Use 
 Full Analysis Set 
Figure 14.2.2.3 
Bar Chart of CGI-I Response over Time by Treatment Group and US COVID-19 status 
at time of enrollment  
 Full Analysis Set 
Figure 14.2.2.4 
Sensitivity Analysis: Bar Chart of CGI-I Response over Time by Treatment Group 
Full Analysis Set 
Figure 14.2.3.1 
 
Line Plot of LS Mean (±SE) Change from Baseline in CGI-S over Time by Treatment 
Group 
 Full Analysis Set 


Statistical Analysis Plan Methods Version 1.0 
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Figure Number 
Title 
Analysis Set 
Figure 14.2.3.2 
 
Line Plot of LS Mean (±SE) Change from Baseline in CGI-S over Time by Treatment 
Group and by Assigned Antidepressant Use 
 Full Analysis Set 
Figure 14.2.3.3 
 
Line Plot of LS Mean (±SE) Change from Baseline in CGI-S over Time by Treatment 
Group 
 Per Protocol Set 
Figure 14.2.3.4 
 
Line Plot of LS Mean (±SE) Change from Baseline in CGI-S over Time by Treatment 
Group and US COVID-19 status at time of enrollment  
  Full Analysis Set 
Figure 14.2.4.1 
 
Line Plot of LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Anxiety (HAM-A) Total Score over Time by Treatment Group 
Full Analysis Set 
Figure 14.2.4.2 
 
Line Plot of LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Anxiety (HAM-A) Total Score over Time by Treatment Group and Assigned 
Antidepressant Use 
Full Analysis Set 
Figure 14.2.4.3 
 
Line Plot of LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Anxiety (HAM-A) Total Score over Time by Treatment Group and US COVID-19 
status at time of enrollment  
Full Analysis Set 
Figure 14.2.5.1 
 
Line Plot of LS Mean (±SE) Change from Baseline in Montgomery-Åsberg Depression 
Rating Scale (MADRS) Total Score over Time by Treatment Group 
Full Analysis Set 
Figure 14.2.5.2 
 
Line Plot of LS Mean (±SE) Change from Baseline in Montgomery-Åsberg Depression 
Rating Scale (MADRS) Total Score over Time by Treatment Group and Assigned 
Antidepressant Use 
Full Analysis Set 


Statistical Analysis Plan Methods Version 1.0 
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Protocol Number: 217-MDD-305 
 
Figure Number 
Title 
Analysis Set 
Figure 14.2.5.3 
 
Line Plot of LS Mean (±SE) Change from Baseline in Montgomery-Åsberg Depression 
Rating Scale (MADRS) Total Score over Time by Treatment Group and US COVID-19 
status at time of enrollment  
Full Analysis Set 
Figure 14.2.5.4 
Bar Chart of Montgomery-Åsberg Depression Rating Scale (MADRS) Response over 
Time by Treatment Group 
Full Analysis Set 
Figure 14.2.5.5 
Bar Chart of Montgomery-Åsberg Depression Rating Scale (MADRS) Remission over 
Time by Treatment Group 
Full Analysis Set 
Figure 14.2.5.6 
Sensitivity Analysis: Bar Chart of Montgomery-Åsberg Depression Rating Scale 
(MADRS) Response over Time by Treatment Group 
Full Analysis Set 
Figure 14.2.5.7 
Sensitivity Analysis: Bar Chart of Montgomery-Åsberg Depression Rating Scale 
(MADRS) Remission over Time by Treatment Group 
Full Analysis Set 


Statistical Analysis Plan Methods Version 1.0 
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Figure Number 
Title 
Analysis Set 
Figure 14.2.8.1.1 
Line Plot of Hamilton Rating Scale for Depression (HAM-D) Percent Retention (%) of 
Day 15 Change from Baseline over Time 
Full Analysis Set – 
Participants who Had 
HAM-D Improvement at 
Day 15 
Figure 14.2.8.1.2 
Line Plot of Hamilton Rating Scale for Depression (HAM-D) Percent Retention (%) of 
Day 15 Change from Baseline over Time by Assigned Antidepressant Use 
Full Analysis Set – 
Participants who Had 
HAM-D Improvement at 
Day 15 
Figure 14.2.8.1.3 
Line Plot of Hamilton Rating Scale for Depression (HAM-D) Percent Retention (%) of 
Day 15 Change from Baseline over Time by US COVID-19 status at time of enrollment  
Full Analysis Set – 
Participants who Had 
HAM-D Improvement at 
Day 15 
Figure 14.2.8.2.1 
Line Plot of Hamilton Rating Scale for Depression (HAM-D) Percent Retention (%) of 
Day 15 Change from Baseline over Time, for HAM-D Responders at Day 15 
Full Analysis Set - HAM-D 
Responders at Day 15 
Figure 14.2.8.2.2 
Line Plot of Hamilton Rating Scale for Depression (HAM-D) Percent Retention (%) of 
Day 15 Change from Baseline over Time, for HAM-D Responders at Day 15 by 
Assigned Antidepressant Use 
Full Analysis Set - HAM-D 
Responders at Day 15 
Figure 14.2.8.2.3 
Line Plot of Hamilton Rating Scale for Depression (HAM-D) Percent Retention (%) of 
Day 15 Change from Baseline over Time, for HAM-D Responders at Day 15 by US 
COVID-19 status at time of enrollment  
 Full Analysis Set - HAM-
D Responders at Day 15 
Figure 14.2.8.3.1 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Response at Post-D15 
Visits, for HAM-D Responders at Day 15 
Full Analysis Set – HAM-D 
Responder at Day 15  
Figure 14.2.8.3.2 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Response at Post-D15 
Visits, for HAM-D Responders at Day 15 by Assigned Antidepressant Use 
 Full Analysis Set – HAM-
D Responder at Day 15  


Statistical Analysis Plan Methods Version 1.0 
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Figure Number 
Title 
Analysis Set 
Figure 14.2.8.3.3 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Response at Post-D15 
Visits, for HAM-D Responders at Day 15 by US COVID-19 status at time of enrollment  
 Full Analysis Set – HAM-
D Responder at Day 15  
Figure 14.2.8.4.1 
Bar Chat of Hamilton Rating Scale for Depression (HAM-D) Remission at Post-D15 
Visits, for HAM-D Remitters at Day 15 
Full Analysis Set – HAM-D 
Remitters at Day 15 
Figure 14.2.8.4.2 
Bar Chat of Hamilton Rating Scale for Depression (HAM-D) Remission at Post-D15 
Visits, for HAM-D Remitters at Day 15 by Assigned Antidepressant Use 
Full Analysis Set – HAM-D 
Remitters at Day 15 
Figure 14.2.8.4.3 
Bar Chat of Hamilton Rating Scale for Depression (HAM-D) Remission at Post-D15 
Visits, for HAM-D Remitters at Day 15 by US COVID-19 status at time of enrollment  
Full Analysis Set – HAM-D 
Remitters at Day 15 
Figure 14.2.8.5.1 
Bar Chart of Clinical Global Impression – Improvement (CGI-I) Response at Post-D15 
Visits, for CGI-I Responders at Day 15 
Full Analysis Set – CGI-I 
Responder at Day 15 
Figure 14.2.8.5.2 
Bar Chart of Clinical Global Impression – Improvement (CGI-I) Response at Post-D15 
Visits, for CGI-I Responders at Day 15 by Assigned Antidepressant Use 
 Full Analysis Set Full 
Analysis Set – CGI-I 
Responder at Day 15 
Figure 14.2.8.5.3 
Bar Chart of Clinical Global Impression – Improvement (CGI-I) Response at Post-D15 
Visits, for CGI-I Responders at Day 15 and US COVID-19 status at time of enrollment  
 Full Analysis Set Full 
Analysis Set – CGI-I 
Responder at Day 15 
Figure 14.2.8.6.1 
Line Plot of Montgomery-Asberg Depression Rating Scale (MADRS) Percent Retention 
(%) of Day 15 Change from Baseline over Time, for MADRS Responders at Day 15 
Full Analysis Set - MADRS 
Responders at Day 15 
Figure 14.2.8.6.2 
Line Plot Montgomery-Asberg Depression Rating Scale (MADRS) Percent Retention 
(%) of Day 15 Change from Baseline over Time, for MADRS Responders at Day 15 by 
Assigned Antidepressant Use 
Full Analysis Set - MADRS 
Responders at Day 15 


Statistical Analysis Plan Methods Version 1.0 
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Figure Number 
Title 
Analysis Set 
Figure 14.2.8.6.3 
Line Plot Montgomery-Asberg Depression Rating Scale (MADRS) Percent Retention 
(%) of Day 15 Change from Baseline over Time, for MADRS Responders at Day 15 by 
US COVID-19 status at time of enrollment  
Full Analysis Set - MADRS 
Responders at Day 15 


Statistical Analysis Plan Methods Version 1.0 
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Listings 
Listing Number 
Title 
Analysis Set 
Listing 16.1.7 
Participant Randomization 
Randomized Set 
Listing 16.2.1.1 
Participant Disposition 
Randomized Set 
Listing 16.2.1.2 
Premature Discontinuation from Blinded Investigational Product and/or Withdrawal 
from the Study 
Safety Set 
Listing 16.2.1.3 
Premature Discontinuation from Assigned Antidepressant and/or Withdrawal from the 
Study 
Safety Set 
Listing 16.2.2.1.1 
Protocol Deviations 
Randomized Set 
Listing 16.2.2.1.2 
Assessments Affected by COVID-19 
Safety Set 
Listing 16.2.2.2 
Incorrect Blinded Investigational Product Consumption 
Safety Set 
Listing 16.2.2.3 
Inclusion/Exclusion Criteria Violations 
Randomized Set 
Listing 16.2.4.1 
Demographics 
Safety Set 
Listing 16.2.4.2 
Baseline Characteristics 
Safety Set 
Listing 16.2.4.3 
Diagnostic Laboratory Results 
Safety Set 
Listing 16.2.4.4 
Child-Bearing Potential at Screening 
Safety Set 
Listing 16.2.4.5 
Medical and Surgical History 
Safety Set 
Listing 16.2.4.6 
Disease History 
Safety Set 
Listing 16.2.4.7 
Participant History of Psychiatric Disorder 
Safety Set 
Listing 16.2.4.8 
Family History of Psychiatric Disorder 
Safety Set 
Listing 16.2.4.9 
Prior and Concomitant Psychotropic Medications 
Safety Set 
Listing 16.2.4.10 
Prior and Concomitant Non-Psychotropic Medications 
Safety Set 
Listing 16.2.4.11 
Concomitant Procedures 
Safety Set 


Statistical Analysis Plan Methods Version 1.0 
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Listing Number 
Title 
Analysis Set 
Listing 16.2.5.1 
Blinded Investigational Product Administration 
Safety Set 
Listing 16.2.5.2 
Assigned Antidepressant Administration 
Safety Set 
Listing 16.2.5.3 
Blinded Investigational Product Exposure 
Safety Set 
Listing 16.2.5.4 
Assigned Antidepressant Exposure 
Safety Set 
Listing 16.2.5.5 
Blinded Investigational Product Adherence 
Safety Set 
Listing 16.2.6.1 
Hamilton Rating Scale for Depression (HAM-D) 
Full Analysis Set 
Listing 16.2.6.2 
Clinical Global Impression (CGI) – Improvement 
Full Analysis Set 
Listing 16.2.6.3 
Clinical Global Impression (CGI) – Severity 
Full Analysis Set 
Listing 16.2.6.4 
Hamilton Anxiety Rating Scale (HAM-A) 
Full Analysis Set 
Listing 16.2.6.5 
Montgomery-Asberg Depression Rating Scale (MADRS) 
Full Analysis Set 
Listing 16.2.6.6 
Patient Health Questionnaire (PHQ-9) 
Full Analysis Set 
Listing 16.2.6.7 
Hamilton Rating Scale for Depression (HAM-D) with Percent Retention (%), Response, 
Remission, Relapse and Rebound 
Full Analysis Set  
Listing 16.2.6.8 
Montgomery-Asberg Depression Rating Scale (MADRS) with Percent Retention (%) 
Full Analysis Set 
Listing 16.2.7.1 
Treatment-Emergent Adverse Events 
Safety Set 
Listing 16.2.7.2 
Non-fatal Serious Adverse Events 
Safety Set 
Listing 16.2.7.3 
Adverse Events Leading to Death 
Safety Set 
Listing 16.2.7.4 
Adverse Events with Onset Prior to First Dose of Investigational Product  
Safety Set 
Listing 16.2.7.5 
Adverse Events leading to Premature Discontinuation of Blinded Investigational 
Product  
Safety Set 
Listing 16.2.7.6 
Adverse Events leading to Premature Discontinuation of Assigned Antidepressant 
Safety Set 
Listing 16.2.7.7 
Treatment Emergent Adverse Events of Participants who had Adverse Event(s) leading 
to Dose Reduction of Blinded IP 
Safety Set 


Statistical Analysis Plan Methods Version 1.0 
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Listing Number 
Title 
Analysis Set 
Listing 16.2.7.8 
Adverse Events leading to Premature Withdrawal from the Study 
Safety Set 
Listing 16.2.7.9 
Adverse Events for Participants who Have Taken Only Assigned Antidepressant, no 
Blinded IP 
Safety Set – ADT Only 
Listing 16.2.8.1.1 
Serum Chemistry Data (excluding Liver Function Tests) 
Safety Set 
Listing 16.2.8.1.2 
Potentially Clinically Significant Serum Chemistry Values (excluding Liver Function 
Tests) 
Safety Set 
Listing 16.2.8.2.1 
Liver Function Tests  
Safety Set 
Listing 16.2.8.2.2 
Potentially Clinically Significant Liver Function Test Values 
Safety Set 
Listing 16.2.8.3.1 
Hematology Data 
Safety Set 
Listing 16.2.8.3.2 
Potentially Clinically Significant Hematology Values 
Safety Set 
Listing 16.2.8.4 
Urinalysis Data 
Safety Set 
Listing 16.2.8.5 
Coagulation Data 
Safety Set 
Listing 16.2.8.6 
Pregnancy Test 
Safety Set 
Listing 16.2.8.7 
Vital Signs 
Safety Set 
Listing 16.2.8.8 
Potentially Clinically Significant Vital Signs 
Safety Set 
Listing 16.2.8.9 
Electrocardiogram (ECG) Data 
Safety Set 
Listing 16.2.8.10 
Potentially Clinically Significant QTcF Values 
Safety Set 
Listing 16.2.8.11 
Physical Examination 
Safety Set 


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Listing Number 
Title 
Analysis Set