Clinical trial NCT04007367
Conditions: Major Depressive Disorder
Keywords: MDD SAGE-217
Sponsor: Biogen
Start date: 2019-08-06; Completion date: 2020-01-06
Enrollment: 53 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a study with an Open-Label (OL) phase followed by a randomized, Double-Blind (DB), placebo-controlled phase to assess efficacy and safety of SAGE-217 on relapse prevention in adults with major depressive disorder (MDD).

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 self-administered SAGE-217, 30 milligrams (mg), oral capsule, once daily (QD) in the evening from Day 1 to Day 14. arm 2: Following the OL Phase, participants who exhibited a Hamilton Rating Scale for Depression (HAM-D) response, defined as a greater than or equal to (≥) 50% reduction from baseline in HAM-D total score were to be randomized to receive SAGE-217 matching placebo capsule, orally, QD, in the evening, in a total of five, 14-day treatment periods, each separated by a 6-week follow-up period during the 40-week DB Phase of the study. However, no participants were randomized to receive SAGE-217 matching placebo due to early study termination. arm 3: Following the OL Phase, participants who exhibited a HAM-D response defined as a ≥ 50% reduction from baseline in HAM-D total score to SAGE-217 were randomized to receive SAGE-217, 30 mg, oral capsule, QD, in the evening, up to study termination date (i.e., up to approximately 22 weeks) during the DB Phase of the study.
Interventions: intervention 1: SAGE-217 intervention 2: Placebo
Intervention descriptions: intervention 1: SAGE-217 capsule intervention 2: SAGE-217 matching placebo capsule

Protocol documents:
Prot_000.pdf: 
Official Title: 
A Phase 3, Randomized, Double-Blind, Placebo-controlled Study of The Efficacy And Safety 
Of Sage-217 With a Fixed, Repeated Treatment Regimen on Relapse Prevention in Adults 
With Major Depressive Disorder 
NCT Number: 
NCT04007367
Document Date: 
Protocol Amendment 1, Version 2.0, 29 August 2019 


Protocol Clinical Protocol 
Sage Therapeutics, Inc. 
217-MDD-302 v2.0
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1.
TITLE PAGE
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY OF THE EFFICACY AND SAFETY OF 
SAGE-217 WITH A FIXED, REPEATED TREATMENT 
REGIMEN ON RELAPSE PREVENTION IN ADULTS WITH 
MAJOR DEPRESSIVE DISORDER 
PROTOCOL 217-MDD-302 
EUDRACT NUMBER: 2019-002640-25 
Study Drug 
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 
 
Tel: 
 
E-mail: 
Date of Original Protocol 
Version 1.0, 24 June 2019 
Date of Amendment 1 
Version 2.0, 27 August 2019 
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-302 clinical 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 Month YYYY) 


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PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Syneos Health Medical 
Monitor – North 
America 
, MD 
 
Email: 
 
Office:
Cell: 
Syneos Health Medical 
Monitor – Europe 
, MD, MPH 
 
Email: 
 
Office:  
 
Sage Study Physician 
, MD, PhD, MSc 
 
Email: 
 
Tel:
 
24-Hour Serious 
Adverse Event 
Reporting 
IQVIA Lifecycle Safety 
Email: Sage.Safety@iqvia.com  
Telephone 
Fax 
 
North America 
 
United Kingdom 
 
Germany 
alt: 
 
Pause 
 
alt: 
 
Pause 
 
 
France 
 
Spain 
 
Denmark 
Product Complaint 
Reporting 
Sage Therapeutics, Inc. 
Email: productcomplaints@sagerx.com  
Tel: 
 
 
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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Sage Therapeutics, Inc. (hereafter referred to as Sage Therapeutics, or Sage) 
Name of Study Drug: SAGE-217 Capsules 
Name of Active Ingredient: SAGE-217 
Title of Study:  
A Phase 3, Randomized, Double-blind, Placebo-controlled Study of the Efficacy and Safety of 
SAGE-217 with a Fixed, Repeated Treatment Regimen on Relapse Prevention in Adults with Major 
Depressive Disorder 
Number of Sites and Study Location: This is a global study that will take place at approximately 70 
sites in the United States, Canada, and Europe. 
Phase of Development: 3 
Planned Duration of Subject Participation: 
The planned duration of subject participation is up to 52 weeks, including a Screening Period (up to 
4 weeks), an Open-label (OL) Phase (8 weeks), and a Double-blind (DB) Phase (40 weeks) 
Objectives: 
Primary: 
x 
To evaluate the efficacy of SAGE-217 with a fixed, repeated treatment regimen in the 
prevention of relapse in subjects with major depressive disorder (MDD) who have responded 
to OL treatment with SAGE-217 
Secondary: 
x 
To evaluate the long-term safety and tolerability of a fixed, repeated treatment regimen of 
SAGE-217 up to 1 year  
 
 
 
 
 
Endpoints: 
Primary: 
x 
Time to relapse during the DB Phase (days; from first dose of study drug in the DB Phase to 
relapse [date] during the DB Phase) 
Secondary: 
x 
Percentage of subjects who relapse during the DB Phase 
x 
Change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D) total 
score at the end of each 14-day treatment period in the DB Phase. 
x 
HAM-D response at the end of each 14-day treatment period in the DB Phase, defined as a 
 reduction in HAM-D score from baseline 
x 
HAM-D remission at the end of each 14-day treatment period in the DB Phase, defined as 
HAM-'WRWDOVFRUH 
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x 
Clinical Global Impression – Improvement (CGI-I) response, defined as “much improved” or 
“very much improved”, at the end of each 14-day treatment period in the DB Phase 
x 
Change from baseline in Clinical Global Impression - Severity (CGI-S) score at the end of 
each 14-day treatment period in the DB Phase 
x 
Change from baseline in 9-item Patient Health Questionnaire (PHQ-9) score at the end of each 
14-day treatment period in the DB Phase 
x 
Time to relapse during the DB phase (days; from first dose of study drug in DB Phase to 
relapse [date] during the DB Phase) for subjects who achieved HAM-D remission in the OL 
Phase 
x 
Incidence of treatment-emergent adverse events (TEAEs) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Description:  
This is a study with an OL phase followed by a randomized, DB, placebo-controlled phase to assess 
the effect of SAGE-217 monotherapy in a fixed, repeated treatment regimen versus placebo on relapse 
prevention in adult subjects with MDD (Montgomery-Åsberg Depression Rating Scale [MADRS] 
HAM-'ZKRDUHQRWFXUUHQWO\WDNLQJDQWLGHSUHVVDQWV. See Figure 1 for a schematic of the study 
design. 
The Screening Period (Table 2) begins with the signature of the informed consent form (ICF); the ICF 
must be signed prior to beginning any screening activities. 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. Subjects will undergo preliminary screening procedures at the Screening Visit to 
determine eligibility, including completion of the MADRS, HAM-D, and CGI-S.  
Beginning on Day 1 of the OL Phase, eligible subjects will self-administer a single dose of study drug 
once daily in the evening with food, on an outpatient basis, for 14 consecutive days. Practical options 
include taking SAGE-217 within 1 hour of dinner or taking SAGE-217 later in the evening with solid 
food. Subjects will return to the study center during the OL treatment and follow-up periods as outlined 
in Table 3. 
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Subjects who complete the OL Phase (through Day 56) with no significant tolerability issues as judged 
by the Investigator and who exhibited a HAM-D response, defined as a ≥50% reduction from baseline 
in HAM-D total score, at Visits 4, 6, 7, and 8 (see Table 3) will be eligible for the DB Phase. One 
excursion of <50% reduction from baseline (but total score ≤21) in HAM-D total score or one missing 
HAM-D total score at Visit 6 or 7, will be permitted for eligibility to the DB Phase. 
Beginning on Day 1 of the DB Phase, eligible subjects will be randomized to receive SAGE-217 
30 mg or matching placebo in a 1:1 ratio. The 40-week DB Phase consists of five 14-day treatment 
periods, each separated by a 6-week follow-up period; the end of each follow-up period coincides with 
the first visit of the next treatment period. During the 14-day treatment periods, subjects will self-
administer a single dose of study drug once daily in the evening with food, on an outpatient basis. 
Subjects will return to the study center during the DB treatment and follow-up periods as outlined in 
Table 3. 
During the follow-up periods of the DB Phase, depressive symptoms will be monitored every 
7 (+3) days via remote PHQ-9; if the PHQ-9 score is ≥10, the subject will return to the site as soon as 
possible to be assessed by the clinician-administered HAM-D (Table 4). If the HAM-D is ≥18 at this 
visit, the subject will return to the site in 7 to 14 days to be reassessed by the HAM-D (Table 4); if the 
HAM-D remains ≥18, the subject will be considered to have relapsed at this visit. A summary of all 
events for which a subject may be considered to have relapsed is presented in the table below. Final 
determination of relapse will be made by an Independent Relapse Adjudication Committee (IRAC) for 
events other than 2 consecutive HAM-D scores ≥18 assessed 7 to 14 days apart.  
Summary of Events Which May Result in Relapse 
Event 
Requires Review by IRAC? 
2 consecutive HAM-D scores ≥18 assessed 7 to 14 days apart 
No 
Any worsening of depression requiring hospitalization 
Yes 
Any Investigator-determined risk of suicide 
Yes 
Worsening of overall depressive symptoms as measured by CGI-S ≥4 
and an increase from baseline in CGI-S score of ≥ 2points 
Yes 
PHQ-9 score ≥10 and subsequent subject withdrawal from study 
Yes 
Single PHQ-9-triggered HAM-D score ≥18 and subsequent subject 
withdrawal from study 
Yes 
Subjects that have 2 consecutive HAM-D total scores ≥18 during a treatment period are encouraged to 
complete the treatment period.  Subjects who experience any of the first 4 events described in the table 
above will not be eligible for further randomized treatment periods; these subjects may receive 
treatment as clinically indicated by their physician and should return to the site for follow-up visits as 
outlined in Table 5. 
If at any time during the study, 30 mg SAGE-217 is not tolerated, as assessed by the occurrence of a 
severe AE judged by the Investigator to be related to study drug, the dose will be reduced to 20 mg and 
continued for the remainder of the treatment period. Dose adjustments related to moderate AEs will be 
at the discretion of the Investigator. Subsequent treatment periods will begin with the 30-mg dose, 
regardless of whether a subject required a dose adjustment in a previous treatment period. Subjects 
who cannot tolerate the 20-mg dose at any time will be terminated from the study upon completion of 
an end of treatment (EOT) visit as soon as possible, and an ET visit 7 days later. 
Number of Subjects (Planned): Approximately 546 subjects are planned to be dosed in the OL Phase 
to ensure at least 300 subjects are dosed in the DB Phase.   


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Eligibility Criteria: 
Inclusion Criteria: 
Qualified subjects will meet all of the following criteria: 
1. Subject has signed an ICF prior to any study-specific procedures being performed. 
2. Subject is a male or female between 18 and 65 years of age, inclusive. 
3. Subject is in good physical health and has no clinically significant findings, as determined by 
the Investigator, on physical examination, 12-lead ECG, or clinical laboratory tests. 
4. Subject agrees to adhere to the study requirements. Subject agrees and understands how to use 
a smartphone for purposes of the study. 
5. Subject 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. Subject has had at least 1 prior major depressive episode (MDE) in the 5 years prior to 
Screening (not including the current episode) as determined by the SCID-5-CT. 
7. Subject has a MADRS total score of ≥32 and a HAM-D total score of ≥22 at Screening and 
Day 1 (prior to dosing) of the OL Phase.  
8. Subject is willing to delay start of any antidepressant, anxiolytic, insomnia, psychostimulant, 
prescription opioid regimens, and new psychotherapy (including Cognitive Behavioral 
Therapy for Insomnia [CBT-I]) until after study completion. 
9. Subjects receiving psychotherapy must have been receiving therapy on a regular schedule for 
at least 60 days prior to Day 1. 
10. Female subject agrees to use one of the following methods of highly effective contraception 
during participation in the study and for 30 days following the last dose of study drug, unless 
they are postmenopausal (defined as no menses for 12 months without an alternative medical 
cause and confirmed by follicular stimulation hormone [FSH] >40 mIU/mL), surgically sterile 
(hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or does not engage in 
sexual relations which carry a risk of pregnancy (does not include abstinence): 
• 
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/occlusion. 
• 
Vasectomized partner. 
11. Male subject agrees to use an acceptable method of effective contraception for the duration of 
study and for 5 days after receiving the last dose of the study drug, unless the subject does not 
engage in sexual relations which carry a risk of pregnancy (does not include abstinence). 
Acceptable methods of effective contraception for males includes vasectomy or a condom with 
spermicide used together with highly effective female contraception methods if the female 


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partner(s) is of child-bearing potential (see Inclusion Criteria #10 for acceptable contraception 
methods).  
12. Male subject is willing to abstain from sperm donation for the duration of the study and for 
5 days after receiving the last dose of the study drug. 
13. Subject agrees to refrain from drugs of abuse and alcohol for the duration of the study. 
Exclusion Criteria: 
Subjects who meet any of the following criteria are disqualified from participation in this study: 
1. Subject has attempted suicide associated with the current episode of MDD. 
2. Subject has a recent history or active clinically significant manifestations of metabolic, hepatic, 
renal, hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, 
dermatological, urogenital, neurological, or eyes, ears, nose, and throat disorders, or any other 
acute or chronic condition that, in the Investigator's opinion, would limit the subject's ability to 
complete or participate in this clinical study. 
3. Subject has a body mass index (BMI) ≤18 or ≥50 kg/m2 at Screening. Note that a BMI of 40 to 
49 kg/m2, inclusive, at Screening is subject to a broader evaluation of medical co-morbidities 
(such as sleep apnea, COPD), concomitant medications, prior tolerability of sedating agents. 
4. Subject 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 two 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. Subject has had vagus nerve stimulation, electroconvulsive therapy, or has taken ketamine 
(including esketamine) within the current major depressive episode. 
6. Subject has taken antidepressants within 60 days prior to Day 1.  
7. Subject is taking or has taken any of the following: 
a. benzodiazepines, barbiturates, or GABAA modulators (eg, eszopiclone, zopiclone, 
zaleplon, zolpidem, brexanolone) at Day -28,  
b. benzodiazepines, barbiturates, or GABAA modulators (eg, eszopiclone, zopiclone, 
zaleplon, zolpidem) daily or near-daily (≥4 days per week) for 1 year, in the last year prior 
to the first dose of study drug.  
c. benzodiazepine or GABAA modulator with a half-life of ≥48 hours (eg, diazepam) from 
60 days prior to Day 1 
8. Subject 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 at Day -14. Note that non-sedating anti-histamines 
are permitted. 
9. Subject is taking psychostimulants (eg, methylphenidate, amphetamine) or opioids, regularly 
or as-needed, at Day -28. 
10. Subject is participating in cognitive behavioral therapy for insomnia (CBT-I) within 28 days 
prior to Day 1. 


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11. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds.  
12. Subject has a positive pregnancy test at screening or on Day 1 prior to dosing.  
13. Subject is breastfeeding at Screening or on Day 1 (prior to administration of study drug) and 
does not agree to temporarily cease giving breast milk to child(ren) from just prior to receiving 
study drug on Day 1 until 7 days after the last dose of study drug in each treatment period.  
14. Subject has detectable hepatitis B surface antigen, anti-hepatitis C virus (HCV) and positive 
HCV viral load, or human immunodeficiency virus (HIV) antibody at screening. 
15. Subject has a clinically significant abnormal 12-lead ECG at the screening or on Day 1 of any 
treatment period. 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.  
16. Subject has active psychosis per Investigator assessment.  
17. Subject has a medical history of seizures.  
18. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder.  
19. Subject 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. 
20. Subject has had exposure to another investigational medication or device within 30 days prior 
to screening.  
21. Subject has previously participated in a SAGE-217 or a SAGE-547 (brexanolone) clinical trial.  
22. Subject has used any known strong inhibitors of cytochrome P450 (CYP)3A4 within 28 days 
or 5 half-lives (whichever is longer) prior to the first dose of study drug or plans to use these 
during any treatment period, or consumed grapefruit juice, grapefruit, or Seville oranges, or 
products containing these within 14 days prior to the first dose of study drug for any treatment 
period or plans to consume these products during any treatment period.  
23. Subject has used any of the following strong CYP3A inducers within 28 days prior to the first 
dose of study drug for any SAGE-217 treatment period: rifampin, carbamazepine, 
enzalutamide, mitotane, phenytoin, and St John’s Wort. 
24. Subject has a positive drug and/or alcohol screen at screening or on Day 1 prior to dosing in 
the Open-label Phase. 
25. Subject plans to undergo elective surgery or procedure requiring general anesthesia at any time 
from Screening through the duration of the study. Procedures requiring conscious sedation and 
ambulatory procedures performed under local anesthesia may be scheduled under the 
following guidelines: 
a. Procedures requiring conscious sedation (eg, colonoscopy) no later than 7 days prior to the 
start of the first dose of each treatment period and no earlier than 7 days after the last dose 
of each treatment period from screening throughout the duration of the study. 
b. Elective ambulatory procedures performed under local anesthesia are allowed at any time 
during the study. 


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26. Subject 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. 
27. Subject has had gastric bypass surgery, has a gastric sleeve or lap band, or has had any related 
procedures that interfere with gastrointestinal transit. 
28. Subject regularly participates in night shift work or expects to perform night shift work during 
any 14-day treatment period (occasional night shift work during follow-up periods is 
permitted). 
SAGE-217 Dosage and Mode of administration:  
SAGE-217 is available as hard gelatin capsules containing a white to off-white powder. In addition to 
SAGE-217 Drug Substance, the SAGE-217 capsules contain croscarmellose sodium, mannitol, 
silicified microcrystalline cellulose (SMCC), colloidal silicon dioxide and sodium stearyl fumarate as 
excipients. Colloidal silicon dioxide may be either a component of the SMCC or a standalone excipient 
in the formulation. SAGE-217 capsules will be orally administered as a 30-mg or 20-mg dose. 
Reference Therapy, Dosage and Mode of Administration:  
In the DB Phase, placebo will be provided as hard gelatin capsules for oral administration in the 
evening with food. 
Duration of Treatment:  
All subjects will receive a daily dose of SAGE-217 from Day 1 through Day 14 in the OL Phase. 
Subjects that exhibit a HAM-D response to SAGE-217 in the OL Phase will be randomized to receive 
either daily doses of SAGE-217 or placebo in 14-day treatment periods, separated by 6-week follow-up 
periods, for 40 weeks in the DB Phase (for a total of six 14-day treatment periods during the 52-week 
study). 
Statistical Methods: 
Detailed description of the statistical analyses to be performed for this study will be provided in a 
statistical analysis plan (SAP). The SAP will be finalized and approved prior to treatment unblinding. 
Any deviations from or changes to the SAP following database lock will be described in detail in the 
clinical study report. 
General Considerations 
Every attempt will be made to avoid missing data. All subjects will be used in the analyses, as per the 
analysis populations, using all non-missing data available. 
Continuous endpoints will be summarized descriptively with n, mean, standard deviation, median, 
minimum, and maximum. For categorical endpoints, descriptive summaries will include counts and 
percentages.  
Analysis Sets 
The Enrolled Set is defined as all subjects who receive a dose of study drug in the OL phase. 
The Randomized Set is defined as all subjects who are randomized in the DB phase. 
The Safety Set is defined as all subjects administered study drug.  
The Full Analysis Set is defined as all randomized subjects in the Safety Set with a valid baseline and 
at least 1 post-baseline HAM-D total score,  
 
Determination of Sample Size 


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The randomization in the DB phase is 1:1, with 150 subjects randomized in each treatment arm – 
placebo and SAGE-$VVXPLQJDUHODSVHUDWHRILQWKHSODFHERDUP(Borges 2014) DQGLQ
the SAGE-217 arm for a fixed 40-week repeated treatment regimen (Hazard ratio = 0.448), this sample 
VL]HZLOOSURYLGHDSRZHUZLWKOevel of significance in comparing time to relapse (through 
comparison of survival curves) by Log-Rank test. Further, DVVXPLQJWKDWRQO\RIWKHVXEMHFWV
dosed in the OL phase will qualify as responders to be randomized in the DB phase, 546 subjects will 
need to be dosed in the OL phase.  
$QLQWHULPDQDO\VLVLVSODQQHGZKHQDERXWRIexpected relapse events occur (ie, 34 of 67 expected 
relapse events happen) to estimate the hazard ratio with a view to re-estimate the sample size. This 
unblinded interim analysis will be performed by an independent third party, external to the Sponsor, 
with specific directions on how to conclude depending on the range of hazard ratio observed. The 
decision will be communicated to the Sponsor only in terms of “no change in sample size necessary” 
or “increase the sample size to XXX”; hence the Sponsor will remain blinded. The final analysis will 
be complete when the last subject completes (or ET) the study. The methods to control the type I error 
rate will be provided in the SAP. 
Analysis of Primary Endpoint 
The estimand is the time to relapse – number of days between the first dose in the first treatment period 
of the DB phase to the day of relapse. The analysis will use the FAS.  Kaplan-Meier survival curves 
will be provided, along with the median time to relapse. Log-rank test will be used to compare the 
survival curves at the significance level of 0.05. 
Analysis of Secondary Endpoints 
Using FAS, the change from baseline will be summarized by randomized treatment group and each 
scheduled time point where the evaluation has been made. Baseline is defined as the last measurement 
prior to dosing in the DB Phase. A mixed effects model for repeated measures (MMRM) will be used 
for analysis; the model will include treatment, baseline value, 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 for the specific study period will be included in the model. Model-based 
point HVWLPDWHVLHOHDVWVTXDUHV>/6@PHDQVFRQILGHQFHLQWHUYDOVDQGS-values) will be reported 
where applicable. An unstructured covariance structure will be used to model the within-subject errors. 
If there is a convergence issue with the unstructured covariance model, Toeplitz compound symmetry 
or Autoregressive (1) [AR(1)] covariance structure will be used, following this sequence until 
convergence is achieved. If the model still does not converge with AR(1) structure, no results will be 
reported. When the covariance structure is not UN, the sandwich estimator for the variance covariance 
matrix will be derived, using the EMPIRICAL option in the PROC MIXED statement in SAS.  
For analysis of binary endpoints, the estimand is the Odds Ratio (OR). The generalized estimating 
equation (GEE) methods will be used for the analysis. GEE models will include terms for treatment, 
baseline value, assessment time point, and time point-by-treatment as explanatory variables. Model-
based point estimates (ie, odds ratiosFRQILGHQFHLQWHUYDOVDQGS-values will be reported.  
Time to relapse for remitters at the end of OL phase will be analyzed the same way as done for primary 
efficacy analysis. 
Endpoints for the OL phase will be summarized by each scheduled timepoint, based on Enrolled Set.  
Analysis of Safety Endpoints 
Safety and tolerability of SAGE-217 will be evaluated by incidence of adverse events/serious adverse 
events, and 
.
 
 Safety Set will be used for safety analyses.  
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The 
 measurements comparison between SAGE-217 and placebo will be assessed 
longitudinally (at baseline and the end of every other active treatment course, and the end of every 
other no-treatment follow up period) as specified in the Schedule of Events. The data will be analyzed 
using an MMRM with the change from baseline as the response variable. 
Safety and tolerability will be summarized for the OL phase using the Enrolled Set. 


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Table 2: 
Schedule of Events (Screening Period) 
 
Screening Period 
Study Day 
-28 to -1 
Visit 
1 
Study Procedure 
 
Informed Consent 
X 
Duplicate Subject Check (US only)a 
X 
Inclusion/Exclusion  
X 
Demographics 
X 
Medical/Family History 
X 
SCID-5 
X 
ICD-10b 
X 
MGH-ATRQ 
X 
Serum FSH testc 
X 
Full Physical Examinationd 
X 
Body Weight/Height 
X 
Drug & Alcohol Screenf 
X 
Serum Pregnancy Test (all female subjects) 
X 
Hepatitis & HIV Screen 
X 
Subject trainingg 
X 
HAM-Dj 
X 
MADRS 
X 
CGI-S 
X 
Adverse Events/SAEsk 
X 
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Screening Period 
Study Day 
-28 to -1 
Visit 
1 
Prior Medications 
X 
CGI-S – Clinical Global Impression - Severity; 
; 
ECG = electrocardiogram; FSH = follicle stimulating hormone; HAM-D = Hamilton Rating Scale for Depression, 
17-item; HIV = human immunodeficiency virus; ICD-10 = International Statistical Classification of Diseases and 
Related Health Problems version 10; MADRS = Montgomery-Åsberg Depression Rating Scale; MGH 
ATRQ = Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; SCID-5 = Structured 
Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; SAE = serious adverse 
event; US = United States 
a Subjects at US sites will be asked to authorize that their unique subject identifiers be entered into a registry with 
the intent of identifying subjects who may meet exclusion criteria for participation in another clinical study. 
b ICD-10 code(s) for the diagnosis of the current major depressive episode to be collected if available. 
c A serum FSH test will be conducted at Screening for female subjects that are not surgically sterile to confirm 
ZKHWKHUDIHPDOHVXEMHFWZLWKPRQWKVRIVSRQWDQHRXVDPHQRUUKHDPHHWVWKHSURWRFRO-defined criteria for 
being post-menopausal. 
d A full physical examination will be conducted, including assessment of body systems (eg, head, eye, ear, nose, and 
throat; heart; lungs; abdomen; and extremities), as well as
and neurological examinations and mental 
status examinations. 
 Urine toxicology for selected drugs of abuse (see Table 8) and breath test for alcohol. 
g Subjects will be trained on use of study drug adherence monitoring and PHQ-9 software applications and devices 
by site personnel. 
j The HAM-D is to be completed as early during the visit as possible. The assessment timeframe for HAM-D will 
refer to the past 7 days (1 week). 
k Adverse events will be collected starting at the time of informed consent and throughout the duration of the 
subject’s participation in the study (Section 12.2). 
 
 
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Table 3: 
Schedule of Events (Open-label and Double-blind Phases) 
 
Open-Label 
 
Double-blind 
Treatment & 
FU 1 
 
Double-blind 
Treatment & 
FU 2 
 
Double-blind 
Treatment & 
FU 3 
 
Double-blind 
Treatment & 
FU 4 
 
Double-blind 
Treatment & 
FU 5 
EOS 
Study Day 
1 
8 
(+1) 
15 
(+1) 
21 
(±1) 
28 
(±1) 
42 
(±1) 
56 
(±1) 
63 
(+1) 
70 
(+1) 
76 
(±3) 
111 
(+3) 
118 
(+1) 
125 
(+1) 
131 
(±3) 
166 
(+3) 
173 
(+1) 
180 
(+1) 
186 
(±3) 
221 
(+3) 
228 
(+1) 
235 
(+1) 
241 
(±3) 
276 
(+3) 
283 
(+1) 
290 
(+1) 
296 
(±3) 
331 
(±3) 
Visit 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 12 
13 
14 
15 16 
17 
18 
19 20 
21 
22 
23 24 
25 
26 
27 
28 
Treatment 
Period Day 
1 
8 
15/ 
EOTa 21 
28 
42 
56/ 
1b 
8 
15/ 
EOTa 21 56/ 
1 
8 
15/ 
EOTa 21 56/ 
1 
8 
15/  
EOTa 21 56/ 
1 
8 
15/ 
EOTa 21 56/ 
1 
8 
15/ 
EOTa 21 
56/ 
ETa 
Study 
Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MADRS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject 
trainingc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviated 
Physical 
Examinationd 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
Body Weight 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Drug & 
Alcohol 
Screenf 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Urine 
Pregnancy 
Testg 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
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Open-Label 
 
Double-blind 
Treatment & 
FU 1 
 
Double-blind 
Treatment & 
FU 2 
 
Double-blind 
Treatment & 
FU 3 
 
Double-blind 
Treatment & 
FU 4 
 
Double-blind 
Treatment & 
FU 5 
EOS 
Study Day 
1 
8 
(+1) 
15 
(+1) 
21 
(±1) 
28 
(±1) 
42 
(±1) 
56 
(±1) 
63 
(+1) 
70 
(+1) 
76 
(±3) 
111 
(+3) 
118 
(+1) 
125 
(+1) 
131 
(±3) 
166 
(+3) 
173 
(+1) 
180 
(+1) 
186 
(±3) 
221 
(+3) 
228 
(+1) 
235 
(+1) 
241 
(±3) 
276 
(+3) 
283 
(+1) 
290 
(+1) 
296 
(±3) 
331 
(±3) 
Visit 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 12 
13 
14 
15 16 
17 
18 
19 20 
21 
22 
23 24 
25 
26 
27 
28 
Treatment 
Period Day 
1 
8 
15/ 
EOTa 21 
28 
42 
56/ 
1b 
8 
15/ 
EOTa 21 56/ 
1 
8 
15/ 
EOTa 21 56/ 
1 
8 
15/  
EOTa 21 56/ 
1 
8 
15/ 
EOTa 21 56/ 
1 
8 
15/ 
EOTa 21 
56/ 
ETa 
HAM-Dk 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
CGI-S 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
CGI-I 
 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
Study Drug 
Dispensation 
X 
X 
 
 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
 
Study Drug 
Administration 
X (daily for 14 
days) 
 
 
 
X (daily for 
14 days) 
 
X (daily for 
14 days) 
 
X (daily for 
14 days) 
 
X (daily for 
14 days) 
 
X (daily for 
14 days) 
 
 
Study Drug 
Accountability/ 
Return 
 
X 
X 
 
 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
PHQ-9m 
X (every 7 [+3] days) 


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Open-Label 
 
Double-blind 
Treatment & 
FU 1 
 
Double-blind 
Treatment & 
FU 2 
 
Double-blind 
Treatment & 
FU 3 
 
Double-blind 
Treatment & 
FU 4 
 
Double-blind 
Treatment & 
FU 5 
EOS 
Study Day 
1 
8 
(+1) 
15 
(+1) 
21 
(±1) 
28 
(±1) 
42 
(±1) 
56 
(±1) 
63 
(+1) 
70 
(+1) 
76 
(±3) 
111 
(+3) 
118 
(+1) 
125 
(+1) 
131 
(±3) 
166 
(+3) 
173 
(+1) 
180 
(+1) 
186 
(±3) 
221 
(+3) 
228 
(+1) 
235 
(+1) 
241 
(±3) 
276 
(+3) 
283 
(+1) 
290 
(+1) 
296 
(±3) 
331 
(±3) 
Visit 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 12 
13 
14 
15 16 
17 
18 
19 20 
21 
22 
23 24 
25 
26 
27 
28 
Treatment 
Period Day 
1 
8 
15/ 
EOTa 21 
28 
42 
56/ 
1b 
8 
15/ 
EOTa 21 56/ 
1 
8 
15/ 
EOTa 21 56/ 
1 
8 
15/  
EOTa 21 56/ 
1 
8 
15/ 
EOTa 21 56/ 
1 
8 
15/ 
EOTa 21 
56/ 
ETa 
Adverse 
Events/SAEsn 
X 
Concomitant 
Medications 
X 
CGI-I = Clinical Global Impression - Improvement; CGI-S – Clinical Global Impression - Severity; 
; 
ECG = electrocardiogram; EOT = end of treatment; 
; EOS = End of study; EOT = end of treatment; ET = early 
termination; FU = follow-up; HAM-D = Hamilton Rating Scale for Depression, 17-item; PHQ-9 = 9-item Patient Health Questionnaire; 
 
; SAE = serious adverse event; 
 
a Subjects 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. The follow-up visits should occur as scheduled relative to the last day of treatment. Subjects who discontinue treatment early will be terminated 
from the study upon completion of their final follow-up visit. If at any time after the EOT visit, a subject decides to terminate the study, the subject should 
return for an early termination (ET) visit. The EOT and ET visits can be on the same day if a subject discontinues study drug and terminates the study on the 
same day during a clinic visit; in this case, all events scheduled for the ET visit will be conducted. 
b The completion of the Open-label Phase for all subjects coincides with the first day of the Double-Blind Phase (Study Day 56, Visit 8). Subjects that do not 
exhibit a response to SAGE-217 in the Open-label Phase (Section 7.1.2) will be terminated from the study on this day upon completion of all assessments. 
c Subjects will be trained on use of study drug adherence monitoring and PHQ-9 software applications and devices by site personnel. 
d An abbreviated physical examination will include assessment of general appearance, cardiovascular, respiratory, gastrointestinal, and neurological systems.  
f Urine toxicology for selected drugs of abuse (Table 8) and breath test for alcohol. 
g Urine pregnancy test for female subjects that are not surgically sterile and do not meet the protocol-defined criteria for being post-menopausal. 
k The HAM-D is to be completed as early during the visit as possible. The assessment timeframe for HAM-D will refer to the past 7 days (1 week) at Days 28 
and 42 of the OL Phase and at each Day 56/1 of the DB Phase; “Since Last Visit” will be used for all other visits. 
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m All PHQ-9 assessments will be performed via web browser. The subject will take the first PHQ-9 on Day 1 and then every 7 days thereafter; if the PHQ-9 score 
is ≥10, the subject will return to the site as soon as possible to be assessed by the clinician-administered HAM-D. If the HAM D is ≥18 at this visit, the subject 
will return to the site in 7 to 14 days to be reassessed by the HAM-D. See Table 4 for the assessments to be conducted at these visits. 
n Adverse events will be collected starting at the time of informed consent and throughout the duration of the subject’s participation in the study (Section 12.2). 
 


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Table 4: 
Schedule of Events (Visits for Assessment of Relapse) 
Study Procedure 
Abbreviated Physical Examinationa 
X 
Urine Pregnancy Testc 
X 
HAM-Df 
X 
CGI-S 
X 
EQ-5D-5L 
X 
Adverse Events/SAEsg 
X 
Concomitant Medications 
X 
CGI-I = Clinical Global Impression - Improvement; CGI-S – Clinical Global Impression - Severity; 
 
; ECG = electrocardiogram; 
; HAM-D = Hamilton Rating Scale for Depression, 17-item; SAE = serious adverse event; 
 
a An abbreviated physical examination will include assessment of general appearance, cardiovascular, respiratory, 
gastrointestinal, and neurological systems.  
c Urine pregnancy test for female subjects that are not surgically sterile and do not meet the protocol-defined criteria 
for being post-menopausal. 
f The HAM-D is to be completed as early during the visit as possible. The assessment timeframe for HAM-D will 
refer to the past 7 days (1 week). 
g Adverse events will be collected starting at the time of informed consent and throughout the duration of the 
subject’s participation in the study (Section 12.2). 
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Table 5: 
Schedule of Events (Follow-up for Subjects that Meet Relapse Criteria) 
Study Day 
111, 166, 221, 276, 331/EOS 
(+3) 
Treatment Period Day 
56/1/ET 
Study Procedure 
 
Drug & Alcohol Screen 
X 
HAM-D 
X 
CGI-S 
X 
CGI-I 
X 
PHQ-9a 
X 
Adverse Events/SAEs 
X 
Concomitant Medications 
X 
CGI-I = Clinical Global Impression - Improvement; CGI-S – Clinical Global Impression - Severity; 
 
; EOS = End of study; ET = 
early termination; HAM-D = Hamilton Rating Scale for Depression, 17-item; PHQ-9 = 9-item Patient Health Questionnaire; 
SAE = serious adverse event; 
 
a The PHQ-9 will be completed by the subject during the visit at the site.  
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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 ...............22 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................27 
5. 
INTRODUCTION ......................................................................................................30 
5.1. 
Background of Major Depressive Disorder and Unmet Medical Need ......................30 
5.2. 
SAGE-217 ...................................................................................................................30 
5.3. 
Potential Risks and Benefits .......................................................................................31 
5.4. 
Dose Justification ........................................................................................................31 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................33 
6.1. 
Study Objective ..........................................................................................................33 
6.1.1. 
Primary Objective .......................................................................................................33 
6.1.2. 
Secondary Objective(s) ...............................................................................................33 
 
33 
6.2. 
Endpoints ....................................................................................................................33 
6.2.1. 
Primary Endpoint ........................................................................................................33 
6.2.2. 
Secondary Endpoint(s) ................................................................................................33 
 
34 
7. 
INVESTIGATIONAL PLAN .....................................................................................35 
7.1. 
Overall Study Design ..................................................................................................35 
7.1.1. 
Open-label Phase ........................................................................................................35 
7.1.2. 
Double-blind Phase .....................................................................................................35 
7.1.2.1. 
Determination of Relapse ...........................................................................................36 
7.2. 
Number of Subjects ....................................................................................................37 
7.3. 
Treatment Assignment ................................................................................................37 
7.4. 
Dose Adjustment Criteria ...........................................................................................37 
7.5. 
Criteria for Study Termination ...................................................................................37 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................38 
8.1. 
Subject Inclusion Criteria ...........................................................................................38 
8.2. 
Subject Exclusion Criteria ..........................................................................................39 
8.3. 
Subject Withdrawal Criteria .......................................................................................41 


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8.3.1. 
Subjects that Meet Relapse Criteria ............................................................................42 
8.3.2. 
Individual Subject Stopping Criteria ..........................................................................42 
8.3.3. 
Replacement of Subjects .............................................................................................42 
9. 
TREATMENT OF SUBJECTS ..................................................................................43 
9.1. 
Study Drug ..................................................................................................................43 
9.2. 
Prior Medications, Concomitant Medications, and Restrictions ................................43 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................43 
9.2.2. 
Prohibited Medications ...............................................................................................43 
9.2.3. 
Other Restrictions .......................................................................................................44 
9.3. 
Treatment Adherence ..................................................................................................44 
9.4. 
Randomization and Blinding ......................................................................................45 
9.4.1. 
Emergency Unblinding ...............................................................................................45 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................47 
10.1. 
Description of Study Drugs ........................................................................................47 
10.2. 
Study Drug Packaging and Labeling ..........................................................................47 
10.3. 
Study Drug Storage .....................................................................................................47 
10.4. 
Study Drug Preparation ..............................................................................................47 
10.5. 
Study Drug Administration.........................................................................................47 
10.6. 
Study Drug Accountability .........................................................................................47 
10.7. 
Study Drug Handling and Disposal ............................................................................48 
10.8. 
Product Complaints ....................................................................................................48 
11. 
ASSESSMENT OF EFFICACY AND PHARMACOKINETICS .............................50 
11.1. 
Efficacy Assessments .................................................................................................50 
11.1.1. 
Hamilton Rating Scale for Depression .......................................................................50 
11.1.2. 
Clinical Global Impression .........................................................................................50 
 
51 
 
51 
11.1.5. 
Patient Health Questionnaire ......................................................................................51 
 
51 
11.2.1. 
Blood Sample Collection ............................................................................................52 
11.2.2. 
Sample Analysis .........................................................................................................52 
12. 
ASSESSMENT OF SAFETY .....................................................................................53 
12.1. 
Safety Parameters .......................................................................................................53 


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12.1.1. 
Demographic/Medical History ...................................................................................53 
12.1.2. 
Weight and Height ......................................................................................................53 
12.1.3. 
Physical Examination .................................................................................................53 
 
53 
 
54 
 
54 
12.1.6.1. 
Drugs of Abuse and Alcohol ......................................................................................55 
12.1.6.2. 
Pregnancy Screen ........................................................................................................56 
 
56 
 
56 
 
56 
12.2. 
Adverse and Serious Adverse Events .........................................................................57 
12.2.1. 
Definition of Adverse Event .......................................................................................57 
12.2.2. 
Serious Adverse Event  Definition .............................................................................57 
12.2.3. 
Relationship to Study Drug ........................................................................................58 
12.2.4. 
Recording Adverse Events .........................................................................................58 
12.2.5. 
Reporting Serious Adverse Events .............................................................................59 
12.3. 
Pregnancy ...................................................................................................................59 
12.4. 
Overdose .....................................................................................................................60 
13. 
STATISTICS ..............................................................................................................61 
13.1. 
Data Analysis Sets ......................................................................................................61 
13.2. 
Handling of Missing Data ...........................................................................................61 
13.3. 
General Considerations ...............................................................................................61 
13.4. 
Demographics and Baseline Characteristics ...............................................................61 
13.5. 
Efficacy Analyses .......................................................................................................61 
13.5.1. 
Primary Efficacy Analysis ..........................................................................................61 
13.5.2. 
Secondary and Other Efficacy Analyses ....................................................................61 
13.6. 
Safety Analyses ..........................................................................................................62 
13.6.1. 
Adverse Events ...........................................................................................................62 
 
63 
13.6.3. 
Physical Examinations ................................................................................................63 
 
63 
 
63 
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13.6.6. 
Prior and Concomitant Medications ...........................................................................63 
 
63 
 
64 
 
64 
 
64 
13.8. 
Determination of Sample Size ....................................................................................64 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................65 
14.1. 
Study Monitoring ........................................................................................................65 
14.2. 
Audits and Inspections ................................................................................................65 
14.3. 
Institutional Review Board or Ethics Committee .......................................................66 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................67 
16. 
ETHICS ......................................................................................................................68 
16.1. 
Ethics Review .............................................................................................................68 
16.2. 
Ethical Conduct of the Study ......................................................................................68 
16.3. 
Written Informed Consent ..........................................................................................68 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................69 
17.1. 
Inspection of Records .................................................................................................69 
17.2. 
Retention of Records ..................................................................................................69 
18. 
PUBLICATION POLICY ..........................................................................................70 
19. 
LIST OF REFERENCES ............................................................................................71 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Schedule of Events (Screening Period) ......................................................................14 
Table 3: 
Schedule of Events (Open-label and Double-blind Phases) .......................................16 
Table 4: 
Schedule of Events (Visits for Assessment of Relapse) .............................................20 
Table 5: 
Schedule of Events (Follow-up for Subjects that Meet Relapse Criteria) ..................21 
Table 6: 
Abbreviations and Specialist Terms ...........................................................................27 
Table 7: 
Summary of Events Which May Result in Relapse ....................................................36 
 
54 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................35 
 
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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 6: 
Abbreviations and Specialist Terms  
Abbreviation or specialist term 
Explanation 
AE 
adverse event 
AR(1) 
Autoregressive (1) 
BMI 
body mass index 
CBT-I 
cognitive behavioral therapy for insomnia 
CGI-I 
Clinical Global Impression – Improvement 
CGI-S 
Clinical Global Impression – Severity 
COPD 
chronic obstructive pulmonary disease 
CRT 
choice reaction time 
CS 
clinically significant 
CYP 
cytochrome P450 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition 
EC 
ethics committee 
eCRF 
electronic case report form 
EOS 
end of study 
EOT 
end of treatment 
ET 
early termination 
FAS 
Full Analysis Set 
FSH 
follicle stimulating hormone 
GABA 
Ȗ-aminobutyric acid 
GEE 
generalized estimating equation 
HAM-D 
Hamilton Rating Scale for Depression 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICD-10 
International Statistical Classification of Diseases and Related 
Health Problems version 10 
ICF 
informed consent form 
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Abbreviation or specialist term 
Explanation 
ID 
identification 
IRAC 
Independent Relapse Adjudication Committee 
IRB 
institutional review board 
IRT 
interactive response technology 
ISI 
Insomnia Severity Index 
LS 
Least squares 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MDD 
major depressive disorder 
MDE 
major depressive episode 
MGH ATRQ 
Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire 
MMRM 
mixed effects model for repeated measures 
NCS 
not clinically significant 
OL 
open label 
OR 
Odds Ratio 
PHQ-9 
9-item Patient Health Questionnaire 
PPD 
postpartum depression 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCID-5-CT 
Structured Clinical Interview for Diagnostic and DSM-5 Clinical 
Trial Version 
SD 
standard deviation 
SDS 
Sheehan Disability Scale 
SMCC 
silicified microcrystalline cellulose 
SRT 
simple reaction time 
SUSAR 
suspected, unexpected, serious adverse reactions 
TEAE 
treatment-emergent adverse event 
THC 
tetrahydrocannabinol 
TSH 
thyroid stimulating hormone 
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Abbreviation or specialist term 
Explanation 
US 
United States 
VAS 
visual analogue scale 
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 (US), 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). 
In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5, American 
Psychiatric Association 2013), depression refers to an overarching set of diagnoses, including 
major depressive disorder (MDD). Diagnostic criteria for MDD includes a set of at least 5 
depressive symptoms out of 9, including 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, serotonin norepinephrine reuptake inhibitors, tricyclic 
antidepressants, monoamine oxidase inhibitors, 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). 
Converging preclinical and clinical evidence (Gerner 1981; Honig 1988; Drugan 1989; 
Luscher 2011; Mann 2014) implicates deficits in γ-aminobutyric acid (GABA)-ergic 
neurotransmission in the pathophysiology of depressive disorders including MDD. Furthermore, 
experimental data implicate deficiencies in the normal regulation of endogenous neuroactive 
steroids in depressive disorders (Maguire 2008; Maguire 2009). Depressed patients show low 
levels of GABA in the brain and of neurosteroids in the cerebrospinal fluid and plasma, and 
antidepressant therapy restores GABA levels in relevant animal models and neurosteroid 
concentrations in depressed patients (Luscher 2011; Schüle 2014). 
5.2. 
SAGE-217 
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 
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 


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for GABAA receptors, and exhibits activity consistent with the actions of other GABAA receptor 
potentiators (Rudolph 2011) when administered in vivo. 
Data from an open-label Phase 2a study of SAGE-217 administered to subjects with moderate to 
severe MDD showed clinically significant improvements from baseline in depression and 
anxiety scale scores (Hamilton Rating Scale for Depression [HAM-D], Montgomery-Åsberg 
Depression Rating Scale [MADRS], Hamilton Anxiety Rating Scale, and Clinical Global 
Impression – Improvement [CGI-I]) as early as Day 2 of the 14-day treatment period, with 
durable responses following the end of treatment. This result was further supported by the 
randomized, double-blind portion of this study including 89 subjects, in which a rapid and 
substantial decrease in HAM-D scores was observed at Day 15 (primary endpoint), starting at 
Day 2. This response pattern was also observed with other efficacy scales, including MADRS, 
CGI-I, and Hamilton Anxiety Rating Scale. 
SAGE-217 has been generally well tolerated in clinical studies to date. The most common 
treatment-emergent adverse events (TEAEs) were sedation, somnolence, dizziness, headache, 
upper respiratory tract infection, diarrhea, and nausea. Among these sedation, somnolence and 
dizziness are considered adverse drug reactions with SAGE-217. Most adverse events (AEs) 
were reported as mild or moderate in intensity and reversible. In completed studies, 2 SAEs have 
been reported in subjects administered SAGE-217 and 1 SAE was reported in a subject 
administered placebo. These include one subject with Essential Tremor who experienced 
transient confusion leading to discontinuation of study drug (SAGE-217 oral solution, 30 mg). 
The second SAE of confusion was noted in a subject with postpartum depression (PPD) which 
resolved upon reduction of the study drug (SAGE-217 oral capsule) dose from 30 mg to 20 mg. 
One subject with PPD in the placebo group experienced obstructive pancreatitis which resolved 
with cholecystectomy. No deaths have been reported in any study of SAGE-217.  
In a multiple-ascending dose study of SAGE-217 in healthy subjects (217-CLP-102), 1 cohort of 
subjects (n=9) was dosed with 30 mg SAGE-217 in the morning for 7 days, and after a washout 
period of 7 days, 7 of the subjects were re-treated with 30 mg SAGE-217 in the evening for 
7 days. The most common TEAE in these 7 subjects after re-treatment with SAGE-217 was 
sedation (n=3, 42.9%), consistent with the pharmacology of the drug and with other clinical 
studies with SAGE-217. No evidence of withdrawal-related events, including seizure, were 
observed in these subjects. 
Additional information on nonclinical and clinical data is provided in the Investigator’s 
Brochure.  
5.3. 
Potential Risks and Benefits 
Given the outcome of the completed studies of SAGE-217 in subjects with MDD and PDD, the 
current significant unmet need in the treatment of depression, and a favorable benefit-risk 
profile, further investigation of SAGE-217 in adults with MDD is justified. 
5.4. 
Dose Justification 
The dose level in this study of 30 mg per day is the dose level that was efficacious and well-
tolerated in a Phase 2 study in subjects with MDD (217-MDD-201). Dose adjustments to 20 mg 
SAGE-217 are permitted; 20 mg SAGE-217 is anticipated to be well tolerated as it is lower than 


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the maximum tolerated dose level. Due to sedation/somnolence observed in previous clinical 
studies when administered in the morning, and improved tolerability when given in the evening, 
SAGE-217 will be administered in the evening in this study. 


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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Study Objective 
6.1.1. 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of SAGE-217 with a fixed, 
repeated treatment regimen in the prevention of relapse in subjects with MDD who have 
responded to open-label (OL) treatment with SAGE-217. 
6.1.2. 
Secondary Objective(s) 
The secondary objective of this study is to evaluate the long-term safety and tolerability of a 
fixed, repeated treatment regimen of SAGE-217 up to 1 year. 
 
 
 
 
 
 
 
 
 
6.2. 
Endpoints 
6.2.1. 
Primary Endpoint 
The primary endpoint of this study is time to relapse during the double-blind (DB) Phase (days; 
from first dose of study drug in the DB Phase to relapse [date] during the DB Phase). 
6.2.2. 
Secondary Endpoint(s) 
Secondary endpoints of this study are: 
• Percentage of subjects who relapse during the DB Phase 
• Change from baseline in the 17-item HAM-D total score at the end of each 14-day 
treatment period in the DB Phase. 
• HAM-D response at the end of each 14-day treatment period in the DB Phase, defined as 
a ≥50% reduction in HAM-D score from baseline 
• HAM-D remission at the end of each 14-day treatment period in the DB Phase, defined as 
HAM-D total score ≤7 
• CGI-I response, defined as “much improved” or “very much improved”, at the end of 
each 14-day treatment period in the DB Phase 
• Change from baseline in Clinical Global Impression - Severity (CGI-S) score at the end 
of each 14-day treatment period in the DB Phase 


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x Change from baseline in 9-item Patient Health Questionnaire (PHQ-9) score at the end of 
each 14-day treatment period in the DB Phase 
x Time to relapse during the DB phase (days; from first dose of study drug in DB Phase to 
relapse [date] during the DB Phase) for subjects who achieved HAM-D remission in the 
OL Phase 
x Incidence of TEAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD
PPD


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a study with an OL phase followed by a randomized, DB, placebo-controlled phase to 
assess the effect of SAGE-217 monotherapy in a fixed, repeated treatment regimen versus 
placebo on relapse prevention in adult subjects with MDD (MADRS ≥32, HAM-D ≥22) who are 
not currently taking antidepressants. See Figure 1 for a schematic of the study design. 
Figure 1: Study Design Schematic 
 
S = SAGE-217; P = Placebo 
7.1.1. 
Open-label Phase 
The Screening Period (Table 2) begins with the signature of the informed consent form (ICF); 
the ICF must be signed prior to beginning any screening activities. The diagnosis of MDD must 
be made according to Structured Clinical Interview for DSM-5 Clinical Trial Version (SCID 5-
CT) performed by a qualified healthcare professional. Subjects will undergo preliminary 
screening procedures at the Screening Visit to determine eligibility, including completion of the 
MADRS, HAM-D and CGI-S.  
Beginning on Day 1 of the OL Phase, eligible subjects will self-administer a single dose of study 
drug once daily in the evening with food, on an outpatient basis, for 14 consecutive days. 
Subjects will return to the study center during the OL treatment and follow-up periods as 
outlined in Table 3. 
7.1.2. 
Double-blind Phase 
Subjects who complete the OL Phase (through Day 56) with no significant tolerability issues as 
judged by the Investigator and who exhibited a HAM-D response, defined as a ≥50% reduction 
from baseline in HAM-D total score, at Visits 4, 6, 7, and 8 (see Table 3) will be eligible for the 
DB Phase. One excursion of <50% reduction from baseline (but total score ≤21) in HAM-D total 


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score or one missing HAM-D total score at Visit 6 or 7 will be permitted for eligibility to the DB 
Phase. 
Beginning on Day 1 of the DB Phase, eligible subjects will be randomized to receive SAGE-217 
30 mg or matching placebo in a 1:1 ratio. The 40-week DB Phase consists of five 14-day 
treatment periods, each separated by a 6-week follow-up period; the end of each follow-up 
period coincides with the first visit of the next treatment period. During the 14-day treatment 
periods, subjects will self-administer a single dose of study drug once daily in the evening with 
food, on an outpatient basis. Subjects will return to the study center during the DB treatment and 
follow-up periods as outlined in Table 3. 
7.1.2.1. 
Determination of Relapse 
During the follow-up periods of the DB Phase, depressive symptoms will be monitored every 
7 (+3) days via remote PHQ-9; if the PHQ-9 score is ≥10, the subject will return to the site as 
soon as possible to be assessed by the clinician-administered HAM-D (Table 4). If the HAM-D 
is ≥18 at this visit, the subject will return to the site in 7 to 14 days to be reassessed by the 
HAM-D (Table 4); if the HAM-D remains ≥18, the subject will be considered to have relapsed at 
this visit. A summary of all reasons a subject may be considered to have relapsed is presented in 
Table 7. Final determination of relapse will be made by an Independent Relapse Adjudication 
Committee (IRAC) for events other than 2 consecutive HAM-D scores ≥18 assessed 7 to 14 days 
apart. The IRAC Charter will include full details of membership and responsibilities. 
Table 7: 
Summary of Events Which May Result in Relapse 
Event 
Requires 
Review by 
IRAC? 
2 consecutive HAM-D scores ≥18 assessed 7 to 14 days apart 
No 
Any worsening of depression requiring hospitalization 
Yes 
Any Investigator-determined risk of suicide 
Yes 
Worsening of overall depressive symptoms as measured by CGI-S ≥4 and an 
increase from baseline in CGI-S score of ≥ 2 points 
Yes 
PHQ-9 score ≥10 and subsequent subject withdrawal from study 
Yes 
Single PHQ-9-triggered HAM-D score ≥18 and subsequent subject withdrawal 
from study 
Yes 
 
Subjects that have 2 consecutive HAM-D total scores ≥18 during a treatment period are 
encouraged to complete the treatment period. Subjects who experience any of the first 4 events 
described in the table above will not be eligible for further randomized treatment periods; these 
subjects may receive treatment as clinically indicated by their physician and should return to the 
site for follow-up visits as outlined in Table 5. 


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7.2. 
Number of Subjects 
It is expected that approximately 546 subjects will need to be dosed in the OL Phase to ensure at 
least 300 subjects are dosed in the DB Phase. An independent interim analysis for sample size re-
estimation will be conducted when approximately 50% of expected relapse events occur 
(Section 13.8).  
7.3. 
Treatment Assignment 
All subjects will receive SAGE-217 in the OL Phase. In the DB Phase, subjects will be randomly 
assigned in a 1:1 ratio to receive SAGE-217 or matching placebo.  
7.4. 
Dose Adjustment Criteria 
If at any time during the study, 30 mg SAGE-217 is not tolerated, as assessed by the occurrence 
of a severe AE judged by the Investigator to be related to study drug, the dose will be reduced to 
20 mg and continued for the remainder of the treatment period. Dose adjustments related to 
moderate AEs will be at the discretion of the Investigator. Subsequent treatment periods will 
begin with the 30-mg dose, regardless of whether a subject required a dose adjustment in a 
previous treatment period. Subjects who cannot tolerate the 20-mg dose at any time will be 
terminated from the study upon completion of an end of treatment (EOT) visit as soon as 
possible, and an ET visit 7 days later. 
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 
subjects, or for administrative reasons. In the event of study termination, Sage Therapeutics will 
provide written notification to the Investigator. Investigational sites must promptly notify their 
Institutional Review Board (IRB) or Ethics Committee and initiate withdrawal procedures for 
participating subjects.  


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
Qualified subjects will meet all of the following criteria: 
1. Subject has signed an ICF prior to any study-specific procedures being performed. 
2. Subject is a male or female between 18 and 65 years of age, inclusive. 
3. Subject is in good physical health and has no clinically significant findings, as 
determined by the Investigator, on physical examination, 12-lead ECG, or clinical 
laboratory tests. 
4. Subject agrees to adhere to the study requirements. Subject agrees and understands how 
to use a smartphone for purposes of the study. 
5. Subject 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. Subject has had at least 1 prior major depressive episode (MDE) in the 5 years prior to 
Screening (not including the current episode) as determined by the SCID-5-CT. 
7. Subject has a MADRS total score of ≥32 and a HAM-D total score of ≥22 at Screening 
and Day 1 (prior to dosing) of the Open-label Phase. 
8. Subject is willing to delay start of any antidepressant, anxiolytic, insomnia, 
psychostimulant, prescription opioid regimens, and new psychotherapy (including 
Cognitive Behavioral Therapy for Insomnia [CBT-I]) until after study completion. 
9. Subjects receiving psychotherapy must have been receiving therapy on a regular schedule 
for at least 60 days prior to Day 1. 
10. Female subject agrees to use one of the following methods of highly effective 
contraception during participation in the study and for 30 days following the last dose of 
study drug, unless they are postmenopausal (defined as no menses for 12 months without 
an alternative medical cause and confirmed by follicular stimulation hormone [FSH] 
>40 mIU/mL), surgically sterile (hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy), or does not engage in sexual relations which carry a risk of pregnancy 
(does not include abstinence): 
• 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/occlusion. 
• Vasectomized partner. 


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11. Male subject agrees to use an acceptable method of effective contraception for the 
duration of study and for 5 days after receiving the last dose of the study drug, unless the 
subject does not engage in sexual relations which carry a risk of pregnancy (does not 
include abstinence). Acceptable methods of effective contraception for males includes 
vasectomy or a condom with spermicide used together with highly effective female 
contraception methods if the female partner(s) is of child-bearing potential (see Inclusion 
Criteria #10 for acceptable contraception methods).  
12. Male subject is willing to abstain from sperm donation for the duration of the study and 
for 5 days after receiving the last dose of the study drug. 
13. Subject agrees to refrain from drugs of abuse and alcohol for the duration of the study. 
8.2. 
Subject Exclusion Criteria 
Subjects who meet any of the following criteria are disqualified from participation in this study: 
1. Subject has attempted suicide associated with the current episode of MDD. 
2. Subject has a recent history or active clinically significant manifestations of metabolic, 
hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, 
musculoskeletal, dermatological, urogenital, neurological, or eyes, ears, nose, and throat 
disorders, or any other acute or chronic condition that, in the Investigator's opinion, 
would limit the subject's ability to complete or participate in this clinical study. 
3. Subject has a body mass index (BMI) ≤18 or ≥50 kg/m2 at Screening. Note that a BMI of 
40 to 49 kg/m2, inclusive, at Screening is subject to a broader evaluation of medical co-
morbidities (such as sleep apnea, COPD), concomitant medications, prior tolerability of 
sedating agents. 
4. Subject 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 two 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. Subject has had vagus nerve stimulation, electroconvulsive therapy, or has taken 
ketamine (including esketamine) within the current major depressive episode. 
6. Subject has taken antidepressants within 60 days prior to Day 1.  
7. Subject is taking or has taken any of the following: 
a. benzodiazepines, barbiturates, or GABAA modulators (eg, eszopiclone, zopiclone, 
zaleplon, zolpidem, brexanolone) at Day -28,  
b. benzodiazepines, barbiturates, or GABAA modulators (eg, eszopiclone, zopiclone, 
zaleplon, zolpidem) daily or near-daily (≥4 days per week) for 1 year, in the last year 
prior to the first dose of study drug.  
c. benzodiazepine or GABAA modulator with a half-life of ≥48 hours (eg, diazepam) 
from 60 days prior to Day 1 
8. Subject 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 


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generation (typical/atypical) antipsychotics at Day -14. Note that non-sedating 
anti-histamines are permitted. 
9. Subject is taking psychostimulants (eg, methylphenidate, amphetamine) or opioids, 
regularly or as-needed, at Day -28. 
10. Subject is participating in CBT-I within 28 days prior to Day 1. 
11. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds.  
12. Subject has a positive pregnancy test at screening or on Day 1 prior to dosing.  
13. Subject is breastfeeding at Screening or on Day 1 (prior to administration of study drug) 
and does not agree to temporarily cease giving breast milk to child(ren) from just prior to 
receiving study drug on Day 1 until 7 days after the last dose of study drug in each 
treatment period.  
14. Subject has detectable hepatitis B surface antigen, anti-hepatitis C virus (HCV) and 
positive HCV viral load, or human immunodeficiency virus (HIV) antibody at Screening. 
15. Subject has a clinically significant abnormal 12-lead ECG at the Screening or on Day 1 
of any treatment period. 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.  
16. Subject has active psychosis per Investigator assessment.  
17. Subject has a medical history of seizures.  
18. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder.  
19. Subject 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. 
20. Subject has had exposure to another investigational medication or device within 30 days 
prior to screening.  
21. Subject has previously participated in a SAGE-217 or a SAGE-547 (brexanolone) clinical 
trial.  
22. Subject has used any known strong inhibitors of cytochrome P450 (CYP)3A4 within 
28 days or 5 half-lives (whichever is longer) prior to the first dose of study drug or plans 
to use these during any treatment period, or consumed grapefruit juice, grapefruit, or 
Seville oranges, or products containing these within 14 days prior to the first dose of 
study drug for any treatment period or plans to consume these products during any 
treatment period.  
23. Subject has used any of the following strong CYP3A inducers within 28 days prior to the 
first dose of study drug for any SAGE-217 treatment period: rifampin, carbamazepine, 
enzalutamide, mitotane, phenytoin, and St John’s Wort. 
24. Subject has a positive drug and/or alcohol screen at screening or on Day 1 prior to dosing 
in the Open-label Phase. 


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25. Subject plans to undergo elective surgery or procedure requiring general anesthesia at any 
time from Screening through the duration of the study. Procedures requiring conscious 
sedation and ambulatory procedures performed under local anesthesia may be scheduled 
under the following guidelines: 
a. Procedures requiring conscious sedation (eg, colonoscopy) no later than 7 days prior 
to the start of the first dose of each treatment period and no earlier than 7 days after 
the last dose of each treatment period from screening throughout the duration of the 
study. 
b. Elective ambulatory procedures performed under local anesthesia are allowed at any 
time during the study. 
26. Subject 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. 
27. Subject has had gastric bypass surgery, has a gastric sleeve or lap band, or has had any 
related procedures that interfere with gastrointestinal transit. 
28. Subject regularly participates in night shift work or expects to perform night shift work 
during any 14-day treatment period (occasional night shift work during follow-up periods 
is permitted). 
8.3. 
Subject Withdrawal Criteria 
Subjects may discontinue from the study drug or terminate from the study at any time for any 
reason. Other than the events outlined in Table 7, the Investigator may withdraw the subject from 
the study drug or from the study for any of the following reasons: 
• The subject is unwilling or unable to adhere to the protocol 
• The subject experiences an intolerable AE 
• Other medical or safety reason, at the discretion of the Investigator and/or the 
Medical Monitor 
The Investigator must notify the Sponsor and/or the Medical Monitor immediately when a 
subject withdraws from study drug or terminates the study for any reason. The reason must be 
recorded in the subject’s electronic case report form (eCRF).  
If a subject is persistently noncompliant, the Investigator should discuss with the Sponsor the 
potential discontinuation of the subject. Any reasons for unwillingness or inability to adhere to 
the protocol must be recorded in the subject’s eCRF, including: 
• missed visits 
• interruptions in the schedule of study drug administration 
• non-permitted medications (see Section 9.2). 
Subjects who discontinue treatment early should return to the site for an EOT visit (Table 3) as 
soon as possible, preferably the day after treatment is discontinued. The follow-up visits should 
occur as scheduled relative to the last day of treatment. Subjects who discontinue treatment early 
will be terminated from the study upon completion of the final follow-up visit in the current 
period. If at any time after the EOT visit, a subject decides to terminate the study, the subject 


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should return for an ET visit. The EOT and ET visits can be on the same day if a subject 
discontinues study drug and terminates the study on the same day during a clinic visit; in this 
case, all events scheduled for the ET visit will be conducted. 
8.3.1. 
Subjects that Meet Relapse Criteria 
Subjects that meet relapse criteria (Table 7) will not be eligible for further randomized treatment 
periods and should return for follow-up visits as outlined in Table 5. Subjects that meet relapse 
criteria during a treatment period and discontinue treatment early should return to the site for an 
EOT visit (Table 3) as soon as possible, preferably the day after treatment is discontinued, and 
thereafter, should return for follow-up visits as outlined in Table 5.  
If at any time after a subject meets relapse criteria, the subject decides to terminate the study, the 
subject should return for an ET visit (Table 5). An EOT visit and an ET visit can be on the same 
day if a subject discontinues study drug and terminates the study on the same day during a clinic 
visit; in this case, all events scheduled for the EOT visit will be conducted. 
8.3.2. 
Individual Subject Stopping Criteria 
Based on known withdrawal symptoms with other GABAergic drugs and non-clinical 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 study drug 
discontinuation or dose reduction are presented to support subject safety: 
1. Any subject reporting a confirmed or suspected seizure at any time will be discontinued 
from treatment and will not be eligible for another treatment period but will continue to 
be followed in the study for safety (Section 12.2.1). 
2. Following the first treatment period, the Investigator should monitor the course of central 
nervous system-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, in consultation with the Sage Medical Monitor, should consider decreasing 
the dose of study drug to 20 mg, stopping treatment to assess the effect on the 
symptom(s) (eg, resolution, improvement, etc), or discontinuing the subject from 
treatment.  
8.3.3. 
Replacement of Subjects 
Subjects will not be replaced. 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Study Drug 
SAGE-217 capsules at doses of 30 mg (or 20 mg for dose reductions), or matched placebo 
capsules, will be self-administered by subjects orally once daily in the evening with food for 
14 days during treatment periods. Practical options include taking SAGE-217 within 1 hour of 
dinner or taking SAGE-217 later in the evening with solid food. 
9.2. 
Prior Medications, Concomitant Medications, and Restrictions 
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 6 months prior to Screening and 
GABAergic medications taken 12 months prior to Screening will be recorded. 
Any medication and/or supplement determined necessary for the welfare of the subject may be 
given at the discretion of the Investigator at any time during the study.  
The following medications intended for contraception are permitted for female subjects: 
• 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 
9.2.2. 
Prohibited Medications 
Initiation of any antidepressant, anxiolytic, insomnia, psychostimulant, or prescription opioid 
regimen is prohibited from Screening and for the duration of the DB Phase (ie, prior to meeting 
relapse criteria). Restrictions on specific classes of medications include the following: 
• Use of benzodiazepines, barbiturates, or GABAA modulators (eg, eszopiclone, zopiclone, 
zaleplon, zolpidem, brexanolone) is prohibited from Day -28 through the duration of the 
DB Phase 
• Use of benzodiazepines or GABAA modulators with a half-life of ≥48 hours (eg, 
diazepam) is prohibited from Day -60 and through the duration of the DB Phase 
• Use of non-GABA anti-insomnia medications (eg, prescribed therapeutics specifically for 
insomnia and/or over the counter sleep aids) is prohibited from Day -14 through the 
duration of the DB Phase. Note that non-sedating anti-histamines are permitted. 
• Use of first generation or second generation (typical/atypical) antipsychotics is prohibited 
from Day -14 through the duration of the DB Phase.  


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• Use of psychostimulants (eg, methylphenidate, amphetamine) or opioids, regularly or as-
needed, is prohibited from Day -28 through the duration of the DB Phase 
• Exposure to another investigational medication or device within 30 days prior to 
Screening and through the duration of the DB Phase is prohibited. 
• Use of known strong inhibitors of CYP3A4 within 28 days or 5 half-lives (whichever is 
longer) is prohibited prior to the first dose of study drug and during any treatment period 
• Use of any of the following strong CYP3A inducers is prohibited within 28 days prior to 
the first dose of study drug for any treatment period and throughout any treatment period: 
rifampin, carbamazepine, enzalutamide, mitotane, phenytoin, and St John’s Wort 
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 the first dose of any treatment period and throughout any 
treatment period. 
Consumption of alcohol or use of drugs of abuse (including tetrahydrocannabinol [THC]) is 
discouraged throughout the duration of the DB Phase. 
Elective surgeries or procedures requiring general anesthesia are prohibited from Screening 
through the duration of the DB Phase. Procedures requiring conscious sedation and ambulatory 
procedures performed under local anesthesia may be scheduled under the following guidelines: 
• Procedures requiring conscious sedation (eg, colonoscopy) no later than 7 days prior to 
the start of the first dose of each treatment period and no earlier than 7 days after the last 
dose of each treatment period from screening throughout the duration of the study. 
• Elective ambulatory procedures performed under local anesthesia are allowed at any time 
during the study. 
Subjects must not participate in night shift work during any treatment period. 
Subjects receiving psychotherapy (except CBT-I) on a regular schedule for at least 60 days prior 
to Day 1 are permitted if the subject intends to continue the therapy for the duration of the DB 
Phase.  
Female subjects who are lactating or actively breastfeeding must stop giving breast milk to the 
baby(ies) from just prior to receiving study drug until 7 days after the last dose of study drug in 
each treatment period. 
Male subjects are prohibited from sperm donation for the duration of the study and for 5 days 
after receiving the last dose of the study drug. 
9.3. 
Treatment Adherence 
Study drug (SAGE-217 or placebo) will be self-administered by subjects once daily in the 
evening with food. Sites will dispense study drug to the subjects to take at home with 
instructions for use (see Section 10.5).  
Administration of study drug will be monitored by a medication adherence monitoring platform 
used on smartphones to visually confirm medication ingestion. Subjects will receive a reminder 


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within a predefined time window to take study drug while using the application. Subjects 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 study drug 
administration, as well as missed doses. 
In addition, the subject will be instructed to bring their dosing kit to the site as outlined in 
Table 3, at which time the Investigator or designee will be responsible for ensuring the kit 
contains sufficient doses for the duration of the treatment period, including ensuring the subject 
has taken the expected number of doses.  
All subjects should be reinstructed about the dosing requirements during study contacts. The 
authorized study personnel conducting the re-education must document the process in the subject 
source records. 
The Investigator(s) will record any reasons for non-adherence in the source documents. 
9.4. 
Randomization and Blinding 
This study contains an open-label phase followed by a randomized double-blind, placebo-
controlled phase. Subjects who complete the OL Phase with no significant tolerability issues as 
judged by the Investigator and who meet HAM-D response criteria (Section 7.1) will be 
randomized in a 1:1 ratio to receive SAGE-217 30 mg or matched placebo. Subjects, clinicians, 
and the study team will be blinded to treatment allocation. Randomization will be performed 
centrally via an interactive response technology (IRT) system.  
Randomization schedules will be generated by an independent statistician. The allocation to 
treatment group 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 randomization schedule will be provided to an independent chemist in order to select 
appropriate 
 (active treatment only). 
An independent third party will be unblinded to conduct an interim analysis to re-estimate the 
sample size with specific directions on how to conclude depending on the range of hazard ratio 
observed (Section 13.8). The decision will be communicated to Sage personnel only in terms of 
“no change in sample size necessary” or “increase the sample size to XXX”; hence Sage 
personnel will remain blinded. Further details will be provided in the Statistical Analysis Plan 
(SAP). 
In exceptional circumstances and for the safety of the study subject, the Investigator may request 
unblinding of an individual subject’s treatment in the study via the IRT.  
9.4.1. 
Emergency Unblinding 
During the DB Phase, the blind is to be broken by the Investigator only when the safety of a 
subject is at risk and the treatment plan is dependent on the study drug received. Unless a subject 
is at immediate risk, the Investigator must make diligent attempts to contact Sage prior to 
unblinding the study drug administered to a subject. Any request from the Investigator about the 
treatment administered to study subjects must be discussed with Sage. If the unblinding occurs 
without Sage’s knowledge, the Investigator must notify Sage as soon as possible and no later 
than the next business morning. All circumstances surrounding a premature unblinding must be 


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clearly documented in the source records. Unless a subject is at immediate risk, any request for 
the unblinding of individual subjects must be made in writing to Sage and approved by the 
appropriate Sage personnel, according to standard operating procedures.  
In all cases where the study drug allocation for a subject is unblinded, pertinent information 
(including the reason for unblinding) must be documented in the subject’s records and on the 
eCRF. If the subject or study center personnel have been unblinded, the subject will be 
permanently discontinued from the study. 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Description of Study Drugs 
SAGE-217 is available as hard gelatin capsules containing a white to off-white powder. In 
addition to SAGE-217 Drug Substance, active SAGE-217 capsules contain croscarmellose 
sodium, mannitol, silicified microcrystalline cellulose (SMCC), colloidal silicon dioxide, and 
sodium stearyl fumarate as excipients. Colloidal silicon dioxide may be either a component of 
the SMCC or a standalone excipient in the formulation. Capsules will be available in 20-mg and 
30-mg dose strengths.  
Matching placebo capsules are hard gelatin capsules containing only the excipients listed for the 
active capsule.  
10.2. 
Study Drug Packaging and Labeling 
SAGE-217 capsules and matched placebo capsules will be provided to the clinic pharmacist 
and/or designated site staff responsible for dispensing the study drug in appropriately labeled, 
subject-specific kits containing sealed unit doses. Each unit dose consists of 1 capsule. Additional 
information regarding the packaging and labeling is provided in the Pharmacy Manual.  
Study drug labels with all required information and conforming to all applicable FDA Code of 
Federal Regulations and Good Manufacturing Practice/Good Clinical Practice guidelines will be 
prepared by Sage Therapeutics. 
10.3. 
Study Drug Storage 
SAGE-217 and matching placebo capsules are to be stored at room temperature (59°F to 86°F; 
15°C to 30°C), safely and separately from other drugs. 
10.4. 
Study Drug Preparation 
Not applicable. 
10.5. 
Study Drug Administration 
SAGE-217 and matched placebo is to be administered orally once daily in the evening with food. 
Practical options include taking study drug within 1 hour of dinner or taking study drug later in 
the evening with solid food. If a subject misses a dose, the subject should skip that dose (ie, they 
should not take the dose in the morning) and take the next scheduled dose in the evening the next 
day. 
10.6. 
Study Drug Accountability 
Upon receipt of study drug, the Investigator(s), or the responsible pharmacist or designee, will 
inspect the study drug and complete and follow the instructions regarding receipt in the 
Pharmacy Manual. A copy of the shipping documentation will be kept in the study files. 
The designated site staff will dispense the supplied subject-specific kits to subjects at the planned 
dispensation visit intervals outlined in Table 3. 


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Site staff will access the IRT at the Screening Visit to obtain a subject identification (ID) number 
for each subject. On Day 1, site staff will access the IRT and provide the necessary subject-
identifying information, including the subject ID number assigned at Screening, to enroll the 
eligible subject into the initial OL treatment period and obtain the medication ID number for the 
study drug to be dispensed to that subject. The medication ID number and the number of 
capsules dispensed must be recorded. 
If eligible, subjects will be randomized at the appropriate visit via the IRT. For this and 
subsequent study drug-dispensing visits for any other treatment periods, the investigator or 
designee will access the IRT, providing the same subject ID number assigned at Screening, to 
obtain the medication ID number for the study drug to be dispensed at that visit. The medication 
ID number, the number of capsules dispensed, and the number of capsules returned by the 
subject at any visit must be recorded. 
If dispensing errors or discrepancies are discovered by site staff or sponsor’s designee, the 
Sponsor must be notified immediately. Additional instructions regarding accountability can be 
found in the Pharmacy Manual.  
The study drug provided is for use only as directed in this protocol. After the study is completed, 
all unused study drug must be returned as directed or destroyed on site per the Sponsor’s 
instructions. The Investigator or designee must keep a record of all study drug received, 
dispensed and 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. 
10.7. 
Study Drug Handling and Disposal 
At the end of the study, all used and unused study drug will be reconciled and returned to Sage 
Therapeutics for destruction or destroyed locally; disposition of study drug will be documented. 
A copy of the inventory record and a record of any clinical supplies that have been received, 
dispensed or destroyed must be documented by the site as directed. This documentation must 
include at least the information below:  
• the number of dispensed units 
• the number of unused units 
• the number of units destroyed at the end of the study 
• the date, method, and location of destruction. 
10.8. 
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 listed in Table 1. 


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Where possible, personnel should segregate any product, materials, or packaging associated with 
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11. 
ASSESSMENT OF EFFICACY AND PHARMACOKINETICS 
All assessments will be conducted according to the schedule of assessments (Table 2, Table 3, 
and Table 4). Study assessments that involve subject interviews, including the HAM-D and 
SCID-5-CT, may be audiotaped for independent quality control purposes. All assessments must 
be conducted by raters that have been trained and certified to conduct assessments in this study. 
11.1. 
Efficacy Assessments 
11.1.1. 
Hamilton Rating Scale for Depression  
Every effort should be made for the same rater to perform all HAM-D assessments for an 
individual subject. An assessment timeframe of 7 days will be used at Screening, at Days 28 and 
42 of the OL Phase, at each Day 56/Day 1 during the DB period, and at any visit for assessment 
of relapse; ‘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 subjects who are already 
diagnosed as depressed (Williams 2013a; 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.  
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. 
Clinical Global Impression  
The CGI is a validated measure often utilized in clinical trials to allow clinicians to integrate 
several sources of information into a single rating of the subject’s condition. The CGI scale 
consists of 3 items. Only the first 2 items are being used in this study.  
The CGI-S uses a 7-point Likert scale to rate the severity of the subject’s illness at the time of 
assessment, relative to the clinician’s past experience with subjects who have the same diagnosis. 
Considering total clinical experience, a subject is assessed on severity of mental illness at the 
time of rating as 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately 
ill; 5=markedly ill; 6=severely ill; and 7= among the most extremely ill patients (Busner 2007a).  
The CGI-I employs a 7-point Likert scale to measure the overall improvement in the subject’s 
condition posttreatment. The Investigator will rate the subject’s total improvement whether or 
not it is due entirely to drug treatment. Response choices include: 0=not assessed, 1=very much 
improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 
6=much worse, and 7=very much worse (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 
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11.1.5. 
Patient Health Questionnaire 
The PHQ-9 is a subject-rated depressive symptom severity scale. To monitor severity over time 
for newly diagnosed subjects or subjects in current treatment for depression, subjects will 
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. 
Subjects will complete the PHQ-9 via web browser. 


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11.2.1. 
Blood Sample Collection 
 
 
 
 (eg, for unusual or severe AEs). 
Each sample will be marked with unique identifiers with at least the study number, subject 
number, and visit day. The date and actual time that the blood sample was taken will be recorded 
on the case report form. 
11.2.2. 
Sample Analysis 
 
 
 


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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
All assessments will be conducted according to the schedule of assessments (Table 2, Table 3, 
and Table 4). 
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, 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 10th revision of the 
International Statistical Classification of Diseases and Related Health Problems should be 
recorded. 
The MGH ATRQ will be used to determine whether the subject has treatment-resistant 
depression, defined as persistent depressive symptoms despite treatment during the current major 
depressive episode with adequate doses of antidepressants from two different classes for at least 
4 weeks of treatment. 
The severity of the depressive episode upon entry into the study will be evaluated using the 
HAM-D (Section 11.1.1) and the MADRS. The MADRS a 10-item diagnostic questionnaire. The 
MADRS total score will be calculated as the sum of the 10 individual item scores. 
12.1.2. 
Weight and Height 
Height (Screening only) and weight will be measured and documented. BMI will be calculated at 
Screening. 
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
and neurological examinations and mental 
status examinations will be conducted and documented. An abbreviated physical examination 
will include assessment of general appearance, cardiovascular, respiratory, gastrointestinal, and 
neurological systems. Whenever possible, the same individual is to perform all physical 
examinations for a given subject. 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.  
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12.1.6.1. Drugs of Abuse and Alcohol 
Urine toxicology tests will be performed for selected drugs of abuse (see Table 8). A breath test 
for alcohol will be performed. 
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12.1.6.2. Pregnancy Screen 
A serum pregnancy test will be conducted for all female subjects at Screening. For female 
subjects that are not surgically sterile and do not meet the protocol-defined criteria for being 
post-menopausal, urine pregnancy tests will be performed at scheduled timepoints. 


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12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
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 drug has been administered. 
A TEAE is defined as an adverse event with onset after the start of study drug, or any worsening 
of a pre-existing medical condition/adverse event with onset after start of study drug and 
throughout the study. The term study drug includes any Sage investigational product, a 
comparator, or a placebo administered in a clinical trial. 
 and changes from baseline in 
, and physical 
examinations are considered AEs if they result in discontinuation or interruption of study drug, 
require therapeutic medical intervention, meet protocol specific criteria (if applicable) and/or if 
the Investigator considers them to be CS. Any abnormality or change from baseline that meets 
the criteria for an SAE should be reported in an expedited manner. 
 and 
changes from baseline in
 and physical examinations 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 subject has signed the ICF and throughout the duration of the study, 
whether or not they are related to the study, must be reported to Sage Therapeutics. 
Subjects who discontinue the study 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 
subject’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 
A serious adverse event is any untoward medical occurrence that at any dose: 
x Results in death 
x Is immediately life-threatening 
x Requires in-patient hospitalization or prolongation of existing hospitalization 
x Results in persistent or significant disability or incapacity 
x Results in a congenital abnormality or birth defect 
An SAE may also be any other medically important event that, in the opinion of the Investigator 
may jeopardize the subject or may require medical intervention to prevent one of the outcomes 
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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 subject 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 subject completes their final 
study visit, will be followed by the Investigator until the event has resolved, stabilized, returned 
to baseline status, or until death or lost to follow up. 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the subject is hospitalized. The site must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was scheduled 
(or on a waiting list to be scheduled) prior to obtaining the subject’s consent to participate 
in the study 
• The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress, in the opinion of the 
Investigator, between the subject’s consent to participate in the study and at the time of 
the procedure or treatment. 
12.2.3. 
Relationship to Study Drug 
The Investigator must make the determination of relationship to the study drug for each adverse 
event (not related, related). The following definitions should be considered when evaluating the 
relationship of AEs and SAEs to the study drug. 
Not Related 
An AE will be considered “not related” to the use of the study drug if there is not a 
reasonable possibility that the event has been caused by the study drug. Factors 
pointing towards this assessment include but are not limited to: the lack of temporal 
relationship between administration of the study drug 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 study drug 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 subject and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. The AE term should be reported in standard medical terminology when 
possible. For each AE, the Investigator will evaluate and report the onset (date and time), 


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resolution (date and time), intensity, causality, action taken, outcome, and seriousness (if 
applicable), and whether or not it caused the subject to discontinue the study drug or withdraw 
early from the study. 
Intensity will be assessed according to the following scale: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities) 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.2.2 . An AE of severe intensity 
may not 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 
Therapeutics, 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 case report form 
and/or study file. 
Serious events 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 study drug. The contact information for reporting SAEs and/or pregnancies is 
located in the study reference manual.  
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 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. Institutional Review Boards 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 study drug, pregnancy 
information must be collected and recorded on the Pregnancy form and submitted to the sponsor 
within 24 hours of learning of the pregnancy. The Investigator will also attempt to collect 
pregnancy information on any participant’s partner who becomes pregnant while the participant 
is participating in study. After obtaining the necessary signed informed consent from the 


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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 a study drug 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 
An overdose is defined as more than 2 capsules of study drug given to a subject or taken by a 
subject in a 24-hour period. Overdoses are not considered AEs and should not be recorded as an 
AE on the eCRF; however, all overdoses must be recorded on an Overdose form and sent to Sage 
or designee within 24 hours of the site becoming aware of the overdose. An overdose must be 
reported to Sage or designee even if the overdose does not result in an AE. If an overdose results 
in an AE, the AE must be recorded. 


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13. 
STATISTICS 
A separate statistical analysis plan (SAP) will provide a detailed description of the analyses to be 
performed in the study. The SAP will be finalized and approved prior to treatment unblinding. 
13.1. 
Data Analysis Sets 
The Enrolled Set is defined as all subjects who receive a dose of study drug in the OL phase. 
The Randomized Set is defined as all subjects who are randomized in the DB phase. 
The Safety Set is defined as all subjects administered study drug.  
The Full Analysis Set is defined as all randomized subjects in the Safety Set with a valid baseline 
and at least 1 post-baseline HAM-D total score.  
 
13.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data. All subjects will be used in the analyses, as 
per the analysis populations, using all non-missing data available.  
13.3. 
General Considerations 
Continuous endpoints will be summarized descriptively with n, mean, standard deviation, 
median, minimum, and maximum. For categorical endpoints, descriptive summaries will include 
counts and percentages. 
13.4. 
Demographics and Baseline Characteristics 
Demographic data (Section 12.1.1) and baseline characteristics, such as height, weight, and BMI, 
will be summarized using the Safety Set.  
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/family history will be listed by subject.  
13.5. 
Efficacy Analyses 
13.5.1. 
Primary Efficacy Analysis 
The estimand is the time to relapse – number of days between the first dose in the first treatment 
period of the DB phase to the day of relapse. The analysis will use the Full Analysis Set. Kaplan-
Meier survival curves will be provided, along with the median time to relapse. Log-rank test will 
be used to compare the survival curves at the significance level of 0.05. 
13.5.2. 
Secondary and 
 
Using FAS, the change from baseline will be summarized by randomized treatment group and 
each scheduled time point where the evaluation has been made. Baseline is defined as the last 
measurement prior to dosing in the DB Phase. A mixed effects model for repeated measures 
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(MMRM) will be used for analysis; the model will include treatment, baseline value, 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 for the specific study period will be 
included in the model. Model-EDVHGSRLQWHVWLPDWHVLHOHDVWVTXDUHV>/6@PHDQV
confidence intervals, and p-values) will be reported where applicable. An unstructured 
covariance structure will be used to model the within-subject errors. If there is a convergence 
issue with the unstructured covariance model, Toeplitz compound symmetry or Autoregressive 
(1) [AR(1)] covariance structure will be used, following this sequence until convergence is 
achieved. If the model still does not converge with AR(1) structure, no results will be reported. 
When the covariance structure is not UN, the sandwich estimator for the variance covariance 
matrix will be derived, using the EMPIRICAL option in the PROC MIXED statement in SAS.  
For analysis of binary endpoints, the estimand is the odds ratio. The Generalized estimating 
equation (GEE) methods will be used for the analysis. GEE models will include terms for 
treatment, baseline value, assessment time point, and time point-by-treatment as explanatory 
variables. Model-EDVHGSRLQWHVWLPDWHVLHRGGVUDWLRVFRQILGHQFHLQWHUYDOVDQGS-values 
will be reported.   
Time to relapse for remitters at the end of OL phase will be analyzed the same way as done for 
primary efficacy analysis. 
Endpoints for the OL phase will be summarized by each scheduled timepoint, based on Enrolled 
Set. 
Analysis of exploratory endpoints will be detailed in the SAP. 
13.6. 
Safety Analyses 
Safety and tolerability of SAGE-217 will be evaluated by incidence of adverse events/serious 
adverse events, and 
 
 Safety Set will be used 
for safety analyses. 
Safety and tolerability will be summarized for the OL phase using the Enrolled Set. 
13.6.1. 
Adverse Events 
The analysis of adverse events will be based on the concept of TEAEs. The incidence of TEAEs 
will be summarized overall and by Medical Dictionary for Regulatory Activities Version 21.0 or 
higher, System Organ Class, and preferred term. Incidences will be presented in order of 
decreasing frequency. In addition, summaries will be provided by intensity (mild, moderate, 
severe) and by causality (related, not related) to study drug.  
Any TEAEs leading to discontinuation and SAEs with onset after the start of study drug will also 
be summarized.  
All AEs and SAEs (including those with onset or worsening before the start of study drug) 
through the end of the study will be listed).  
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13.6.3. 
Physical Examinations 
The occurrence of a physical examination (Y/N) and the date performed will be listed by subject.  
 
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 signing the ICF through the duration of the study 
will be recorded. In addition, all psychotropic medications taken 6 months prior to Screening and 
all GABAergic medications taken 12 months prior to Screening will be recorded. Those 
medications taken prior to the initiation of the start of study drug will be denoted “Prior”. Those 
medications taken prior to the initiation of the study drug and continuing beyond the initiation of 
the study drug or those medications started at the same time or after the initiation of the study 
drug will be denoted “Concomitant” (ie, those with a start date on or after the first dose of study 
drug, or those with a start date before the first dose of study drug that are ongoing or with a stop 
date on or after the first dose of study drug).  
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 subject, start date, and verbatim 
term.  
PPD
PPD


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13.8. 
Determination of Sample Size 
The randomization in the DB phase is 1:1, with 150 subjects randomized in each treatment arm – 
placebo and SAGE-217. Assuming a relapse rate of 34% in the placebo arm (Borges 2014) and 
17% in the SAGE-217 arm for a fixed 40-week repeated treatment regimen (Hazard ratio = 
0.448), this sample size will provide a 90% power with 0.05 level of significance in comparing 
time to relapse (through comparison of survival curves) by Log-Rank test. Further, assuming that 
only 55% of the subjects dosed in the OL phase will qualify as responders to be randomized in 
the DB phase, 546 subjects will need to be dosed in the OL phase.  
An interim analysis is planned when about 50% of expected relapse events occur (ie, 34 of 
67 expected relapse events) to estimate the hazard ratio with a view to re-estimate the sample 
size. This unblinded interim analysis will be performed by an independent third party, external to 
the Sponsor, with specific directions on how to conclude depending on the range of hazard ratio 
observed. The final analysis will be performed after the last randomized subject completes (or 
ET) the study. The methods to control the type I error rate will be provided in the SAP. 


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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Before an investigational site can enter a subject 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 investigational product 
accountability checks are being performed 
• Perform source data verification. This includes a comparison of the data in the case report 
forms with the subject’s medical records at the hospital or practice, and other records 
relevant to the study. This will require direct access to all original records for each 
subject (eg, clinic charts). 
• Record and report any protocol deviations not previously sent to Sage Therapeutics. 
• 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 EC. 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
14.2. 
Audits and Inspections 
Authorized representatives of Sage Therapeutics, a regulatory authority, an Independent Ethics 
Committee or an Institutional Review Board may visit the site to perform audits or inspections, 
including source data verification. The purpose of a Sage Therapeutics audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, Good Clinical Practice guidelines of the 
International Conference on Harmonization, and any applicable regulatory requirements. The 
investigator should contact Sage Therapeutics immediately if contacted by a regulatory agency 
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14.3. 
Institutional Review Board or Ethics Committee  
The Principal Investigator must obtain IRB (or EC) approval for the investigation. Initial IRB (or 
EC) approval, and all materials approved by the IRB (or EC) for this study including the subject 
consent form and recruitment materials must be maintained by the Investigator and made 
available for inspection. 
 


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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. Please see Section 14.2 for more 
details regarding the audit process. 
 


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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or EC as appropriate. The investigator must submit 
written approval to Sage Therapeutics before he or she can enroll any subject into the study. 
The Principal Investigator is responsible for informing the IRB or EC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or EC must approve all 
advertising used to recruit subjects for the study. The protocol must be re-approved by the IRB 
or EC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB or EC 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 EC according to local regulations and guidelines. 
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Council for Technical 
Requirements for Pharmaceuticals for Human Use (ICH)/Good Clinical Practice, applicable 
regulatory requirements. 
16.3. 
Written Informed Consent 
The Principal Investigator(s) at each center will ensure that the subject is given full and adequate 
oral and written information about the nature, purpose, possible risk and benefit of the study. 
Subjects must also be notified that they are free to discontinue from the study at any time. The 
subject should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
The subject’s signed and dated informed consent must be obtained before conducting any study 
procedures. 
The Principal Investigator(s) must maintain the original, signed Informed Consent Form. A copy 
of the signed Informed Consent Form must be given to the subject. 
 


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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Inspection of Records 
Sage Therapeutics and its representative will be allowed to conduct site visits to the investigation 
facilities for the purpose of monitoring any aspect of the study. The Investigator agrees to allow 
the monitor to inspect the drug storage area, study drug stocks, drug accountability records, 
subject charts and study source documents, and other records relative to study conduct. 
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, whichever is longer. If not approved, documentation must be maintained for 2 years 
following the discontinuance of the test article for investigation. If it becomes necessary for Sage 
Therapeutics or the Regulatory Authority to review any documentation relating to the study, the 
Investigator must permit access to such records. 
 


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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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SAP_001.pdf: