Conditions: Major Depressive Disorder
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 581
Healthy volunteers: no

Brief summary:
This study is a phase 3, multicenter, double-blind, randomized, placebo-controlled study evaluating the efficacy of SAGE-217 in the treatment of adult participants 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 matched placebo capsules, orally, once daily in the evening with food for 14 days. arm 2: Participants self-administered SAGE-217 20 milligrams (mg) capsules, orally, once daily in the evening with food for 14 days. arm 3: Participants self-administered SAGE-217 30 mg capsules, orally, once daily in the evening with food for 14 days.

Interventions: intervention 1: SAGE-217 intervention 2: Placebo
Intervention descriptions: intervention 1: SAGE-217 hard gelatin capsules. intervention 2: SAGE-217 matched placebo hard gelatin capsules.

Protocol document:
Prot_000.pdf: 
Official Title: 
A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study 
Evaluating the Efficacy of SAGE-217 in the Treatment of Adult Subjects With 
Major Depressive Disorder
NCT Number: 
NCT03672175
Document Dates:
Protocol Version 5.0: 25 March 2019
Protocol Version 4.0: 07 March 2019 
Protocol Version 3.0: 11 October 2018 
Protocol Version 2.0: 25 September 2018 
Protocol Version 1.0: 16 July 2018


Clinical Study Report 
 
217-MDD-301 Part A 
16.1 Study Information 
 
1 
 
 
  
 
1. 
PROTOCOL AND AMENDMENTS 
The original protocol (Version 1) was amended 4 times during the conduct of Part A.  Links to 
each version of the protocol are provided below. 
Protocol Versions  
Version 1, 16 July 2018 
Amendment 1, Version 2, 25 September 2018 
• 
Summary of Changes from Amendment 1 
Amendment 2, Version 3, 11 October 2018 
• 
Summary of Changes from Amendment 2 
Amendment 3, Version 4, 07 March 2019 
• 
Summary of Changes from Amendment 3 
Amendment 4, Version 5, 25 March 2019 
• 
Summary of Changes from Amendment 4 
 
Administrative Letters 
Administrative Letter #1, 08 November 2018 
Administrative Letter #2, 15 August 2019 
Administrative Letter #3, 29 August 2019 
 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-MDD-301 v1.0 
 
CONFIDENTIAL 
 
 
1 
 
1. 
TITLE PAGE 
 
 
STUDY TITLE: A PHASE 3, MULTICENTER, DOUBLE-
BLIND, RANDOMIZED, PLACEBO-CONTROLLED 
STUDY EVALUATING THE EFFICACY OF SAGE-217 
IN THE TREATMENT OF ADULT SUBJECTS WITH 
MAJOR DEPRESSIVE DISORDER 
 
PROTOCOL NUMBER: 217-MDD-301 
 
Study Drug 
SAGE-217 
Clinical Phase 
Phase 3 
Sponsor 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 
Sponsor Contact 
 
Tel: 
email:
Sponsor Medical Monitor 
 MD, MBA 
Tel:
email:
Date of Original Protocol 
Version 1.0, 16 JUL 2018 
 
 
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-301 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) 
 


Clinical Protocol 
 
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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Sage Therapeutics 
Name of Investigational Product: 
SAGE-217 Capsules 
Name of Active Ingredient: 
SAGE-217 
Title of Study: A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study 
Evaluating the Efficacy of SAGE-217 in the Treatment of Adult Subjects with Major Depressive 
Disorder 
Number of Sites and Study Location: Approximately 55 sites in the United States 
Phase of development: 3 
Planned Duration of Subject Participation: 
Up to 73 days (up to 28-day Screening Period, 14-day Treatment Period, and 28-day (±3 days) 
Follow-up Period) 
Objectives: 
Primary:  
• 
To evaluate the efficacy of SAGE-217 in the treatment of major depressive disorder 
(MDD) compared to placebo. 
Secondary: 
• 
To evaluate the effect of SAGE-217 on sleep.  
• 
To assess patient-reported outcome (PRO) measures as they relate to health-related 
quality of life. 
Safety: 
• 
To evaluate the safety and tolerability of SAGE 217. 
 
 
 
  
 
 
Endpoints: 
Primary: 
• 
The primary efficacy endpoint is the change from baseline in the 17-item Hamilton 
Rating Scale for Depression (HAM-D) total score at Day 15. 
Secondary: 
• 
Change from baseline in the 17-item HAM-D total score at other timepoints 
• 
HAM-D response at Day 15 and all other time points, defined as a ≥50% reduction in 
HAM-D score from baseline  
• 
HAM-D remission at Day 15 and all other time points, defined as HAM-D total score 
≤7  
• 
Clinical Global Impression - Improvement (CGI-I) response at Day 15 and all other 
time points, defined as “much improved” or “very much improved”  


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• 
Change from baseline in Clinical Global Impression - Severity (CGI-S) score at Day 15 
and all other time points 
• 
Change from baseline in Hamilton Anxiety Rating Scale (HAM-A) total score at Day 15 
and all other time points  
• 
Change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) 
total score at Day 15 and all other time points 
• 
Change from baseline in HAM-D subscale and individual item scores at all time points 
• 
Improvements in sleep at Day 15 and all other time points, as assessed by 
o Insomnia Severity Index (ISI) 
o Subjective sleep parameters collected with the Core Consensus Sleep Diary 
• 
PRO measures of health-related quality of life, as assessed by responses to the 36-item 
Short Form survey version 2 (SF-36v2) 
Safety Endpoints: 
• 
Incidence and severity of adverse events/serious adverse events  
• 
Changes from baseline in clinical laboratory measures, vital signs, and 
electrocardiograms (ECGs) 
• 
Suicidal ideation and behavior using the Columbia Suicide Severity Rating Scale 
(C-SSRS)  
 
 
  
 
  
 
 
 
 
 
 
Study Description:  
This is a randomized, double-blind, parallel-group, placebo-controlled study in subjects with 
MDD (HAM-D total score ≥22). Randomization will be stratified based on use of antidepressant 
treatment (current/stable or not treated/withdrawn ≥60 days) at baseline and carried out within 
each stratum in a 1:1:1 ratio to receive SAGE-217 20 mg, SAGE-217 30 mg, or matching 
placebo; subjects will be treated for 14 days beginning on Day 1.  
The study will consist of a Screening Period of up to 28 days, a 14-day Treatment Period, and a 
4-week Follow-up Period.  
The Screening Period begins with the signing of the informed consent form (ICF) at the 
Screening Visit; 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 
HAM-D and CGI-S.  
Antidepressants are permitted provided subjects are on a stable dose for at least 60 days prior to 
Day 1 and agree to continue on the stable dose through the follow-up period (Day 42). Initiation 
of new antidepressants or any other medications that may potentially have an impact on efficacy 


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or safety endpoints will not be allowed between screening and completion of the Day 42 
assessments.  
Eligible subjects will be stratified based on use of antidepressant treatment (current/stable or not 
treated/withdrawn ≥60 days) and randomized within each stratum to one of 3 treatment groups 
(SAGE-217 20 mg, SAGE-217 30 mg, or matching placebo) in a 1:1:1 ratio. Subjects will self-
administer a single dose of study drug once daily at bedtime with food, on an outpatient basis, 
for 14 days. Subjects will return to the study center during the treatment and follow-up periods 
as outlined in Table 1. 
Subjects who cannot tolerate study drug will be discontinued from study drug and will receive 
treatment as clinically indicated. 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. Follow-up visits should take place every 7 days after the last dose of treatment for 
a total of 4 follow-up visits. 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 both visits will be conducted. 
Number of Subjects (planned):  
Approximately 450 subjects will be randomized and dosed to obtain 399 evaluable subjects. 
Eligibility Criteria: 
Inclusion Criteria: 
1. Subject has signed an ICF prior to any study-specific procedures being performed. 
2. Subject is an ambulatory 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.  
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 a HAM-D total score of ≥22 at screening and Day 1 (prior to dosing).  
7. If subject presents for the study while currently receiving psychotropic medications that 
are used with the intent to treat depressive symptoms such as antidepressants, atypical 
antipsychotics, etc., the medications must have been taken at the same dose for at least 
60 days prior to Day 1.  
8. Subject is willing to delay start of other antidepressant or antianxiety medications and 
any new pharmacotherapy regimens, including as-needed benzodiazepine anxiolytics 
and sleep aids, until after study completion.  
9. Female subject agrees to use one of the following methods of contraception during 
participation in the study and for 30 days following the last dose of study drug, unless 
they are postmenopausal (defined as no menses for 12 months without an alternative 
medical cause and confirmed by follicle stimulating hormone [FSH] >40 mIU/mL) 
and/or surgically sterile (hysterectomy or bilateral oophorectomy): 


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• 
Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation 
• 
Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation  
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system 
• 
Bilateral tubal ligation/occlusion 
• 
Vasectomized partner 
• 
Sexual abstinence (no sexual intercourse) 
10. 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. 
Acceptable methods of effective contraception for males includes sexual abstinence, 
vasectomy, or a condom with spermicide used together with highly effective female 
contraception methods if the female partner is of child-bearing potential (see Inclusion 
Criteria #9 for acceptable contraception methods). 
11. 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. 
12. Subject agrees to refrain from drugs of abuse and alcohol for the duration of the study. 
Exclusion Criteria: 
1. Subject has attempted suicide associated with the current episode of MDD. 
2. Subject had onset of the current depressive episode during pregnancy or 4 weeks 
postpartum, or the subject has presented for screening during the 6-month postpartum 
period. 
3. 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.  
4. Subject has a history of treatment-resistant depression, defined as persistent depressive 
symptoms despite treatment with adequate doses of antidepressants (excluding 
antipsychotics) from two different classes for an adequate amount of time (ie, at least 4 
weeks of treatment). Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire (MGH ATRQ) will be used for this purpose. 
5. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds.  
6. Subject has a positive pregnancy test at screening or on Day 1 prior to the start of study 
drug administration.  
7. Subject has detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus 
(HCV) and positive HCV viral load, or human immunodeficiency virus (HIV) antibody 
at screening. 


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8. Subject has a clinically significant abnormal 12-lead ECG at the screening or baseline 
visits. NOTE: mean QT interval calculated using the Fridericia method (QTcF) of 
>450 msec in males or >470 msec in females will be the basis for exclusion from the 
study.  
9. Subject has active psychosis per Investigator assessment.  
10. Subject has a medical history of seizures.  
11. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder.  
12. 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. 
13. Subject has had exposure to another investigational medication or device within 30 days 
prior to screening.  
14. Subject has previously participated in a SAGE-217 or a SAGE-547 (brexanolone) 
clinical trial.  
15. Use of any known strong inhibitors of cytochrome P450 (CYP)3A4 within 28 days or 
five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, or Seville 
oranges, or products containing these within 14 days prior to the first dose of study 
drug.  
16. Use of any CYP inducer, such as such as rifampin, carbamazepine, ritonavir, 
enzalutamide, efavirenz, nevirapine, phenytoin, phenobarbital and St John’s Wort, 
within 28 days prior to the first dose of study drug. 
17. Subject has a positive drug and/or alcohol screen at screening or on Day 1 prior to 
dosing. 
18. Subject plans to undergo elective surgery during participation in the study. 
Study Drug, 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: 
Placebo will be provided as hard gelatin capsules for oral administration containing only the 
excipients listed above for the active capsule.  
Duration of Treatment: 14 days 
Statistical methods: 
A detailed description of the analyses to be performed in the study will be provided in the 
Statistical Analysis Plan (SAP). The SAP will be finalized and approved prior to database lock 
and treatment unblinding. Any deviations from or changes to the SAP following database lock 
will be described in detail in the Clinical Study Report. 


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General Considerations 
For the purpose of all safety and efficacy analyses where applicable, baseline is defined as the 
last measurement prior to the start of study drug administration.  
Continuous endpoints will be summarized descriptively with n, mean, standard deviation, 
median, minimum, and maximum. In addition, change from baseline values will be calculated at 
each time point and summarized descriptively. For categorical endpoints, descriptive summaries 
will include counts and percentages.  
Analysis Sets 
The Randomized Set, defined as all subjects who are randomized, will be used for all data 
listings, unless otherwise specified. 
The Safety Set, defined as all subjects administered study drug, will be used to provide 
descriptive summaries of safety data.  
The Efficacy Set, defined as all subjects in the Safety Set with at least 1 post-baseline HAM D 
evaluation, will be used for analysis of efficacy data.  
 
 
Determination of Sample Size 
Assuming a two-sided alpha level of 0.05, a sample size of 399 evaluable subjects would 
provide 90% power to detect a placebo-adjusted treatment difference of approximately 4 points 
in the primary endpoint, change from baseline in HAM-D total score at Day 15, assuming 
standard deviation (SD) of 10 points. Assuming a 11% dropout rate and a 1:1:1 randomization 
ratio within each stratum (antidepressant use at baseline, yes or no), approximately 450 total 
randomized subjects will be required to obtain 399 evaluable subjects. Evaluable subjects are 
defined as those randomized subjects who receive study drug and have valid baseline and at 
least 1 post-baseline HAM-D assessment. Additional subjects may be randomized if the dropout 
rate is greater than 11%. 
Analysis of Primary Endpoint 
The primary efficacy endpoint, the change from baseline to each assessment in HAM-D total 
score, will be analyzed using a mixed effects model for repeated measures (MMRM); the model 
will include treatment, baseline HAM-D total score, stratification factor, assessment time point, 
and time point-by-treatment as explanatory variables. All explanatory variables will be treated 
as fixed effects. All post-baseline time points will be included in the model. The main 
comparison will be between SAGE-217 and placebo at the 15-day time point. Model-based 
point estimates (ie, least squares [LS] means, 95% confidence intervals, and p-values) will be 
reported where applicable. An unstructured covariance structure will be used to model the 
within-subject errors. The Toeplitz or compound symmetry covariance structure will be used if 
there is a convergence issue with the unstructured covariance model.  
Analysis of Secondary Endpoints 
Similar to those methods described above for the primary endpoint, an MMRM will be used for 
the analysis of the change from baseline in other time points in HAM-D total score, MADRS 
total score, HAM-A total score, SF-36v2 score, sleep endpoints (eg, sleep latency (SL), total 
sleep time (TST), wake after sleep onset (WASO), ISI score and selected individual items and/or 
subscale scores.  
Generalized estimating equation (GEE) methods will be used for the analysis of HAM-D 
response (defined as ≥50% reduction from baseline in HAM-D total score) and HAM-D 
remission (defined as HAM-D total score of ≤7.0). GEE models will include terms for 
treatment, baseline score, stratification factor, assessment time point, and time point-by-


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treatment as explanatory variables. The comparison of interest will be the difference between 
SAGE-217 and matching placebo at the 15-day time point. Model-based point estimates (ie, 
odds ratios), 95% confidence intervals, and p-values will be reported.  
A GEE method will also be used for the analysis of CGI-I response including terms for 
treatment, baseline CGI-S score, stratification factor, assessment time point, and time point-by-
treatment as explanatory variables. 
 
 
Safety Analysis 
Safety and tolerability of study drug will be evaluated by incidence of adverse events/serious 
adverse events, concomitant medication usage, vital signs, clinical laboratory evaluations, and 
12-lead ECG. Suicidality will be monitored by the C-SSRS. 
 
 
 
 
 


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Table 1: 
Schedule of Events 
Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
Follow-up Period 
Visit Days 
D-28 to D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(±1d) 
and/or 
EOTa 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
or 
ET 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Duplicate Subject Checkb 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
 
Serum FSH testc 
X 
 
 
 
 
 
 
 
 
 
SCID-5-CT 
X 
 
 
 
 
 
 
 
 
 
MGH ATRQ 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical/Family History 
X 
 
 
 
 
 
 
 
 
 
Subject trainingd 
X 
X 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Physical Examinatione 
X 
X 
 
 
 
 
 
 
 
X 
Body Weight/Height 
X 
 
 
 
 
X (wt 
only) 
 
 
 
X (wt 
only) 
Clinical Laboratory 
Assessmentsf 
X 
X 
 
X 
 
X 
X 
X 
 
X 
Drug & Alcohol Screeng 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Testh 
X 
X 
 
 
 
X 
 
X 
 
X 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
Vital Signsk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGl 
X 
X 
 
 
 
X 
 
 
 
X 
C-SSRSm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAM-Dn, o 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MADRS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAM-Ao 
 
X 
 
X 
 
X 
 
X 
 
X 
CGI-S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
X 
X 
X 
X 
X 


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Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
Follow-up Period 
Visit Days 
D-28 to D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(±1d) 
and/or 
EOTa 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
or 
ET 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
SF-36v2 
X 
X 
 
X 
 
X 
 
X 
 
X 
ISI 
 
X 
 
X 
 
X 
X 
X 
 
X 
Sleep diaryp 
X 
X 
 
 
Study Drug Dispensation 
 
X 
 
X 
 
 
 
 
 
 
Study Drug Administration 
 
X (Day 1 through Day 14) 
 
 
 
 
Study Drug 
Accountability/Return 
 
 
 
X 
 
X 
 
 
 
Xr 
Adverse Events/SAEss 
X 
Prior/Concomitant 
Medications/Procedurest 
X 
CGI-I = Clinical Global Impression – Improvement; CGI-S – Clinical Global Impression – Severity; 
 
 C-SSRS = Columbia Suicide Severity Rating Scale; D = day; EOT = end of 
treatment; ET = early termination; ECG = electrocardiogram; 
; FSH = follicle 
stimulating hormone; HAM-A = Hamilton Anxiety Rating Scale; HAM-D = Hamilton Rating Scale for Depression, 17-item; 
HIV = human immunodeficiency virus; ISI = Insomnia Severity Index; MADRS = Montgomery-Åsberg Depression Rating 
Scale; MGH ATRQ = Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; O = Optional; 
 SCID-5-CT = Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition Clinical Trials Version; SF-36v2 = 36-item Short Form survey version 2; V = visit; wt = weight 
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. Follow-up visits should take place every 7 days after the last dose of 
treatment for a total of 4 follow-up visits. 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 both visits will be 
conducted.  
b Subjects will be asked to authorize that their unique subject identifiers be entered into a registry (www.subjectregistry.com) 
with the intent of identifying subjects who may meet exclusion criteria for participation in another clinical study. 
c A serum follicle stimulating hormone test will be conducted at Screening for female subjects that are not surgically sterile to 
confirm whether a female subject with ≥12 months of spontaneous amenorrhea meets the protocol-defined criteria for being 
post-menopausal. 
d Subjects will be trained on use of software applications and devices necessary for the conduct of the study by site personnel. 
e A full physical examination will be conducted at Screening and abbreviated physical examinations will be conducted thereafter. 
A full physical examination includes assessment of body systems (eg, head, eye, ear, nose, and throat; heart; lungs; abdomen; 
and extremities). 
f Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. 
g Urine toxicology for selected drugs of abuse (as per the lab manual) and breath test for alcohol. 
h Serum pregnancy test at screening and urine pregnancy test thereafter for female subjects that are not surgically sterile and do 
not meet the protocol-defined criteria for being post-menopausal. 
 
 
 
 


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k Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing). Heart rate and 
blood pressure to be collected in supine position at all scheduled time points after the subject has been resting for 5 minutes and 
then after 1 minute in the standing position. Vital signs may be repeated at the discretion of the Investigator as clinically 
indicated. 
l Triplicate ECGs will be collected. 
 
 
m The “Baseline/Screening” C-SSRS form will be completed at screening. The “Since Last Visit” C-SSRS form will be 
completed at any time of day at all subsequent time points. 
n The HAM-D is to be completed as early during the visit as possible. 
o The assessment timeframe for HAM-D and HAM-A scales will refer to the past 7 days (1 week) at Screening and “Since Last 
Visit” for all other visits. 
p Subjects are instructed to complete the Core Consensus Sleep Diary starting at least 7 days prior to Day 1 and then daily 
through Day 28. 
 
 
 
 
r To be performed at the ET visit only. 
s Adverse events will be collected starting at the time of informed consent and throughout the duration of the subject’s 
participation in the study. 
t Prior medications will be collected at Screening and concomitant medications and/or procedures will be collected at each 
subsequent visit. 
 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............14 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................19 
5. 
INTRODUCTION ......................................................................................................21 
5.1. 
Background of Major Depressive Disorder and Unmet Medical Need ......................21 
5.2. 
SAGE-217 ...................................................................................................................21 
5.3. 
Potential Risks and Benefits .......................................................................................22 
5.4. 
Dose Justification ........................................................................................................22 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................23 
6.1. 
Study Objective ..........................................................................................................23 
6.1.1. 
Primary Objective .......................................................................................................23 
6.1.2. 
Secondary Objective(s) ...............................................................................................23 
6.1.3. 
Safety Objective ..........................................................................................................23 
 
23 
6.2. 
Endpoints ....................................................................................................................23 
6.2.1. 
Primary Endpoint ........................................................................................................23 
6.2.2. 
Secondary Endpoint(s) ................................................................................................23 
6.2.3. 
Safety Endpoint(s) ......................................................................................................24 
 
24 
7. 
INVESTIGATIONAL PLAN .....................................................................................25 
7.1. 
Overall Study Design ..................................................................................................25 
7.2. 
Number of Subjects ....................................................................................................25 
7.3. 
Treatment Assignment ................................................................................................25 
7.4. 
Dose Adjustment Criteria ...........................................................................................26 
7.5. 
Criteria for Study Termination ...................................................................................26 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................27 
8.1. 
Subject Inclusion Criteria ...........................................................................................27 
8.2. 
Subject Exclusion Criteria ..........................................................................................28 
8.3. 
Subject Withdrawal Criteria .......................................................................................29 


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8.3.1. 
Replacement of Subjects .............................................................................................30 
9. 
TREATMENT OF SUBJECTS ..................................................................................31 
9.1. 
Study Drug ..................................................................................................................31 
9.2. 
Prior Medications, Concomitant Medications, and Restrictions ................................31 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................31 
9.2.2. 
Prohibited Medications ...............................................................................................31 
9.2.3. 
Other Restrictions .......................................................................................................31 
9.3. 
Treatment Adherence ..................................................................................................32 
9.4. 
Randomization and Blinding ......................................................................................32 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................33 
10.1. 
Description of Study Drug ..........................................................................................33 
10.2. 
Study Drug Packaging and Labeling ..........................................................................33 
10.3. 
Study Drug Storage .....................................................................................................33 
10.4. 
Study Drug Preparation ..............................................................................................33 
10.5. 
Study Drug Administration.........................................................................................33 
10.6. 
Study Drug Accountability .........................................................................................33 
10.7. 
Study Drug Handling and Disposal ............................................................................34 
11. 
ASSESSMENT OF EFFICACY 
 .............................35 
11.1. 
Efficacy Assessments .................................................................................................35 
11.1.1. 
Hamilton Rating Scale for Depression (HAM-D) ......................................................35 
11.1.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) ........................................35 
11.1.3. 
Hamilton Anxiety Rating Scale (HAM-A) .................................................................35 
11.1.4. 
Clinical Global Impression (CGI) ..............................................................................36 
11.1.5. 
Short Form-36 Version 2 (SF-36v2) ...........................................................................36 
11.1.6. 
Insomnia Severity Index (ISI) ....................................................................................36 
11.1.7. 
Core Consensus Sleep Diary ......................................................................................37 
 
37 
 
37 
 
37 
 
37 
 
38 
12. 
ASSESSMENT OF SAFETY .....................................................................................39 


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12.1. 
Safety Parameters .......................................................................................................39 
12.1.1. 
Demographic/Medical History ...................................................................................39 
12.1.2. 
Weight and Height ......................................................................................................39 
12.1.3. 
Physical Examination .................................................................................................39 
12.1.4. 
Vital Signs ..................................................................................................................39 
12.1.5. 
Electrocardiogram (ECG) ...........................................................................................40 
12.1.6. 
Laboratory Assessments .............................................................................................40 
12.1.6.1. 
Drugs of Abuse and Alcohol ......................................................................................42 
12.1.6.2. 
Pregnancy Screen ........................................................................................................42 
12.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................42 
12.2. 
Adverse and Serious Adverse Events .........................................................................42 
12.2.1. 
Definition of Adverse Events .....................................................................................42 
12.2.1.1. 
Adverse Event (AE) ....................................................................................................42 
12.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................43 
12.3. 
Relationship to Study Drug ........................................................................................43 
12.4. 
Recording Adverse Events .........................................................................................44 
12.5. 
Reporting Serious Adverse Events .............................................................................45 
12.6. 
Emergency Identification of Study Drug ....................................................................45 
13. 
STATISTICS ..............................................................................................................46 
13.1. 
Data Analysis Sets ......................................................................................................46 
13.2. 
Handling of Missing Data ...........................................................................................46 
13.3. 
General Considerations ...............................................................................................46 
13.4. 
Demographics and Baseline Characteristics ...............................................................46 
13.5. 
Efficacy Analyses .......................................................................................................47 
13.6. 
Safety Analyses ..........................................................................................................47 
13.6.1. 
Adverse Events ...........................................................................................................47 
13.6.2. 
Clinical Laboratory Evaluations .................................................................................48 
13.6.3. 
Physical Examinations ................................................................................................48 
13.6.4. 
Vital Signs ..................................................................................................................48 
13.6.5. 
12-Lead Electrocardiogram ........................................................................................48 
13.6.6. 
Prior and Concomitant Medications ...........................................................................48 
13.6.7. 
Columbia Suicide Severity Rating Scale ....................................................................49 


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13.8. 
Determination of Sample Size ....................................................................................49 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................50 
14.1. 
Study Monitoring ........................................................................................................50 
14.2. 
Audits and Inspections ................................................................................................50 
14.3. 
Institutional Review Board (IRB) or Ethics Committee (EC) ....................................51 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................52 
16. 
ETHICS ......................................................................................................................53 
16.1. 
Ethics Review .............................................................................................................53 
16.2. 
Ethical Conduct of the Study ......................................................................................53 
16.3. 
Written Informed Consent ..........................................................................................53 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................54 
17.1. 
Inspection of Records .................................................................................................54 
17.2. 
Retention of Records ..................................................................................................54 
18. 
PUBLICATION POLICY ..........................................................................................55 
19. 
LIST OF REFERENCES ............................................................................................56 
 


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LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................11 
Table 2: 
Abbreviations and specialist terms .............................................................................19 
Table 3: 
Clinical Laboratory Tests ...........................................................................................40 
Table 4: 
Relationship to Study Drug ........................................................................................44 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and specialist terms 
Abbreviation or specialist term 
Explanation 
AE 
adverse event 
CGI-I 
Clinical Global Impression – Improvement 
CGI-S 
Clinical Global Impression – Severity 
CRF 
case report form 
CS 
clinically significant 
 
 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CYP 
cytochrome P450 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
end of treatment 
ET 
early termination 
 
 
FSH 
follicle stimulating hormone 
GABA 
γ-aminobutyric acid 
GEE 
generalized estimating equation 
HAM-A 
Hamilton Rating Scale for Anxiety 
HAM-D 
Hamilton Rating Scale for Depression 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ID 
identification  
IRB 
institutional review board 
IRT 
interactive response technology 
ISI 
Insomnia Severity Index 
MADRS 
Montgomery Åsberg Depression Rating Scale 


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Abbreviation or specialist term 
Explanation 
MDD 
major depressive disorder 
MGH ATRQ 
Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire 
MMRM 
mixed effects model for repeated measures 
NCS 
not clinically significant 
PCS 
Potentially clinically significant 
PK 
pharmacokinetic 
PRO 
patient-reported outcome 
QTcF 
QT corrected according to Fridericia’s formula 
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 
SF-36v2 
36-item Short Form version 2 
SUSAR 
suspected, unexpected, serious, adverse reactions 
TEAE 
treatment-emergent adverse event 
WHO 
World Health Organization 
 


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5. 
INTRODUCTION 
5.1. 
Background of Major Depressive Disorder and Unmet Medical Need 
The World Health Organization (WHO) has identified depression as the leading cause of 
disability worldwide, and as a major contributor to the overall global burden of disease 
(http://www.who.int/mediacentre/factsheets/fs369/en/). Globally, depression has been estimated 
to affect over 300 million people. 
In the United States, the economic burden of depression, including workplace costs, direct costs 
and suicide-related costs, was estimated to be $210.5 billion in 2010 (Greenberg 2015). As per 
WHO statistics, over 800,000 people die due to suicide every year, and suicide is the second 
leading cause of death in 15- to 29-year-olds. The rate of US adults making a suicide attempt has 
increased (0.62% from 2004 to 2005 to 0.79% from 2012 to 2013), with a shift to more attempts 
among younger adults (42% to 50%, respectively) and among those with a depressive disorder 
(26% to 54%, respectively; Olfson 2017). 
In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), 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 (SSRIs), 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 (CSF) 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, consistent with the actions of other GABAA receptor potentiators 
(Rudolph 2011), exhibits potent anticonvulsant, anxiolytic, and sedative activity 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 [HAM-A], 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 HAM-A. 
SAGE-217 has been generally well tolerated in clinical studies to date. The most common 
treatment-emergent adverse events (TEAEs) were sedation, somnolence, and dizziness. Most 
adverse events (AEs) were reported as mild or moderate in intensity. Among the over 260 
subjects exposed to SAGE-217 in clinical trials, there have been no deaths and only one subject 
with essential tremor experienced a serious adverse event (SAE) of transient confusion leading to 
discontinuation of study drug. No other SAEs have been reported in any study of SAGE-217.  
Additional information on nonclinical and clinical data is provided in the Investigator’s 
Brochure.  
5.3. 
Potential Risks and Benefits 
Nonserious events of sedation, somnolence, and dizziness were the most commonly reported 
AEs with SAGE-217. Given the outcome of the Phase 2a study of SAGE-217 in subjects with 
MDD, the current significant unmet need in the treatment of depression, and a favorable benefit-
risk profile, further investigation of SAGE-217 in patients with MDD is justified. 
5.4. 
Dose Justification 
There will be 2 dose levels of SAGE-217 in this study in order to study dose ranging: 30 mg per 
day and 20 mg per day. The higher dose level of 30 mg per day is the maximum tolerated dose in 
the multiple ascending dose study of SAGE-217 in healthy subjects and is also the dose level that 
was effective and generally well tolerated in a Phase 2 study in subjects with MDD (217-MDD-
201). The lower dose of 20 mg per day will be studied in subjects with MDD for the first time in 
the current study and is anticipated to be well tolerated as it is lower than the maximum tolerated 
dose level. Due to sedation/somnolence observed in previous clinical trials when administered in 
the morning, and improved tolerability when given in the evening, both doses of SAGE-217 will 
be administered at bedtime in this study. 


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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Study Objective 
6.1.1. 
Primary Objective 
The primary objective is to evaluate the efficacy of SAGE-217 in the treatment of MDD 
compared to placebo. 
6.1.2. 
Secondary Objective(s) 
Secondary objectives are: 
• To evaluate the effect of SAGE-217 on sleep  
• To assess patient-reported outcome (PRO) measures as they relate to health-related 
quality of life 
6.1.3. 
Safety Objective 
The safety objective is to evaluate the safety and tolerability of SAGE-217. 
 
 
 
 
 
 
 
 
6.2. 
Endpoints 
6.2.1. 
Primary Endpoint 
The primary endpoint of this study is the change from baseline in the 17-item HAM-D total score 
at Day 15. 
6.2.2. 
Secondary Endpoint(s) 
• Change from baseline in the 17-item HAM-D total score at other time points 
• HAM-D response at Day 15 and all other time points, defined as a ≥50% reduction in 
HAM-D score from baseline 
• HAM-D remission at Day 15 and all other time points, defined as HAM-D total 
score ≤7  
• CGI-I response at Day 15 and all other time points, defined as “much improved” or 
“very much improved” 
• Change from baseline in Clinical Global Impression - Severity (CGI-S) score at 
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• Change from baseline in HAM-A total score at Day 15 and all other time points  
• Change from baseline in the MADRS total score at Day 15 and all other time points 
• Change from baseline in HAM-D subscale and individual item scores at all time 
points 
• Improvements in sleep at Day 15 and all other time points, as assessed by: 
 Insomnia Severity Index (ISI) 
 Subjective sleep parameters collected with the Core Consensus Sleep Diary 
• Patient-reported outcome measures of health-related quality of life, as assessed by 
responses to the 36-item Short Form survey (SF-36) version 2 
6.2.3. 
Safety Endpoint(s) 
• Incidence and severity of adverse events/serious adverse events  
• Changes from baseline in clinical laboratory measures, vital signs, and 
electrocardiograms (ECGs) 
• Suicidal ideation and behavior using the Columbia Suicide Severity Rating Scale 
(C-SSRS)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7.
INVESTIGATIONAL PLAN
7.1. 
Overall Study Design
This is a randomized, double-blind, parallel-group, placebo-controlled study in subjects with 
MDD (HAM-D total score ≥22). The study will consist of a Screening Period of up to 28 days, a 
14-day Treatment Period, and a 4-week Follow-up Period.
The Screening Period begins with the signing of the informed consent form (ICF) at the 
Screening Visit; the ICF must be signed prior to beginning any screening activities. At the time 
of providing informed consent for the study, subjects will also be asked to authorize that their 
unique subject identifiers be entered into a registry (www.subjectregistry.com) with the intent of 
identifying subjects who may meet exclusion criteria due to participation in another clinical 
study (Section 8.2). 
The diagnosis of MDD must be made according to Structured Clinical Interview for Diagnostic 
and 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 HAM-D and CGI-S.  
Antidepressants are permitted provided subjects are on a stable dose for at least 60 days prior to 
Day 1 and agree to continue on the stable dose through the follow-up period (Day 42). Initiation 
of new antidepressants or any other medications that may potentially have an impact on efficacy 
or safety endpoints is prohibited between screening and completion of the Day 42 assessments.  
Eligible subjects will be stratified based on use of antidepressant treatment (current/stable or not 
treated/withdrawn ≥60 days) and randomized within each stratum to one of 3 treatment groups 
(SAGE-217 20 mg, SAGE-217 30 mg, or matching placebo) in a 1:1:1 ratio. Subjects will self-
administer a single dose of study drug with food once daily at bedtime on an outpatient basis, for 
14 days. Dose reductions are not permitted. Study drug administration will be monitored via a 
clinical monitoring service (see Section 9.3). 
Subjects will return to the study center during the treatment and follow-up periods as outlined in 
Table 1. 
7.2. 
Number of Subjects 
Approximately 450 subjects will be randomized and dosed to obtain 399 evaluable subjects (see 
Section 13.8). 
7.3. 
Treatment Assignment 
Subjects will be randomly assigned to a treatment group on Day 1. Randomization will be 
stratified based on use of antidepressant treatment (current/stable or not treated/withdrawn ≥60 
days) at baseline and performed within each stratum in a 1:1:1 ratio to receive SAGE-217 20 mg, 
SAGE-217 30 mg, or matching placebo. 


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7.4. 
Dose Adjustment Criteria 
Dose adjustments are not permitted in this study. Subjects who cannot tolerate study drug will be 
discontinued from study drug and will receive treatment as clinically indicated (see Section 8.3). 
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 
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 an ambulatory 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.  
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 a HAM-D total score of ≥22 at screening and Day 1 (prior to dosing).  
7. If subject presents for the study while currently receiving psychotropic medications that 
are used with the intent to treat depressive symptoms such as antidepressants, atypical 
antipsychotics, etc., the medications must have been taken at the same dose for at least 
60 days prior to Day 1.  
8. Subject is willing to delay start of other antidepressant or antianxiety medications and 
any new pharmacotherapy regimens, including as-needed benzodiazepine anxiolytics and 
sleep aids, until after study completion.  
9. Female subject agrees to use one of the following methods of contraception during 
participation in the study and for 30 days following the last dose of study drug, unless 
they are postmenopausal (defined as no menses for 12 months without an alternative 
medical cause and confirmed by follicle stimulating hormone [FSH] >40 mIU/mL) 
and/or surgically sterile (hysterectomy or bilateral oophorectomy): 
• 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. 
• Sexual abstinence (no sexual intercourse). 
10. 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. 
Acceptable methods of effective contraception for males includes sexual abstinence, 
vasectomy, or a condom with spermicide used together with highly effective female 
contraception methods if the female partner is of child-bearing potential (see Inclusion 
Criteria #9 for acceptable contraception methods). 


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11. 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. 
12. 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 had onset of the current depressive episode during pregnancy or 4 weeks 
postpartum, or the subject has presented for screening during the 6-month postpartum 
period. 
3. 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.  
4. Subject has a history of treatment-resistant depression, defined as persistent depressive 
symptoms despite treatment with adequate doses of antidepressants (excluding 
antipsychotics) from two different classes for an adequate amount of time (ie, at least 4 
weeks of treatment). Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire (MGH ATRQ) will be used for this purpose. 
5. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds.  
6. Subject has a positive pregnancy test at screening or on Day 1 prior to the start of study 
drug administration.  
7. Subject has detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) 
and positive HCV viral load, or human immunodeficiency virus (HIV) antibody at 
screening. 
8. Subject has a clinically significant abnormal 12-lead ECG at the screening or baseline 
visits. NOTE: mean QT interval calculated using the Fridericia method (QTcF) of 
>450 msec in males or >470 msec in females will be the basis for exclusion from the 
study.  
9. Subject has active psychosis per Investigator assessment.  
10. Subject has a medical history of seizures.  
11. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder.  
12. 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. 
13. Subject has had exposure to another investigational medication or device within 30 days 
prior to screening.  


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14. Subject has previously participated in a SAGE-217 or a SAGE-547 (brexanolone) clinical 
trial.  
15. Use of any known strong inhibitors of cytochrome P450 (CYP)3A4 within 28 days or 
five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, or Seville 
oranges, or products containing these within 14 days prior to the first dose of study drug.  
16. Use of any CYP inducer, such as such as rifampin, carbamazepine, ritonavir, 
enzalutamide, efavirenz, nevirapine, phenytoin, phenobarbital and St John’s Wort, within 
28 days prior to the first dose of study drug. 
17. Subject has a positive drug and/or alcohol screen at screening or on Day 1 prior to 
dosing. 
18. Subject plans to undergo elective surgery during participation in the study. 
8.3. 
Subject Withdrawal Criteria 
Subjects may withdraw from the study drug or terminate from the study at any time for any 
reason. 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 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.  
Subjects who discontinue study drug early should return to the site for an end of treatment (EOT) 
visit as soon as possible, preferably the day after treatment is discontinued. Follow-up visits 
should take place every 7 days after the last dose of treatment for 28 days. 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.  


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A subject will be deemed lost to follow-up after attempts at contacting the subject have been 
unsuccessful. 
8.3.1. 
Replacement of Subjects 
Subjects will not be replaced. Additional subjects may be randomized if the drop-out rate is 
higher than anticipated (Section 13.8). 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Study Drug 
Subjects will self-administer SAGE-217 (20 or 30 mg) or matching placebo orally once daily at 
bedtime with food for 14 days.  
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 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.  
Antidepressants, atypical antipsychotics, or sleep aids that have been taken at the same dose for 
at least 60 days prior to Day 1 are permitted if the subject intends to continue the stable dose 
through the follow-up period (Day 42). 
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 
The following specific classes of medications are prohibited at any time during the treatment 
period: 
• Initiation of new psychotropic medications  
• Exposure to another investigational medication or device 
• Any known strong inhibitors CYP3A4  
• Use of any CYP inducer, such as such as rifampin, carbamazepine, ritonavir, 
enzalutamide, efavirenz, nevirapine, phenytoin, phenobarbital 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 throughout the treatment period. 


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Consumption of alcohol or use of drugs of abuse is discouraged throughout the duration of the 
study. 
9.3. 
Treatment Adherence 
SAGE-217 or placebo will be self-administered by subjects once daily at bedtime with food. 
Sites will dispense study drug to the subjects to take at home with instructions for use (see 
Section 10.4 and Table 1).  
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 
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 by dose level, as well as missed doses. 
In addition, the subject will be instructed to bring their dosing kit to the site as outlined in 
Table 1, at which time the Investigator or designee will be responsible for ensuring the kit 
contains sufficient doses for the duration of the treatment period.  
All subjects should be reinstructed about the dosing requirement 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-compliance in the source documents. 
9.4. 
Randomization and Blinding 
This is a randomized double-blind, placebo-controlled study. Subjects who meet the entrance 
criteria will be randomized in a stratified manner based on use of antidepressant treatment 
(current/stable or not treated/withdrawn ≥60 days) at baseline; randomization will be done within 
each stratum in a 1:1:1 ratio to receive SAGE-217 20 mg, 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 (SAGE-217 20 mg, SAGE-217 30 mg, or placebo) will be based on the 
randomization schedule. The randomization schedules will be kept strictly confidential, 
accessible only to authorized personnel until the time of unblinding. 
In 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 (see Section 12.6 for 
more details related to unblinding).  


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Description of Study Drug 
SAGE-217 is available as hard gelatin capsules containing a white to off-white powder. In 
addition to the specified amount of SAGE-217 Drug Substance, active SAGE-217 Capsules 
contain croscarmellose sodium, mannitol, silicified microcrystalline cellulose (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 Practices/Good Clinical Practices guidelines will 
be prepared by the Sponsor. 
10.3. 
Study Drug Storage 
SAGE-217 and matched placebo 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 is to be administered orally once daily at bedtime with food. If a subject misses a 
dose at bedtime, the subject should skip that dose (ie, they should not take the dose in the 
morning) and take the next scheduled dose at bedtime 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 1.  


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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 randomize the 
eligible subject into the study 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. 
At the subsequent study drug-dispensing visit, 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 this visit must be 
recorded.  
If dispensing errors or discrepancies are discovered by site staff or sponsor’s designee, the 
Sponsor must be notified immediately. 
The 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. 


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11. 
ASSESSMENT OF EFFICACY 
 
All assessments will be conducted according to the schedule of assessments (Table 1). 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 (HAM-D) 
The primary outcome measure is the change from baseline in 17-item HAM-D total score at the 
end of the Treatment Period (Day 15). Every effort should be made for the same rater to perform 
all HAM-D assessments for an individual subject. An assessment timeframe of 7 days will be 
used at Screening and ‘Since Last Visit’ will be used for all other visits. 
The 17-item HAM-D will be used to rate the severity of depression in 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.  
In addition to the primary efficacy endpoint of change from baseline in HAM-D total score, 
several secondary efficacy endpoints will be derived for the HAM-D. Hamilton Rating Scale for 
Depression subscale scores will be calculated as the sum of the items comprising each subscale. 
Hamilton Rating Scale for Depression response will be defined as having a 50% or greater 
reduction from baseline in HAM-D total score. Hamilton Rating Scale for Depression remission 
will be defined as having a HAM-D total score of ≤7.  
11.1.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive 
episodes in subjects with mood disorders. It was designed as an adjunct to the HAM-D that 
would be more sensitive to the changes brought on by antidepressants and other forms of 
treatment than the Hamilton Scale.  
Higher MADRS scores indicate more severe depression, and each item yields a score of 0 to 6. 
The overall score ranges from 0 to 60 (Williams 2008). 
The MADRS total score will be calculated as the sum of the 10 individual item scores.  
11.1.3. 
Hamilton Anxiety Rating Scale (HAM-A) 
The 14-item HAM-A will be used to rate the severity of symptoms of anxiety (Williams 2013c; 
Williams 2013d). Each of the 14 items is defined by a series of symptoms, and measures both 
psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical 
complaints related to anxiety). Scoring for HAM-A is calculated by assigning scores of 0 (not 


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present) to 4 (very severe), with a total score range of 0 to 56, where <17 indicates mild severity, 
18 to 24, mild to moderate severity, and 25 to 30, moderate to severe severity. The HAM-A total 
score will be calculated as the sum of the 14 individual item scores. 
11.1.4. 
Clinical Global Impression (CGI) 
The CGI is a validated measure often utilized in clinical trials to allow clinicians to integrate 
several sources of information into a single rating of the subject’s condition. The CGI scale 
consists of 3 items. Only the first 2 items are being used in this study.  
The CGI-S uses a 7-point Likert scale to rate the severity of the subject’s illness at the time of 
assessment, relative to the clinician’s past experience with subjects who have the same diagnosis. 
Considering total clinical experience, a subject is assessed on severity of mental illness at the 
time of rating as 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately 
ill; 5=markedly ill; 6=severely ill; and 7=extremely ill (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 
“much improved.”  
11.1.5. 
Short Form-36 Version 2 (SF-36v2) 
The Medical Outcomes Study SF-36v2 is a 36-item measure of health status that has undergone 
validation in many different disease states (Ware 2007). The SF-36v2 covers eight health 
dimensions including four physical health status domains (physical functioning, role 
participation with physical health problems [role-physical], bodily pain, and general health) and 
four mental health status domains (vitality, social functioning, role participation with emotional 
health problems [role-emotional], and mental health). In addition, two summary scores, physical 
component summary and mental component summary, are produced by taking a weighted linear 
combination of the eight individual domains. The SF-36v2 is available with two recall periods: 
the standard recall period is 4 weeks and the acute recall period is 1 week. This study will use the 
acute version, which asks patients to respond to questions as they pertain to the past week. 
Higher SF-36v2 scores indicate a better state of health.  
11.1.6. 
Insomnia Severity Index (ISI) 
The ISI is a validated questionnaire designed to assess the nature, severity, and impact of 
insomnia (Morin 2011). The ISI uses a 5-point Likert Scale to measure various aspects of 
insomnia severity (0 = none, 1 = mild, 2 = moderate; 3 = severe; 4 = very severe), satisfaction 
with current sleep pattern (0 = very satisfied, 1 = satisfied, 2 = moderately satisfied, 3 = 
dissatisfied, 4 = very dissatisfied), and various aspects of the impact of insomnia on daily 
functioning (0 = not at all, 1 = a little, 2 = somewhat, 3 = much, 4 = very much). A total score of 
0 to 7 = “no clinically significant insomnia,” 8 to 14 = subthreshold insomnia,” 15 to 21 = 
“clinical insomnia (moderate severity),” and 22 to 28 = “clinical insomnia (severe).”  


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11.1.7. 
Core Consensus Sleep Diary 
The Core Consensus Sleep Diary collects subjective sleep parameters, including sleep onset 
latency, total sleep time, and wake after sleep onset, number of awakenings, and sleep quality. 
The take-home subject sleep diary assessment will be administered using an eDiary solution. The 
eDiary will be captured using either a provisioned smartphone device or bring-your-own-device 
(BYOD) solution, depending on the subject’s preference. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
All assessments will be conducted according to the schedule of assessments (Table 1). 
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 (ICD-10) should be recorded. 
The Massachusetts General Hospital Antidepressant Treatment Response Questionnaire 
(MGH ATRQ) will be used to determine whether the subject has a history of treatment-resistant 
depression, defined as persistent depressive symptoms despite treatment with adequate doses of 
antidepressants from two different classes for an adequate amount of time (ie, at least 4 weeks of 
treatment). 
12.1.2. 
Weight and Height 
Height (Screening only) and weight will be measured and documented. 
12.1.3. 
Physical Examination 
Physical examinations assessing body systems (eg, head, eyes, ears, nose, and throat; heart; 
lungs; abdomen; and extremities), as well as cognitive and neurological examinations and mental 
status examinations will be conducted and documented. 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. 
New or worsening abnormalities that are judged to be clinically significant will be recorded as 
AEs, assessed according to Section 12.2.1.1. 
12.1.4. 
Vital Signs 
Vital signs comprise both supine and standing for systolic and diastolic blood pressure and heart 
rate measurements. Heart rate and blood pressure are to be collected in supine position after the 
subject has been resting for 5 minutes and then after 1 minute in the standing position. 
Respiratory rate, pulse oximetry and temperature are collected once, in either position. Vital 
signs will be documented. When vital signs are scheduled at the same time as blood draws, vital 
signs will be obtained first. 
Any abnormality in vital signs will be interpreted by the Investigator as abnormal, NCS or 
abnormal, CS in source documents. New or worsening abnormalities that are judged to be 
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12.1.5. 
Electrocardiogram (ECG) 
Supine 12-lead ECGs will be performed in triplicate at all scheduled time points. The standard 
intervals (heart rate, PR, QRS, QT, and QTcF) as well as any rhythm abnormalities will be 
recorded. 
 
 
12.1.6. 
Laboratory Assessments 
Samples will be collected in accordance with acceptable laboratory procedures detailed in the 
laboratory manual.   
The clinical laboratory tests to be performed are listed in Table 3. 
Table 3: 
Clinical Laboratory Tests 
Hematology  
Serum Chemistry 
Urinalysis 
Coagulation 
Red blood cell count 
Hemoglobin  
Hematocrit  
White blood cell count with 
differential  
Reticulocytes 
Platelet count 
Red blood cell morphology 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
Total protein 
Creatinine 
Blood urea nitrogen 
Creatine kinase 
Gamma-glutamyl transferase 
Potassium 
Sodium 
Lactate dehydrogenase 
Glucose 
Chloride 
Bicarbonate 
Calcium 
Phosphorus 
Triglycerides 
Thyroid stimulating hormone 
pH 
Specific gravity 
Protein 
Glucose 
Red blood cell 
Nitrite 
Leukocyte 
esterase 
Ketones 
Bilirubin 
Urobilinogen 
Activated partial 
thromboplastin 
time 
Prothrombin time 
International 
normalized ratio 
Diagnostic  
 
 
 
Serum 
Urine 
Breathalyzer 
 
Hepatitis B 
Hepatitis C 
Reflex HCV RNA 
Drug screen including: 
amphetamines, 
barbiturates, 
benzodiazepines, 
Alcohol 
 


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HIV-1 and -2 
Female subjects that are not 
surgically sterile and do not 
meet the protocol-defined 
criteria for being post-
menopausal: serum hCG 
Female subjects, if 
menopause is suspected 
and not surgically sterile: 
FSH 
cannabinoids, cocaine, 
opiates, phencyclidine, and 
propoxyphene 
Female subjects that are not 
surgically sterile and do not 
meet the protocol-defined 
criteria for being post-
menopausal: urine hCG  
Abbreviations: FSH = follicle stimulating hormone; hCG = human chorionic gonadotropin; HCV = hepatitis C 
virus; HIV = human immunodeficiency virus 
The central laboratory will perform laboratory tests for hematology, serum chemistry, urinalysis, 
and coagulation. The results of laboratory tests will be returned to the Investigator, who is 
responsible for reviewing and filing these results. All laboratory safety data will be transferred 
electronically to Sage Therapeutics or designee in the format requested by Sage Therapeutics.  
Laboratory reports must be signed and dated by the Investigator or subinvestigator indicating 
that the report has been reviewed and any abnormalities have been assessed for clinical 
significance. Any abnormalities identified prior to first dose will require clear and complete 
documentation in the source documents as to the investigator’s assessment of not clinically 
significant before proceeding with randomization.  
All clinical laboratory test results outside the central laboratory’s reference range will be 
interpreted by the Investigator as abnormal, NCS; or abnormal, CS in source documents. New or 
worsening abnormalities that are judged to be clinically significant will be recorded as AEs, 
assessed according to Section 12.2.1.1. A clinically significant laboratory abnormality following 
subject randomization will be followed until the abnormality returns to an acceptable level or a 
satisfactory explanation has been obtained. 
A serum follicle stimulating hormone test will be conducted at Screening to confirm whether a 
female subject with ≥12 months of spontaneous amenorrhea meets the protocol-defined criteria 
for being post-menopausal (Section 8.1). 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 3). A breath test 
for alcohol will be performed. 
12.1.6.2. Pregnancy Screen 
For female subjects that are not surgically sterile and do not meet the protocol-defined criteria 
for being post-menopausal, a serum pregnancy test will be performed at Screening and a urine 
pregnancy test will be performed at all other scheduled timepoints thereafter, including the ET 
visit for subjects who prematurely discontinue. 
12.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011). This scale 
consists of a baseline evaluation that assesses the lifetime experience of the subject with suicidal 
ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last 
study visit. The C-SSRS includes ‘yes’ or ‘no’ responses for assessment of suicidal ideation and 
behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being 
the most severe).  
The “Baseline/Screening” C-SSRS form will be completed at screening (lifetime history and past 
24 months). The “Since Last Visit” C-SSRS form will be completed at all subsequent time 
points, as outlined in Table 1. 
12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Definition of Adverse Events 
12.2.1.1. Adverse Event (AE) 
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 treatment has been administered. 
A TEAE is an AE that occurs after the first administration of any study drug. The term study 
drug includes any Sage investigational product, a comparator, or a placebo administered in a 
clinical trial. 
Laboratory abnormalities and changes from baseline in vital signs, ECGs, and physical 
examinations are considered AEs if they result in discontinuation or interruption of study 
treatment, require therapeutic medical intervention, meet protocol specific criteria (if applicable) 
and/or if the Investigator considers them to be clinically significant. Laboratory values and vital 
signs that meet the criteria for an SAE should be reported in an expedited manner. Laboratory 
abnormalities and changes from baseline in vital signs, ECGs, and physical examinations that are 


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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. 
12.2.1.2. Serious Adverse Event (SAE) 
A serious adverse event is any untoward medical occurrence that at any dose: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
An SAE may also be any other medically important event that, in the opinion of the Investigator 
may jeopardize the subject or may require medical intervention to prevent one of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization). 
All SAEs that occur after any 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 form provided 
by Sage Therapeutics. Serious adverse events occurring after a subject’s final visit (including the 
last follow-up visit) should be reported to Sage or designee only if the Investigator considers the 
SAE to be related to study treatment.  
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.  
12.3. 
Relationship to Study Drug 
The Investigator must make the determination of relationship to the study drug for each adverse 
event (not related, possibly related or probably related). The Investigator should decide whether, 
in his or her medical judgment, there is a reasonable possibility that the event may have been 
caused by the investigational product. If no valid reason exists for suggesting a relationship, then 
the adverse event should be classified as “not related.” If there is any valid reason, even if 
undetermined, for suspecting a possible cause-and-effect relationship between the investigational 


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product and the occurrence of the adverse event, then the adverse event should be considered at 
least “possibly related.”  
Table 4: 
Relationship to Study Drug 
Relationship 
Definition 
Not Related: 
No relationship between the experience and the administration of study drug; related to 
other etiologies such as concomitant medications or subject’s clinical state. 
Possibly Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug.  
The reaction might have been produced by the subject’s clinical state or other modes of 
therapy administered to the subject, but this is not known for sure. 
Probably Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug.  
The reaction cannot be reasonably explained by the known characteristics of the subject’s 
clinical state or other modes of therapy administered to the subject. 
If the relationship between the adverse event/serious adverse event and the investigational 
product is determined to be “possible” or “probable”, the event will be considered related to the 
investigational product for the purposes of expedited regulatory reporting. 
12.4. 
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), 
resolution (date and time), intensity, causality, action taken, serious outcome (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 12.2.1.2. An AE of severe intensity 
may not be considered serious. 
Should a pregnancy occur, it must be reported and recorded on the Sage Therapeutics pregnancy 
notification form. Pregnancy in itself is not regarded as an AE unless there is a suspicion that an 
investigational product may have interfered with the effectiveness of a contraceptive medication. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented on the Sage Therapeutics 
pregnancy outcome form, even if the subject was discontinued from the study. All reports of 


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congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should also be 
reported and handled as SAEs.  
12.5. 
Reporting Serious Adverse Events 
All SAEs must be reported to Sage, or designee, immediately. A written account of the SAE 
must be sent to Sage, or designee, within 24 hours of the first awareness of the event by the 
investigator and/or his staff. The Investigator must complete, sign and date the SAE form, verify 
the accuracy of the information recorded on the SAE pages 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 
(CRF) and/or study file. 
Any SAEs discovered by the Investigator after the designated follow up time for the study, 
should be promptly reported to Sage, or designee, according to the timelines noted above.  
Sage, or designee, is responsible for notifying the relevant regulatory authorities of certain 
events. It is the Principal Investigator’s responsibility to notify the ethics committee 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. Ethics Committee 
(EC)/Institutional Review Boards (IRBs) will be notified of SAEs and/or SUSARs as required by 
local law. In addition, appropriate Sponsor Drug Safety and Pharmacovigilance personnel, or 
designee, will unblind SUSARs for the purpose of regulatory reporting. The Sponsor, or 
designee, will submit SUSARs (in blinded or unblinded fashion) to regulatory agencies 
according to local law. The Sponsor, or designee, will submit SUSARs to investigators in a 
blinded fashion. 
12.6. 
Emergency Identification of Study Drug 
During the study, 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 treatment received. Unless a subject is at 
immediate risk, the Investigator must make diligent attempts to contact Sage prior to unblinding 
the study treatment administered to a subject. Any request from the Investigator about the 
treatment administered to study subjects must be discussed with Sage. If the unblinding occurs 
without Sage’s knowledge, the Investigator must notify Sage as soon as possible and no later 
than the next business morning. All circumstances surrounding a premature unblinding must be 
clearly documented in the source records. Unless a subject is at immediate risk, any request for 
the unblinding of individual subjects must be made in writing to Sage and approved by the 
appropriate Sage personnel, according to standard operating procedures.  
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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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 database lock. Any 
deviations from or changes to the SAP following database lock will be described in detail in the 
clinical study report. 
13.1. 
Data Analysis Sets 
The Randomized set, defined as all subjects who are randomized, will be used for all data 
listings, unless otherwise specified. 
The Safety Set, defined as all subjects administered study drug, will be used to provide 
descriptive summaries of safety data.  
The Efficacy Set, defined as all subjects in the Safety Set with at least 1 post-baseline HAM-D 
evaluation, will be used for analysis of efficacy data.  
 
  
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. No imputation process will be 
used to estimate missing data. A sensitivity analysis will be used to investigate the impact of 
missing data if ≥5% of subjects in any treatment group have missing data. 
13.3. 
General Considerations 
For the purpose of all safety and efficacy analyses where applicable, baseline is defined as the 
last measurement prior to the start of study drug administration.  
Continuous endpoints will be summarized with number (n), mean, standard deviation (SD), 
median, minimum, and maximum. In addition, change from baseline values will be calculated at 
each time point and summarized descriptively. For categorical endpoints, descriptive summaries 
will include counts and percentages.  
13.4. 
Demographics and Baseline Characteristics 
Demographic data (Section 12.1.1) and baseline characteristics, such as height, weight, and body 
mass index (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.  


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13.5. 
Efficacy Analyses 
Efficacy data will be summarized using appropriate descriptive statistics and other data 
presentation methods where applicable; subject listings will be provided for all efficacy data. 
Subjects will be analyzed according to randomized treatment.  
The primary efficacy endpoint, the change from baseline to each assessment in HAM-D total 
score, will be analyzed using a mixed effects model for repeated measures (MMRM); the model 
will include treatment, baseline HAM-D total score, stratification factor, assessment time point, 
and time point-by-treatment as explanatory variables. All explanatory variables will be treated as 
fixed effects. All post-baseline time points will be included in the model. The main comparison 
will be between SAGE-217 and placebo at the 15-day time point. Model-based point estimates 
(ie, least squares [LS] means, 95% confidence intervals, and p-values) will be reported where 
applicable. An unstructured covariance structure will be used to model the within-subject errors. 
The Toeplitz or compound symmetry covariance structure will be used if there is a convergence 
issue with the unstructured covariance model.  
Similar to those methods described above for the primary endpoint, an MMRM will be used for 
the analysis of the change from baseline in other time points in HAM-D total score, MADRS 
total score, HAM-A total score, SF-36v2 score, sleep endpoints (eg, sleep latency (SL), total 
sleep time (TST), wake after sleep onset (WASO), ISI score and selected individual items and/or 
subscale scores.  
Generalized estimating equation (GEE) methods will be used for the analysis of HAM-D 
response (defined as ≥50% reduction from baseline in HAM-D total score) and HAM-D 
remission (defined as HAM-D total score of ≤7.0). GEE models will include terms for treatment, 
baseline score, stratification factor, assessment time point, and time point-by-treatment as 
explanatory variables. The comparison of interest will be the difference between SAGE-217 and 
matching placebo at the 15-day time point. Model-based point estimates (ie, odds ratios), 95% 
confidence intervals, and p-values will be reported.  
A GEE method will also be used for the analysis of CGI-I response including terms for 
treatment, baseline CGI-S score, stratification factor, assessment time point, and time point-by-
treatment as explanatory variables. 
 
13.6. 
Safety Analyses 
Safety and tolerability of study drug will be evaluated by incidence of adverse events/serious 
adverse events, concomitant medication usage, vital signs, clinical laboratory evaluations, and 
12-lead ECG. Suicidality will be monitored by the C-SSRS. Safety data will be listed by subject 
and summarized by treatment group. All safety summaries will be performed on the Safety Set. 
Where applicable, ranges of potentially clinical significant (PCS) values are provided in the 
SAP. 
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 (MedDRA) 


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Version 18.1 or higher, System Organ Class (SOC), 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 (see Section 12.3).  
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).  
13.6.2. 
Clinical Laboratory Evaluations 
Results of clinical laboratory parameters in each scheduled visit and mean changes from baseline 
will be summarized.in standard units. Normal range of each parameter is provided by the 
laboratory; shift from baseline to post-baseline values in abnormality of results will be provided. 
Potentially clinically significant values will be summarized by treatment. Any abnormal values 
deemed clinically significant by the investigator will be reported as an AE (see Section 12.2). 
Clinical laboratory results will be listed by subject and timing of collection. 
13.6.3. 
Physical Examinations 
The occurrence of a physical examination (Y/N) and the date performed will be listed by subject. 
Any clinically significant observation in physical examination will be reported as an AE (see 
Section 12.2). 
13.6.4. 
Vital Signs 
Results from each visit and mean changes from baseline in vital signs will be summarized by 
scheduled visit. Any abnormality deemed clinically significant by the investigator will be 
reported as an AE (see Section 12.2). Potentially clinically significant values will be summarized 
by treatment. Vital sign results will be listed by subject and timing of collection. 
13.6.5. 
12-Lead Electrocardiogram 
The following ECG parameters will be listed for each of the triplicate ECGs for each subject: 
heart rate, PR, QRS, QT, and QTcF; the derived mean of each parameter will also be listed. Any 
clinically significant abnormalities or changes in mean ECGs should be reported as an AE (see 
Section 12.2). Mean ECG data will be summarized by visit. Potentially clinically significant  
values of QTcF will be summarized by treatment. Electrocardiogram findings will be listed by 
subject and visit.  
13.6.6. 
Prior and Concomitant Medications 
Medications will be recorded at each study visit during the study and will be coded using World 
Health Organization-Drug dictionary (WHO-DD) September 2015, or later.  
All medications taken within 30 days prior to signing the ICF through the duration of the study 
will be recorded. In addition, all psychotropic medications taken 6 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 


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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.  
13.6.7. 
Columbia Suicide Severity Rating Scale 
Suicidality data collected on the C-SSRS at baseline and by visit during the Treatment Period 
will be summarized by treatment. Listings will include all data, including behavior type and/or 
category for Suicidal Ideation and Suicidal Behavior of the C-SSRS.  
 
 
 
 
 
 
13.8. 
Determination of Sample Size 
Assuming a two-sided alpha level of 0.05, a sample size of 399 evaluable subjects would provide 
90% power to detect a placebo-adjusted treatment difference of approximately 4 points in the 
primary endpoint, change from baseline in HAM-D total score at Day 15, assuming SD of 10 
points. Assuming an 11% dropout rate and a 1:1:1 randomization ratio within each stratum 
(antidepressant use at baseline, yes or no), approximately 450 total randomized subjects will be 
required to obtain 399 evaluable subjects. Evaluable subjects are defined as those randomized 
subjects who receive study drug and have valid baseline and at least 1 post-baseline HAM-D 
assessment. Additional subjects may be randomized if the dropout rate is greater than 11%. 


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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 (or designee) will visit the investigational study site per Sage Standard Operating 
Procedures 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. 
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 
about an inspection. 


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14.3. 
Institutional Review Board (IRB) or Ethics Committee (EC) 
The Principal Investigator must obtain IRB (or EC) approval for the 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 Practices 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 Informed Consent Form, 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 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 Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use and Good Clinical Practice 
guidelines, as well as all 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 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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19. 
LIST OF REFERENCES 
Busner J, Targum S. CGI-S. (2007a), as adapted from Kay, Stanley R, Positive and Negative 
Symptoms in Schizophrenia:Assessment and Research.  Clinical and Experimental Psychiatry, 
Monograph No. 5.  Brunner/Mazel, 1991.  Modified from Guy W. Clinical Global Impressions: 
In ECDEU Assessment Manual for Psychopharmacology. 1976; 218-22. Revised DHEW Pub. 
(ADM) Rockville, MD: National Institute for Mental Health.   
Busner J, Targum S. CGI-I.  (2007b), as adapted from Spearing, et al.  Psychiatry Research, 
1997;73:159-71.  Modified from Guy W. Clinical Global Impressions: In ECDEU Assessment 
Manual for Psychopharmacology. 1976; 218-22. Revised DHEW Pub. (ADM) Rockville, MD: 
National Institute for Mental Health.   
Conradi HJ, Ormel J, de Jonge P. Presence of individual (residual) symptoms during depressive 
episodes and periods of remission: a 3-year prospective study. Psychol Med. 2011 
Jun;41(6):1165-74. 
Drugan RC, Morrow AL, Weizman R, et al. Stress-induced behavioral depression in the rat is 
associated with a decrease in GABA receptor-mediated chloride ion flux and brain 
benzodiazepine receptor occupancy. Brain Res. 1989;487: 45–51. 
DSM-5.  Diagnostic and statistical manual of mental disorders (5th ed.).  American Psychiatric 
Association 2013.  Arlington, VA: American Psychiatric Publishing. 
Gerner RH, Hare TA. GABA in normal subjects and patients with depression, schizophrenia, 
mania, and anorexia nervosa. Am J Psychiatry. 1981;138:1098–101. 
Greenberg PE, Fournier AA, Sisitsky T, Pike CT, Kessler RC. The economic burden of adults 
with major depressive disorder in the United States (2005 and 2010). J Clin Psychiatry. 2015 
Feb;76(2):155-62. 
Honig A, Bartlett JR, Bouras N, Bridges PK. Amino acid levels in depression: a preliminary 
investigation. J Psychiatr Res. 1988; 22:159–64. 
Luscher B, Shen Q, Sahir N. The GABAergic deficit hypothesis of major depressive disorder. 
Mol Psychiatry. 2011;16(4):383-406. 
Maguire J, Mody I. GABA(A)R plasticity during pregnancy: Relevance to postpartum 
depression. Neuron. 2008;59(2);207-13.   
Maguire J, Ferando I, Simonsen C, Mody I. Excitability changes related to GABAA receptor 
plasticity during pregnancy. J Neurosci. 2009;29(30):9592-601.   
Mann JJ, Oguendo MA, Watson KT, et al. Anxiety in major depression and cerebrospinal fluid 
free gamma-aminobutyric acid. Depress Anxiety. 2014;31(10):814-21. 
 
   
Morin CM, Belleville G, Bélanger L, Ivers H. The Insomnia Severity Index: Psychometric 
Indicators to Detect Insomnia Cases and Evaluate Treatment Response. Sleep. 2011;34(5):601-
608. 


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Olfson M, Marcus SC, Shaffer D. Antidepressant drug therapy and suicide in severely depressed 
children and adults: A case-control study. Archives of general psychiatry. 2006:63(8);865-872. 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The Columbia-
Suicide Severity Rating Scale: initial validity and internal consistency findings from three 
multisite studies with adolescents and adults. Am J Psychiatry. 2011 Dec;168(12):1266-77. 
Romera I, Pérez V, Ciudad A, et al. Residual symptoms and functioning in depression, does the 
type of residual symptom matter? A post-hoc analysis. BMC Psychiatry. 2013 Feb 11;13:51. 
Rudolph U, Knoflach F. Beyond classical benzodiazepines: novel therapeutic potential of 
GABAA receptor subtypes. Nat Rev Drug Discov. 2011 Jul 29;10(9):685-97. 
Schüle C, Nothdurfter C, Rupprecht R.  The role of allopregnanolone in depression and anxiety. 
Prog Neurobiol. 2014 Feb;113:79-87. 
Trivedi MH, Rush AJ, Wisniewski SR, et al. (STAR*D Study Team). Evaluation of outcomes 
with citalopram for depression using measurement-based care in STAR*D: implications for 
clinical practice. Am J Psychiatry. 2006 Jan;163(1):28-40. 
Ware JE Jr, Kosinski M, Bjorner JB, et al.  User's Manual for the SF-36v2 Health Survey.  2nd 
ed.  Lincoln, RI:  QualityMetric Incorporated; 2007. 
Williams JBW, Kobak KA. Development and reliability of a structured interview guide for the 
Montgomery-Asberg Depression Rating Scale (SIGMA). Br J Psychiatry. 2008;192:52-8. 
Williams JBW.  SIGH-D 24hr: V1.3 – 24 HR Version. 2013a. 
Williams JBW.  SIGH-D Past week:  Past Week Version. 2013b. 
Williams JBW.  SIGH-A 24hr: V1.3 – 24 HR Version. 2013c. 
Williams JBW.  SIGH-A Past week:  Past Week Version. 2013d. 
 


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1. 
TITLE PAGE 
 
 
STUDY TITLE: A PHASE 3, MULTICENTER, DOUBLE-
BLIND, RANDOMIZED, PLACEBO-CONTROLLED 
STUDY EVALUATING THE EFFICACY OF SAGE-217 
IN THE TREATMENT OF ADULT SUBJECTS WITH 
MAJOR DEPRESSIVE DISORDER 
 
PROTOCOL NUMBER: 217-MDD-301 
 
Study Drug 
SAGE-217 
Clinical Phase 
Phase 3 
Sponsor 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 
Sponsor Contact 
 
Tel:
email:
Sponsor Medical Monitor 
, MD, MBA 
Tel:
email:
Date of Original Protocol 
Version 1.0, 16 JUL 2018 
Date of Amendment 1 
Version 2.0, 25 SEP 2018 
 
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-301 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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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Sage Therapeutics 
Name of Investigational Product: 
SAGE-217 Capsules 
Name of Active Ingredient: 
SAGE-217 
Title of Study: A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study 
Evaluating the Efficacy of SAGE-217 in the Treatment of Adult Subjects with Major Depressive 
Disorder 
Number of Sites and Study Location: Approximately 55 sites in the United States 
Phase of development: 3 
Planned Duration of Subject Participation: 
Up to 73 days (up to 28-day Screening Period, 14-day Treatment Period, and 28-day (±3 days) 
Follow-up Period) 
Objectives: 
Primary:  
• 
To evaluate the efficacy of SAGE-217 in the treatment of major depressive disorder 
(MDD) compared to placebo. 
Secondary: 
• 
To evaluate the effect of SAGE-217 on sleep.  
• 
To assess patient-reported outcome (PRO) measures as they relate to health-related 
quality of life. 
Safety: 
• 
To evaluate the safety and tolerability of SAGE 217. 
 
 
 
  
 
 
Endpoints: 
Primary: 
• 
The primary efficacy endpoint is the change from baseline in the 17-item Hamilton 
Rating Scale for Depression (HAM-D) total score at Day 15. 
Secondary: 
• 
Change from baseline in the 17-item HAM-D total score at other timepoints 
• 
HAM-D response at Day 15 and all other time points, defined as a ≥50% reduction in 
HAM-D score from baseline  
• 
HAM-D remission at Day 15 and all other time points, defined as HAM-D total score 
≤7  
• 
Clinical Global Impression - Improvement (CGI-I) response at Day 15 and all other 
time points, defined as “much improved” or “very much improved”  


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• 
Change from baseline in Clinical Global Impression - Severity (CGI-S) score at Day 15 
and all other time points 
• 
Change from baseline in Hamilton Anxiety Rating Scale (HAM-A) total score at Day 15 
and all other time points  
• 
Change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) 
total score at Day 15 and all other time points 
• 
Change from baseline in HAM-D subscale and individual item scores at all time points 
• 
Improvements in sleep at Day 15 and all other time points, as assessed by 
o Insomnia Severity Index (ISI) 
o Subjective sleep parameters collected with the Core Consensus Sleep Diary 
• 
PRO measures of health-related quality of life, as assessed by responses to the 36-item 
Short Form survey version 2 (SF-36v2) 
Safety Endpoints: 
• 
Incidence and severity of adverse events/serious adverse events  
• 
Changes from baseline in clinical laboratory measures, vital signs, and 
electrocardiograms (ECGs) 
• 
Suicidal ideation and behavior using the Columbia Suicide Severity Rating Scale 
(C-SSRS)  
 
 
  
 
  
 
 
 
 
 
Study Description:  
This is a randomized, double-blind, parallel-group, placebo-controlled study in subjects with 
MDD (HAM-D total score ≥22). Randomization will be stratified based on use of antidepressant 
treatment (current/stable or not treated/withdrawn ≥60 days) at baseline and carried out within 
each stratum in a 1:1:1 ratio to receive SAGE-217 20 mg, SAGE-217 30 mg, or matching 
placebo; subjects will be treated for 14 days beginning on Day 1.  
The study will consist of a Screening Period of up to 28 days, a 14-day Treatment Period, and a 
4-week Follow-up Period.  
The Screening Period begins with the signing of the informed consent form (ICF) at the 
Screening Visit; 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 
HAM-D and CGI-S.  
Antidepressants are permitted provided subjects are on a stable dose for at least 60 days prior to 
Day 1 and agree to continue on the stable dose through the follow-up period (Day 42). Initiation 
of new antidepressants or any other medications that may potentially have an impact on efficacy 


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or safety endpoints will not be allowed between screening and completion of the Day 42 
assessments.  
Eligible subjects will be stratified based on use of antidepressant treatment (current/stable or not 
treated/withdrawn ≥60 days) and randomized within each stratum to one of 3 treatment groups 
(SAGE-217 20 mg, SAGE-217 30 mg, or matching placebo) in a 1:1:1 ratio. Subjects will self-
administer a single dose of study drug once daily in the evening with food, on an outpatient 
basis, for 14 days. Subjects will return to the study center during the treatment and follow-up 
periods as outlined in Table 1. 
Subjects who cannot tolerate study drug will be discontinued from study drug and will receive 
treatment as clinically indicated. 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. Follow-up visits should take place every 7 days after the last dose of treatment for 
a total of 4 follow-up visits. 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 both visits will be conducted. 
Number of Subjects (planned):  
Approximately 450 subjects will be randomized and dosed to obtain 399 evaluable subjects. 
Eligibility Criteria: 
Inclusion Criteria: 
1. Subject has signed an ICF prior to any study-specific procedures being performed. 
2. Subject is an ambulatory 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.  
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 a HAM-D total score of ≥22 at screening and Day 1 (prior to dosing).  
7. Subjects taking psychotropic medications used to treat major depressive disorder (eg, 
antidepressants, atypical antipsychotics) must have been taking these medications at the 
same dose for at least 60 days prior to Day 1.  
8. Subjects taking benzodiazepines or GABAA modulators for insomnia (eg, eszopiclone, 
zopiclone, zaleplon, and zolpidem) have had these medications discontinued by 
Day -14. 
9. Subject is willing to delay start of other antidepressant or antianxiety medications and 
any new pharmacotherapy regimens, including as-needed benzodiazepine anxiolytics 
and sleep aids, until after study completion.  
10. Female subject agrees to use one of the following methods of contraception during 
participation in the study and for 30 days following the last dose of study drug, unless 
they are postmenopausal (defined as no menses for 12 months without an alternative 


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medical cause and confirmed by follicle stimulating hormone [FSH] >40 mIU/mL) 
and/or surgically sterile (hysterectomy or bilateral oophorectomy): 
• 
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 
• 
Sexual abstinence (no sexual intercourse) 
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. 
Acceptable methods of effective contraception for males includes sexual abstinence, 
vasectomy, or a condom with spermicide used together with highly effective female 
contraception methods if the female partner is of child-bearing potential (see Inclusion 
Criteria #9 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: 
1. Subject has attempted suicide associated with the current episode of MDD. 
2. Subject had onset of the current depressive episode during pregnancy or 4 weeks 
postpartum, or the subject has presented for screening during the 6-month postpartum 
period. 
3. 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.  
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 a known allergy to SAGE-217, allopregnanolone, or related compounds.  
6. Subject has a positive pregnancy test at screening or on Day 1 prior to the start of study 
drug administration or, if she is breastfeeding at Screening or on Day 1 (prior to 
administration of study drug), she does not agree to temporarily cease giving breast milk 


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to her child(ren) from just prior to receiving study drug on Day 1 until 7 days after the 
last dose of study drug.  
7. Subject has detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus 
(HCV) and positive HCV viral load, or human immunodeficiency virus (HIV) antibody 
at screening. 
8. Subject has a clinically significant abnormal 12-lead ECG at the screening or baseline 
visits. NOTE: mean QT interval calculated using the Fridericia method (QTcF) of 
>450 msec in males or >470 msec in females will be the basis for exclusion from the 
study.  
9. Subject has active psychosis per Investigator assessment.  
10. Subject has a medical history of seizures.  
11. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder.  
12. 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. 
13. Subject has had exposure to another investigational medication or device within 30 days 
prior to screening.  
14. Subject has previously participated in a SAGE-217 or a SAGE-547 (brexanolone) 
clinical trial.  
15. Use of any known strong inhibitors of cytochrome P450 (CYP)3A4 within 28 days or 
five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, or Seville 
oranges, or products containing these within 14 days prior to the first dose of study 
drug.  
16. Use of any CYP inducer, such as such as rifampin, carbamazepine, ritonavir, 
enzalutamide, efavirenz, nevirapine, phenytoin, phenobarbital and St John’s Wort, 
within 28 days prior to the first dose of study drug. 
17. Subject has a positive drug and/or alcohol screen at screening or on Day 1 prior to 
dosing. 
18. Subject plans to undergo elective surgery during participation in the study. 
19. Subject is taking benzodiazepines or GABAA modulators at Day -14. 
Study Drug, 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: 
Placebo will be provided as hard gelatin capsules for oral administration containing only the 
excipients listed above for the active capsule.  


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Duration of Treatment: 14 days 
Statistical methods: 
A detailed description of the analyses to be performed in the study will be provided in the 
Statistical Analysis Plan (SAP). The SAP will be finalized and approved prior to database lock 
and treatment unblinding. Any deviations from or changes to the SAP following database lock 
will be described in detail in the Clinical Study Report. 
General Considerations 
For the purpose of all safety and efficacy analyses where applicable, baseline is defined as the 
last measurement prior to the start of study drug administration.  
Continuous endpoints will be summarized descriptively with n, mean, standard deviation, 
median, minimum, and maximum. In addition, change from baseline values will be calculated at 
each time point and summarized descriptively. For categorical endpoints, descriptive summaries 
will include counts and percentages.  
Analysis Sets 
The Randomized Set, defined as all subjects who are randomized, will be used for all data 
listings, unless otherwise specified. 
The Safety Set, defined as all subjects administered study drug, will be used to provide 
descriptive summaries of safety data.  
The Efficacy Set, defined as all subjects in the Safety Set with at least 1 post-baseline HAM D 
evaluation, will be used for analysis of efficacy data.  
 
 
Determination of Sample Size 
Assuming a two-sided alpha level of 0.05, a sample size of 399 evaluable subjects would 
provide 90% power to detect a placebo-adjusted treatment difference of approximately 4 points 
in the primary endpoint, change from baseline in HAM-D total score at Day 15, assuming 
standard deviation (SD) of 10 points. Assuming a 11% dropout rate and a 1:1:1 randomization 
ratio within each stratum (antidepressant use at baseline, yes or no), approximately 450 total 
randomized subjects will be required to obtain 399 evaluable subjects. Evaluable subjects are 
defined as those randomized subjects who receive study drug and have valid baseline and at 
least 1 post-baseline HAM-D assessment. Additional subjects may be randomized if the dropout 
rate is greater than 11%. 
Analysis of Primary Endpoint 
The primary efficacy endpoint, the change from baseline to each assessment in HAM-D total 
score, will be analyzed using a mixed effects model for repeated measures (MMRM); the model 
will include treatment, baseline HAM-D total score, stratification factor, assessment time point, 
and time point-by-treatment as explanatory variables. All explanatory variables will be treated 
as fixed effects. All post-baseline time points will be included in the model. The main 
comparison will be between SAGE-217 and placebo at the 15-day time point. Model-based 
point estimates (ie, least squares [LS] means, 95% confidence intervals, and p-values) will be 
reported where applicable. An unstructured covariance structure will be used to model the 
within-subject errors. The Toeplitz or compound symmetry covariance structure will be used if 
there is a convergence issue with the unstructured covariance model.  
Analysis of Secondary Endpoints 
Similar to those methods described above for the primary endpoint, an MMRM will be used for 
the analysis of the change from baseline in other time points in HAM-D total score, MADRS 


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total score, HAM-A total score, SF-36v2 score, sleep endpoints (eg, sleep latency (SL), total 
sleep time (TST), wake after sleep onset (WASO), ISI score and selected individual items and/or 
subscale scores.  
Generalized estimating equation (GEE) methods will be used for the analysis of HAM-D 
response (defined as ≥50% reduction from baseline in HAM-D total score) and HAM-D 
remission (defined as HAM-D total score of ≤7.0). GEE models will include terms for 
treatment, baseline score, stratification factor, assessment time point, and time point-by-
treatment as explanatory variables. The comparison of interest will be the difference between 
SAGE-217 and matching placebo at the 15-day time point. Model-based point estimates (ie, 
odds ratios), 95% confidence intervals, and p-values will be reported.  
A GEE method will also be used for the analysis of CGI-I response including terms for 
treatment, baseline CGI-S score, stratification factor, assessment time point, and time point-by-
treatment as explanatory variables. 
 
 
Safety Analysis 
Safety and tolerability of study drug will be evaluated by incidence of adverse events/serious 
adverse events, concomitant medication usage, vital signs, clinical laboratory evaluations, and 
12-lead ECG. Suicidality will be monitored by the C-SSRS. 
 
 


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Table 1: 
Schedule of Events 
Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
Follow-up Period 
Visit Days 
D-28 to D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(±1d) 
and/or 
EOTa 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
or 
ET 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Duplicate Subject Checkb 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
 
Serum FSH testc 
X 
 
 
 
 
 
 
 
 
 
SCID-5-CT 
X 
 
 
 
 
 
 
 
 
 
MGH ATRQ 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical/Family History 
X 
 
 
 
 
 
 
 
 
 
Subject trainingd 
X 
X 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Physical Examinatione 
X 
X 
 
 
 
 
 
 
 
X 
Body Weight/Height 
X 
 
 
 
 
X (wt 
only) 
 
 
 
X (wt 
only) 
Clinical Laboratory 
Assessmentsf 
X 
X 
 
X 
 
X 
X 
X 
 
X 
Drug & Alcohol Screeng 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Testh 
X 
X 
 
 
 
X 
 
X 
 
X 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
Vital Signsk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGl 
X 
X 
 
 
 
X 
 
 
 
X 
C-SSRSm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAM-Dn, o 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MADRS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAM-Ao 
 
X 
 
X 
 
X 
 
X 
 
X 
CGI-S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
X 
X 
X 
X 
X 


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Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
Follow-up Period 
Visit Days 
D-28 to D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(±1d) 
and/or 
EOTa 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
or 
ET 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
SF-36v2 
X 
X 
 
X 
 
X 
 
X 
 
X 
ISI 
 
X 
 
X 
 
X 
X 
X 
 
X 
Sleep diaryp 
X 
X 
 
 
Study Drug Dispensation 
 
X 
 
X 
 
 
 
 
 
 
Study Drug Administration 
 
X (Day 1 through Day 14) 
 
 
 
 
Study Drug 
Accountability/Return 
 
 
 
X 
 
X 
 
 
 
Xr 
Adverse Events/SAEss 
X 
Prior/Concomitant 
Medications/Procedurest 
X 
CGI-I = Clinical Global Impression – Improvement; CGI-S – Clinical Global Impression – Severity; 
 
 Short Form; C-SSRS = Columbia Suicide Severity Rating Scale; D = day; EOT = end of 
treatment; ET = early termination; ECG = electrocardiogram; 
; FSH = follicle 
stimulating hormone; HAM-A = Hamilton Anxiety Rating Scale; HAM-D = Hamilton Rating Scale for Depression, 17-item; 
HIV = human immunodeficiency virus; ISI = Insomnia Severity Index; MADRS = Montgomery-Åsberg Depression Rating 
Scale; MGH ATRQ = Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; O = Optional; 
; SCID-5-CT = Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition Clinical Trials Version; SF-36v2 = 36-item Short Form survey version 2; V = visit; wt = weight 
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. Follow-up visits should take place every 7 days after the last dose of 
treatment for a total of 4 follow-up visits. 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 both visits will be 
conducted.  
b Subjects will be asked to authorize that their unique subject identifiers be entered into a registry (www.subjectregistry.com) 
with the intent of identifying subjects who may meet exclusion criteria for participation in another clinical study. 
c A serum follicle stimulating hormone test will be conducted at Screening for female subjects that are not surgically sterile to 
confirm whether a female subject with ≥12 months of spontaneous amenorrhea meets the protocol-defined criteria for being 
post-menopausal. 
d Subjects will be trained on use of software applications and devices necessary for the conduct of the study by site personnel. 
e A full physical examination will be conducted at Screening and abbreviated physical examinations will be conducted thereafter. 
A full physical examination includes assessment of body systems (eg, head, eye, ear, nose, and throat; heart; lungs; abdomen; 
and extremities). 
f Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. 
g Urine toxicology for selected drugs of abuse (as per the lab manual) and breath test for alcohol. 
h Serum pregnancy test at screening and urine pregnancy test thereafter for female subjects that are not surgically sterile and do 
not meet the protocol-defined criteria for being post-menopausal. 
 
 
 


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k Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing). Heart rate and 
blood pressure to be collected in supine position at all scheduled time points after the subject has been resting for 5 minutes and 
then after 1 minute in the standing position. Vital signs may be repeated at the discretion of the Investigator as clinically 
indicated. 
l Triplicate ECGs will be collected. 
 
m The “Baseline/Screening” C-SSRS form will be completed at screening. The “Since Last Visit” C-SSRS form will be 
completed at any time of day at all subsequent time points. 
n The HAM-D is to be completed as early during the visit as possible. 
o The assessment timeframe for HAM-D  scales will refer to the past 7 days (1 week) at Screening and “Since Last Visit” for all 
other visits. The assessment timeframe for HAM-A scale will refer to the past 7 days (1 week) at all visits. 
p Subjects are instructed to complete the Core Consensus Sleep Diary starting at least 7 days prior to Day 1 and then daily 
through Day 28. 
 
 
 
 
r To be performed at the ET visit only. 
s Adverse events will be collected starting at the time of informed consent and throughout the duration of the subject’s 
participation in the study. 
t Prior medications will be collected at Screening and concomitant medications and/or procedures will be collected at each 
subsequent visit. 
 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............14 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................18 
5. 
INTRODUCTION ......................................................................................................20 
5.1. 
Background of Major Depressive Disorder and Unmet Medical Need ......................20 
5.2. 
SAGE-217 ...................................................................................................................20 
5.3. 
Potential Risks and Benefits .......................................................................................21 
5.4. 
Dose Justification ........................................................................................................21 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................22 
6.1. 
Study Objective ..........................................................................................................22 
6.1.1. 
Primary Objective .......................................................................................................22 
6.1.2. 
Secondary Objective(s) ...............................................................................................22 
6.1.3. 
Safety Objective ..........................................................................................................22 
 
22 
6.2. 
Endpoints ....................................................................................................................22 
6.2.1. 
Primary Endpoint ........................................................................................................22 
6.2.2. 
Secondary Endpoint(s) ................................................................................................22 
6.2.3. 
Safety Endpoint(s) ......................................................................................................23 
 
23 
7. 
INVESTIGATIONAL PLAN .....................................................................................24 
7.1. 
Overall Study Design ..................................................................................................24 
7.2. 
Number of Subjects ....................................................................................................24 
7.3. 
Treatment Assignment ................................................................................................24 
7.4. 
Dose Adjustment Criteria ...........................................................................................25 
7.5. 
Criteria for Study Termination ...................................................................................25 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................26 
8.1. 
Subject Inclusion Criteria ...........................................................................................26 
8.2. 
Subject Exclusion Criteria ..........................................................................................27 
8.3. 
Subject Withdrawal Criteria .......................................................................................28 


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8.3.1. 
Replacement of Subjects .............................................................................................29 
9. 
TREATMENT OF SUBJECTS ..................................................................................30 
9.1. 
Study Drug ..................................................................................................................30 
9.2. 
Prior Medications, Concomitant Medications, and Restrictions ................................30 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................30 
9.2.2. 
Prohibited Medications ...............................................................................................30 
9.2.3. 
Other Restrictions .......................................................................................................31 
9.3. 
Treatment Adherence ..................................................................................................31 
9.4. 
Randomization and Blinding ......................................................................................31 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................32 
10.1. 
Description of Study Drug ..........................................................................................32 
10.2. 
Study Drug Packaging and Labeling ..........................................................................32 
10.3. 
Study Drug Storage .....................................................................................................32 
10.4. 
Study Drug Preparation ..............................................................................................32 
10.5. 
Study Drug Administration.........................................................................................32 
10.6. 
Study Drug Accountability .........................................................................................32 
10.7. 
Study Drug Handling and Disposal ............................................................................33 
11. 
ASSESSMENT OF EFFICACY 
 .............................34 
11.1. 
Efficacy Assessments .................................................................................................34 
11.1.1. 
Hamilton Rating Scale for Depression (HAM-D) ......................................................34 
11.1.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) ........................................34 
11.1.3. 
Hamilton Anxiety Rating Scale (HAM-A) .................................................................34 
11.1.4. 
Clinical Global Impression (CGI) ..............................................................................35 
11.1.5. 
Short Form-36 Version 2 (SF-36v2) ...........................................................................35 
11.1.6. 
Insomnia Severity Index (ISI) ....................................................................................35 
11.1.7. 
Core Consensus Sleep Diary ......................................................................................36 
 
36 
 
36 
 
36 
 
36 
 
37 
12. 
ASSESSMENT OF SAFETY .....................................................................................38 


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12.1. 
Safety Parameters .......................................................................................................38 
12.1.1. 
Demographic/Medical History ...................................................................................38 
12.1.2. 
Weight and Height ......................................................................................................38 
12.1.3. 
Physical Examination .................................................................................................38 
12.1.4. 
Vital Signs ..................................................................................................................38 
12.1.5. 
Electrocardiogram (ECG) ...........................................................................................39 
12.1.6. 
Laboratory Assessments .............................................................................................39 
12.1.6.1. 
Drugs of Abuse and Alcohol ......................................................................................41 
12.1.6.2. 
Pregnancy Screen ........................................................................................................41 
12.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................41 
12.2. 
Adverse and Serious Adverse Events .........................................................................41 
12.2.1. 
Definition of Adverse Events .....................................................................................41 
12.2.1.1. 
Adverse Event (AE) ....................................................................................................41 
12.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................42 
12.3. 
Relationship to Study Drug ........................................................................................43 
12.4. 
Recording Adverse Events .........................................................................................43 
12.5. 
Reporting Serious Adverse Events .............................................................................44 
12.6. 
Emergency Identification of Study Drug ....................................................................45 
13. 
STATISTICS ..............................................................................................................46 
13.1. 
Data Analysis Sets ......................................................................................................46 
13.2. 
Handling of Missing Data ...........................................................................................46 
13.3. 
General Considerations ...............................................................................................46 
13.4. 
Demographics and Baseline Characteristics ...............................................................46 
13.5. 
Efficacy Analyses .......................................................................................................47 
13.6. 
Safety Analyses ..........................................................................................................47 
13.6.1. 
Adverse Events ...........................................................................................................47 
13.6.2. 
Clinical Laboratory Evaluations .................................................................................48 
13.6.3. 
Physical Examinations ................................................................................................48 
13.6.4. 
Vital Signs ..................................................................................................................48 
13.6.5. 
12-Lead Electrocardiogram ........................................................................................48 
13.6.6. 
Prior and Concomitant Medications ...........................................................................48 
13.6.7. 
Columbia Suicide Severity Rating Scale ....................................................................49 


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49 
13.8. 
Determination of Sample Size ....................................................................................49 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................50 
14.1. 
Study Monitoring ........................................................................................................50 
14.2. 
Audits and Inspections ................................................................................................50 
14.3. 
Institutional Review Board (IRB) or Ethics Committee (EC) ....................................51 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................52 
16. 
ETHICS ......................................................................................................................53 
16.1. 
Ethics Review .............................................................................................................53 
16.2. 
Ethical Conduct of the Study ......................................................................................53 
16.3. 
Written Informed Consent ..........................................................................................53 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................54 
17.1. 
Inspection of Records .................................................................................................54 
17.2. 
Retention of Records ..................................................................................................54 
18. 
PUBLICATION POLICY ..........................................................................................55 
19. 
LIST OF REFERENCES ............................................................................................56 
 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................11 
Table 2: 
Abbreviations and specialist terms .............................................................................18 
Table 3: 
Clinical Laboratory Tests ...........................................................................................39 
Table 4: 
Relationship to Study Drug ........................................................................................43 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and specialist terms 
Abbreviation or specialist term 
Explanation 
AE 
adverse event 
CGI-I 
Clinical Global Impression – Improvement 
CGI-S 
Clinical Global Impression – Severity 
CRF 
case report form 
CS 
clinically significant 
 
 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CYP 
cytochrome P450 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
end of treatment 
ET 
early termination 
 
 
FSH 
follicle stimulating hormone 
GABA 
γ-aminobutyric acid 
GEE 
generalized estimating equation 
HAM-A 
Hamilton Rating Scale for Anxiety 
HAM-D 
Hamilton Rating Scale for Depression 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ID 
identification  
IRB 
institutional review board 
IRT 
interactive response technology 
ISI 
Insomnia Severity Index 
MADRS 
Montgomery Åsberg Depression Rating Scale 


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Table 2: 
Abbreviations and specialist terms (Continued) 
Abbreviation or specialist term 
Explanation 
MDD 
major depressive disorder 
MGH ATRQ 
Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire 
MMRM 
mixed effects model for repeated measures 
NCS 
not clinically significant 
PCS 
Potentially clinically significant 
PK 
pharmacokinetic 
PRO 
patient-reported outcome 
QTcF 
QT corrected according to Fridericia’s formula 
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 
SF-36v2 
36-item Short Form version 2 
SUSAR 
suspected, unexpected, serious, adverse reactions 
TEAE 
treatment-emergent adverse event 
WHO 
World Health Organization 
 


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5. 
INTRODUCTION 
5.1. 
Background of Major Depressive Disorder and Unmet Medical Need 
The World Health Organization (WHO) has identified depression as the leading cause of 
disability worldwide, and as a major contributor to the overall global burden of disease 
(http://www.who.int/mediacentre/factsheets/fs369/en/). Globally, depression has been estimated 
to affect over 300 million people. 
In the United States, the economic burden of depression, including workplace costs, direct costs 
and suicide-related costs, was estimated to be $210.5 billion in 2010 (Greenberg 2015). As per 
WHO statistics, over 800,000 people die due to suicide every year, and suicide is the second 
leading cause of death in 15- to 29-year-olds. The rate of US adults making a suicide attempt has 
increased (0.62% from 2004 to 2005 to 0.79% from 2012 to 2013), with a shift to more attempts 
among younger adults (42% to 50%, respectively) and among those with a depressive disorder 
(26% to 54%, respectively; Olfson 2017). 
In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), 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 (SSRIs), 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 (CSF) 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, consistent with the actions of other GABAA receptor potentiators 
(Rudolph 2011), exhibits potent anticonvulsant, anxiolytic, and sedative activity 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 [HAM-A], 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 HAM-A. 
SAGE-217 has been generally well tolerated in clinical studies to date. The most common 
treatment-emergent adverse events (TEAEs) were sedation, somnolence, and dizziness. Most 
adverse events (AEs) were reported as mild or moderate in intensity. Among the over 260 
subjects exposed to SAGE-217 in clinical trials, there have been no deaths and only one subject 
with essential tremor experienced a serious adverse event (SAE) of transient confusion leading to 
discontinuation of study drug. No other SAEs have been reported in any study of SAGE-217.  
Additional information on nonclinical and clinical data is provided in the Investigator’s 
Brochure.  
5.3. 
Potential Risks and Benefits 
Nonserious events of sedation, somnolence, and dizziness were the most commonly reported 
AEs with SAGE-217. Given the outcome of the Phase 2a study of SAGE-217 in subjects with 
MDD, the current significant unmet need in the treatment of depression, and a favorable benefit-
risk profile, further investigation of SAGE-217 in patients with MDD is justified. 
5.4. 
Dose Justification 
There will be 2 dose levels of SAGE-217 in this study in order to study dose ranging: 30 mg per 
day and 20 mg per day. The higher dose level of 30 mg per day is the maximum tolerated dose in 
the multiple ascending dose study of SAGE-217 in healthy subjects and is also the dose level that 
was effective and generally well tolerated in a Phase 2 study in subjects with MDD (217-MDD-
201). The lower dose of 20 mg per day will be studied in subjects with MDD for the first time in 
the current study and is anticipated to be well tolerated as it is lower than the maximum tolerated 
dose level. Due to sedation/somnolence observed in previous clinical trials when administered in 
the morning, and improved tolerability when given in the evening, both doses of 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 is to evaluate the efficacy of SAGE-217 in the treatment of MDD 
compared to placebo. 
6.1.2. 
Secondary Objective(s) 
Secondary objectives are: 
• To evaluate the effect of SAGE-217 on sleep  
• To assess patient-reported outcome (PRO) measures as they relate to health-related 
quality of life 
6.1.3. 
Safety Objective 
The safety objective is to evaluate the safety and tolerability of SAGE-217. 
 
 
 
 
 
 
 
 
6.2. 
Endpoints 
6.2.1. 
Primary Endpoint 
The primary endpoint of this study is the change from baseline in the 17-item HAM-D total score 
at Day 15. 
6.2.2. 
Secondary Endpoint(s) 
• Change from baseline in the 17-item HAM-D total score at other time points 
• HAM-D response at Day 15 and all other time points, defined as a ≥50% reduction in 
HAM-D score from baseline 
• HAM-D remission at Day 15 and all other time points, defined as HAM-D total 
score ≤7  
• CGI-I response at Day 15 and all other time points, defined as “much improved” or 
“very much improved” 
• Change from baseline in Clinical Global Impression - Severity (CGI-S) score at 
Day 15 and all other time points 


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• Change from baseline in HAM-A total score at Day 15 and all other time points  
• Change from baseline in the MADRS total score at Day 15 and all other time points 
• Change from baseline in HAM-D subscale and individual item scores at all time 
points 
• Improvements in sleep at Day 15 and all other time points, as assessed by: 
− Insomnia Severity Index (ISI) 
− Subjective sleep parameters collected with the Core Consensus Sleep Diary 
• Patient-reported outcome measures of health-related quality of life, as assessed by 
responses to the 36-item Short Form survey (SF-36) version 2 
6.2.3. 
Safety Endpoint(s) 
• Incidence and severity of adverse events/serious adverse events  
• Changes from baseline in clinical laboratory measures, vital signs, and 
electrocardiograms (ECGs) 
• Suicidal ideation and behavior using the Columbia Suicide Severity Rating Scale 
(C-SSRS)  
 
 
 
 
 
 
 
 
 
 
 
 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a randomized, double-blind, parallel-group, placebo-controlled study in subjects with 
MDD (HAM-D total score ≥22). The study will consist of a Screening Period of up to 28 days, a 
14-day Treatment Period, and a 4-week Follow-up Period.  
The Screening Period begins with the signing of the informed consent form (ICF) at the 
Screening Visit; the ICF must be signed prior to beginning any screening activities. At the time 
of providing informed consent for the study, subjects will also be asked to authorize that their 
unique subject identifiers be entered into a registry (www.subjectregistry.com) with the intent of 
identifying subjects who may meet exclusion criteria due to participation in another clinical 
study (Section 8.2). 
The diagnosis of MDD must be made according to Structured Clinical Interview for Diagnostic 
and 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 HAM-D and CGI-S.  
Antidepressants are permitted provided subjects are on a stable dose for at least 60 days prior to 
Day 1 and agree to continue on the stable dose through the follow-up period (Day 42). Initiation 
of new antidepressants or any other medications that may potentially have an impact on efficacy 
or safety endpoints is prohibited between screening and completion of the Day 42 assessments.  
Eligible subjects will be stratified based on use of antidepressant treatment (current/stable or not 
treated/withdrawn ≥60 days) and randomized within each stratum to one of 3 treatment groups 
(SAGE-217 20 mg, SAGE-217 30 mg, or matching placebo) in a 1:1:1 ratio. Subjects will self-
administer a single dose of study drug with food once daily in the evening on an outpatient basis, 
for 14 days. Dose reductions are not permitted. Study drug administration will be monitored via 
a clinical monitoring service (see Section 9.3). 
Subjects will return to the study center during the treatment and follow-up periods as outlined in 
Table 1. 
7.2. 
Number of Subjects 
Approximately 450 subjects will be randomized and dosed to obtain 399 evaluable subjects (see 
Section 13.8). 
7.3. 
Treatment Assignment 
Subjects will be randomly assigned to a treatment group on Day 1. Randomization will be 
stratified based on use of antidepressant treatment (current/stable or not treated/withdrawn 
≥60 days) at baseline and performed within each stratum in a 1:1:1 ratio to receive SAGE-217 
20 mg, SAGE-217 30 mg, or matching placebo. 


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7.4. 
Dose Adjustment Criteria 
Dose adjustments are not permitted in this study. Subjects who cannot tolerate study drug will be 
discontinued from study drug and will receive treatment as clinically indicated (see Section 8.3). 
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 
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 an ambulatory 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.  
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 a HAM-D total score of ≥22 at screening and Day 1 (prior to dosing).  
7. Subjects taking psychotropic medications used to treat major depressive disorder (eg, 
antidepressants, atypical antipsychotics) must have been taking these medications at the 
same dose for at least 60 days prior to Day 1.  
8. Subjects taking benzodiazepines or GABAA modulators for insomnia (eg, eszopiclone, 
zopiclone, zaleplon, and zolpidem) have had these medications discontinued by Day -14. 
9. Subject is willing to delay start of other antidepressant or antianxiety medications and 
any new pharmacotherapy regimens, including as-needed benzodiazepine anxiolytics and 
sleep aids, until after study completion.  
10. Female subject agrees to use one of the following methods of contraception during 
participation in the study and for 30 days following the last dose of study drug, unless 
they are postmenopausal (defined as no menses for 12 months without an alternative 
medical cause and confirmed by follicle stimulating hormone [FSH] >40 mIU/mL) 
and/or surgically sterile (hysterectomy or bilateral oophorectomy): 
• 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. 
• Sexual abstinence (no sexual intercourse). 
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. 
Acceptable methods of effective contraception for males includes sexual abstinence, 
vasectomy, or a condom with spermicide used together with highly effective female 


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contraception methods if the female partner is of child-bearing potential (see Inclusion 
Criteria #9 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 had onset of the current depressive episode during pregnancy or 4 weeks 
postpartum, or the subject has presented for screening during the 6-month postpartum 
period. 
3. 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.  
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 a known allergy to SAGE-217, allopregnanolone, or related compounds.  
6. Subject has a positive pregnancy test at screening or on Day 1 prior to the start of study 
drug administration or, if she is breastfeeding at Screening or on Day 1 (prior to 
administration of study drug), she does not agree to temporarily cease giving breast milk 
to her child(ren) from just prior to receiving study drug on Day 1 until 7 days after the 
last dose of study drug.  
7. Subject has detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) 
and positive HCV viral load, or human immunodeficiency virus (HIV) antibody at 
screening. 
8. Subject has a clinically significant abnormal 12-lead ECG at the screening or baseline 
visits. NOTE: mean QT interval calculated using the Fridericia method (QTcF) of 
>450 msec in males or >470 msec in females will be the basis for exclusion from the 
study.  
9. Subject has active psychosis per Investigator assessment.  
10. Subject has a medical history of seizures.  
11. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder.  


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12. 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. 
13. Subject has had exposure to another investigational medication or device within 30 days 
prior to screening.  
14. Subject has previously participated in a SAGE-217 or a SAGE-547 (brexanolone) clinical 
trial.  
15. Use of any known strong inhibitors of cytochrome P450 (CYP)3A4 within 28 days or 
five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, or Seville 
oranges, or products containing these within 14 days prior to the first dose of study drug.  
16. Use of any CYP inducer, such as such as rifampin, carbamazepine, ritonavir, 
enzalutamide, efavirenz, nevirapine, phenytoin, phenobarbital and St John’s Wort, within 
28 days prior to the first dose of study drug. 
17. Subject has a positive drug and/or alcohol screen at screening or on Day 1 prior to 
dosing. 
18. Subject plans to undergo elective surgery during participation in the study. 
19. Subject is taking benzodiazepines or GABAA modulators at Day -14. 
8.3. 
Subject Withdrawal Criteria 
Subjects may withdraw from the study drug or terminate from the study at any time for any 
reason. 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 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.  


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Subjects who discontinue study drug early should return to the site for an end of treatment (EOT) 
visit as soon as possible, preferably the day after treatment is discontinued. Follow-up visits 
should take place every 7 days after the last dose of treatment for 28 days. 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.  
A subject will be deemed lost to follow-up after attempts at contacting the subject have been 
unsuccessful. 
8.3.1. 
Replacement of Subjects 
Subjects will not be replaced. Additional subjects may be randomized if the drop-out rate is 
higher than anticipated (Section 13.8). 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Study Drug 
Subjects will self-administer SAGE-217 (20 or 30 mg) or matching placebo orally once daily in 
the evening with food for 14 days.  
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 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.  
Antidepressants or atypical antipsychotics that have been taken at the same dose for at least 
60 days prior to Day 1 are permitted if the subject intends to continue the stable dose through the 
follow-up period (Day 42). 
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 
The following specific classes of medications are prohibited at any time during the treatment 
period: 
• Initiation of new psychotropic medications  
• Use of any benzodiazepines, GABAA modulators, or GABAA-like acting drugs 
• Exposure to another investigational medication or device 
• Any known strong inhibitors CYP3A4  
• Use of any CYP inducer, such as such as rifampin, carbamazepine, ritonavir, 
enzalutamide, efavirenz, nevirapine, phenytoin, phenobarbital and St John’s Wort. 


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9.2.3. 
Other Restrictions 
The consumption of grapefruit juice, grapefruit, or Seville oranges, or products containing these 
is prohibited throughout the treatment period. 
Consumption of alcohol or use of drugs of abuse is discouraged throughout the duration of the 
study. 
Female subjects who are lactating or actively breastfeeding must stop giving breast milk to the 
baby(ies) starting on Day 1 until 7 days after the last dose of study drug. 
9.3. 
Treatment Adherence 
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 10.4 and Table 1).  
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 
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 by dose level, as well as missed doses. 
In addition, the subject will be instructed to bring their dosing kit to the site as outlined in 
Table 1, at which time the Investigator or designee will be responsible for ensuring the kit 
contains sufficient doses for the duration of the treatment period.  
All subjects should be reinstructed about the dosing requirement 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-compliance in the source documents. 
9.4. 
Randomization and Blinding 
This is a randomized double-blind, placebo-controlled study. Subjects who meet the entrance 
criteria will be randomized in a stratified manner based on use of antidepressant treatment 
(current/stable or not treated/withdrawn ≥60 days) at baseline; randomization will be done within 
each stratum in a 1:1:1 ratio to receive SAGE-217 20 mg, 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 (SAGE-217 20 mg, SAGE-217 30 mg, or placebo) will be based on the 
randomization schedule. The randomization schedules will be kept strictly confidential, 
accessible only to authorized personnel until the time of unblinding. 
In 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 (see Section 12.6 for 
more details related to unblinding).  


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Description of Study Drug 
SAGE-217 is available as hard gelatin capsules containing a white to off-white powder. In 
addition to the specified amount of SAGE-217 Drug Substance, active SAGE-217 Capsules 
contain croscarmellose sodium, mannitol, silicified microcrystalline cellulose (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 Practices/Good Clinical Practices guidelines will 
be prepared by the Sponsor. 
10.3. 
Study Drug Storage 
SAGE-217 and matched placebo 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 is to be administered orally once daily in the evening with 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 1.  


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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 randomize the 
eligible subject into the study 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. 
At the subsequent study drug-dispensing visit, 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 this visit must be 
recorded.  
If dispensing errors or discrepancies are discovered by site staff or sponsor’s designee, the 
Sponsor must be notified immediately. 
The 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. 


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11. 
ASSESSMENT OF EFFICACY 
 
All assessments will be conducted according to the schedule of assessments (Table 1). 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 (HAM-D) 
The primary outcome measure is the change from baseline in 17-item HAM-D total score at the 
end of the Treatment Period (Day 15). Every effort should be made for the same rater to perform 
all HAM-D assessments for an individual subject. An assessment timeframe of 7 days will be 
used at Screening and ‘Since Last Visit’ will be used for all other visits. 
The 17-item HAM-D will be used to rate the severity of depression in 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.  
In addition to the primary efficacy endpoint of change from baseline in HAM-D total score, 
several secondary efficacy endpoints will be derived for the HAM-D. Hamilton Rating Scale for 
Depression subscale scores will be calculated as the sum of the items comprising each subscale. 
Hamilton Rating Scale for Depression response will be defined as having a 50% or greater 
reduction from baseline in HAM-D total score. Hamilton Rating Scale for Depression remission 
will be defined as having a HAM-D total score of ≤7.  
11.1.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive 
episodes in subjects with mood disorders. It was designed as an adjunct to the HAM-D that 
would be more sensitive to the changes brought on by antidepressants and other forms of 
treatment than the Hamilton Scale.  
Higher MADRS scores indicate more severe depression, and each item yields a score of 0 to 6. 
The overall score ranges from 0 to 60 (Williams 2008). 
The MADRS total score will be calculated as the sum of the 10 individual item scores.  
11.1.3. 
Hamilton Anxiety Rating Scale (HAM-A) 
The 14-item HAM-A will be used to rate the severity of symptoms of anxiety (Williams 2013c; 
Williams 2013d). Each of the 14 items is defined by a series of symptoms, and measures both 
psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical 
complaints related to anxiety). Scoring for HAM-A is calculated by assigning scores of 0 (not 


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present) to 4 (very severe), with a total score range of 0 to 56, where <17 indicates mild severity, 
18 to 24, mild to moderate severity, and 25 to 30, moderate to severe severity. The HAM-A total 
score will be calculated as the sum of the 14 individual item scores. 
11.1.4. 
Clinical Global Impression (CGI) 
The CGI is a validated measure often utilized in clinical trials to allow clinicians to integrate 
several sources of information into a single rating of the subject’s condition. The CGI scale 
consists of 3 items. Only the first 2 items are being used in this study.  
The CGI-S uses a 7-point Likert scale to rate the severity of the subject’s illness at the time of 
assessment, relative to the clinician’s past experience with subjects who have the same diagnosis. 
Considering total clinical experience, a subject is assessed on severity of mental illness at the 
time of rating as 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately 
ill; 5=markedly ill; 6=severely ill; and 7=extremely ill (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 
“much improved.”  
11.1.5. 
Short Form-36 Version 2 (SF-36v2) 
The Medical Outcomes Study SF-36v2 is a 36-item measure of health status that has undergone 
validation in many different disease states (Ware 2007). The SF-36v2 covers eight health 
dimensions including four physical health status domains (physical functioning, role 
participation with physical health problems [role-physical], bodily pain, and general health) and 
four mental health status domains (vitality, social functioning, role participation with emotional 
health problems [role-emotional], and mental health). In addition, two summary scores, physical 
component summary and mental component summary, are produced by taking a weighted linear 
combination of the eight individual domains. The SF-36v2 is available with two recall periods: 
the standard recall period is 4 weeks and the acute recall period is 1 week. This study will use the 
acute version, which asks patients to respond to questions as they pertain to the past week. 
Higher SF-36v2 scores indicate a better state of health.  
11.1.6. 
Insomnia Severity Index (ISI) 
The ISI is a validated questionnaire designed to assess the nature, severity, and impact of 
insomnia (Morin 2011). The ISI uses a 5-point Likert Scale to measure various aspects of 
insomnia severity (0 = none, 1 = mild, 2 = moderate; 3 = severe; 4 = very severe), satisfaction 
with current sleep pattern (0 = very satisfied, 1 = satisfied, 2 = neutral, 3 = dissatisfied, 4 = very 
dissatisfied), and various aspects of the impact of insomnia on daily functioning (0 = not at all, 
1 = a little, 2 = somewhat, 3 = much, 4 = very much). A total score of 0 to 7 = “no clinically 
significant insomnia,” 8 to 14 = subthreshold insomnia,” 15 to 21 = “clinical insomnia (moderate 
severity),” and 22 to 28 = “clinical insomnia (severe).”  


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11.1.7. 
Core Consensus Sleep Diary 
The Core Consensus Sleep Diary collects subjective sleep parameters, including sleep onset 
latency, total sleep time, and wake after sleep onset, number of awakenings, and sleep quality. 
The take-home subject sleep diary assessment will be administered using an eDiary solution. The 
eDiary will be captured using either a provisioned smartphone device or bring-your-own-device 
(BYOD) solution, depending on the subject’s preference. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
All assessments will be conducted according to the schedule of assessments (Table 1). 
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 (ICD-10) should be recorded. 
The Massachusetts General Hospital Antidepressant Treatment Response Questionnaire 
(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. 
12.1.2. 
Weight and Height 
Height (Screening only) and weight will be measured and documented. 
12.1.3. 
Physical Examination 
Physical examinations assessing body systems (eg, head, eyes, ears, nose, and throat; heart; 
lungs; abdomen; and extremities), as well as cognitive and neurological examinations and mental 
status examinations will be conducted and documented. 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. 
New or worsening abnormalities that are judged to be clinically significant will be recorded as 
AEs, assessed according to Section 12.2.1.1. 
12.1.4. 
Vital Signs 
Vital signs comprise both supine and standing for systolic and diastolic blood pressure and heart 
rate measurements. Heart rate and blood pressure are to be collected in supine position after the 
subject has been resting for 5 minutes and then after 1 minute in the standing position. 
Respiratory rate, pulse oximetry and temperature are collected once, in either position. Vital 
signs will be documented. When vital signs are scheduled at the same time as blood draws, vital 
signs will be obtained first. 
Any abnormality in vital signs will be interpreted by the Investigator as abnormal, NCS or 
abnormal, CS in source documents. New or worsening abnormalities that are judged to be 
clinically significant will be recorded as AEs, assessed according to Section 12.2.1.1.  


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12.1.5. 
Electrocardiogram (ECG) 
Supine 12-lead ECGs will be performed in triplicate at all scheduled time points. The standard 
intervals (heart rate, PR, QRS, QT, and QTcF) as well as any rhythm abnormalities will be 
recorded.
 
 
12.1.6. 
Laboratory Assessments 
Samples will be collected in accordance with acceptable laboratory procedures detailed in the 
laboratory manual.   
The clinical laboratory tests to be performed are listed in Table 3. 
Table 3: 
Clinical Laboratory Tests 
Hematology  
Serum Chemistry 
Urinalysis 
Coagulation 
Red blood cell count 
Hemoglobin  
Hematocrit  
White blood cell count with 
differential  
Platelet count 
Red blood cell morphology 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
Total protein 
Creatinine 
Blood urea nitrogen 
Creatine kinase 
Gamma-glutamyl transferase 
Potassium 
Sodium 
Lactate dehydrogenase 
Glucose 
Chloride 
Bicarbonate 
Calcium 
Phosphorus 
Triglycerides 
Thyroid stimulating hormone 
pH 
Specific gravity 
Protein 
Glucose 
Red blood cell 
Nitrite 
Leukocyte 
esterase 
Ketones 
Bilirubin 
Urobilinogen 
Activated partial 
thromboplastin 
time 
Prothrombin time 
International 
normalized ratio 


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Table 3: 
Clinical Laboratory Tests (Continued) 
Hematology  
Serum Chemistry 
Urinalysis 
Coagulation 
Diagnostic  
 
 
 
Serum 
Urine 
Breathalyzer 
 
Hepatitis B 
Hepatitis C 
Reflex HCV RNA 
HIV-1 and -2 
Female subjects that are not 
surgically sterile and do not 
meet the protocol-defined 
criteria for being post-
menopausal: serum hCG 
Female subjects, if 
menopause is suspected 
and not surgically sterile: 
FSH 
Drug screen including: 
amphetamines, 
barbiturates, 
benzodiazepines, 
cannabinoids, cocaine, 
opiates, phencyclidine, and 
propoxyphene 
Female subjects that are not 
surgically sterile and do not 
meet the protocol-defined 
criteria for being post-
menopausal: urine hCG  
Alcohol 
 
Abbreviations: FSH = follicle stimulating hormone; hCG = human chorionic gonadotropin; HCV = hepatitis C 
virus; HIV = human immunodeficiency virus 
The central laboratory will perform laboratory tests for hematology, serum chemistry, urinalysis, 
and coagulation. The results of laboratory tests will be returned to the Investigator, who is 
responsible for reviewing and filing these results. All laboratory safety data will be transferred 
electronically to Sage Therapeutics or designee in the format requested by Sage Therapeutics.  
Laboratory reports must be signed and dated by the Investigator or subinvestigator indicating 
that the report has been reviewed and any abnormalities have been assessed for clinical 
significance. Any abnormalities identified prior to first dose will require clear and complete 
documentation in the source documents as to the investigator’s assessment of not clinically 
significant before proceeding with randomization.  
All clinical laboratory test results outside the central laboratory’s reference range will be 
interpreted by the Investigator as abnormal, NCS; or abnormal, CS in source documents. New or 
worsening abnormalities that are judged to be clinically significant will be recorded as AEs, 
assessed according to Section 12.2.1.1. A clinically significant laboratory abnormality following 
subject randomization will be followed until the abnormality returns to an acceptable level or a 
satisfactory explanation has been obtained. 
A serum follicle stimulating hormone test will be conducted at Screening to confirm whether a 
female subject with ≥12 months of spontaneous amenorrhea meets the protocol-defined criteria 
for being post-menopausal (Section 8.1). 
 
 
 
 


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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 3). A breath test 
for alcohol will be performed. 
12.1.6.2. Pregnancy Screen 
For female subjects that are not surgically sterile and do not meet the protocol-defined criteria 
for being post-menopausal, a serum pregnancy test will be performed at Screening and a urine 
pregnancy test will be performed at all other scheduled timepoints thereafter, including the ET 
visit for subjects who prematurely discontinue. 
12.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011). This scale 
consists of a baseline evaluation that assesses the lifetime experience of the subject with suicidal 
ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last 
study visit. The C-SSRS includes ‘yes’ or ‘no’ responses for assessment of suicidal ideation and 
behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being 
the most severe).  
The “Baseline/Screening” C-SSRS form will be completed at screening (lifetime history and past 
24 months). The “Since Last Visit” C-SSRS form will be completed at all subsequent time 
points, as outlined in Table 1. 
12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Definition of Adverse Events 
12.2.1.1. Adverse Event (AE) 
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 treatment has been administered. 


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A TEAE is an AE that occurs after the first administration of any study drug. The term study 
drug includes any Sage investigational product, a comparator, or a placebo administered in a 
clinical trial. 
Laboratory abnormalities and changes from baseline in vital signs, ECGs, and physical 
examinations are considered AEs if they result in discontinuation or interruption of study 
treatment, require therapeutic medical intervention, meet protocol specific criteria (if applicable) 
and/or if the Investigator considers them to be clinically significant. Laboratory values and vital 
signs that meet the criteria for an SAE should be reported in an expedited manner. Laboratory 
abnormalities and changes from baseline in vital signs, ECGs, 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. 
12.2.1.2. Serious Adverse Event (SAE) 
A serious adverse event is any untoward medical occurrence that at any dose: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
An SAE may also be any other medically important event that, in the opinion of the Investigator 
may jeopardize the subject or may require medical intervention to prevent one of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization). 
All SAEs that occur after any 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 within 24 hours of first awareness (Section 12.5). All SAEs 
should to be followed until the event resolved, the condition stabilized, was no longer considered 
clinically significant or the subject was lost to follow-up. Serious adverse events occurring after 
a subject’s final visit (including the last follow-up visit) should be reported to Sage or designee 
only if the Investigator considers the SAE to be related to study treatment.  
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 


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Investigator, between the subject’s consent to participate in the study and at the time of 
the procedure or treatment.  
12.3. 
Relationship to Study Drug 
The Investigator must make the determination of relationship to the study drug for each adverse 
event (not related, possibly related or probably related). The Investigator should decide whether, 
in his or her medical judgment, there is a reasonable possibility that the event may have been 
caused by the investigational product. If no valid reason exists for suggesting a relationship, then 
the adverse event should be classified as “not related.” If there is any valid reason, even if 
undetermined, for suspecting a possible cause-and-effect relationship between the investigational 
product and the occurrence of the adverse event, then the adverse event should be considered at 
least “possibly related.”  
Table 4: 
Relationship to Study Drug 
Relationship 
Definition 
Not Related: 
No relationship between the experience and the administration of study drug; related to 
other etiologies such as concomitant medications or subject’s clinical state. 
Possibly Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug.  
The reaction might have been produced by the subject’s clinical state or other modes of 
therapy administered to the subject, but this is not known for sure. 
Probably Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug.  
The reaction cannot be reasonably explained by the known characteristics of the subject’s 
clinical state or other modes of therapy administered to the subject. 
If the relationship between the adverse event/serious adverse event and the investigational 
product is determined to be “possible” or “probable”, the event will be considered related to the 
investigational product for the purposes of expedited regulatory reporting. 
12.4. 
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), 
resolution (date and time), intensity, causality, action taken, serious outcome (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) 


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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 12.2.1.2. An AE of severe intensity 
may not be considered serious. 
If a female subject becomes pregnant during this study, pregnancy information must be collected 
and recorded on the Sage Therapeutics 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 male subject’s female partner who becomes pregnant while the male subject 
is participating in study. After obtaining the necessary signed informed consent from the 
pregnant female partner directly, the investigator will follow the same pregnancy reporting 
procedures specified for pregnant female subjects. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented even if the subject was 
discontinued from the study. If the pregnancy ends for any reason before the anticipated date, the 
investigator should notify the sponsor. 
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 or a complication relating to 
the pregnancy occurs (e.g., spontaneous abortion). If the outcome of the pregnancy meets the 
criteria for immediate classification as an SAE (i.e., postpartum complication, spontaneous 
abortion, stillbirth, neonatal death, or congenital anomaly/birth defects), the investigator should 
follow the procedures for reporting an SAE. 
12.5. 
Reporting Serious Adverse Events 
All SAEs must be reported to Sage, or designee, immediately. A written account of the SAE 
must be sent to Sage, or designee, within 24 hours of the first awareness of the event by the 
investigator and/or his staff. 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 
(CRF) and/or study file. 
Any SAEs discovered by the Investigator after the designated follow up time for the study, 
should be promptly reported to Sage, or designee, according to the timelines noted above.  
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 ethics committee 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. Ethics Committee 
(EC)/Institutional Review Boards (IRBs) will be notified of SAEs and/or SUSARs as required by 
local law. In addition, appropriate Sponsor Drug Safety and Pharmacovigilance personnel, or 
designee, will unblind SUSARs for the purpose of regulatory reporting. The Sponsor, or 


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designee, will submit SUSARs (in blinded or unblinded fashion) to regulatory agencies 
according to local law. The Sponsor, or designee, will submit SUSARs to investigators in a 
blinded fashion. 
12.6. 
Emergency Identification of Study Drug 
During the study, 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 treatment received. Unless a subject is at 
immediate risk, the Investigator must make diligent attempts to contact Sage prior to unblinding 
the study treatment administered to a subject. Any request from the Investigator about the 
treatment administered to study subjects must be discussed with Sage. If the unblinding occurs 
without Sage’s knowledge, the Investigator must notify Sage as soon as possible and no later 
than the next business morning. All circumstances surrounding a premature unblinding must be 
clearly documented in the source records. Unless a subject is at immediate risk, any request for 
the unblinding of individual subjects must be made in writing to Sage and approved by the 
appropriate Sage personnel, according to standard operating procedures.  
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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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 database lock. Any 
deviations from or changes to the SAP following database lock will be described in detail in the 
clinical study report. 
13.1. 
Data Analysis Sets 
The Randomized set, defined as all subjects who are randomized, will be used for all data 
listings, unless otherwise specified. 
The Safety Set, defined as all subjects administered study drug, will be used to provide 
descriptive summaries of safety data.  
The Efficacy Set, defined as all subjects in the Safety Set with at least 1 post-baseline HAM-D 
evaluation, will be used for analysis of efficacy data.  
 
  
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. No imputation process will be 
used to estimate missing data. A sensitivity analysis will be used to investigate the impact of 
missing data if ≥5% of subjects in any treatment group have missing data. 
13.3. 
General Considerations 
For the purpose of all safety and efficacy analyses where applicable, baseline is defined as the 
last measurement prior to the start of study drug administration.  
Continuous endpoints will be summarized with number (n), mean, standard deviation (SD), 
median, minimum, and maximum. In addition, change from baseline values will be calculated at 
each time point and summarized descriptively. For categorical endpoints, descriptive summaries 
will include counts and percentages.  
13.4. 
Demographics and Baseline Characteristics 
Demographic data (Section 12.1.1) and baseline characteristics, such as height, weight, and body 
mass index (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.  


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13.5. 
Efficacy Analyses 
Efficacy data will be summarized using appropriate descriptive statistics and other data 
presentation methods where applicable; subject listings will be provided for all efficacy data. 
Subjects will be analyzed according to randomized treatment.  
The primary efficacy endpoint, the change from baseline to each assessment in HAM-D total 
score, will be analyzed using a mixed effects model for repeated measures (MMRM); the model 
will include treatment, baseline HAM-D total score, stratification factor, assessment time point, 
and time point-by-treatment as explanatory variables. All explanatory variables will be treated as 
fixed effects. All post-baseline time points will be included in the model. The main comparison 
will be between SAGE-217 and placebo at the 15-day time point. Model-based point estimates 
(ie, least squares [LS] means, 95% confidence intervals, and p-values) will be reported where 
applicable. An unstructured covariance structure will be used to model the within-subject errors. 
The Toeplitz or compound symmetry covariance structure will be used if there is a convergence 
issue with the unstructured covariance model.  
Similar to those methods described above for the primary endpoint, an MMRM will be used for 
the analysis of the change from baseline in other time points in HAM-D total score, MADRS 
total score, HAM-A total score, SF-36v2 score, sleep endpoints (eg, sleep latency (SL), total 
sleep time (TST), wake after sleep onset (WASO), ISI score and selected individual items and/or 
subscale scores.  
Generalized estimating equation (GEE) methods will be used for the analysis of HAM-D 
response (defined as ≥50% reduction from baseline in HAM-D total score) and HAM-D 
remission (defined as HAM-D total score of ≤7.0). GEE models will include terms for treatment, 
baseline score, stratification factor, assessment time point, and time point-by-treatment as 
explanatory variables. The comparison of interest will be the difference between SAGE-217 and 
matching placebo at the 15-day time point. Model-based point estimates (ie, odds ratios), 95% 
confidence intervals, and p-values will be reported.  
A GEE method will also be used for the analysis of CGI-I response including terms for 
treatment, baseline CGI-S score, stratification factor, assessment time point, and time point-by-
treatment as explanatory variables. 
 
13.6. 
Safety Analyses 
Safety and tolerability of study drug will be evaluated by incidence of adverse events/serious 
adverse events, concomitant medication usage, vital signs, clinical laboratory evaluations, and 
12-lead ECG. Suicidality will be monitored by the C-SSRS. Safety data will be listed by subject 
and summarized by treatment group. All safety summaries will be performed on the Safety Set. 
Where applicable, ranges of potentially clinical significant (PCS) values are provided in the 
SAP. 
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 (MedDRA) 


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Version 18.1 or higher, System Organ Class (SOC), 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 (see Section 12.3).  
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).  
13.6.2. 
Clinical Laboratory Evaluations 
Results of clinical laboratory parameters in each scheduled visit and mean changes from baseline 
will be summarized.in standard units. Normal range of each parameter is provided by the 
laboratory; shift from baseline to post-baseline values in abnormality of results will be provided. 
Potentially clinically significant values will be summarized by treatment. Any abnormal values 
deemed clinically significant by the investigator will be reported as an AE (see Section 12.2). 
Clinical laboratory results will be listed by subject and timing of collection. 
13.6.3. 
Physical Examinations 
The occurrence of a physical examination (Y/N) and the date performed will be listed by subject. 
Any clinically significant observation in physical examination will be reported as an AE (see 
Section 12.2). 
13.6.4. 
Vital Signs 
Results from each visit and mean changes from baseline in vital signs will be summarized by 
scheduled visit. Any abnormality deemed clinically significant by the investigator will be 
reported as an AE (see Section 12.2). Potentially clinically significant values will be summarized 
by treatment. Vital sign results will be listed by subject and timing of collection. 
13.6.5. 
12-Lead Electrocardiogram 
The following ECG parameters will be listed for each of the triplicate ECGs for each subject: 
heart rate, PR, QRS, QT, and QTcF; the derived mean of each parameter will also be listed. Any 
clinically significant abnormalities or changes in mean ECGs should be reported as an AE (see 
Section 12.2). Mean ECG data will be summarized by visit. Potentially clinically significant  
values of QTcF will be summarized by treatment. Electrocardiogram findings will be listed by 
subject and visit.  
13.6.6. 
Prior and Concomitant Medications 
Medications will be recorded at each study visit during the study and will be coded using World 
Health Organization-Drug dictionary (WHO-DD) September 2015, or later.  
All medications taken within 30 days prior to signing the ICF through the duration of the study 
will be recorded. In addition, all psychotropic medications taken 6 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 


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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.  
13.6.7. 
Columbia Suicide Severity Rating Scale 
Suicidality data collected on the C-SSRS at baseline and by visit during the Treatment Period 
will be summarized by treatment. Listings will include all data, including behavior type and/or 
category for Suicidal Ideation and Suicidal Behavior of the C-SSRS.  
 
 
 
 
 
 
13.8. 
Determination of Sample Size 
Assuming a two-sided alpha level of 0.05, a sample size of 399 evaluable subjects would provide 
90% power to detect a placebo-adjusted treatment difference of approximately 4 points in the 
primary endpoint, change from baseline in HAM-D total score at Day 15, assuming SD of 10 
points. Assuming an 11% dropout rate and a 1:1:1 randomization ratio within each stratum 
(antidepressant use at baseline, yes or no), approximately 450 total randomized subjects will be 
required to obtain 399 evaluable subjects. Evaluable subjects are defined as those randomized 
subjects who receive study drug and have valid baseline and at least 1 post-baseline HAM-D 
assessment. Additional subjects may be randomized if the dropout rate is greater than 11%. 


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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 (or designee) will visit the investigational study site per Sage Standard Operating 
Procedures 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. 
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 
about an inspection. 


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14.3. 
Institutional Review Board (IRB) or Ethics Committee (EC) 
The Principal Investigator must obtain IRB (or EC) approval for the 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 Practices 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 Informed Consent Form, 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 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 Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use and Good Clinical Practice 
guidelines, as well as all 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 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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19. 
LIST OF REFERENCES 
Busner J, Targum S. CGI-S. (2007a), as adapted from Kay, Stanley R, Positive and Negative 
Symptoms in Schizophrenia:Assessment and Research.  Clinical and Experimental Psychiatry, 
Monograph No. 5.  Brunner/Mazel, 1991.  Modified from Guy W. Clinical Global Impressions: 
In ECDEU Assessment Manual for Psychopharmacology. 1976; 218-22. Revised DHEW Pub. 
(ADM) Rockville, MD: National Institute for Mental Health.   
Busner J, Targum S. CGI-I.  (2007b), as adapted from Spearing, et al.  Psychiatry Research, 
1997;73:159-71.  Modified from Guy W. Clinical Global Impressions: In ECDEU Assessment 
Manual for Psychopharmacology. 1976; 218-22. Revised DHEW Pub. (ADM) Rockville, MD: 
National Institute for Mental Health.   
Conradi HJ, Ormel J, de Jonge P. Presence of individual (residual) symptoms during depressive 
episodes and periods of remission: a 3-year prospective study. Psychol Med. 2011 
Jun;41(6):1165-74. 
Drugan RC, Morrow AL, Weizman R, et al. Stress-induced behavioral depression in the rat is 
associated with a decrease in GABA receptor-mediated chloride ion flux and brain 
benzodiazepine receptor occupancy. Brain Res. 1989;487: 45–51. 
DSM-5.  Diagnostic and statistical manual of mental disorders (5th ed.).  American Psychiatric 
Association 2013.  Arlington, VA: American Psychiatric Publishing. 
Gerner RH, Hare TA. GABA in normal subjects and patients with depression, schizophrenia, 
mania, and anorexia nervosa. Am J Psychiatry. 1981;138:1098–101. 
Greenberg PE, Fournier AA, Sisitsky T, Pike CT, Kessler RC. The economic burden of adults 
with major depressive disorder in the United States (2005 and 2010). J Clin Psychiatry. 2015 
Feb;76(2):155-62. 
Honig A, Bartlett JR, Bouras N, Bridges PK. Amino acid levels in depression: a preliminary 
investigation. J Psychiatr Res. 1988; 22:159–64. 
Luscher B, Shen Q, Sahir N. The GABAergic deficit hypothesis of major depressive disorder. 
Mol Psychiatry. 2011;16(4):383-406. 
Maguire J, Mody I. GABA(A)R plasticity during pregnancy: Relevance to postpartum 
depression. Neuron. 2008;59(2);207-13.   
Maguire J, Ferando I, Simonsen C, Mody I. Excitability changes related to GABAA receptor 
plasticity during pregnancy. J Neurosci. 2009;29(30):9592-601.   
Mann JJ, Oguendo MA, Watson KT, et al. Anxiety in major depression and cerebrospinal fluid 
free gamma-aminobutyric acid. Depress Anxiety. 2014;31(10):814-21. 
   
Morin CM, Belleville G, Bélanger L, Ivers H. The Insomnia Severity Index: Psychometric 
Indicators to Detect Insomnia Cases and Evaluate Treatment Response. Sleep. 2011;34(5):601-
608. 


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Olfson M, Marcus SC, Shaffer D. Antidepressant drug therapy and suicide in severely depressed 
children and adults: A case-control study. Archives of general psychiatry. 2006:63(8);865-872. 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The Columbia-
Suicide Severity Rating Scale: initial validity and internal consistency findings from three 
multisite studies with adolescents and adults. Am J Psychiatry. 2011 Dec;168(12):1266-77. 
Romera I, Pérez V, Ciudad A, et al. Residual symptoms and functioning in depression, does the 
type of residual symptom matter? A post-hoc analysis. BMC Psychiatry. 2013 Feb 11;13:51. 
Rudolph U, Knoflach F. Beyond classical benzodiazepines: novel therapeutic potential of 
GABAA receptor subtypes. Nat Rev Drug Discov. 2011 Jul 29;10(9):685-97. 
Schüle C, Nothdurfter C, Rupprecht R.  The role of allopregnanolone in depression and anxiety. 
Prog Neurobiol. 2014 Feb;113:79-87. 
Trivedi MH, Rush AJ, Wisniewski SR, et al. (STAR*D Study Team). Evaluation of outcomes 
with citalopram for depression using measurement-based care in STAR*D: implications for 
clinical practice. Am J Psychiatry. 2006 Jan;163(1):28-40. 
Ware JE Jr, Kosinski M, Bjorner JB, et al.  User's Manual for the SF-36v2 Health Survey.  2nd 
ed.  Lincoln, RI:  QualityMetric Incorporated; 2007. 
Williams JBW, Kobak KA. Development and reliability of a structured interview guide for the 
Montgomery-Asberg Depression Rating Scale (SIGMA). Br J Psychiatry. 2008;192:52-8. 
Williams JBW.  SIGH-D 24hr: V1.3 – 24 HR Version. 2013a. 
Williams JBW.  SIGH-D Past week:  Past Week Version. 2013b. 
Williams JBW.  SIGH-A 24hr: V1.3 – 24 HR Version. 2013c. 
Williams JBW.  SIGH-A Past week:  Past Week Version. 2013d. 
 


Protocol 217-MDD-301 Summary of Changes  
 
 
 
 
 
 
 
Sage Therapeutics 
Amendment #1, Version 2.0 
CONFIDENTIAL 
 
1 
Protocol 217-MDD-301 Amendment 1 
Date of Amendment: 25 September 2018 
A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study Evaluating 
the Efficacy of SAGE-217 in the Treatment of Adult Subjects with Major Depressive 
Disorder 
Rationale for Protocol Amendment 
The primary purpose for this protocol amendment is to prohibit the concomitant use of 
benzodiazepines, GABAA modulators, or GABAA-like acting drugs with SAGE-217 treatment. 
Additional changes are being implemented as outlined below. 
• Update terminology regarding timing of dosing (‘bedtime’ changed to ‘evening’) 
• Clarify exclusion criteria regarding treatment-resistant depression 
• Remove reticulocytes and propoxyphene from clinical laboratory assessments 
• Update language for reporting SAEs  
• Update language for reporting pregnancies, including partner pregnancies 
• Correct an error regarding version of HAM-A scale to be used 
• Prohibit breastfeeding during SAGE-217 treatment 
• Correct a response category for the Insomnia Severity Index 
 
A detailed summary of changes is provided in Table 1. Corrections to typographical errors, 
punctuation, grammar, abbreviations, and formatting are not detailed individually, nor are 
administrative updates such as revising the document date, updating the document header and 
version number, and updating the table of contents. 
 


Protocol 217-MDD-301 Summary of Changes  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Amendment #1, Version 2.0 
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Table 1: 
Protocol Amendment 1 Detailed Summary of Changes 
The primary section of the protocol affected by the changes in Protocol Amendment 1 is indicated. The corresponding related text has 
been revised throughout the protocol. Deleted text is indicated by strikeout; added text is indicated by bold font. 
Purpose: Prohibit the concomitant use of benzodiazepines, GABAA modulators, or GABAA-like acting drugs with SAGE-217 treatment 
The primary change occurs in 9.2.2. Prohibited Medications 
Changed text: 
The following specific classes of medications are prohibited at any time during the treatment period: 
• 
Initiation of new psychotropic medications  
• 
Use of any benzodiazepines, GABAA modulators, or GABAA-like acting drugs 
• 
Exposure to another investigational medication or device 
• 
Any known strong inhibitors CYP3A4  
• 
Use of any CYP inducer, such as such as rifampin, carbamazepine, ritonavir, enzalutamide, efavirenz, nevirapine, 
phenytoin, phenobarbital and St John’s Wort. 
Sections also affected by this change:  
• 
Synopsis, 8.1. Subject Inclusion Criteria (updated #7, added new #8), 8.2. Subject Exclusion Criteria (added #19), 9.2.1 Prior and 
Concomitant Medications and/or Supplements 
Purpose: Update terminology regarding timing of dosing 
The primary change occurs in Section 9.1 Study Drug 
Changed text: 
Subjects will self-administer SAGE-217 (20 or 30 mg) or matching placebo orally once daily in the evening at bedtime 
with food for 14 days. 
Sections also affected by this change:  
• 
Synopsis, 5.4.Dose Justification, 7.1. Overall Study Design, 9.3. Treatment Adherence, 10.5. Study Drug Administration 


Protocol 217-MDD-301 Summary of Changes  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Amendment #1, Version 2.0 
CONFIDENTIAL 
 
3 
Purpose: Clarify exclusion criteria regarding treatment-resistant depression 
The primary change occurs in Section 8.2. Subject Exclusion Criteria #4 
Changed text: 
4. Subject has a history of 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 an adequate amount of time (ie, at least 4 weeks of treatment). Massachusetts General Hospital 
Antidepressant Treatment Response Questionnaire (MGH ATRQ) will be used for this purpose. 
Sections also affected by this change:  
• 
Synopsis, Section 12.1.1. Demographic/Medical History 
Purpose: Remove reticulocytes from clinical laboratory assessments 
The primary change occurs in Table 3 ‘Clinical Laboraotry Tests’ 
Changed text: 
Hematology  
Red blood cell count 
Hemoglobin  
Hematocrit  
White blood cell count with differential  
Reticulocytes 
Platelet count 
Red blood cell morphology 
Sections also affected by this change:  
• 
Not applicable 


Protocol 217-MDD-301 Summary of Changes  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Amendment #1, Version 2.0 
CONFIDENTIAL 
 
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Purpose: Update language for reporting SAEs to be consistent with current program standards 
The primary change occurs in 12.2.1.2. Serious Adverse Event (SAE) 
Changed text: 
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 within 24 hours of first 
awareness (Section 12.5). All SAEs should to be followed until the event resolved, the condition stabilized, was no 
longer considered clinically significant or the subject was lost to follow-up. Serious adverse events occurring after a 
subject’s final visit (including the last follow-up visit) should be reported to Sage or designee only if the Investigator 
considers the SAE to be related to study treatment. 
Sections also affected by this change:  
• 
Not applicable 
Purpose: Update language for reporting pregnancies, including partner pregnancies to be consistent with current program standards 
The primary change occurs in Section 12.4. Recording Adverse Events 
Formerly read: 
If a female subject becomes pregnant during this study, pregnancy information must be collected and recorded on 
the Sage Therapeutics 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 male subject’s female partner who 
becomes pregnant while the male subject is participating in study. After obtaining the necessary signed informed 
consent from the pregnant female partner directly, the investigator will follow the same pregnancy reporting 
procedures specified for pregnant female subjects. Should a pregnancy occur, it must be reported and recorded on the 
Sage Therapeutics pregnancy notification form. Pregnancy in itself is not regarded as an AE unless there is a suspicion 
that an investigational product may have interfered with the effectiveness of a contraceptive medication. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or congenital abnormality) 
must be followed up and documented on the Sage Therapeutics pregnancy outcome form, even if the subject was 
discontinued from the study. If the pregnancy ends for any reason before the anticipated date, the investigator 
should notify the sponsor. All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages 
should also be reported and handled as SAEs.  
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 or a complication relating to the pregnancy occurs (e.g., 
spontaneous abortion). If the outcome of the pregnancy meets the criteria for immediate classification as an SAE 
(i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly/birth 
defects), the investigator should follow the procedures for reporting an SAE. 


Protocol 217-MDD-301 Summary of Changes  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Amendment #1, Version 2.0 
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Now reads: 
If a female subject becomes pregnant during this study, pregnancy information must be collected and recorded on the 
Sage Therapeutics 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 male subject’s female partner who becomes 
pregnant while the male subject is participating in study. After obtaining the necessary signed informed consent from the 
pregnant female partner directly, the investigator will follow the same pregnancy reporting procedures specified for 
pregnant female subjects.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or congenital abnormality) 
must be followed up and documented even if the subject was discontinued from the study. If the pregnancy ends for any 
reason before the anticipated date, the investigator should notify the sponsor.  
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 or a complication relating to the pregnancy occurs (e.g., spontaneous 
abortion). If the outcome of the pregnancy meets the criteria for immediate classification as an SAE (i.e., postpartum 
complication, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly/birth defects), the investigator 
should follow the procedures for reporting an SAE. 
Sections also affected by this change:  
• 
Not applicable 
Purpose: Correct an error regarding version of HAM-A scale to be used  
The primary change occurs in footnote ‘o’ in Table 1 ‘Schedule of Events’ 
Changed text: 
The assessment timeframe for HAM-D and HAM-A scales will refer to the past 7 days (1 week) at Screening and “Since 
Last Visit” for all other visits. The assessment timeframe for HAM-A scale will refer to the past 7 days (1 week) at 
all visits. 
Sections also affected by this change:  
• 
Not applicable 


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Amendment #1, Version 2.0 
CONFIDENTIAL 
 
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Purpose: Prohibit breastfeeding during SAGE-217 treatment 
The primary change occurs in Section 9.2.3. Other Restrictions 
Added text: 
Female subjects who are lactating or actively breastfeeding must stop giving breast milk to the baby(ies) starting 
on Day 1 until 7 days after the last dose of study drug. 
Sections also affected by this change:  
• 
Synopsis, 8.2. Subject Exclusion Criteria 
Purpose: Correct a response category for the Insomnia Severity Index 
The primary change occurs in Section 11.1.6. Insomnia Severity Index (ISI) 
Changed text: 
The ISI is a validated questionnaire designed to assess the nature, severity, and impact of insomnia (Morin 2011). The ISI 
uses a 5-point Likert Scale to measure various aspects of insomnia severity (0 = none, 1 = mild, 2 = moderate; 3 = severe; 
4 = very severe), satisfaction with current sleep pattern (0 = very satisfied, 1 = satisfied, 2 = moderately satisfiedneutral, 
3 = dissatisfied, 4 = very dissatisfied), and various aspects of the impact of insomnia on daily functioning (0 = not at all, 1 
= a little, 2 = somewhat, 3 = much, 4 = very much). A total score of 0 to 7 = “no clinically significant insomnia,” 8 to 14 
= subthreshold insomnia,” 15 to 21 = “clinical insomnia (moderate severity),” and 22 to 28 = “clinical insomnia (severe).” 
Sections also affected by this change:  
• 
Not applicable 
 


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1. 
TITLE PAGE 
 
 
STUDY TITLE: A PHASE 3, MULTICENTER, DOUBLE-
BLIND, RANDOMIZED, PLACEBO-CONTROLLED 
STUDY EVALUATING THE EFFICACY OF SAGE-217 
IN THE TREATMENT OF ADULT SUBJECTS WITH 
MAJOR DEPRESSIVE DISORDER 
 
PROTOCOL NUMBER: 217-MDD-301 
 
Study Drug 
SAGE-217 
Clinical Phase 
Phase 3 
Sponsor 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 
Sponsor Contact 
Tel:
email:
Sponsor Medical Monitor 
 MD, MBA 
Tel: 
emai
Date of Original Protocol 
Version 1.0, 16 JUL 2018 
Date of Amendment 1 
Version 2.0, 25 SEP 2018 
Date of Amendment 2 
Version 3.0, 11 OCT 2018 
 
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. 


065
065


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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-301 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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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Sage Therapeutics 
Name of Investigational Product: 
SAGE-217 Capsules 
Name of Active Ingredient: 
SAGE-217 
Title of Study: A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study 
Evaluating the Efficacy of SAGE-217 in the Treatment of Adult Subjects with Major Depressive 
Disorder 
Number of Sites and Study Location: Approximately 55 sites in the United States 
Phase of development: 3 
Planned Duration of Subject Participation: 
Up to 73 days (up to 28-day Screening Period, 14-day Treatment Period, and 28-day (±3 days) 
Follow-up Period) 
Objectives: 
Primary:  
• 
To evaluate the efficacy of SAGE-217 in the treatment of major depressive disorder 
(MDD) compared to placebo. 
Secondary: 
• 
To evaluate the effect of SAGE-217 on sleep.  
• 
To assess patient-reported outcome (PRO) measures as they relate to health-related 
quality of life and depressive symptoms. 
Safety: 
• 
To evaluate the safety and tolerability of SAGE 217. 
 
 
 
  
 
 
Endpoints: 
Primary: 
• 
The primary efficacy endpoint is the change from baseline in the 17-item Hamilton 
Rating Scale for Depression (HAM-D) total score at Day 15. 
Secondary: 
• 
Change from baseline in the 17-item HAM-D total score at other timepoints 
• 
HAM-D response at Day 15 and all other time points, defined as a ≥50% reduction in 
HAM-D score from baseline  
• 
HAM-D remission at Day 15 and all other time points, defined as HAM-D total score 
≤7  
• 
Clinical Global Impression - Improvement (CGI-I) response at Day 15 and all other 
time points, defined as “much improved” or “very much improved”  


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• 
Change from baseline in Clinical Global Impression - Severity (CGI-S) score at Day 15 
and all other time points 
• 
Change from baseline in Hamilton Anxiety Rating Scale (HAM-A) total score at Day 15 
and all other time points  
• 
Change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) 
total score at Day 15 and all other time points 
• 
Change from baseline in HAM-D subscale and individual item scores at all time points 
• 
Change in sleep at Day 15 and all other time points, as assessed by 
o Insomnia Severity Index (ISI) 
o Subjective sleep parameters collected with the Core Consensus Sleep Diary 
• 
Change from baseline in PRO measures of health-related quality of life, as assessed by 
responses to the 36-item Short Form survey version 2 (SF-36v2), and of depressive 
symptoms, as assessed by the 9-item Patient Health Questionnaire 
Safety Endpoints: 
• 
Incidence and severity of adverse events/serious adverse events  
• 
Changes from baseline in clinical laboratory measures, vital signs, and 
electrocardiograms (ECGs) 
• 
Suicidal ideation and behavior using the Columbia Suicide Severity Rating Scale 
(C-SSRS)  
• 
Potential withdrawal symptoms using the 20-item Physician Withdrawal Checklist 
(PWC-20) 
 
 
  
 
  
 
 
 
 
 
Study Description:  
This is a randomized, double-blind, parallel-group, placebo-controlled study in subjects with 
MDD (MADRS total score ≥30). Randomization will be stratified based on use of 
antidepressant treatment (current/stable or not treated/withdrawn ≥60 days) at baseline and 
carried out within each stratum in a 1:1:1 ratio to receive SAGE-217 20 mg, SAGE-217 30 mg, 
or matching placebo; subjects will be treated for 14 days beginning on Day 1.  
The study will consist of a Screening Period of up to 28 days, a 14-day Treatment Period, and a 
4-week Follow-up Period.  
The Screening Period begins with the signing of the informed consent form (ICF) at the 
Screening Visit; 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 and CGI-S.  


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Antidepressants are permitted provided subjects are on a stable dose for at least 60 days prior to 
Day 1 and agree to continue on the stable dose through the follow-up period (Day 42). Initiation 
of new antidepressants or any other medications that may potentially have an impact on efficacy 
or safety endpoints will not be allowed between screening and completion of the Day 42 
assessments.  
Eligible subjects will be stratified based on use of antidepressant treatment (current/stable or not 
treated/withdrawn ≥60 days) and randomized within each stratum to one of 3 treatment groups 
(SAGE-217 20 mg, SAGE-217 30 mg, or matching placebo) in a 1:1:1 ratio. Subjects will self-
administer a single dose of study drug once daily in the evening with food, on an outpatient 
basis, for 14 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 treatment and follow-up periods as outlined in Table 1. 
Subjects who cannot tolerate study drug will be discontinued from study drug and will receive 
treatment as clinically indicated. 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. Follow-up visits should take place every 7 days after the last dose of treatment for 
a total of 4 follow-up visits. 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 both visits will be conducted. 
Number of Subjects (planned):  
Approximately 450 subjects will be randomized and dosed to obtain 399 evaluable subjects. 
Eligibility Criteria: 
Inclusion 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.  
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 a MADRS total score of ≥30 at screening and Day 1 (prior to dosing).  
7. Subjects taking psychotropic medications used to treat major depressive disorder (eg, 
antidepressants, atypical antipsychotics) must have been taking these medications at the 
same dose for at least 60 days prior to Day 1.  
8. Subject is willing to delay start of other antidepressant or antianxiety medications and 
any new pharmacotherapy regimens, including as-needed benzodiazepine anxiolytics 
and sleep aids, until after study completion.  
9. Female subject agrees to use one of the following methods of contraception during 
participation in the study and for 30 days following the last dose of study drug, unless 
they are postmenopausal (defined as no menses for 12 months without an alternative 


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medical cause and confirmed by follicle stimulating hormone [FSH] >40 mIU/mL), 
surgically sterile (hysterectomy or bilateral oophorectomy), or in sexual relationship(s) 
which do not carry a risk of pregnancy (eg, same-sex relationship(s)): 
• 
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 
• 
Sexual abstinence (no sexual intercourse) 
10. 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 is in sexual relationship(s) which do not carry a risk of pregnancy (eg, same-
sex relationship(s)). Acceptable methods of effective contraception for males includes 
sexual abstinence, 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 #9 for acceptable contraception methods). 
11. 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. 
12. Subject agrees to refrain from drugs of abuse and alcohol for the duration of the study. 
Exclusion Criteria: 
1. Subject has attempted suicide associated with the current episode of MDD. 
2. Subject had onset of the current depressive episode during pregnancy or 4 weeks 
postpartum, or the subject has presented for screening during the 6-month postpartum 
period. 
3. 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.  
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 within the current major depressive episode. 
6. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds.  


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7. Subject has a positive pregnancy test at screening or on Day 1 prior to the start of study 
drug administration or, if she is breastfeeding at Screening or on Day 1 (prior to 
administration of study drug), she does not agree to temporarily cease giving breast milk 
to her child(ren) from just prior to receiving study drug on Day 1 until 7 days after the 
last dose of study drug.  
8. Subject has detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus 
(HCV) and positive HCV viral load, or human immunodeficiency virus (HIV) antibody 
at screening. 
9. Subject has a clinically significant abnormal 12-lead ECG at the screening or baseline 
visits. NOTE: mean QT interval calculated using the Fridericia method (QTcF) of 
>450 msec in males or >470 msec in females will be the basis for exclusion from the 
study.  
10. Subject has active psychosis per Investigator assessment.  
11. Subject has a medical history of seizures.  
12. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder.  
13. 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. 
14. Subject has had exposure to another investigational medication or device within 30 days 
prior to screening.  
15. Subject has previously participated in a SAGE-217 or a SAGE-547 (brexanolone) 
clinical trial.  
16. Use of any known strong inhibitors of cytochrome P450 (CYP)3A4 within 28 days or 
five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, or Seville 
oranges, or products containing these within 14 days prior to the first dose of study 
drug.  
17. Use of any CYP inducer, such as such as rifampin, carbamazepine, ritonavir, 
enzalutamide, efavirenz, nevirapine, phenytoin, phenobarbital and St John’s Wort, 
within 28 days prior to the first dose of study drug. 
18. Subject has a positive drug and/or alcohol screen at screening or on Day 1 prior to 
dosing. 
19. Subject plans to undergo elective surgery during participation in the study. 
20. Subject is taking benzodiazepines or GABAA modulators/GABA-containing agents (eg, 
eszopiclone, zopiclone, zaleplon, and zolpidem) at Day -28. 
21. Subject is taking non-GABA anti-insomnia medications (eg melatonin, Benadryl [anti-
histamines], trazodone, low dose quetiapine, mirtazapine, etc) at Day -14.  
22. Subject has been diagnosed with and/or treated for any type of cancer (excluding basal 
cell carcinoma and in situ melanoma) within the past year prior to Screening. 


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23. Subject has a history of sleep apnea. 
24. Subject has had gastric bypass surgery, has a gastric sleeve or lap band, or has had any 
related procedures that interfere with gastrointestinal transit. 
Study Drug, 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: 
Placebo will be provided as hard gelatin capsules for oral administration containing only the 
excipients listed above for the active capsule.  
Duration of Treatment: 14 days 
Statistical methods: 
A detailed description of the analyses to be performed in the study will be provided in the 
Statistical Analysis Plan (SAP). The SAP will be finalized and approved prior to database lock 
and treatment unblinding. Any deviations from or changes to the SAP following database lock 
will be described in detail in the Clinical Study Report. 
General Considerations 
For the purpose of all safety and efficacy analyses where applicable, baseline is defined as the 
last measurement prior to the start of study drug administration.  
Continuous endpoints will be summarized descriptively with n, mean, standard deviation, 
median, minimum, and maximum. In addition, change from baseline values will be calculated at 
each time point and summarized descriptively. For categorical endpoints, descriptive summaries 
will include counts and percentages.  
Analysis Sets 
The Randomized Set, defined as all subjects who are randomized, will be used for all data 
listings, unless otherwise specified. 
The Safety Set, defined as all subjects administered study drug, will be used to provide 
descriptive summaries of safety data.  
The Efficacy Set, defined as all subjects in the Safety Set with at least 1 post-baseline HAM D 
evaluation, will be used for analysis of efficacy data.  
 
 
Determination of Sample Size 
Assuming a two-sided alpha level of 0.05, a sample size of 399 evaluable subjects would 
provide 90% power to detect a placebo-adjusted treatment difference of approximately 4 points 
in the primary endpoint, change from baseline in HAM-D total score at Day 15, assuming 
standard deviation (SD) of 10 points. Assuming a 11% dropout rate and a 1:1:1 randomization 
ratio within each stratum (antidepressant use at baseline, yes or no), approximately 450 total 
randomized subjects will be required to obtain 399 evaluable subjects. Evaluable subjects are 
defined as those randomized subjects who receive study drug and have valid baseline and at 


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least 1 post-baseline HAM-D assessment. Additional subjects may be randomized if the dropout 
rate is greater than 11%. 
Analysis of Primary Endpoint 
The estimand for the primary efficacy analysis is the mean change from baseline in HAM-D 
total score at Day 15. This will be analyzed using a mixed effects model for repeated measures 
(MMRM); the model will include treatment, baseline HAM-D total score, stratification factor, 
assessment time point, and time point-by-treatment as explanatory variables. All explanatory 
variables will be treated as fixed effects. All post-baseline time points will be included in the 
model. The main comparison will be between SAGE-217 and placebo at the 15-day time point. 
Model-based point estimates (ie, least squares [LS] means, 95% confidence intervals, and p-
values) will be reported where applicable. An unstructured covariance structure will be used to 
model the within-subject errors. 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.  
Analysis of Secondary Endpoints 
Similar to those methods described above for the primary endpoint, an MMRM will be used for 
the analysis of the change from baseline in other time points in HAM-D total score, MADRS 
total score, HAM-A total score, SF-36v2 score, PHQ-9 score, sleep endpoints (eg, sleep latency 
(SL), total sleep time (TST), wake after sleep onset (WASO)), ISI score and selected individual 
items and/or subscale scores in HAM-D for change from baseline.  
Generalized estimating equation (GEE) methods will be used for the analysis of HAM-D 
response (defined as ≥50% reduction from baseline in HAM-D total score) and HAM-D 
remission (defined as HAM-D total score of ≤7.0). GEE models will include terms for 
treatment, baseline score, stratification factor, assessment time point, and time point-by-
treatment as explanatory variables. The comparison of interest will be the difference between 
SAGE-217 and matching placebo at the 15-day time point. Model-based point estimates (ie, 
odds ratios), 95% confidence intervals, and p-values will be reported.  
A GEE method will also be used for the analysis of CGI-I response including terms for 
treatment, baseline CGI-S score, stratification factor, assessment time point, and time point-by-
treatment as explanatory variables. 
 
 
Safety Analysis 
Safety and tolerability of study drug will be evaluated by incidence of adverse events/serious 
adverse events, concomitant medication usage, vital signs, clinical laboratory evaluations, and 
12-lead ECG. Suicidality will be monitored by the C-SSRS. Potential withdrawal symptoms 
after discontinuation of SAGE-217 will be assessed using the PWC-20. 
 
 
 
 


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Table 1: 
Schedule of Events 
Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
Follow-up Period 
Visit Days 
D-28 to D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(±1d) 
and/or 
EOTa 
D18 
(±1d) 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
or 
ET 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
 
V7 
V8 
V9 
V10 
V11 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Duplicate Subject 
Checkb 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
 
 
Serum FSH testc 
X 
 
 
 
 
 
 
 
 
 
 
SCID-5-CT 
X 
 
 
 
 
 
 
 
 
 
 
MGH ATRQ 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Family History 
X 
 
 
 
 
 
 
 
 
 
 
Subject trainingd 
X 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Physical Examinatione 
X 
X 
 
 
 
 
 
 
 
 
X 
Body Weight/Height 
X 
 
 
 
 
X (wt 
only) 
 
 
 
 
X (wt 
only) 
Clinical Laboratory 
Assessmentsf 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
Drug & Alcohol Screeng 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Testh 
X 
X 
 
 
 
X 
 
 
X 
 
X 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signsk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGl 
X 
X 
 
 
 
X 
 
 
 
 
X 
C-SSRSm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAM-Dn, o 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MADRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAM-Ao 
 
X 
 
X 
 
X 
X 
 
X 
 
X 


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Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
Follow-up Period 
Visit Days 
D-28 to D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(±1d) 
and/or 
EOTa 
D18 
(±1d) 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
or 
ET 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
 
V7 
V8 
V9 
V10 
V11 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
CGI-S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SF-36v2 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
PHQ-9 
 
X 
 
X 
 
X 
 
X 
 
 
X 
ISI 
 
X 
 
X 
 
X 
X 
X 
X 
 
X 
PWC-20 
 
X 
 
 
 
X 
X 
X 
 
 
 
Sleep diaryp 
X 
 
 
Study Drug Dispensation 
 
X 
 
X 
 
 
 
 
 
 
 
Study Drug 
Administration 
 
X (Day 1 through Day 14) 
 
 
 
 
 
Study Drug 
Accountability/Return 
 
 
 
X 
 
X 
 
 
 
 
Xr 
Adverse Events/SAEss 
X 
Prior/Concomitant 
Medications/Procedurest 
X 
CGI-I = Clinical Global Impression – Improvement; CGI-S – Clinical Global Impression – Severity; 
 
 C-SSRS = Columbia Suicide Severity Rating Scale; D = day; EOT = end of 
treatment; ET = early termination; ECG = electrocardiogram; 
 FSH = follicle 
stimulating hormone; HAM-A = Hamilton Anxiety Rating Scale; HAM-D = Hamilton Rating Scale for Depression, 17-item; 
HIV = human immunodeficiency virus; ISI = Insomnia Severity Index; MADRS = Montgomery-Åsberg Depression Rating 
Scale; MGH ATRQ = Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; PHQ-9 = 9-item 
Patient Health Questionnaire; PWC-20 = 20-item Physician Withdrawal Checklist; O = Optional; 
; SCID-
5-CT = Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition Clinical Trials 
Version; SF-36v2 = 36-item Short Form survey version 2; V = visit; wt = weight 
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. Follow-up visits should take place every 7 days after the last dose of 
treatment for a total of 4 follow-up visits. 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 both visits will be 
conducted.  
b Subjects will be asked to authorize that their unique subject identifiers be entered into a registry (www.subjectregistry.com) 
with the intent of identifying subjects who may meet exclusion criteria for participation in another clinical study. 
c A serum follicle stimulating hormone test will be conducted at Screening for female subjects that are not surgically sterile to 
confirm whether a female subject with ≥12 months of spontaneous amenorrhea meets the protocol-defined criteria for being 
post-menopausal. 
d Subjects will be trained on use of software applications and devices necessary for the conduct of the study by site personnel. 


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e A full physical examination will be conducted at Screening and abbreviated physical examinations will be conducted thereafter. 
A full physical examination includes assessment of body systems (eg, head, eye, ear, nose, and throat; heart; lungs; abdomen; 
and extremities). 
f Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. 
g Urine toxicology for selected drugs of abuse (as per the lab manual) and breath test for alcohol. 
h Serum pregnancy test at screening and urine pregnancy test thereafter for female subjects that are not surgically sterile and do 
not meet the protocol-defined criteria for being post-menopausal. 
 
 
 
k Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing). Heart rate and 
blood pressure to be collected in supine position at all scheduled time points after the subject has been resting for 5 minutes and 
then after 1 minute in the standing position. Vital signs may be repeated at the discretion of the Investigator as clinically 
indicated. 
l Triplicate ECGs will be collected. 
 
m The “Baseline/Screening” C-SSRS form will be completed at screening. The “Since Last Visit” C-SSRS form will be 
completed at any time of day at all subsequent time points. 
n The HAM-D is to be completed as early during the visit as possible. 
o The assessment timeframe for HAM-D scales will refer to the past 7 days (1 week) at Day 1 and “Since Last Visit” for all other 
visits. The assessment timeframe for HAM-A scale will refer to the past 7 days (1 week) at all visits. 
p Subjects are instructed to complete the Core Consensus Sleep Diary starting at least 7 days prior to Day 1 and then daily 
through Day 28. 
 
 
 
 
r To be performed at the ET visit only. 
s Adverse events will be collected starting at the time of informed consent and throughout the duration of the subject’s 
participation in the study. 
t Prior medications will be collected at Screening and concomitant medications and/or procedures will be collected at each 
subsequent visit. 
 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............14 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................19 
5. 
INTRODUCTION ......................................................................................................21 
5.1. 
Background of Major Depressive Disorder and Unmet Medical Need ......................21 
5.2. 
SAGE-217 ...................................................................................................................21 
5.3. 
Potential Risks and Benefits .......................................................................................22 
5.4. 
Dose Justification ........................................................................................................22 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................23 
6.1. 
Study Objective ..........................................................................................................23 
6.1.1. 
Primary Objective .......................................................................................................23 
6.1.2. 
Secondary Objective(s) ...............................................................................................23 
6.1.3. 
Safety Objective ..........................................................................................................23 
 
23 
6.2. 
Endpoints ....................................................................................................................23 
6.2.1. 
Primary Endpoint ........................................................................................................23 
6.2.2. 
Secondary Endpoint(s) ................................................................................................23 
6.2.3. 
Safety Endpoint(s) ......................................................................................................24 
 
24 
7. 
INVESTIGATIONAL PLAN .....................................................................................25 
7.1. 
Overall Study Design ..................................................................................................25 
7.2. 
Number of Subjects ....................................................................................................25 
7.3. 
Treatment Assignment ................................................................................................25 
7.4. 
Dose Adjustment Criteria ...........................................................................................26 
7.5. 
Criteria for Study Termination ...................................................................................26 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................27 
8.1. 
Subject Inclusion Criteria ...........................................................................................27 
8.2. 
Subject Exclusion Criteria ..........................................................................................28 
8.3. 
Subject Withdrawal Criteria .......................................................................................29 


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8.3.1. 
Replacement of Subjects .............................................................................................30 
9. 
TREATMENT OF SUBJECTS ..................................................................................31 
9.1. 
Study Drug ..................................................................................................................31 
9.2. 
Prior Medications, Concomitant Medications, and Restrictions ................................31 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................31 
9.2.2. 
Prohibited Medications ...............................................................................................31 
9.2.3. 
Other Restrictions .......................................................................................................32 
9.3. 
Treatment Adherence ..................................................................................................32 
9.4. 
Randomization and Blinding ......................................................................................32 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................34 
10.1. 
Description of Study Drug ..........................................................................................34 
10.2. 
Study Drug Packaging and Labeling ..........................................................................34 
10.3. 
Study Drug Storage .....................................................................................................34 
10.4. 
Study Drug Preparation ..............................................................................................34 
10.5. 
Study Drug Administration.........................................................................................34 
10.6. 
Study Drug Accountability .........................................................................................34 
10.7. 
Study Drug Handling and Disposal ............................................................................35 
11. 
ASSESSMENT OF EFFICACY 
 .............................36 
11.1. 
Efficacy Assessments .................................................................................................36 
11.1.1. 
Hamilton Rating Scale for Depression (HAM-D) ......................................................36 
11.1.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) ........................................36 
11.1.3. 
Hamilton Anxiety Rating Scale (HAM-A) .................................................................36 
11.1.4. 
Clinical Global Impression (CGI) ..............................................................................37 
11.1.5. 
Short Form-36 Version 2 (SF-36v2) ...........................................................................37 
11.1.6. 
Patient Health Questionnaire (PHQ-9) .......................................................................37 
11.1.7. 
Insomnia Severity Index (ISI) ....................................................................................38 
11.1.8. 
Core Consensus Sleep Diary ......................................................................................38 
 
38 
 
38 
 
39 
 
39 
 
39 


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12. 
ASSESSMENT OF SAFETY .....................................................................................40 
12.1. 
Safety Parameters .......................................................................................................40 
12.1.1. 
Demographic/Medical History ...................................................................................40 
12.1.2. 
Weight and Height ......................................................................................................40 
12.1.3. 
Physical Examination .................................................................................................40 
12.1.4. 
Vital Signs ..................................................................................................................40 
12.1.5. 
Electrocardiogram (ECG) ...........................................................................................41 
12.1.6. 
Laboratory Assessments .............................................................................................41 
12.1.6.1. 
Drugs of Abuse and Alcohol ......................................................................................43 
12.1.6.2. 
Pregnancy Screen ........................................................................................................43 
12.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................43 
12.1.8. 
Physician Withdrawal Checklist .................................................................................43 
12.2. 
Adverse and Serious Adverse Events .........................................................................44 
12.2.1. 
Definition of Adverse Events .....................................................................................44 
12.2.1.1. 
Adverse Event (AE) ....................................................................................................44 
12.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................44 
12.3. 
Relationship to Study Drug ........................................................................................45 
12.4. 
Recording Adverse Events .........................................................................................46 
12.5. 
Reporting Serious Adverse Events .............................................................................46 
12.6. 
Emergency Identification of Study Drug ....................................................................47 
13. 
STATISTICS ..............................................................................................................48 
13.1. 
Data Analysis Sets ......................................................................................................48 
13.2. 
Handling of Missing Data ...........................................................................................48 
13.3. 
General Considerations ...............................................................................................48 
13.4. 
Demographics and Baseline Characteristics ...............................................................48 
13.5. 
Efficacy Analyses .......................................................................................................49 
13.6. 
Safety Analyses ..........................................................................................................49 
13.6.1. 
Adverse Events ...........................................................................................................50 
13.6.2. 
Clinical Laboratory Evaluations .................................................................................50 
13.6.3. 
Physical Examinations ................................................................................................50 
13.6.4. 
Vital Signs ..................................................................................................................50 
13.6.5. 
12-Lead Electrocardiogram ........................................................................................50 


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13.6.6. 
Prior and Concomitant Medications ...........................................................................51 
13.6.7. 
Columbia Suicide Severity Rating Scale ....................................................................51 
13.6.8. 
Physician Withdrawal Checklist .................................................................................51 
 
51 
13.8. 
Determination of Sample Size ....................................................................................51 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................52 
14.1. 
Study Monitoring ........................................................................................................52 
14.2. 
Audits and Inspections ................................................................................................52 
14.3. 
Institutional Review Board (IRB) or Ethics Committee (EC) ....................................53 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................54 
16. 
ETHICS ......................................................................................................................55 
16.1. 
Ethics Review .............................................................................................................55 
16.2. 
Ethical Conduct of the Study ......................................................................................55 
16.3. 
Written Informed Consent ..........................................................................................55 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................56 
17.1. 
Inspection of Records .................................................................................................56 
17.2. 
Retention of Records ..................................................................................................56 
18. 
PUBLICATION POLICY ..........................................................................................57 
19. 
LIST OF REFERENCES ............................................................................................58 
 


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LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................11 
Table 2: 
Abbreviations and specialist terms .............................................................................19 
Table 3: 
Clinical Laboratory Tests ...........................................................................................41 
Table 4: 
Relationship to Study Drug ........................................................................................45 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and specialist terms 
Abbreviation or specialist term 
Explanation 
AE 
adverse event 
CGI-I 
Clinical Global Impression – Improvement 
CGI-S 
Clinical Global Impression – Severity 
CRF 
case report form 
CS 
clinically significant 
 
 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CYP 
cytochrome P450 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
end of treatment 
ET 
early termination 
 
 
FSH 
follicle stimulating hormone 
GABA 
γ-aminobutyric acid 
GEE 
generalized estimating equation 
HAM-A 
Hamilton Rating Scale for Anxiety 
HAM-D 
Hamilton Rating Scale for Depression 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ID 
identification  
IRB 
institutional review board 
IRT 
interactive response technology 
ISI 
Insomnia Severity Index 
MADRS 
Montgomery Åsberg Depression Rating Scale 


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Table 2: 
Abbreviations and specialist terms (Continued) 
Abbreviation or specialist term 
Explanation 
MDD 
major depressive disorder 
MGH ATRQ 
Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire 
MMRM 
mixed effects model for repeated measures 
NCS 
not clinically significant 
PCS 
Potentially clinically significant 
PHQ-9 
9-item Patient Health Questionnaire 
PK 
pharmacokinetic 
PRO 
patient-reported outcome 
PWC-20 
20-item Physician Withdrawal Checklist 
QTcF 
QT corrected according to Fridericia’s formula 
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 
SF-36v2 
36-item Short Form version 2 
SUSAR 
suspected, unexpected, serious, adverse reactions 
TEAE 
treatment-emergent adverse event 
WHO 
World Health Organization 
 


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5. 
INTRODUCTION 
5.1. 
Background of Major Depressive Disorder and Unmet Medical Need 
The World Health Organization (WHO) has identified depression as the leading cause of 
disability worldwide, and as a major contributor to the overall global burden of disease 
(http://www.who.int/mediacentre/factsheets/fs369/en/). Globally, depression has been estimated 
to affect over 300 million people. 
In the United States, the economic burden of depression, including workplace costs, direct costs 
and suicide-related costs, was estimated to be $210.5 billion in 2010 (Greenberg 2015). As per 
WHO statistics, over 800,000 people die due to suicide every year, and suicide is the second 
leading cause of death in 15- to 29-year-olds. The rate of US adults making a suicide attempt has 
increased (0.62% from 2004 to 2005 to 0.79% from 2012 to 2013), with a shift to more attempts 
among younger adults (42% to 50%, respectively) and among those with a depressive disorder 
(26% to 54%, respectively; Olfson 2017). 
In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), 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 (SSRIs), 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 (CSF) 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, consistent with the actions of other GABAA receptor potentiators 
(Rudolph 2011), exhibits potent anticonvulsant, anxiolytic, and sedative activity 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 [HAM-A], 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 HAM-A. 
SAGE-217 has been generally well tolerated in clinical studies to date. The most common 
treatment-emergent adverse events (TEAEs) were sedation, somnolence, and dizziness. Most 
adverse events (AEs) were reported as mild or moderate in intensity. Among the over 260 
subjects exposed to SAGE-217 in clinical trials, there have been no deaths and only one subject 
with essential tremor experienced a serious adverse event (SAE) of transient confusion leading to 
discontinuation of study drug. No other SAEs have been reported in any study of SAGE-217.  
Additional information on nonclinical and clinical data is provided in the Investigator’s 
Brochure.  
5.3. 
Potential Risks and Benefits 
Nonserious events of sedation, somnolence, and dizziness were the most commonly reported 
AEs with SAGE-217. Given the outcome of the Phase 2a study of SAGE-217 in subjects with 
MDD, the current significant unmet need in the treatment of depression, and a favorable benefit-
risk profile, further investigation of SAGE-217 in patients with MDD is justified. 
5.4. 
Dose Justification 
There will be 2 dose levels of SAGE-217 in this study in order to study dose ranging: 30 mg per 
day and 20 mg per day. The higher dose level of 30 mg per day is the maximum tolerated dose in 
the multiple ascending dose study of SAGE-217 in healthy subjects and is also the dose level that 
was effective and generally well tolerated in a Phase 2 study in subjects with MDD (217-MDD-
201). The lower dose of 20 mg per day will be studied in subjects with MDD for the first time in 
the current study and is anticipated to be well tolerated as it is lower than the maximum tolerated 
dose level. Due to sedation/somnolence observed in previous clinical trials when administered in 
the morning, and improved tolerability when given in the evening, both doses of 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 is to evaluate the efficacy of SAGE-217 in the treatment of MDD 
compared to placebo. 
6.1.2. 
Secondary Objective(s) 
Secondary objectives are: 
• To evaluate the effect of SAGE-217 on sleep  
• To assess patient-reported outcome (PRO) measures as they relate to health-related 
quality of life and depressive symptoms 
6.1.3. 
Safety Objective 
The safety objective is to evaluate the safety and tolerability of SAGE-217. 
 
 
 
 
 
 
 
 
6.2. 
Endpoints 
6.2.1. 
Primary Endpoint 
The primary endpoint of this study is the change from baseline in the 17-item HAM-D total score 
at Day 15. 
6.2.2. 
Secondary Endpoint(s) 
• Change from baseline in the 17-item HAM-D total score at other time points 
• HAM-D response at Day 15 and all other time points, defined as a ≥50% reduction in 
HAM-D score from baseline 
• HAM-D remission at Day 15 and all other time points, defined as HAM-D total 
score ≤7  
• CGI-I response at Day 15 and all other time points, defined as “much improved” or 
“very much improved” 
• Change from baseline in Clinical Global Impression - Severity (CGI-S) score at 
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• Change from baseline in HAM-A total score at Day 15 and all other time points  
• Change from baseline in the MADRS total score at Day 15 and all other time points 
• Change from baseline in HAM-D subscale and individual item scores at all time 
points 
• Change in sleep at Day 15 and all other time points, as assessed by: 
− Insomnia Severity Index (ISI) 
− Subjective sleep parameters collected with the Core Consensus Sleep Diary 
• Change from baseline in patient-reported outcome measures of health-related quality 
of life, as assessed by responses to the 36-item Short Form survey (SF-36) version 2, 
and of depressive symptoms, as assessed by the 9-item Patient Health Questionnaire 
(PHQ-9) 
6.2.3. 
Safety Endpoint(s) 
• Incidence and severity of adverse events/serious adverse events  
• Changes from baseline in clinical laboratory measures, vital signs, and 
electrocardiograms (ECGs) 
• Suicidal ideation and behavior using the Columbia Suicide Severity Rating Scale 
(C-SSRS)  
• Potential withdrawal symptoms using the 20-item Physician Withdrawal Checklist 
(PWC-20) 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a randomized, double-blind, parallel-group, placebo-controlled study in subjects with 
MDD (MADRS total score ≥30). The study will consist of a Screening Period of up to 28 days, a 
14-day Treatment Period, and a 4-week Follow-up Period.  
The Screening Period begins with the signing of the informed consent form (ICF) at the 
Screening Visit; the ICF must be signed prior to beginning any screening activities. At the time 
of providing informed consent for the study, subjects will also be asked to authorize that their 
unique subject identifiers be entered into a registry (www.subjectregistry.com) with the intent of 
identifying subjects who may meet exclusion criteria due to participation in another clinical 
study (Section 8.2). 
The diagnosis of MDD must be made according to Structured Clinical Interview for Diagnostic 
and 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 and CGI-S.  
Antidepressants are permitted provided subjects are on a stable dose for at least 60 days prior to 
Day 1 and agree to continue on the stable dose through the follow-up period (Day 42). Initiation 
of new antidepressants or any other medications that may potentially have an impact on efficacy 
or safety endpoints is prohibited between screening and completion of the Day 42 assessments.  
Eligible subjects will be stratified based on use of antidepressant treatment (current/stable or not 
treated/withdrawn ≥60 days) and randomized within each stratum to one of 3 treatment groups 
(SAGE-217 20 mg, SAGE-217 30 mg, or matching placebo) in a 1:1:1 ratio. Subjects will self-
administer a single dose of study drug with food once daily in the evening on an outpatient basis, 
for 14 days. Dose reductions are not permitted. Study drug administration will be monitored via 
a clinical monitoring service (see Section 9.3). 
Subjects will return to the study center during the treatment and follow-up periods as outlined in 
Table 1. 
7.2. 
Number of Subjects 
Approximately 450 subjects will be randomized and dosed to obtain 399 evaluable subjects (see 
Section 13.8). 
7.3. 
Treatment Assignment 
Subjects will be randomly assigned to a treatment group on Day 1. Randomization will be 
stratified based on use of antidepressant treatment (current/stable or not treated/withdrawn 
≥60 days) at baseline and performed within each stratum in a 1:1:1 ratio to receive SAGE-217 
20 mg, SAGE-217 30 mg, or matching placebo. 


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7.4. 
Dose Adjustment Criteria 
Dose adjustments are not permitted in this study. Subjects who cannot tolerate study drug will be 
discontinued from study drug and will receive treatment as clinically indicated (see Section 8.3). 
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 
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.  
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 a MADRS total score of ≥30 at screening and Day 1 (prior to dosing).  
7. Subjects taking psychotropic medications used to treat major depressive disorder (eg, 
antidepressants, atypical antipsychotics) must have been taking these medications at the 
same dose for at least 60 days prior to Day 1.  
8. Subject is willing to delay start of other antidepressant or antianxiety medications and 
any new pharmacotherapy regimens, including as-needed benzodiazepine anxiolytics and 
sleep aids, until after study completion.  
9. Female subject agrees to use one of the following methods of contraception during 
participation in the study and for 30 days following the last dose of study drug, unless 
they are postmenopausal (defined as no menses for 12 months without an alternative 
medical cause and confirmed by follicle stimulating hormone [FSH] >40 mIU/mL) 
and/or surgically sterile (hysterectomy or bilateral oophorectomy), or in sexual 
relationship(s) which do not carry a risk of pregnancy (eg, same-sex relationship(s)): 
• 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. 
• Sexual abstinence (no sexual intercourse). 
10. 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 is in sexual relationship(s) which do not carry a risk of pregnancy (eg, same-sex 
relationship(s)). Acceptable methods of effective contraception for males includes sexual 
abstinence, vasectomy, or a condom with spermicide used together with highly effective 


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female contraception methods if the female partner is of child-bearing potential (see 
Inclusion Criteria #9 for acceptable contraception methods). 
11. 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. 
12. 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 had onset of the current depressive episode during pregnancy or 4 weeks 
postpartum, or the subject has presented for screening during the 6-month postpartum 
period. 
3. 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.  
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 within the current major depressive episode. 
6. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds.  
7. Subject has a positive pregnancy test at screening or on Day 1 prior to the start of study 
drug administration or, if she is breastfeeding at Screening or on Day 1 (prior to 
administration of study drug), she does not agree to temporarily cease giving breast milk 
to her child(ren) from just prior to receiving study drug on Day 1 until 7 days after the 
last dose of study drug.  
8. Subject has detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) 
and positive HCV viral load, or human immunodeficiency virus (HIV) antibody at 
screening. 
9. Subject has a clinically significant abnormal 12-lead ECG at the screening or baseline 
visits. NOTE: mean QT interval calculated using the Fridericia method (QTcF) of 
>450 msec in males or >470 msec in females will be the basis for exclusion from the 
study.  
10. Subject has active psychosis per Investigator assessment.  
11. Subject has a medical history of seizures.  


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12. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder.  
13. 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. 
14. Subject has had exposure to another investigational medication or device within 30 days 
prior to screening.  
15. Subject has previously participated in a SAGE-217 or a SAGE-547 (brexanolone) clinical 
trial.  
16. Use of any known strong inhibitors of cytochrome P450 (CYP)3A4 within 28 days or 
five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, or Seville 
oranges, or products containing these within 14 days prior to the first dose of study drug.  
17. Use of any CYP inducer, such as such as rifampin, carbamazepine, ritonavir, 
enzalutamide, efavirenz, nevirapine, phenytoin, phenobarbital and St John’s Wort, within 
28 days prior to the first dose of study drug. 
18. Subject has a positive drug and/or alcohol screen at screening or on Day 1 prior to 
dosing. 
19. Subject plans to undergo elective surgery during participation in the study. 
20. Subject is taking benzodiazepines or GABAA modulators/GABA-containing agents (eg, 
eszopiclone, zopiclone, zaleplon, and zolpidem) at Day -28. 
21. Subject is taking non-GABA anti-insomnia medications (eg melatonin, Benadryl [anti-
histamines], trazodone, low dose quetiapine, mirtazapine, etc) at Day -14.  
22. Subject has been diagnosed with and/or treated for any type of cancer (excluding basal 
cell carcinoma and in situ melanoma) within the past year prior to Screening. 
23. Subject has a history of sleep apnea. 
24. Subject has had gastric bypass surgery, has a gastric sleeve or lap band, or has had any 
related procedures that interfere with gastrointestinal transit. 
8.3. 
Subject Withdrawal Criteria 
Subjects may withdraw from the study drug or terminate from the study at any time for any 
reason. 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).  


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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 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.  
Subjects who discontinue study drug early should return to the site for an end of treatment (EOT) 
visit as soon as possible, preferably the day after treatment is discontinued. Follow-up visits 
should take place every 7 days after the last dose of treatment for 28 days. 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.  
A subject will be deemed lost to follow-up after attempts at contacting the subject have been 
unsuccessful. 
8.3.1. 
Replacement of Subjects 
Subjects will not be replaced. Additional subjects may be randomized if the drop-out rate is 
higher than anticipated (Section 13.8). 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Study Drug 
Subjects will self-administer SAGE-217 (20 or 30 mg) or matching placebo orally once daily in 
the evening with food for 14 days.  
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 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.  
Antidepressants or atypical antipsychotics that have been taken at the same dose for at least 
60 days prior to Day 1 are permitted if the subject intends to continue the stable dose through the 
follow-up period (Day 42). 
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 
The following specific classes of medications are prohibited: 
• Initiation of new psychotropic medications at any time during the study 
• Initiation of new antidepressant therapy from 60 days prior to Day 1 through the 
duration of the study 
• Use of any benzodiazepines, GABAA modulators, GABAA-like acting drugs, or 
GABA-containing agents from Day -28 through the duration of the study 
• Use of any non-GABA anti-insomnia medications (eg, melatonin, Benadryl [anti-
histamines], trazodone, low dose quetiapine, mirtazapine, etc) from Day -14 through 
the duration of the study 
• Exposure to another investigational medication or device from 30 days prior to 
Screening through the duration of the study 


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• Any known strong inhibitors CYP3A4 from Day -28 or 5 half-lives prior to Day 1 
(whichever is longer) through the duration of the study 
• Use of any CYP inducer, such as such as rifampin, carbamazepine, ritonavir, 
enzalutamide, efavirenz, nevirapine, phenytoin, phenobarbital and St John’s Wort 
from Day -28 through the duration of the study. 
9.2.3. 
Other Restrictions 
The consumption of grapefruit juice, grapefruit, or Seville oranges, or products containing these 
is prohibited throughout the treatment period. 
Consumption of alcohol or use of drugs of abuse is discouraged throughout the duration of the 
study. 
Female subjects who are lactating or actively breastfeeding must stop giving breast milk to the 
baby(ies) starting on Day 1 until 7 days after the last dose of study drug. 
Elective surgeries or procedures are prohibited during participation in the study. 
9.3. 
Treatment Adherence 
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 10.4 and Table 1).  
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 
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 by dose level, as well as missed doses. 
In addition, the subject will be instructed to bring their dosing kit to the site as outlined in 
Table 1, at which time the Investigator or designee will be responsible for ensuring the kit 
contains sufficient doses for the duration of the treatment period.  
All subjects should be reinstructed about the dosing requirement 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-compliance in the source documents. 
9.4. 
Randomization and Blinding 
This is a randomized double-blind, placebo-controlled study. Subjects who meet the entrance 
criteria will be randomized in a stratified manner based on use of antidepressant treatment 
(current/stable or not treated/withdrawn ≥60 days) at baseline; randomization will be done within 
each stratum in a 1:1:1 ratio to receive SAGE-217 20 mg, 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.  


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Randomization schedules will be generated by an independent statistician. The allocation to 
treatment group (SAGE-217 20 mg, SAGE-217 30 mg, or placebo) will be based on the 
randomization schedule. The randomization schedules will be kept strictly confidential, 
accessible only to authorized personnel until the time of unblinding. 
In 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 (see Section 12.6 for 
more details related to unblinding).  


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Description of Study Drug 
SAGE-217 is available as hard gelatin capsules containing a white to off-white powder. In 
addition to the specified amount of SAGE-217 Drug Substance, active SAGE-217 Capsules 
contain croscarmellose sodium, mannitol, silicified microcrystalline cellulose (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 Practices/Good Clinical Practices guidelines will 
be prepared by the Sponsor. 
10.3. 
Study Drug Storage 
SAGE-217 and matched placebo 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 is to be administered orally once daily in the evening with food. Practical options 
include taking SAGE-217 within 1 hour of dinner or taking SAGE-217 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 1.  


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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 randomize the 
eligible subject into the study 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. 
At the subsequent study drug-dispensing visit, 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 this visit must be 
recorded.  
If dispensing errors or discrepancies are discovered by site staff or sponsor’s designee, the 
Sponsor must be notified immediately. 
The 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. 


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11. 
ASSESSMENT OF EFFICACY 
 
All assessments will be conducted according to the schedule of assessments (Table 1). 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 (HAM-D) 
The primary outcome measure is the change from baseline in 17-item HAM-D total score at the 
end of the Treatment Period (Day 15). Every effort should be made for the same rater to perform 
all HAM-D assessments for an individual subject. An assessment timeframe of 7 days will be 
used on Day 1 and ‘Since Last Visit’ will be used for all other visits. 
The 17-item HAM-D will be used to rate the severity of depression in 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.  
In addition to the primary efficacy endpoint of change from baseline in HAM-D total score, 
several secondary efficacy endpoints will be derived for the HAM-D. Hamilton Rating Scale for 
Depression subscale scores will be calculated as the sum of the items comprising each subscale. 
Hamilton Rating Scale for Depression response will be defined as having a 50% or greater 
reduction from baseline in HAM-D total score. Hamilton Rating Scale for Depression remission 
will be defined as having a HAM-D total score of ≤7.  
11.1.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive 
episodes in subjects with mood disorders. It was designed as an adjunct to the HAM-D that 
would be more sensitive to the changes brought on by antidepressants and other forms of 
treatment than the Hamilton Scale.  
Higher MADRS scores indicate more severe depression, and each item yields a score of 0 to 6. 
The overall score ranges from 0 to 60 (Williams 2008). 
The MADRS total score will be calculated as the sum of the 10 individual item scores.  
11.1.3. 
Hamilton Anxiety Rating Scale (HAM-A) 
The 14-item HAM-A will be used to rate the severity of symptoms of anxiety (Williams 2013c; 
Williams 2013d). Each of the 14 items is defined by a series of symptoms, and measures both 
psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical 
complaints related to anxiety). Scoring for HAM-A is calculated by assigning scores of 0 (not 


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present) to 4 (very severe), with a total score range of 0 to 56, where <17 indicates mild severity, 
18 to 24, mild to moderate severity, and 25 to 30, moderate to severe severity. The HAM-A total 
score will be calculated as the sum of the 14 individual item scores. 
11.1.4. 
Clinical Global Impression (CGI) 
The CGI is a validated measure often utilized in clinical trials to allow clinicians to integrate 
several sources of information into a single rating of the subject’s condition. The CGI scale 
consists of 3 items. Only the first 2 items are being used in this study.  
The CGI-S uses a 7-point Likert scale to rate the severity of the subject’s illness at the time of 
assessment, relative to the clinician’s past experience with subjects who have the same diagnosis. 
Considering total clinical experience, a subject is assessed on severity of mental illness at the 
time of rating as 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately 
ill; 5=markedly ill; 6=severely ill; and 7=extremely ill (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 
“much improved.”  
11.1.5. 
Short Form-36 Version 2 (SF-36v2) 
The Medical Outcomes Study SF-36v2 is a 36-item measure of health status that has undergone 
validation in many different disease states (Ware 2007). The SF-36v2 covers eight health 
dimensions including four physical health status domains (physical functioning, role 
participation with physical health problems [role-physical], bodily pain, and general health) and 
four mental health status domains (vitality, social functioning, role participation with emotional 
health problems [role-emotional], and mental health). In addition, two summary scores, physical 
component summary and mental component summary, are produced by taking a weighted linear 
combination of the eight individual domains. The SF-36v2 is available with two recall periods: 
the standard recall period is 4 weeks and the acute recall period is 1 week. This study will use the 
acute version, which asks patients to respond to questions as they pertain to the past week. 
Higher SF-36v2 scores indicate a better state of health.  
11.1.6. 
Patient Health Questionnaire (PHQ-9) 
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 may 
complete questionnaires at baseline and at regular intervals thereafter. Scoring is based on 
responses to specific questions, as follows: 0=not at all; 1=several days; 2=more than half the 
days; and 3=nearly every day.  
The PHQ-9 total score will be calculated as the sum of the 9 individual item scores. The PHQ-9 
total score will be categorized as follows: 1 to 4=minimal depression, 5 to 9=mild depression, 10 


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to 14=moderate depression, 15 to 19=moderately severe depression; and 20 to 27=severe 
depression. 
11.1.7. 
Insomnia Severity Index (ISI) 
The ISI is a validated questionnaire designed to assess the nature, severity, and impact of 
insomnia (Morin 2011). The ISI uses a 5-point Likert Scale to measure various aspects of 
insomnia severity (0 = none, 1 = mild, 2 = moderate; 3 = severe; 4 = very severe), satisfaction 
with current sleep pattern (0 = very satisfied, 1 = satisfied, 2 = neutral, 3 = dissatisfied, 4 = very 
dissatisfied), and various aspects of the impact of insomnia on daily functioning (0 = not at all, 
1 = a little, 2 = somewhat, 3 = much, 4 = very much). A total score of 0 to 7 = “no clinically 
significant insomnia,” 8 to 14 = subthreshold insomnia,” 15 to 21 = “clinical insomnia (moderate 
severity),” and 22 to 28 = “clinical insomnia (severe).”  
11.1.8. 
Core Consensus Sleep Diary 
The Core Consensus Sleep Diary collects subjective sleep parameters, including sleep onset 
latency, total sleep time, and wake after sleep onset, number of awakenings, and sleep quality. 
The take-home subject sleep diary assessment will be administered using an eDiary solution. The 
eDiary will be captured using either a provisioned smartphone device or bring-your-own-device 
(BYOD) solution, depending on the subject’s preference. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
All assessments will be conducted according to the schedule of assessments (Table 1). 
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 (ICD-10) should be recorded. 
The Massachusetts General Hospital Antidepressant Treatment Response Questionnaire 
(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. 
12.1.2. 
Weight and Height 
Height (Screening only) and weight will be measured and documented. 
12.1.3. 
Physical Examination 
Physical examinations assessing body systems (eg, head, eyes, ears, nose, and throat; heart; 
lungs; abdomen; and extremities), as well as cognitive and neurological examinations and mental 
status examinations will be conducted and documented. 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. 
New or worsening abnormalities that are judged to be clinically significant will be recorded as 
AEs, assessed according to Section 12.2.1.1. 
12.1.4. 
Vital Signs 
Vital signs comprise both supine and standing for systolic and diastolic blood pressure and heart 
rate measurements. Heart rate and blood pressure are to be collected in supine position after the 
subject has been resting for 5 minutes and then after 1 minute in the standing position. 
Respiratory rate, pulse oximetry and temperature are collected once, in either position. Vital 
signs will be documented. When vital signs are scheduled at the same time as blood draws, vital 
signs will be obtained first. 
Any abnormality in vital signs will be interpreted by the Investigator as abnormal, NCS or 
abnormal, CS in source documents. New or worsening abnormalities that are judged to be 
clinically significant will be recorded as AEs, assessed according to Section 12.2.1.1.  


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12.1.5. 
Electrocardiogram (ECG) 
Supine 12-lead ECGs will be performed in triplicate at all scheduled time points. The standard 
intervals (heart rate, PR, QRS, QT, and QTcF) as well as any rhythm abnormalities will be 
recorded.
 
 
12.1.6. 
Laboratory Assessments 
Samples will be collected in accordance with acceptable laboratory procedures detailed in the 
laboratory manual.   
The clinical laboratory tests to be performed are listed in Table 3. 
Table 3: 
Clinical Laboratory Tests 
Hematology  
Serum Chemistry 
Urinalysis 
Coagulation 
Red blood cell count 
Hemoglobin  
Hematocrit  
White blood cell count with 
differential  
Platelet count 
Red blood cell morphology 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
Total protein 
Creatinine 
Blood urea nitrogen 
Creatine kinase 
Gamma-glutamyl transferase 
Potassium 
Sodium 
Lactate dehydrogenase 
Glucose 
Chloride 
Bicarbonate 
Calcium 
Phosphorus 
Triglycerides 
Thyroid stimulating hormone 
pH 
Specific gravity 
Protein 
Glucose 
Red blood cell 
Nitrite 
Leukocyte 
esterase 
Ketones 
Bilirubin 
Urobilinogen 
Activated partial 
thromboplastin 
time 
Prothrombin time 
International 
normalized ratio 


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Table 3: 
Clinical Laboratory Tests (Continued) 
Diagnostic  
 
 
 
Serum 
Urine 
Breathalyzer 
 
Hepatitis B 
Hepatitis C 
Reflex HCV RNA 
HIV-1 and -2 
Female subjects that are not 
surgically sterile and do not 
meet the protocol-defined 
criteria for being post-
menopausal: serum hCG 
Female subjects, if 
menopause is suspected 
and not surgically sterile: 
FSH 
Drug screen including: 
amphetamines, 
barbiturates, 
benzodiazepines, 
cannabinoids, cocaine, 
opiates, phencyclidine 
Female subjects that are not 
surgically sterile and do not 
meet the protocol-defined 
criteria for being post-
menopausal: urine hCG  
Alcohol 
 
Abbreviations: FSH = follicle stimulating hormone; hCG = human chorionic gonadotropin; HCV = hepatitis C 
virus; HIV = human immunodeficiency virus 
The central laboratory will perform laboratory tests for hematology, serum chemistry, urinalysis, 
and coagulation. The results of laboratory tests will be returned to the Investigator, who is 
responsible for reviewing and filing these results. All laboratory safety data will be transferred 
electronically to Sage Therapeutics or designee in the format requested by Sage Therapeutics.  
Laboratory reports must be signed and dated by the Investigator or subinvestigator indicating 
that the report has been reviewed and any abnormalities have been assessed for clinical 
significance. Any abnormalities identified prior to first dose will require clear and complete 
documentation in the source documents as to the investigator’s assessment of not clinically 
significant before proceeding with randomization.  
All clinical laboratory test results outside the central laboratory’s reference range will be 
interpreted by the Investigator as abnormal, NCS; or abnormal, CS in source documents. New or 
worsening abnormalities that are judged to be clinically significant will be recorded as AEs, 
assessed according to Section 12.2.1.1. A clinically significant laboratory abnormality following 
subject randomization will be followed until the abnormality returns to an acceptable level or a 
satisfactory explanation has been obtained. 
A serum follicle stimulating hormone test will be conducted at Screening to confirm whether a 
female subject with ≥12 months of spontaneous amenorrhea meets the protocol-defined criteria 
for being post-menopausal (Section 8.1). 
 
 
 
 
 
 


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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 3). A breath test 
for alcohol will be performed. 
12.1.6.2. Pregnancy Screen 
For female subjects that are not surgically sterile and do not meet the protocol-defined criteria 
for being post-menopausal, a serum pregnancy test will be performed at Screening and a urine 
pregnancy test will be performed at all other scheduled timepoints thereafter, including the ET 
visit for subjects who prematurely discontinue. 
12.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011). This scale 
consists of a baseline evaluation that assesses the lifetime experience of the subject with suicidal 
ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last 
study visit. The C-SSRS includes ‘yes’ or ‘no’ responses for assessment of suicidal ideation and 
behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being 
the most severe).  
The “Baseline/Screening” C-SSRS form will be completed at screening (lifetime history and past 
24 months). The “Since Last Visit” C-SSRS form will be completed at all subsequent time 
points, as outlined in Table 1. 
12.1.8. 
Physician Withdrawal Checklist 
The PWC is based on the 35-item Penn Physician Withdrawal Checklist that was developed in 
the 1960s to measure benzodiazepine and benzodiazepine-like discontinuation symptoms. The 
PWC-20 is a shorter version of the Penn Physician Withdrawal Checklist based on the 20 items 
that provided the best differentiation from placebo in previous trials. The PWC-20 is made up of 
a list of 20 symptoms (eg, loss of appetite, nausea-vomiting, diarrhea, anxiety-nervousness, 
irritability, etc) that are rated on a scale of 0 (not present) to 3 (severe) (Rickels 2008). The 
PWC-20 will be used to monitor for the presence of potential withdrawal symptoms following 
discontinuation of SAGE-217. 


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12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Definition of Adverse Events 
12.2.1.1. Adverse Event (AE) 
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 treatment has been administered. 
A TEAE is an AE that occurs after the first administration of any study drug. The term study 
drug includes any Sage investigational product, a comparator, or a placebo administered in a 
clinical trial. 
Laboratory abnormalities and changes from baseline in vital signs, ECGs, and physical 
examinations are considered AEs if they result in discontinuation or interruption of study 
treatment, require therapeutic medical intervention, meet protocol specific criteria (if applicable) 
and/or if the Investigator considers them to be clinically significant. Laboratory values and vital 
signs that meet the criteria for an SAE should be reported in an expedited manner. Laboratory 
abnormalities and changes from baseline in vital signs, ECGs, 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. 
12.2.1.2. Serious Adverse Event (SAE) 
A serious adverse event is any untoward medical occurrence that at any dose: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
An SAE may also be any other medically important event that, in the opinion of the Investigator 
may jeopardize the subject or may require medical intervention to prevent one of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization). 
All SAEs that occur after any 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 


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provided by Sage Therapeutics within 24 hours of first awareness (Section 12.5). All SAEs 
should to be followed until the event resolved, the condition stabilized, was no longer considered 
clinically significant or the subject was lost to follow-up. Serious adverse events occurring after 
a subject’s final visit (including the last follow-up visit) should be reported to Sage or designee 
only if the Investigator considers the SAE to be related to study treatment.  
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.  
12.3. 
Relationship to Study Drug 
The Investigator must make the determination of relationship to the study drug for each adverse 
event (not related, possibly related or probably related). The Investigator should decide whether, 
in his or her medical judgment, there is a reasonable possibility that the event may have been 
caused by the investigational product. If no valid reason exists for suggesting a relationship, then 
the adverse event should be classified as “not related.” If there is any valid reason, even if 
undetermined, for suspecting a possible cause-and-effect relationship between the investigational 
product and the occurrence of the adverse event, then the adverse event should be considered at 
least “possibly related.”  
Table 4: 
Relationship to Study Drug 
Relationship 
Definition 
Not Related: 
No relationship between the experience and the administration of study drug; related to 
other etiologies such as concomitant medications or subject’s clinical state. 
Possibly Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug.  
The reaction might have been produced by the subject’s clinical state or other modes of 
therapy administered to the subject, but this is not known for sure. 
Probably Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug.  
The reaction cannot be reasonably explained by the known characteristics of the subject’s 
clinical state or other modes of therapy administered to the subject. 
If the relationship between the adverse event/serious adverse event and the investigational 
product is determined to be “possible” or “probable”, the event will be considered related to the 
investigational product for the purposes of expedited regulatory reporting. 


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12.4. 
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), 
resolution (date and time), intensity, causality, action taken, serious outcome (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 12.2.1.2. An AE of severe intensity 
may not be considered serious. 
If a female subject becomes pregnant during this study, pregnancy information must be collected 
and recorded on the Sage Therapeutics 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 male subject’s female partner who becomes pregnant while the male subject 
is participating in study. After obtaining the necessary signed informed consent from the 
pregnant female partner directly, the investigator will follow the same pregnancy reporting 
procedures specified for pregnant female subjects. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented even if the subject was 
discontinued from the study. If the pregnancy ends for any reason before the anticipated date, the 
investigator should notify the sponsor. 
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 or a complication relating to 
the pregnancy occurs (e.g., spontaneous abortion). If the outcome of the pregnancy meets the 
criteria for immediate classification as an SAE (i.e., postpartum complication, spontaneous 
abortion, stillbirth, neonatal death, or congenital anomaly/birth defects), the investigator should 
follow the procedures for reporting an SAE. 
12.5. 
Reporting Serious Adverse Events 
All SAEs must be reported to Sage, or designee, immediately. A written account of the SAE 
must be sent to Sage, or designee, within 24 hours of the first awareness of the event by the 
investigator and/or his staff. 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.  


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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 
(CRF) and/or study file. 
Any SAEs discovered by the Investigator after the designated follow up time for the study, 
should be promptly reported to Sage, or designee, according to the timelines noted above.  
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 ethics committee 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. Ethics Committee 
(EC)/Institutional Review Boards (IRBs) will be notified of SAEs and/or SUSARs as required by 
local law. In addition, appropriate Sponsor Drug Safety and Pharmacovigilance personnel, or 
designee, will unblind SUSARs for the purpose of regulatory reporting. The Sponsor, or 
designee, will submit SUSARs (in blinded or unblinded fashion) to regulatory agencies 
according to local law. The Sponsor, or designee, will submit SUSARs to investigators in a 
blinded fashion. 
12.6. 
Emergency Identification of Study Drug 
During the study, 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 treatment received. Unless a subject is at 
immediate risk, the Investigator must make diligent attempts to contact Sage prior to unblinding 
the study treatment administered to a subject. Any request from the Investigator about the 
treatment administered to study subjects must be discussed with Sage. If the unblinding occurs 
without Sage’s knowledge, the Investigator must notify Sage as soon as possible and no later 
than the next business morning. All circumstances surrounding a premature unblinding must be 
clearly documented in the source records. Unless a subject is at immediate risk, any request for 
the unblinding of individual subjects must be made in writing to Sage and approved by the 
appropriate Sage personnel, according to standard operating procedures.  
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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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 database lock. Any 
deviations from or changes to the SAP following database lock will be described in detail in the 
clinical study report. 
13.1. 
Data Analysis Sets 
The Randomized set, defined as all subjects who are randomized, will be used for all data 
listings, unless otherwise specified. 
The Safety Set, defined as all subjects administered study drug, will be used to provide 
descriptive summaries of safety data.  
The Efficacy Set, defined as all subjects in the Safety Set with at least 1 post-baseline HAM-D 
evaluation, will be used for analysis of efficacy data.  
 
  
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. No imputation process will be 
used to estimate missing data. A sensitivity analysis will be used to investigate the impact of 
missing data if ≥5% of subjects in any treatment group have missing data. 
13.3. 
General Considerations 
For the purpose of all safety and efficacy analyses where applicable, baseline is defined as the 
last measurement prior to the start of study drug administration.  
Continuous endpoints will be summarized with number (n), mean, standard deviation (SD), 
median, minimum, and maximum. In addition, change from baseline values will be calculated at 
each time point and summarized descriptively. For categorical endpoints, descriptive summaries 
will include counts and percentages.  
13.4. 
Demographics and Baseline Characteristics 
Demographic data (Section 12.1.1) and baseline characteristics, such as height, weight, and body 
mass index (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.  


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13.5. 
Efficacy Analyses 
Efficacy data will be summarized using appropriate descriptive statistics and other data 
presentation methods where applicable; subject listings will be provided for all efficacy data. 
Subjects will be analyzed according to randomized treatment.  
The estimand for the primary efficacy analysis is the mean change from baseline in HAM-D total 
score at Day 15. This will be analyzed using a mixed effects model for repeated measures 
(MMRM); the model will include treatment, baseline HAM-D total score, stratification factor, 
assessment time point, and time point-by-treatment as explanatory variables. All explanatory 
variables will be treated as fixed effects. All post-baseline time points will be included in the 
model. The main comparison will be between SAGE-217 and placebo at the 15-day time point. 
Model-based point estimates (ie, least squares [LS] means, 95% confidence intervals, and p-
values) will be reported where applicable. An unstructured covariance structure will be used to 
model the within-subject errors. 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. 
Similar to those methods described above for the primary endpoint, an MMRM will be used for 
the analysis of the change from baseline in other time points in HAM-D total score, MADRS 
total score, HAM-A total score, SF-36v2 score, PHQ-9 score, sleep endpoints (eg, sleep latency 
(SL), total sleep time (TST), wake after sleep onset (WASO)), ISI score and selected individual 
items and/or subscale scores in HAM-D for change from baseline.  
Generalized estimating equation (GEE) methods will be used for the analysis of HAM-D 
response (defined as ≥50% reduction from baseline in HAM-D total score) and HAM-D 
remission (defined as HAM-D total score of ≤7.0). GEE models will include terms for treatment, 
baseline score, stratification factor, assessment time point, and time point-by-treatment as 
explanatory variables. The comparison of interest will be the difference between SAGE-217 and 
matching placebo at the 15-day time point. Model-based point estimates (ie, odds ratios), 95% 
confidence intervals, and p-values will be reported.  
A GEE method will also be used for the analysis of CGI-I response including terms for 
treatment, baseline CGI-S score, stratification factor, assessment time point, and time point-by-
treatment as explanatory variables. 
 
13.6. 
Safety Analyses 
Safety and tolerability of study drug will be evaluated by incidence of adverse events/serious 
adverse events, concomitant medication usage, vital signs, clinical laboratory evaluations, and 
12-lead ECG. Suicidality will be monitored by the C-SSRS. Potential withdrawal symptoms after 
discontinuation of SAGE-217 will be assessed using the PWC-20. Safety data will be listed by 
subject and summarized by treatment group. All safety summaries will be performed on the 


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Safety Set. Where applicable, ranges of potentially clinical significant (PCS) values are provided 
in the SAP. 
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 (MedDRA) 
Version 18.1 or higher, System Organ Class (SOC), 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 (see Section 12.3).  
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).  
13.6.2. 
Clinical Laboratory Evaluations 
Results of clinical laboratory parameters in each scheduled visit and mean changes from baseline 
will be summarized.in standard units. Normal range of each parameter is provided by the 
laboratory; shift from baseline to post-baseline values in abnormality of results will be provided. 
Potentially clinically significant values will be summarized by treatment. Any abnormal values 
deemed clinically significant by the investigator will be reported as an AE (see Section 12.2). 
Clinical laboratory results will be listed by subject and timing of collection. 
13.6.3. 
Physical Examinations 
The occurrence of a physical examination (Y/N) and the date performed will be listed by subject. 
Any clinically significant observation in physical examination will be reported as an AE (see 
Section 12.2). 
13.6.4. 
Vital Signs 
Results from each visit and mean changes from baseline in vital signs will be summarized by 
scheduled visit. Any abnormality deemed clinically significant by the investigator will be 
reported as an AE (see Section 12.2). Potentially clinically significant values will be summarized 
by treatment. Vital sign results will be listed by subject and timing of collection. 
13.6.5. 
12-Lead Electrocardiogram 
The following ECG parameters will be listed for each of the triplicate ECGs for each subject: 
heart rate, PR, QRS, QT, and QTcF; the derived mean of each parameter will also be listed. Any 
clinically significant abnormalities or changes in mean ECGs should be reported as an AE (see 
Section 12.2). Mean ECG data will be summarized by visit. Potentially clinically significant 
values of QTcF will be summarized by treatment. Electrocardiogram findings will be listed by 
subject and visit.  


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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 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.  
13.6.7. 
Columbia Suicide Severity Rating Scale 
Suicidality data collected on the C-SSRS at baseline and by visit during the Treatment Period 
will be summarized by treatment. Listings will include all data, including behavior type and/or 
category for Suicidal Ideation and Suicidal Behavior of the C-SSRS.  
13.6.8. 
Physician Withdrawal Checklist 
Potential withdrawal symptoms collected on the PWC-20 will be summarized by visit and 
treatment. Listings will include all data by subject. 
 
 
 
 
 
 
13.8. 
Determination of Sample Size 
Assuming a two-sided alpha level of 0.05, a sample size of 399 evaluable subjects would provide 
90% power to detect a placebo-adjusted treatment difference of approximately 4 points in the 
primary endpoint, change from baseline in HAM-D total score at Day 15, assuming SD of 
10 points. Assuming an 11% dropout rate and a 1:1:1 randomization ratio within each stratum 
(antidepressant use at baseline, yes or no), approximately 450 total randomized subjects will be 
required to obtain 399 evaluable subjects. Evaluable subjects are defined as those randomized 
subjects who receive study drug and have valid baseline and at least 1 post-baseline HAM-D 
assessment. Additional subjects may be randomized if the dropout rate is greater than 11%. 


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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 (or designee) will visit the investigational study site per Sage Standard Operating 
Procedures 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. 
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 
about an inspection. 


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14.3. 
Institutional Review Board (IRB) or Ethics Committee (EC) 
The Principal Investigator must obtain IRB (or EC) approval for the 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 Practices 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 Informed Consent Form, 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 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 Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use and Good Clinical Practice 
guidelines, as well as all 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 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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19. 
LIST OF REFERENCES 
Busner J, Targum S. CGI-S. (2007a), as adapted from Kay, Stanley R, Positive and Negative 
Symptoms in Schizophrenia:Assessment and Research.  Clinical and Experimental Psychiatry, 
Monograph No. 5.  Brunner/Mazel, 1991.  Modified from Guy W. Clinical Global Impressions: 
In ECDEU Assessment Manual for Psychopharmacology. 1976; 218-22. Revised DHEW Pub. 
(ADM) Rockville, MD: National Institute for Mental Health.   
Busner J, Targum S. CGI-I.  (2007b), as adapted from Spearing, et al.  Psychiatry Research, 
1997;73:159-71.  Modified from Guy W. Clinical Global Impressions: In ECDEU Assessment 
Manual for Psychopharmacology. 1976; 218-22. Revised DHEW Pub. (ADM) Rockville, MD: 
National Institute for Mental Health.   
Conradi HJ, Ormel J, de Jonge P. Presence of individual (residual) symptoms during depressive 
episodes and periods of remission: a 3-year prospective study. Psychol Med. 2011 
Jun;41(6):1165-74. 
Drugan RC, Morrow AL, Weizman R, et al. Stress-induced behavioral depression in the rat is 
associated with a decrease in GABA receptor-mediated chloride ion flux and brain 
benzodiazepine receptor occupancy. Brain Res. 1989;487: 45–51. 
DSM-5.  Diagnostic and statistical manual of mental disorders (5th ed.).  American Psychiatric 
Association 2013.  Arlington, VA: American Psychiatric Publishing. 
Gerner RH, Hare TA. GABA in normal subjects and patients with depression, schizophrenia, 
mania, and anorexia nervosa. Am J Psychiatry. 1981;138:1098–101. 
Greenberg PE, Fournier AA, Sisitsky T, Pike CT, Kessler RC. The economic burden of adults 
with major depressive disorder in the United States (2005 and 2010). J Clin Psychiatry. 2015 
Feb;76(2):155-62. 
Honig A, Bartlett JR, Bouras N, Bridges PK. Amino acid levels in depression: a preliminary 
investigation. J Psychiatr Res. 1988; 22:159–64. 
Luscher B, Shen Q, Sahir N. The GABAergic deficit hypothesis of major depressive disorder. 
Mol Psychiatry. 2011;16(4):383-406. 
Maguire J, Mody I. GABA(A)R plasticity during pregnancy: Relevance to postpartum 
depression. Neuron. 2008;59(2);207-13.   
Maguire J, Ferando I, Simonsen C, Mody I. Excitability changes related to GABAA receptor 
plasticity during pregnancy. J Neurosci. 2009;29(30):9592-601.   
Mann JJ, Oguendo MA, Watson KT, et al. Anxiety in major depression and cerebrospinal fluid 
free gamma-aminobutyric acid. Depress Anxiety. 2014;31(10):814-21. 
   
Morin CM, Belleville G, Bélanger L, Ivers H. The Insomnia Severity Index: Psychometric 
Indicators to Detect Insomnia Cases and Evaluate Treatment Response. Sleep. 2011;34(5):601-
608. 


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Olfson M, Marcus SC, Shaffer D. Antidepressant drug therapy and suicide in severely depressed 
children and adults: A case-control study. Archives of general psychiatry. 2006:63(8);865-872. 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The Columbia-
Suicide Severity Rating Scale: initial validity and internal consistency findings from three 
multisite studies with adolescents and adults. Am J Psychiatry. 2011 Dec;168(12):1266-77. 
Rickels K, Garcia-Espana F, Mandos LA, Case GW. Physician Withdrawal Checklist (PWC-20). 
J Clin Psychopharmacol. 2008;28(4):447-451. 
Romera I, Pérez V, Ciudad A, et al. Residual symptoms and functioning in depression, does the 
type of residual symptom matter? A post-hoc analysis. BMC Psychiatry. 2013 Feb 11;13:51. 
Rudolph U, Knoflach F. Beyond classical benzodiazepines: novel therapeutic potential of 
GABAA receptor subtypes. Nat Rev Drug Discov. 2011 Jul 29;10(9):685-97. 
Schüle C, Nothdurfter C, Rupprecht R.  The role of allopregnanolone in depression and anxiety. 
Prog Neurobiol. 2014 Feb;113:79-87. 
Trivedi MH, Rush AJ, Wisniewski SR, et al. (STAR*D Study Team). Evaluation of outcomes 
with citalopram for depression using measurement-based care in STAR*D: implications for 
clinical practice. Am J Psychiatry. 2006 Jan;163(1):28-40. 
Ware JE Jr, Kosinski M, Bjorner JB, et al.  User's Manual for the SF-36v2 Health Survey.  2nd 
ed.  Lincoln, RI:  QualityMetric Incorporated; 2007. 
Williams JBW, Kobak KA. Development and reliability of a structured interview guide for the 
Montgomery-Asberg Depression Rating Scale (SIGMA). Br J Psychiatry. 2008;192:52-8. 
Williams JBW.  SIGH-D 24hr: V1.3 – 24 HR Version. 2013a. 
Williams JBW.  SIGH-D Past week:  Past Week Version. 2013b. 
Williams JBW.  SIGH-A 24hr: V1.3 – 24 HR Version. 2013c. 
Williams JBW.  SIGH-A Past week:  Past Week Version. 2013d. 
 


Protocol 217-MDD-301 Summary of Changes  
 
 
 
 
 
 
 
Sage Therapeutics 
Amendment #2, Version 3.0 
CONFIDENTIAL 
 
1 
Protocol 217-MDD-301 Amendment 2 
Date of Amendment: 11 October 2018 
A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study Evaluating 
the Efficacy of SAGE-217 in the Treatment of Adult Subjects with Major Depressive 
Disorder 
Rationale for Protocol Amendment 
The primary purpose for this protocol amendment is as follows: 
• 
Add the 9-item Patient Health Questionnaire (PHQ-9) as a secondary endpoint to supplement 
efficacy assessments with a patient-reported outcome (PRO) measure that provides balanced 
assessment of the core symptoms of a major depressive episode 
• 
Add the 20-item Physician Withdrawal Checklist (PWC-20) as a safety endpoint to better 
characterize the clinical effects of the proposed time-limited use of SAGE-217 
• 
Add a Day 18 follow-up visit to evaluate potential withdrawal symptoms of SAGE-217 
• 
Replace HAM-D with MADRS as the assessment of MDD at screening to better capture 
depresstion presentations featuring hypersomnia 
• 
Increase exclusionary period for use of benzodiazepines and GABAA modulators/GABA-
containing agents to avoid confounding by the natural resolution of prolonged mild 
GABAergic withdrawal symptoms 
Additional changes are being implemented as outlined below: 
• 
Exclude subjects that have taken non-GABA anti-insomnia medications (eg melatonin, 
Benadryl [anti-histamines], trazodone, low dose quetiapine, mirtazapine, etc) within 14 days 
of initition of study drug. 
• 
Remove criterion that subjects must be ambulatory 
• 
Remove duplicate inclusion criterion #8 (reflected in exclusion criteria) 
• 
Include exception to contraception criteria for subjects in same-sex relationship(s) which do 
not carry a risk of pregnancy 
• 
Enhance exclusion of subjects with treatment-resistant depression within the current major 
depressive episode 
• 
Exclude subjects with and/or treated for any type of cancer (excluding basal cell carcinoma 
and in situ melanoma) within the past year 
• 
Exclude subjects with a history of sleep apnea 
• 
Exclude subjects that have had procedures that interfere with gastrointestinal transit 
• 
Define timeframes for each type of prohibited medication 
• 
Reiterate exclusion criterion prohibiting elective surgeries or procedures during participating 
in the study 
• 
Offer practical options for taking study drug with food in the evening 


Protocol 217-MDD-301 Summary of Changes  
 
 
 
 
 
 
 
Sage Therapeutics 
Amendment #2, Version 3.0 
CONFIDENTIAL 
 
2 
• 
Remove propoxyphene from urine laboratory panel 
• 
Clarify statical analyses of primary efficacy endpoint 
A detailed summary of changes is provided in Table 1. Corrections to typographical errors, 
punctuation, grammar, abbreviations, and formatting are not detailed individually, nor are 
administrative updates such as revising the document date, updating the document header and 
version number, and updating the table of contents. 
 


Protocol 217-MDD-301 Summary of Changes  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Amendment #2, Version 3.0 
CONFIDENTIAL 
 
3 
Table 1: 
Protocol Amendment 2 Detailed Summary of Changes 
The primary section of the protocol affected by the changes in Protocol Amendment 2 is indicated. The corresponding related text has 
been revised throughout the protocol. Deleted text is indicated by strikeout; added text is indicated by bold font. 
Purpose: Add PHQ-9 as a secondary endpoint to supplement efficacy assessments with a patient-reported outcome (PRO) measure that provides 
balanced assessment of the core symptoms of a major depressive episode. 
The primary change occurs in Section 6.2.2. Secondary Endpoint(s) 
Changed text: 
Change from baseline in patient-reported outcome measures of health-related quality of life, as assessed by responses to 
the 36-item Short Form survey (SF-36) version 2, and of depressive symptoms, as assessed by the 9-item Patient 
Health Questionnaire (PHQ-9) 
Sections also affected by this change:  
• 
Synopsis, Table 1 Schedule of Events, 6.1.2 Secondary Objective, new Section 11.1.6 Patient Health Questionnaire (PHQ-9), 13.5 
Efficacy Analyses 
Purpose: Add PWC-20 as a safety endpoint to better characterize the clinical effects of the proposed time-limited use of SAGE-217. 
The primary change occurs in Section 6.2.3. Safety Endpoint(s) 
Changed text: 
• 
Incidence and severity of adverse events/serious adverse events  
• 
Changes from baseline in clinical laboratory measures, vital signs, and electrocardiograms (ECGs) 
• 
Suicidal ideation and behavior using the Columbia Suicide Severity Rating Scale (C-SSRS)  
• 
Potential withdrawal symptoms using the 20-item Physician Withdrawal Checklist (PWC-20) 
Sections also affected by this change:  
• 
Synopsis, Table 1 Schedule of Events, new Section 12.1.8 Physician Withdrawal Checklist, 13.6 Safety Analyses, new 
section 13.6.8 Physician Withdrawal Checklist, 19 List of References 


Protocol 217-MDD-301 Summary of Changes  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sage Therapeutics 
Amendment #2, Version 3.0 
CONFIDENTIAL 
 
4 
Purpose: Add a Day 18 follow-up visit to evaluate potential withdrawal symptoms of SAGE-217. 
The primary change occurs in Table 1 Schedule of Events 
Changed text: 
 
Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
Follow-up Period 
Visit Days 
D-28 to D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(±1d) 
and/or 
EOTa 
D18 
(±1d) 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
or 
ET 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
 
V7 
V78 
V89 
V910 
V101 
Sections also affected by this change:  
• 
Not applicable 
Purpose: Remove criterion that subjects must be ambulatory. 
The primary change occurs in Section 8.1 Subject Inclusion Criteria 
Changed text: 
2. Subject is an ambulatory male or female between 18 and 65 years of age, inclusive. 
Sections also affected by this change:  
• 
Synopsis 
Purpose: Replace HAM-D with MADRS as assessment of MDD at screening to better capture depresstion presentations featuring hypersomnia. 
The primary change occurs in Section 8.1 Subject Inclusion Criteria 
Changed text: 
6. Subject has a MADRS HAM-D total score of ≥2230 at screening and Day 1 (prior to dosing). 
Sections also affected by this change:  
• 
Synopsis, 7.1. Overall Study Design 


Protocol 217-MDD-301 Summary of Changes  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sage Therapeutics 
Amendment #2, Version 3.0 
CONFIDENTIAL 
 
5 
Purpose: Remove HAM-D at Screening and update timeframe of assessments to reflect first HAM-D assessment on Day 1. 
The primary change occurs in Table 1 Schedule of Events  
Changed text: 
o The assessment timeframe for HAM-D scales will refer to the past 7 days (1 week) at Screening Day 1 and “Since Last 
Visit” for all other visits. The assessment timeframe for HAM-A scale will refer to the past 7 days (1 week) at all visits. 
Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
Follow-up Period 
Visit Days 
D-28 to D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(±1d) 
and/or 
EOTa 
D18 
(±1d) 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
or 
ET 
HAM-Dn, o 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sections also affected by this change:  
• 
11.1.1 Hamilton Rating Scale for Depression (HAM-D) 
Purpose: Remove duplicate inclusion criterion #8 (reflected in exclusion criteria). 
The primary change occurs in Section 8.1. Subject Inclusion Criteria 
Deleted text: 
8. Subjects taking benzodiazepines or GABAA modulators for insomnia (eg, eszopiclone, zopiclone, zaleplon, and 
zolpidem) have had these medications discontinued by Day -14. 
Sections also affected by this change:  
• 
Synopsis 


Protocol 217-MDD-301 Summary of Changes  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sage Therapeutics 
Amendment #2, Version 3.0 
CONFIDENTIAL 
 
6 
Purpose: Include exception to contraception criteria for subjects in same-sex relationship(s) which do not carry a risk of pregnancy. 
The primary change occurs in Section 8.1. Subject Inclusion Criteria 
Changed text: 
109. 
Female subject agrees to use one of the following methods of contraception during participation in the study and 
for 30 days following the last dose of study drug, unless they are postmenopausal (defined as no menses for 12 months 
without an alternative medical cause and confirmed by follicle stimulating hormone [FSH] >40 mIU/mL) and/or 
surgically sterile (hysterectomy or bilateral oophorectomy), or in sexual relationship(s) which do not carry a risk of 
pregnancy (eg, same-sex relationship(s)): 
• 
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. 
• 
Sexual abstinence (no sexual intercourse). 
110. 
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 is in sexual relationship(s) which do not carry a 
risk of pregnancy (eg, same-sex relationship(s)). Acceptable methods of effective contraception for males includes 
sexual abstinence, vasectomy, or a condom with spermicide used together with highly effective female contraception 
methods if the female partner is of child-bearing potential (see Inclusion Criteria #9 for acceptable contraception 
methods). 
Sections also affected by this change:  
• 
Synopsis 
Purpose: Enhance exclusion of subjects with treatment-resistant depression within the current major depressive episode. 
The primary change occurs in Section 8.2 Subject Exclusion Criteria 
Added text: 
5. Subject has had vagus nerve stimulation, electroconvulsive therapy, or has taken ketamine within the current 
major depressive episode. 
Sections also affected by this change:  
• 
Synopsis 


Protocol 217-MDD-301 Summary of Changes  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sage Therapeutics 
Amendment #2, Version 3.0 
CONFIDENTIAL 
 
7 
Purpose: Increase exclusionary period for use of benzodiazepines and GABAA modulators/GABA-containing agents to avoid confounding by the 
natural resolution of prolonged mild GABAergic withdrawal symptoms. 
The primary change occurs in Section 8.2 Subject Exclusion Criteria 
Changed text: 
1920. Subject is taking benzodiazepines or GABAA modulators at Day -14/GABA-containing agents (eg, eszopiclone, 
zopiclone, zaleplon, and zolpidem) at Day -28. 
Sections also affected by this change:  
• 
Synopsis, 9.2.2 Prohibited Medications 
Purpose: Exclude subjects that have taken non-GABA anti-insomnia medications (eg melatonin, Benadryl [anti-histamines], trazodone, low dose 
quetiapine, mirtazapine, etc) within 14 days of initition of study drug. 
The primary change occurs in Section 8.2 Subject Exclusion Criteria 
Added text: 
21. Subject is taking non-GABA anti-insomnia medications (eg melatonin, Benadryl [anti-histamines], trazodone, 
low dose quetiapine, mirtazapine, etc) at Day -14. 
Sections also affected by this change:  
• 
Synopsis, 9.2.2 Prohibited Medications 
Purpose: Exclude subjects with and/or treated for any type of cancer (excluding basal cell carcinoma and in situ melanoma) within the past year. 
The primary change occurs in Section 8.2 Subject Exclusion Criteria 
Added text: 
22. Subject has been diagnosed with and/or treated for any type of cancer (excluding basal cell carcinoma and in 
situ melanoma) within the past year prior to Screening. 
Sections also affected by this change:  
• 
Synopsis 
Purpose: Exclude subjects with a history of sleep apnea. 
The primary change occurs in Section 8.2 Subject Exclusion Criteria 
Added text: 
23. Subject has a history of sleep apnea. 
Sections also affected by this change:  
• 
Synopsis 
Purpose: Exclude subjects that have had procedures that interfere with gastrointestinal transit. 


Protocol 217-MDD-301 Summary of Changes  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sage Therapeutics 
Amendment #2, Version 3.0 
CONFIDENTIAL 
 
8 
The primary change occurs in Section 8.2 Subject Exclusion Criteria 
Added text: 
24. Subject has had gastric bypass surgery, has a gastric sleeve or lap band, or has had any related procedures 
that interfere with gastrointestinal transit. 
Sections also affected by this change:  
• 
Synopsis 
Purpose: Define timeframes for each type of prohibited medication. 
The primary change occurs in Section 9.2.2 Prohibited Medications 
Changed text: 
The following specific classes of medications are prohibited at any time during the treatment period: 
• 
Initiation of new psychotropic medications at any time during the study 
• 
Initiation of new antidepressant therapy from 60 days prior to Day 1 through the duration of the study 
• 
Use of any benzodiazepines, GABAA modulators, or GABAA-like acting drugs, or GABA-containing agents from 
Day -28 through the duration of the study 
• 
Use of any non-GABA anti-insomnia medications (eg, melatonin, Benadryl [anti-histamines], trazodone, low 
dose quetiapine, mirtazapine, etc) from Day -14 through the duration of the study 
• 
Exposure to another investigational medication or device from 30 days prior to Screening through the duration of 
the study 
• 
Any known strong inhibitors CYP3A4 from Day -28 or 5 half-lives prior to Day 1 (whichever is longer) through 
the duration of the study 
• 
Use of any CYP inducer, such as such as rifampin, carbamazepine, ritonavir, enzalutamide, efavirenz, nevirapine, 
phenytoin, phenobarbital and St John’s Wort from Day -28 through the duration of the study. 
Sections also affected by this change:  
• 
Not applicable 
Purpose: Reiterate exclusion criterion prohibiting elective surgeries or procedures during participating in the study. 
The primary change occurs in Section 9.2.3 Other Restrictions 
Added text: 
Elective surgeries or procedures are prohibited during participation in the study. 
Sections also affected by this change:  
• 
Not applicable 


Protocol 217-MDD-301 Summary of Changes  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sage Therapeutics 
Amendment #2, Version 3.0 
CONFIDENTIAL 
 
9 
Purpose: Offer practical options for taking study drug with food in the evening. 
The primary change occurs in Section 10.5 Study Drug Administration 
Added text: 
SAGE-217 is to be administered orally once daily in the evening with food. Practical options include taking SAGE-217 
within 1 hour of dinner or taking SAGE-217 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. 
Sections also affected by this change:  
• 
Synopsis 
Purpose: Remove propoxyphene from urine laboratory panel. 
The primary change occurs in Table 3 Clinical Laboratory Tests 
Removed text: 
Urine 
Drug screen including: amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates, phencyclidine, and 
propoxyphene 
Female subjects that are not surgically sterile and do not meet the protocol-defined criteria for being post-menopausal: 
urine hCG 
Sections also affected by this change:  
• 
Not applicable 


Protocol 217-MDD-301 Summary of Changes  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sage Therapeutics 
Amendment #2, Version 3.0 
CONFIDENTIAL 
 
10 
Purpose: To clarify statical analyses of primary efficacy endpoint. 
The primary change occurs in Section 13.5 Efficacy Analyses 
Changed text: 
The estimand for the primary efficacy analysis is the mean change from baseline in HAM-D total score at Day 15. 
This primary efficacy endpoint, the change from baseline to each assessment in HAM-D total score, will be analyzed 
using a mixed effects model for repeated measures (MMRM); the model will include treatment, baseline HAM-D total 
score, stratification factor, assessment time point, and time point-by-treatment as explanatory variables. All explanatory 
variables will be treated as fixed effects. All post-baseline time points will be included in the model. The main 
comparison will be between SAGE-217 and placebo at the 15-day time point. Model-based point estimates (ie, least 
squares [LS] means, 95% confidence intervals, and p-values) will be reported where applicable. An unstructured 
covariance structure will be used to model the within-subject errors. The Toeplitz or compound symmetry covariance 
structure will be used if there is a convergence issue with the unstructured covariance model. 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. 
Sections also affected by this change:  
• 
Synopsis 
 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-MDD-301 v4.0 
 
CONFIDENTIAL 
 
1 
 
1. 
TITLE PAGE 
 
 
A PHASE 3, MULTICENTER, DOUBLE-BLIND, 
RANDOMIZED, PLACEBO-CONTROLLED STUDY 
EVALUATING THE EFFICACY OF SAGE-217 IN THE 
TREATMENT OF ADULT SUBJECTS WITH MAJOR 
DEPRESSIVE DISORDER 
 
PROTOCOL NUMBER: 217-MDD-301 
 
Study Drug 
SAGE-217 
Clinical Phase 
Phase 3 
Sponsor 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 
Sponsor Contact 
Tel:
email
Sponsor Medical Monitor 
MD, MBA 
Tel:
email:
Date of Original Protocol 
Version 1.0, 16 JUL 2018 
Date of Amendment 1 
Version 2.0, 25 SEP 2018 
Date of Amendment 2 
Version 3.0, 11 OCT 2018 
Date of Amendment 3 
Version 4.0, 07 March 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. 


065
065


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-MDD-301 v4.0 
 
CONFIDENTIAL 
 
3 
 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for SAGE-217. I have read the 
217-MDD-301 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) 
 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-MDD-301 v4.0 
 
CONFIDENTIAL 
 
4 
 
2. 
SYNOPSIS 
Name of Sponsor/Company: 
Sage Therapeutics 
Name of Investigational Product: 
SAGE-217 Capsules 
Name of Active Ingredient: 
SAGE-217 
Title of Study: A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study 
Evaluating the Efficacy of SAGE-217 in the Treatment of Adult Subjects with Major Depressive 
Disorder 
Number of Sites and Study Location: Approximately 55 sites in the United States 
Phase of development: 3 
Planned Duration of Subject Participation: 
Up to 213 days (up to 28-day Screening Period, 14-day Double-blind Treatment Period, and up 
to 6 months (168 days) of Follow-up) 
Objectives: 
Primary:  
• 
To evaluate the efficacy of SAGE-217 in the treatment of major depressive disorder 
(MDD) compared to placebo. 
Secondary: 
• 
To evaluate the effect of SAGE-217 on sleep.  
• 
To assess patient-reported outcome (PRO) measures as they relate to health-related 
quality of life and depressive symptoms. 
Safety: 
• 
To evaluate the safety and tolerability of SAGE-217. 
 
 
 
  
 
 
Endpoints: 
Primary: 
• 
The primary efficacy endpoint is the change from baseline in the 17-item Hamilton 
Rating Scale for Depression (HAM-D) total score at Day 15. 
Secondary: 
• 
Change from baseline in the 17-item HAM-D total score at other timepoints 
• 
HAM-D response at Day 15 and all other time points, defined as a ≥50% reduction in 
HAM-D score from baseline  
• 
HAM-D remission at Day 15 and all other time points, defined as HAM-D total score 
≤7 
• 
Clinical Global Impression - Improvement (CGI-I) response at Day 15 and all other 


Clinical Protocol 
Sage Therapeutics, Inc. 
217-MDD-301 v4.0
CONFIDENTIAL 
5 
time points, defined as “much improved” or “very much improved” 
•
Change from baseline in Clinical Global Impression - Severity (CGI-S) score at Day 15
and all other time points
•
Change from baseline in Hamilton Anxiety Rating Scale (HAM-A) total score at Day 15
and all other time points
•
Change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS)
total score at Day 15 and all other time points
•
Change from baseline in HAM-D subscale and individual item scores at all time points
•
Change in sleep at Day 15 and all other time points, as assessed by
o
Insomnia Severity Index (ISI)
o
Subjective sleep parameters collected with the Core Consensus Sleep Diary
•
Change from baseline in PRO measures of health-related quality of life, as assessed by
responses to the 36-item Short Form survey version 2 (SF-36v2), and of depressive
symptoms, as assessed by the 9-item Patient Health Questionnaire (PHQ-9)
Safety Endpoints: 
•
Incidence and severity of adverse events/serious adverse events
•
Changes from baseline in clinical laboratory measures, vital signs, and
electrocardiograms (ECGs)
•
Suicidal ideation and behavior using the Columbia Suicide Severity Rating Scale
(C-SSRS)
•
Potential withdrawal symptoms using the 20-item Physician Withdrawal Checklist
(PWC-20)
 
Study Description: 
This is a randomized, double-blind, parallel-group, placebo-controlled study in subjects with 
MDD (MADRS total score ≥30). Randomization will be stratified based on use of 
antidepressant treatment (current/stable or not treated/withdrawn ≥60 days) at baseline and 
carried out within each stratum in a 1:1:1 ratio to receive SAGE-217 20 mg, SAGE-217 30 mg, 
or matching placebo; subjects will be treated for 14 days beginning on Day 1.  
The study will consist of a Screening Period of up to 28 days, a 14-day Treatment Period, a 28-
day follow-up period, and an extended follow-up period through Day 182 (6 months following 
the last dose).  
The Screening Period begins with the signing of the informed consent form (ICF) at the 
Screening Visit; 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 


Clinical Protocol 
Sage Therapeutics, Inc. 
217-MDD-301 v4.0
CONFIDENTIAL 
6 
MADRS and CGI-S. 
Antidepressants are permitted provided subjects are on a stable dose for at least 60 days prior to 
Day 1 and agree to continue on the stable dose through the follow-up period (Day 42). Initiation 
of new antidepressants or any other medications that may potentially have an impact on efficacy 
or safety endpoints will not be allowed between screening and completion of the Day 42 
assessments.  
Eligible subjects will be stratified based on use of antidepressant treatment (current/stable or not 
treated/withdrawn ≥60 days) and randomized within each stratum to one of 3 treatment groups 
(SAGE-217 20 mg, SAGE-217 30 mg, or matching placebo) in a 1:1:1 ratio. Subjects will self-
administer a single dose of study drug once daily in the evening with food, on an outpatient 
basis, for 14 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 treatment and follow-up periods as outlined in Table 1. 
Subjects who cannot tolerate study drug will be discontinued from study drug and will receive 
treatment as clinically indicated. 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. Follow-up visits should take place as scheduled relative to the last dose of 
treatment (eg, if a subject’s last dose is on Day 13, their first follow-up visit (Visit 7,) should 
occur 4 days later). 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 both visits will be conducted. 
Number of Subjects (planned):  
Approximately 450 subjects will be randomized and dosed to obtain 399 evaluable subjects. 
Eligibility Criteria: 
Inclusion 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, including not participating in night
shift work.
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 a MADRS total score of ≥30 at screening and Day 1 (prior to dosing).
7.
Subjects taking antidepressants must have been taking these medications at the same
dose for at least 60 days prior to Day 1. Subjects receiving psychotherapy must have
been receiving therapy on a regular schedule for at least 60 days prior to Day 1.
8.
Subject is willing to delay start of other antidepressant or antianxiety medications and
any new pharmacotherapy regimens, including as-needed benzodiazepine anxiolytics
and sleep aids, until after completion of the Day 42 visit.


Clinical Protocol 
Sage Therapeutics, Inc. 
217-MDD-301 v4.0
CONFIDENTIAL 
7 
9.
Female subject agrees to use one of the following methods of contraception during the
treatment period and for 30 days following the last dose of study drug, unless she is
postmenopausal (defined as no menses for 12 months without an alternative medical
cause and confirmed by follicle stimulating hormone [FSH] >40 mIU/mL), surgically
sterile (hysterectomy or bilateral oophorectomy), or does not engage in sexual relations
which  carry a risk of pregnancy:
•
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
10. Male subject agrees to use an acceptable method of effective contraception during the
treatment period 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. 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 #9 for acceptable
contraception methods).
11. Male subject is willing to abstain from sperm donation during the treatment period and
for 5 days after receiving the last dose of the study drug.
12. Subject agrees to refrain from drugs of abuse and alcohol for the duration of the study.
Exclusion Criteria: 
1.
Subject has attempted suicide associated with the current episode of MDD.
2.
Subject had onset of the current depressive episode during pregnancy or 4 weeks
postpartum, or the subject has presented for screening during the 6-month postpartum
period.
3.
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. A body
mass index (BMI) ≤18 or ≥50 kg/m2 at Screening is exclusionary; 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, chronic obstructive pulmonary disease [COPD]),
concomitant medications, and 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


Clinical Protocol 
Sage Therapeutics, Inc. 
217-MDD-301 v4.0
CONFIDENTIAL 
8 
Response Questionnaire (MGH ATRQ) will be used for this purpose. 
5.
Subject has had vagus nerve stimulation, electroconvulsive therapy, or has taken
ketamine within the current major depressive episode.
6.
Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds.
7.
Subject has a positive pregnancy test at screening or on Day 1 prior to the start of study
drug administration or, if she is breastfeeding at Screening or on Day 1 (prior to
administration of study drug), she does not agree to temporarily cease giving breast milk
to her child(ren) from just prior to receiving study drug on Day 1 until 7 days after the
last dose of study drug.
8.
Subject has detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus
(HCV) and positive HCV viral load, or human immunodeficiency virus (HIV) antibody
at screening.
9.
Subject has a clinically significant abnormal 12-lead ECG at the screening or baseline
visits. NOTE: mean QT interval calculated using the Fridericia method (QTcF) of
>450 msec in males or >470 msec in females will be the basis for exclusion from the
study.
10. Subject has active psychosis per Investigator assessment.
11. Subject has a medical history of seizures.
12. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective
disorder.
13. 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.
14. Subject has had exposure to another investigational medication or device within 30 days
prior to screening.
15. Subject has previously participated in a SAGE-217 or a SAGE-547 (brexanolone)
clinical trial.
16. Use of any known strong inhibitors of cytochrome P450 (CYP)3A4 within 28 days or
five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, or Seville
oranges, or products containing these within 14 days prior to the first dose of study
drug.
17. Use of any strong CYP3A inducer, such as rifampin, carbamazepine, enzalutamide,
mitotane, phenytoin, or St John’s Wort, within 28 days prior to the first dose of study
drug.
18. Subject has a positive drug and/or alcohol screen at screening or on Day 1 prior to
dosing.
19. Subject plans to undergo elective surgery before completion of the Day 42 visit.
20. Subject is taking benzodiazepines, barbiturates, or GABAA modulators (eg, eszopiclone,
zopiclone, zaleplon, and zolpidem) at Day -28, or has been using these agents daily or
near-daily (≥4 times per week) for more than 1 year. Subject is taking any


Clinical Protocol 
Sage Therapeutics, Inc. 
217-MDD-301 v4.0
CONFIDENTIAL 
9 
benzodiazepine or GABA modulator with a half-life of ≥48 hours (eg, diazepam) from 
60 days prior to Day 1. 
21. Subject is taking non-GABA anti-insomnia medications (eg melatonin, Benadryl [anti-
histamines], trazodone), or first or second generation (typical/atypical) antipsychotics at
Day -14.
22. 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.
23. Subject has a history of sleep apnea.
24. Subject has had gastric bypass surgery, has a gastric sleeve or lap band, or has had any
related procedures that interfere with gastrointestinal transit.
25. Subject is taking psychostimulants (eg, methylphenidate, amphetamine) or opioids,
regularly or as-needed, at Day -28.
Study Drug, 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: 
Placebo will be provided as hard gelatin capsules for oral administration containing only the 
excipients listed above for the active capsule.  
Duration of Treatment: 14 days 
Statistical methods: 
A detailed description of the analyses to be performed in the study will be provided in the 
Statistical Analysis Plan (SAP). The SAP will be finalized and approved prior to treatment 
unblinding.  
When all subjects complete the Day 42 visit, the database will be locked, followed by treatment 
unblinding to the Sponsor and data analyses (site personnel and subjects will remain blinded). 
The extended follow-up period will continue as scheduled; the final database lock will occur 
when all subjects complete the extended follow-up period. 
General Considerations 
For the purpose of all safety and efficacy analyses where applicable, baseline is defined as the 
last measurement prior to the start of study drug administration.  
Continuous endpoints will be summarized descriptively with n, mean, standard deviation, 
median, minimum, and maximum. In addition, change from baseline values will be calculated at 
each time point and summarized descriptively. For categorical endpoints, descriptive summaries 
will include counts and percentages.  
Analysis Sets 
The Randomized Set is defined as all subjects who are randomized. 
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 HAM-D total score at least 1 post-baseline HAM-D total score.  


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Determination of Sample Size 
Assuming a two-sided alpha level of 0.05, a sample size of 399 evaluable subjects would 
provide 90% power to detect a placebo-adjusted treatment difference of approximately 4 points 
in the primary endpoint, change from baseline in HAM-D total score at Day 15, assuming 
standard deviation (SD) of 10 points. Assuming a 11% dropout rate and a 1:1:1 randomization 
ratio within each stratum (antidepressant use at baseline, yes or no), approximately 450 total 
randomized subjects will be required to obtain 399 evaluable subjects. Evaluable subjects are 
defined as those randomized subjects who receive study drug and have valid baseline and at 
least 1 post-baseline HAM-D assessment. Additional subjects may be randomized if the dropout 
rate is greater than 11%. 
Analysis of Primary Endpoint 
The estimand for the primary efficacy analysis is the mean change from baseline in HAM-D 
total score at Day 15. This will be analyzed using a mixed effects model for repeated measures 
(MMRM); the model will include treatment, baseline HAM-D total score, stratification factor, 
assessment time point, and time point-by-treatment as explanatory variables. All explanatory 
variables will be treated as fixed effects. All post-baseline time points will be included in the 
model. The main comparison will be between SAGE-217 and placebo at the 15-day time point. 
Model-based point estimates (ie, least squares [LS] means, 95% confidence intervals, and p-
values) will be reported where applicable. An unstructured covariance structure will be used to 
model the within-subject errors. 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.  
Analysis of Secondary Endpoints 
Similar to those methods described above for the primary endpoint, an MMRM will be used for 
the analysis of the change from baseline in other time points in HAM-D total score, MADRS 
total score, HAM-A total score, SF-36v2 score, PHQ-9 score, sleep diary endpoints (eg, sleep 
latency (SL), total sleep time (TST), wake after sleep onset (WASO)), ISI score and selected 
individual items and/or subscale scores in HAM-D for change from baseline.  
Generalized estimating equation (GEE) methods will be used for the analysis of HAM-D 
response (defined as ≥50% reduction from baseline in HAM-D total score) and HAM-D 
remission (defined as HAM-D total score of ≤7.0). GEE models will include terms for 
treatment, baseline score, stratification factor, assessment time point, and time point-by-
treatment as explanatory variables. The comparison of interest will be the difference between 
SAGE-217 and matching placebo at the 15-day time point. Model-based point estimates (ie, 
odds ratios), 95% confidence intervals, and p-values will be reported.  
A GEE method will also be used for the analysis of CGI-I response including terms for 
treatment, baseline CGI-S score, stratification factor, assessment time point, and time point-by-
treatment as explanatory variables. 
 
 
Safety Analysis 
Safety and tolerability of study drug will be evaluated by incidence of adverse events/serious 
adverse events, vital signs, clinical laboratory evaluations, and 12-lead ECG. Suicidality will be 
monitored by the C-SSRS. Potential withdrawal symptoms after discontinuation of SAGE-217 


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will be assessed using the PWC-20. 
 
 
 
 


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Table 1: 
Schedule of Events 
Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
Follow-up Period 
Extended Follow-Up 
Visit Days 
D-28 to D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(+1d) 
and/or 
EOTa 
D18 
(±1d) 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
or 
ET 
D70, D126, D182 
(±7d) 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12, V13, V14 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Duplicate Subject Checkb 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
 
 
 
Serum FSH testc 
X 
 
 
 
 
 
 
 
 
 
 
 
SCID-5-CT 
X 
 
 
 
 
 
 
 
 
 
 
 
MGH ATRQ 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/Family History 
X 
 
 
 
 
 
 
 
 
 
 
 
Subject trainingd 
X 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examinatione 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Body Weight/Height 
X 
 
 
 
 
X (wt only) 
 
 
 
 
X (wt 
only) 
 
Clinical Laboratory 
Assessmentsf 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
Drug & Alcohol Screeng 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy Testh 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
 


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Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
Follow-up Period 
Extended Follow-Up 
Visit Days 
D-28 to D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(+1d) 
and/or 
EOTa 
D18 
(±1d) 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
or 
ET 
D70, D126, D182 
(±7d) 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12, V13, V14 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGl 
X 
X 
 
 
 
X 
 
 
 
 
X 
X (Day 182 only) 
C-SSRSm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAM-Dn, o 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MADRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
HAM-Ao 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
CGI-S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SF-36v2 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
PHQ-9 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
ISI 
 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
PWC-20 
 
X 
 
 
 
X 
X 
X 
 
 
 
 
Sleep diaryp 
X 
 
 
 
Study Drug Dispensation 
 
X 
 
X 
 
 
 
 
 
 
 
 
Study Drug Administration 
 
X (Day 1 through Day 14) 
 
 
 
 
 
 


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Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
Follow-up Period 
Extended Follow-Up 
Visit Days 
D-28 to D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(+1d) 
and/or 
EOTa 
D18 
(±1d) 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
or 
ET 
D70, D126, D182 
(±7d) 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12, V13, V14 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug 
Accountability/Return 
 
 
 
X 
 
X 
 
 
 
 
Xr 
 
Adverse Events/SAEss 
X 
Prior/Concomitant 
Medications/Procedurest 
X 
CGI-I = Clinical Global Impression – Improvement; CGI-S – Clinical Global Impression – Severity; 
 C-
SSRS = Columbia Suicide Severity Rating Scale; D = day; EOT = end of treatment; ET = early termination; ECG = electrocardiogram
FSH = follicle stimulating hormone; HAM-A = Hamilton Anxiety Rating Scale; HAM-D = Hamilton Rating Scale for Depression, 17-item; HIV = human 
immunodeficiency virus; ISI = Insomnia Severity Index; MADRS = Montgomery-Åsberg Depression Rating Scale; MGH ATRQ = Massachusetts General Hospital 
Antidepressant Treatment Response Questionnaire; PHQ-9 = 9-item Patient Health Questionnaire; PWC-20 = 20-item Physician Withdrawal Checklist; O = Optional; 
 SCID-5-CT = Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition Clinical Trials Version; SF-36v2 = 
36-item Short Form survey version 2; V = visit; wt = weight 
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. 
Follow-up visits should take place as scheduled relative to the last dose of treatment. 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 both visits will be conducted.  
b Subjects will be asked to authorize that their unique subject identifiers be entered into a registry (www.subjectregistry.com) with the intent of identifying subjects who may meet 
exclusion criteria for participation in another clinical study. 
c A serum follicle stimulating hormone test will be conducted at Screening for female subjects that are not surgically sterile to confirm whether a female subject with ≥12 months 
of spontaneous amenorrhea meets the protocol-defined criteria for being post-menopausal. 
d Subjects will be trained on use of software applications and devices necessary for the conduct of the study by site personnel. 
e A full physical examination will be conducted at Screening and abbreviated physical examinations will be conducted thereafter. A full physical examination includes assessment 
of body systems (eg, head, eye, ear, nose, and throat; heart; lungs; abdomen; and extremities). 
f Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. 
g Urine toxicology for selected drugs of abuse (as per the lab manual) and breath test for alcohol. 
h Serum pregnancy test at screening and urine pregnancy test thereafter for female subjects that are not surgically sterile and do not meet the protocol-defined criteria for being 
post-menopausal. 
 
 
 


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k Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing). Heart rate and blood pressure to be collected in supine position at 
all scheduled time points after the subject has been resting for 5 minutes and then after approximately 3 minutes in the standing position. Vital signs may be repeated at the 
discretion of the Investigator as clinically indicated. 
l Triplicate ECGs will be collected. 
 
m The “Baseline/Screening” C-SSRS form will be completed at screening. The “Since Last Visit” C-SSRS form will be completed at any time of day at all subsequent time points. 
n The HAM-D is to be completed as early during the visit as possible. 
o The assessment timeframe for HAM-D scales will refer to the past 7 days (1 week) at Day 1 and “Since Last Visit” for all other visits. The assessment timeframe for HAM-A 
scale will refer to the past 7 days (1 week) at all visits. 
p Subjects are instructed to complete the Core Consensus Sleep Diary starting at least 7 days prior to Day 1 and then daily through Day 28. 
 
 
r To be performed at the ET visit only. 
s Adverse events will be collected starting at the time of informed consent and throughout the duration of the subject’s participation in the study. 
t Prior medications will be collected at Screening and concomitant medications and/or procedures will be collected at each subsequent visit. 
 


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3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF
FIGURES
1.
TITLE PAGE ................................................................................................................1 
2.
SYNOPSIS ...................................................................................................................4 
3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............16 
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................21 
5.
INTRODUCTION ......................................................................................................23 
5.1. 
Background of Major Depressive Disorder and Unmet Medical Need ......................23 
5.2. 
SAGE-217 ...................................................................................................................23 
5.3. 
Potential Risks and Benefits .......................................................................................24 
5.4. 
Dose Justification ........................................................................................................24 
6.
STUDY OBJECTIVES AND PURPOSE ..................................................................25 
6.1. 
Study Objective ..........................................................................................................25 
6.1.1. 
Primary Objective .......................................................................................................25 
6.1.2. 
Secondary Objective(s) ...............................................................................................25 
6.1.3. 
Safety Objective ..........................................................................................................25 
 
25 
6.2. 
Endpoints ....................................................................................................................25 
6.2.1. 
Primary Endpoint ........................................................................................................25 
6.2.2. 
Secondary Endpoint(s) ................................................................................................25 
6.2.3. 
Safety Endpoint(s) ......................................................................................................26 
 
26 
7.
INVESTIGATIONAL PLAN .....................................................................................27 
7.1. 
Overall Study Design ..................................................................................................27 
7.2. 
Number of Subjects ....................................................................................................27 
7.3. 
Treatment Assignment ................................................................................................27 
7.4. 
Dose Adjustment Criteria ...........................................................................................28 
7.5. 
Criteria for Study Termination ...................................................................................28 
8.
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................29 
8.1. 
Subject Inclusion Criteria ...........................................................................................29 
8.2. 
Subject Exclusion Criteria ..........................................................................................30 


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8.3. 
Subject Withdrawal Criteria .......................................................................................32 
8.3.1. 
Replacement of Subjects .............................................................................................32 
9. 
TREATMENT OF SUBJECTS ..................................................................................33 
9.1. 
Study Drug ..................................................................................................................33 
9.2. 
Prior Medications, Concomitant Medications, and Restrictions ................................33 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................33 
9.2.2. 
Prohibited Medications ...............................................................................................33 
9.2.3. 
Other Restrictions .......................................................................................................34 
9.3. 
Treatment Adherence ..................................................................................................34 
9.4. 
Randomization and Blinding ......................................................................................35 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................36 
10.1. 
Description of Study Drug ..........................................................................................36 
10.2. 
Study Drug Packaging and Labeling ..........................................................................36 
10.3. 
Study Drug Storage .....................................................................................................36 
10.4. 
Study Drug Preparation ..............................................................................................36 
10.5. 
Study Drug Administration .........................................................................................36 
10.6. 
Study Drug Accountability .........................................................................................36 
10.7. 
Study Drug Handling and Disposal ............................................................................37 
11. 
ASSESSMENT OF EFFICACY 
 .............................38 
11.1. 
Efficacy Assessments .................................................................................................38 
11.1.1. 
Hamilton Rating Scale for Depression (HAM-D) ......................................................38 
11.1.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) ........................................38 
11.1.3. 
Hamilton Anxiety Rating Scale (HAM-A) .................................................................38 
11.1.4. 
Clinical Global Impression (CGI) ..............................................................................39 
11.1.5. 
Short Form-36 Version 2 (SF-36v2) ...........................................................................39 
11.1.6. 
Patient Health Questionnaire (PHQ-9) .......................................................................39 
11.1.7. 
Insomnia Severity Index (ISI) ....................................................................................40 
11.1.8. 
Core Consensus Sleep Diary ......................................................................................40 
 
40 
 
40 
 
41 
 
41 


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41 
12. 
ASSESSMENT OF SAFETY .....................................................................................42 
12.1. 
Safety Parameters .......................................................................................................42 
12.1.1. 
Demographic/Medical History ...................................................................................42 
12.1.2. 
Weight and Height ......................................................................................................42 
12.1.3. 
Physical Examination .................................................................................................42 
12.1.4. 
Vital Signs ..................................................................................................................42 
12.1.5. 
Electrocardiogram (ECG) ...........................................................................................43 
12.1.6. 
Laboratory Assessments .............................................................................................43 
12.1.6.1. 
Drugs of Abuse and Alcohol ......................................................................................45 
12.1.6.2. 
Pregnancy Screen ........................................................................................................45 
12.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................45 
12.1.8. 
Physician Withdrawal Checklist .................................................................................45 
12.2. 
Adverse and Serious Adverse Events .........................................................................46 
12.2.1. 
Definition of Adverse Events .....................................................................................46 
12.2.1.1. 
Adverse Event (AE) ....................................................................................................46 
12.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................46 
12.3. 
Relationship to Study Drug ........................................................................................47 
12.4. 
Recording Adverse Events .........................................................................................48 
12.5. 
Reporting Serious Adverse Events .............................................................................48 
12.6. 
Emergency Identification of Study Drug ....................................................................49 
13. 
STATISTICS ..............................................................................................................50 
13.1. 
Data Analysis Sets ......................................................................................................50 
13.2. 
Handling of Missing Data ...........................................................................................50 
13.3. 
General Considerations ...............................................................................................50 
13.4. 
Demographics and Baseline Characteristics ...............................................................50 
13.5. 
Efficacy Analyses .......................................................................................................51 
13.6. 
Safety Analyses ..........................................................................................................51 
13.6.1. 
Adverse Events ...........................................................................................................52 
13.6.2. 
Clinical Laboratory Evaluations .................................................................................52 
13.6.3. 
Physical Examinations ................................................................................................52 
13.6.4. 
Vital Signs ..................................................................................................................52 


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13.6.5. 
12-Lead Electrocardiogram ........................................................................................52 
13.6.6. 
Prior and Concomitant Medications ...........................................................................52 
13.6.7. 
Columbia Suicide Severity Rating Scale ....................................................................53 
13.6.8. 
Physician Withdrawal Checklist .................................................................................53 
 
53 
13.8. 
Determination of Sample Size ....................................................................................53 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................54 
14.1. 
Study Monitoring ........................................................................................................54 
14.2. 
Audits and Inspections ................................................................................................54 
14.3. 
Institutional Review Board (IRB) or Ethics Committee (EC) ....................................55 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................56 
16. 
ETHICS ......................................................................................................................57 
16.1. 
Ethics Review .............................................................................................................57 
16.2. 
Ethical Conduct of the Study ......................................................................................57 
16.3. 
Written Informed Consent ..........................................................................................57 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................58 
17.1. 
Inspection of Records .................................................................................................58 
17.2. 
Retention of Records ..................................................................................................58 
18. 
PUBLICATION POLICY ..........................................................................................59 
19. 
LIST OF REFERENCES ............................................................................................60 
 


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LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................12 
Table 2: 
Abbreviations and specialist terms .............................................................................21 
Table 3: 
Clinical Laboratory Tests ...........................................................................................43 
Table 4: 
Relationship to Study Drug ........................................................................................47 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and specialist terms 
Abbreviation or specialist term 
Explanation 
AE 
adverse event 
CGI-I 
Clinical Global Impression – Improvement 
CGI-S 
Clinical Global Impression – Severity 
CRF 
case report form 
CS 
clinically significant 
 
 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CYP 
cytochrome P450 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
end of treatment 
ET 
early termination 
 
 
FSH 
follicle stimulating hormone 
GABA 
γ-aminobutyric acid 
GEE 
generalized estimating equation 
HAM-A 
Hamilton Rating Scale for Anxiety 
HAM-D 
Hamilton Rating Scale for Depression 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ID 
identification  
IRB 
institutional review board 
IRT 
interactive response technology 
ISI 
Insomnia Severity Index 


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Table 2: 
Abbreviations and specialist terms (Continued) 
Abbreviation or specialist term 
Explanation 
MADRS 
Montgomery Åsberg Depression Rating Scale 
MDD 
major depressive disorder 
MGH ATRQ 
Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire 
MMRM 
mixed effects model for repeated measures 
NCS 
not clinically significant 
PCS 
Potentially clinically significant 
PHQ-9 
9-item Patient Health Questionnaire 
PK 
pharmacokinetic 
PRO 
patient-reported outcome 
PWC-20 
20-item Physician Withdrawal Checklist 
QTcF 
QT corrected according to Fridericia’s formula 
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 
SF-36v2 
36-item Short Form version 2 
SUSAR 
suspected, unexpected, serious, adverse reactions 
TEAE 
treatment-emergent adverse event 
WHO 
World Health Organization 
 


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5. 
INTRODUCTION 
5.1. 
Background of Major Depressive Disorder and Unmet Medical Need 
The World Health Organization (WHO) has identified depression as the leading cause of 
disability worldwide, and as a major contributor to the overall global burden of disease 
(http://www.who.int/mediacentre/factsheets/fs369/en/). Globally, depression has been estimated 
to affect over 300 million people. 
In the United States, the economic burden of depression, including workplace costs, direct costs 
and suicide-related costs, was estimated to be $210.5 billion in 2010 (Greenberg 2015). As per 
WHO statistics, over 800,000 people die due to suicide every year, and suicide is the second 
leading cause of death in 15- to 29-year-olds. The rate of US adults making a suicide attempt has 
increased (0.62% from 2004 to 2005 to 0.79% from 2012 to 2013), with a shift to more attempts 
among younger adults (42% to 50%, respectively) and among those with a depressive disorder 
(26% to 54%, respectively; Olfson 2017). 
In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), 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 (SSRIs), 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 (CSF) 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 


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and is generally expected to have good extravascular exposure. In exploratory in vitro receptor 
and ion channel assays and in vivo safety pharmacology studies, SAGE-217 was highly selective 
for GABAA receptors, and, consistent with the actions of other GABAA receptor potentiators 
(Rudolph 2011), exhibits potent anticonvulsant, anxiolytic, and sedative activity when 
administered in vivo. 
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 [HAM-A], 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 HAM-A. 
SAGE-217 has been generally well tolerated in clinical studies to date. The most common 
treatment-emergent adverse events (TEAEs) were sedation, somnolence, and dizziness. Most 
adverse events (AEs) were reported as mild or moderate in intensity. There have been no deaths 
and only one subject with essential tremor experienced a serious adverse event (SAE) of 
transient confusion leading to discontinuation of study drug. No other SAEs have been reported 
in any study of SAGE-217.  
Additional information on nonclinical and clinical data is provided in the Investigator’s 
Brochure.  
5.3. 
Potential Risks and Benefits 
Non-serious events of sedation, somnolence, and dizziness were the most commonly reported 
AEs with SAGE-217. Given the outcome of the Phase 2 study of SAGE-217 in subjects with 
MDD, the current significant unmet need in the treatment of depression, and a favorable benefit-
risk profile, further investigation of SAGE-217 in patients with MDD is justified. 
5.4. 
Dose Justification 
There will be 2 dose levels of SAGE-217 in this study in order to study dose ranging: 30 mg per 
day and 20 mg per day. The higher dose level of 30 mg per day is the maximum tolerated dose in 
the multiple ascending dose study of SAGE-217 in healthy subjects and is also the dose level that 
was effective and generally well tolerated in a Phase 2 study in subjects with MDD (217-MDD-
201). The lower dose of 20 mg per day will be studied in subjects with MDD for the first time in 
the current study and is anticipated to be well tolerated as it is lower than the maximum tolerated 
dose level. Due to sedation/somnolence observed in previous clinical trials when administered in 
the morning, and improved tolerability when given in the evening, both doses of 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 is to evaluate the efficacy of SAGE-217 in the treatment of MDD 
compared to placebo. 
6.1.2. 
Secondary Objective(s) 
Secondary objectives are: 
• To evaluate the effect of SAGE-217 on sleep.  
• To assess patient-reported outcome (PRO) measures as they relate to health-related 
quality of life and depressive symptoms. 
6.1.3. 
Safety Objective 
The safety objective is to evaluate the safety and tolerability of SAGE-217. 
 
 
 
 
 
 
 
 
6.2. 
Endpoints 
6.2.1. 
Primary Endpoint 
The primary endpoint of this study is the change from baseline in the 17-item HAM-D total score 
at Day 15. 
6.2.2. 
Secondary Endpoint(s) 
• Change from baseline in the 17-item HAM-D total score at other time points 
• HAM-D response at Day 15 and all other time points, defined as a ≥50% reduction in 
HAM-D score from baseline 
• HAM-D remission at Day 15 and all other time points, defined as HAM-D total 
score ≤7  
• CGI-I response at Day 15 and all other time points, defined as “much improved” or 
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• Change from baseline in Clinical Global Impression - Severity (CGI-S) score at 
Day 15 and all other time points 
• Change from baseline in HAM-A total score at Day 15 and all other time points  
• Change from baseline in the MADRS total score at Day 15 and all other time points 
• Change from baseline in HAM-D subscale and individual item scores at all time 
points 
• Change in sleep at Day 15 and all other time points, as assessed by: 
− Insomnia Severity Index (ISI) 
− Subjective sleep parameters collected with the Core Consensus Sleep Diary 
• Change from baseline in PRO measures of health-related quality of life, as assessed 
by responses to the 36-item Short Form survey version 2 (SF-36v2), and of 
depressive symptoms, as assessed by the 9-item Patient Health Questionnaire (PHQ-
9) 
6.2.3. 
Safety Endpoint(s) 
• Incidence and severity of adverse events/serious adverse events  
• Changes from baseline in clinical laboratory measures, vital signs, and 
electrocardiograms (ECGs) 
• Suicidal ideation and behavior using the Columbia Suicide Severity Rating Scale 
(C-SSRS)  
• Potential withdrawal symptoms using the 20-item Physician Withdrawal Checklist 
(PWC-20) 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a randomized, double-blind, parallel-group, placebo-controlled study in subjects with 
MDD (MADRS total score ≥30). The study will consist of a Screening Period of up to 28 days, a 
14-day Treatment Period, a 28-day follow-up period, and an extended follow-up period through 
Day 182 (6 months following the last dose).  
The Screening Period begins with the signing of the informed consent form (ICF) at the 
Screening Visit; the ICF must be signed prior to beginning any screening activities. At the time 
of providing informed consent for the study, subjects will also be asked to authorize that their 
unique subject identifiers be entered into a registry (www.subjectregistry.com) with the intent of 
identifying subjects who may meet exclusion criteria due to participation in another clinical 
study (Section 8.2). 
The diagnosis of MDD must be made according to Structured Clinical Interview for Diagnostic 
and 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 and CGI-S.  
Antidepressants are permitted provided subjects are on a stable dose for at least 60 days prior to 
Day 1 and agree to continue on the stable dose through the 28-day follow-up period (Day 42). 
Initiation of new antidepressants or any other medications that may potentially have an impact on 
efficacy or safety endpoints is prohibited between screening and completion of the Day 42 
assessments.  
Eligible subjects will be stratified based on use of antidepressant treatment (current/stable or not 
treated/withdrawn ≥60 days) and randomized within each stratum to one of 3 treatment groups 
(SAGE-217 20 mg, SAGE-217 30 mg, or matching placebo) in a 1:1:1 ratio. Subjects will self-
administer a single dose of study drug with food once daily in the evening on an outpatient basis, 
for 14 days. Dose reductions are not permitted. Study drug administration will be monitored via 
a clinical monitoring service (see Section 9.3). 
Subjects will return to the study center during the treatment and follow-up periods as outlined in 
Table 1. 
7.2. 
Number of Subjects 
Approximately 450 subjects will be randomized and dosed to obtain 399 evaluable subjects (see 
Section 13.8). 
7.3. 
Treatment Assignment 
Subjects will be randomly assigned to a treatment group on Day 1. Randomization will be 
stratified based on use of antidepressant treatment (current/stable or not treated/withdrawn 
≥60 days) at baseline and performed within each stratum in a 1:1:1 ratio to receive SAGE-217 
20 mg, SAGE-217 30 mg, or matching placebo. 


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7.4. 
Dose Adjustment Criteria 
Dose adjustments are not permitted in this study. Subjects who cannot tolerate study drug will be 
discontinued from study drug and will receive treatment as clinically indicated (see Section 8.3). 
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 
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, including not participating in night 
shift work.  
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 a MADRS total score of ≥30 at screening and Day 1 (prior to dosing).  
7. Subjects taking antidepressants must have been taking these medications at the same dose 
for at least 60 days prior to Day 1. Subjects receiving psychotherapy must have been 
receiving therapy on a regular schedule for at least 60 days prior to Day 1. 
8. Subject is willing to delay start of other antidepressant or antianxiety medications and 
any new pharmacotherapy regimens, including as-needed benzodiazepine anxiolytics and 
sleep aids, until after completion of the Day 42 visit.  
9. Female subject agrees to use one of the following methods of contraception during the 
treatment period and for 30 days following the last dose of study drug, unless she is 
postmenopausal (defined as no menses for 12 months without an alternative medical 
cause and confirmed by follicle stimulating hormone [FSH] >40 mIU/mL), surgically 
sterile (hysterectomy or bilateral oophorectomy), or does not engage in sexual relations 
which carry a risk of pregnancy: 
• 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. 
10. Male subject agrees to use an acceptable method of effective contraception during the 
treatment period 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. Acceptable 
methods of effective contraception for males includes vasectomy, or a condom with 
spermicide used together with highly effective female contraception methods if the 


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female partner is of child-bearing potential (see Inclusion Criteria #9 for acceptable 
contraception methods). 
11. Male subject is willing to abstain from sperm donation the treatment period and for 5 
days after receiving the last dose of the study drug. 
12. 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 had onset of the current depressive episode during pregnancy or 4 weeks 
postpartum, or the subject has presented for screening during the 6-month postpartum 
period. 
3. 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. A body 
mass index (BMI) ≤18 or ≥50 kg/m2 at Screening is exclusionary; 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, chronic obstructive pulmonary disease [COPD]), 
concomitant medications, and 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 within the current major depressive episode. 
6. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds.  
7. Subject has a positive pregnancy test at screening or on Day 1 prior to the start of study 
drug administration or, if she is breastfeeding at Screening or on Day 1 (prior to 
administration of study drug), she does not agree to temporarily cease giving breast milk 
to her child(ren) from just prior to receiving study drug on Day 1 until 7 days after the 
last dose of study drug.  
8. Subject has detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) 
and positive HCV viral load, or human immunodeficiency virus (HIV) antibody at 
screening. 
9. Subject has a clinically significant abnormal 12-lead ECG at the screening or baseline 
visits. NOTE: mean QT interval calculated using the Fridericia method (QTcF) of 


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>450 msec in males or >470 msec in females will be the basis for exclusion from the 
study.  
10. Subject has active psychosis per Investigator assessment.  
11. Subject has a medical history of seizures.  
12. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder.  
13. 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. 
14. Subject has had exposure to another investigational medication or device within 30 days 
prior to screening.  
15. Subject has previously participated in a SAGE-217 or a SAGE-547 (brexanolone) clinical 
trial.  
16. Use of any known strong inhibitors of cytochrome P450 (CYP)3A4 within 28 days or 
five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, or Seville 
oranges, or products containing these within 14 days prior to the first dose of study drug.  
17. Use of any strong CYP3A inducer, such as rifampin, carbamazepine, enzalutamide, 
mitotane, phenytoin, or St John’s Wort, within 28 days prior to the first dose of study 
drug. 
18. Subject has a positive drug and/or alcohol screen at screening or on Day 1 prior to 
dosing. 
19. Subject plans to undergo elective surgery before completion of the Day 42 visit. 
20. Subject is taking benzodiazepines, barbiturates, or GABAA modulators (eg, eszopiclone, 
zopiclone, zaleplon, and zolpidem) at Day -28, or has been using these agents daily or 
near-daily (≥4 times per week) for more than 1 year. Subject is taking any 
benzodiazepine or GABA modulator with a half-life of ≥48 hours (eg, diazepam) from 60 
days prior to Day 1. 
21. Subject is taking non-GABA anti-insomnia medications (eg melatonin, Benadryl [anti-
histamines], trazodone), or first or second generation (typical/atypical) antipsychotics at 
Day -14.  
22. 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. 
23. Subject has a history of sleep apnea. 
24. Subject has had gastric bypass surgery, has a gastric sleeve or lap band, or has had any 
related procedures that interfere with gastrointestinal transit. 
25. Subject is taking psychostimulants (eg, methylphenidate, amphetamine) or opioids, 
regularly or as-needed, at Day -28. 


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8.3. 
Subject Withdrawal Criteria 
Subjects may withdraw from the study drug or terminate from the study at any time for any 
reason. 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 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.  
Subjects who discontinue study drug early should return to the site for an end of treatment (EOT) 
visit as soon as possible, preferably the day after treatment is discontinued. Follow-up visits 
should take place as scheduled relative to the last dose of treatment (eg, if a subject’s last dose is 
on Day 13, their first follow-up visit (Visit 7) should occur 4 days later). 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.  
A subject will be deemed lost to follow-up after attempts at contacting the subject have been 
unsuccessful. 
8.3.1. 
Replacement of Subjects 
Subjects will not be replaced. Additional subjects may be randomized if the drop-out rate is 
higher than anticipated (Section 13.8). 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Study Drug 
Subjects will self-administer SAGE-217 (20 or 30 mg) or matching placebo orally once daily in 
the evening with food for 14 days.  
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 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.  
Antidepressants that have been taken at the same dose for at least 60 days prior to Day 1 are 
permitted if the subject intends to continue the stable dose through Day 42. 
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 
The following specific classes of medications are prohibited: 
• Initiation of new psychotropic medications through the Day 42 visit 
• Initiation of new antidepressant therapy from 60 days prior to Day 1 through the Day 
42 visit 
• Use of any benzodiazepines, barbiturates, GABAA modulators, GABA-containing 
agents from Day -28 through the Day 42 visit (from Day -60 for benzodiazepine or 
GABA modulators with a half-life of ≥48 hours) 
• Chronic or as-needed psychostimulants (eg, methylphenidate, amphetamine) or 
opioids from Day -28 through the Day 42 visit 


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• First generation (typical) antipsychotics (eg, haloperidol, perphenazine) and second 
generation (atypical) antipsychotics (eg, aripiprazole, quetiapine) from Day -14 
through the Day 42 visit 
• Use of any non-GABA anti-insomnia medications (eg, melatonin, Benadryl [anti-
histamines], trazodone, low dose quetiapine, mirtazapine, etc) from Day -14 through 
the Day 42 visit 
• Exposure to another investigational medication or device from 30 days prior to 
Screening through the Day 42 visit 
• Any known strong inhibitors CYP3A4 from Day -28 or 5 half-lives prior to Day 1 
(whichever is longer) through the treatment period 
• Use of any strong CYP3A inducer, such as rifampin, carbamazepine, enzalutamide, 
mitotane, phenytoin, or St John’s Wort from Day -28 through the treatment period. 
9.2.3. 
Other Restrictions 
The consumption of grapefruit juice, grapefruit, or Seville oranges, or products containing these 
is prohibited throughout the treatment period. 
Consumption of alcohol or use of drugs of abuse is discouraged throughout the duration of the 
study. 
Female subjects who are lactating or actively breastfeeding must stop giving breast milk to the 
baby(ies) starting on Day 1 until 7 days after the last dose of study drug. 
Elective surgeries or procedures are prohibited through the Day 42 visit. 
Subjects must not participate in night shift work. 
Subjects receiving psychotherapy on a regular schedule for at least 60 days prior to Day 1 are 
permitted if the subject intends to continue the stable dose through the follow-up period 
(Day 42). 
9.3. 
Treatment Adherence 
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 10.4 and Table 1).  
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 
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 by dose level, as well as missed doses. 
In addition, the subject will be instructed to bring their dosing kit to the site as outlined in 
Table 1, at which time the Investigator or designee will be responsible for ensuring the kit 
contains sufficient doses for the duration of the treatment period.  


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All subjects should be reinstructed about the dosing requirement 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-compliance in the source documents. 
9.4. 
Randomization and Blinding 
This is a randomized double-blind, placebo-controlled study. Subjects who meet the entrance 
criteria will be randomized in a stratified manner based on use of antidepressant treatment 
(current/stable or not treated/withdrawn ≥60 days) at baseline; randomization will be done within 
each stratum in a 1:1:1 ratio to receive SAGE-217 20 mg, 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 (SAGE-217 20 mg, SAGE-217 30 mg, or placebo) will be based on the 
randomization schedule. The randomization schedules will be kept strictly confidential, 
accessible only to authorized personnel until the time of unblinding.  
The Sponsor will be unblinded following the first database lock when all subjects complete the 
Day 42 visit; site personnel and subjects will remain blinded throughout the extended follow-up 
until the final database lock when all subjects complete the Day 182 visit. 
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 (see Section 12.6 for 
more details related to unblinding).  


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Description of Study Drug 
SAGE-217 is available as hard gelatin capsules containing a white to off-white powder. In 
addition to the specified amount of SAGE-217 Drug Substance, active SAGE-217 Capsules 
contain croscarmellose sodium, mannitol, silicified microcrystalline cellulose (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 Practices/Good Clinical Practices guidelines will 
be prepared by the Sponsor. 
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 is to be administered orally once daily in the evening with food. Practical options 
include taking SAGE-217 within 1 hour of dinner or taking SAGE-217 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. 


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The designated site staff will dispense the supplied subject-specific kits to subjects at the planned 
dispensation visit intervals outlined in Table 1.  
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 randomize the 
eligible subject into the study 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. 
At the subsequent study drug-dispensing visit, 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 this visit must be 
recorded.  
If dispensing errors or discrepancies are discovered by site staff or sponsor’s designee, the 
Sponsor must be notified immediately. 
The 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. 


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11. 
ASSESSMENT OF EFFICACY 
 
All assessments will be conducted according to the schedule of assessments (Table 1). 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 (HAM-D) 
The primary outcome measure is the change from baseline in 17-item HAM-D total score at the 
end of the Treatment Period (Day 15). Every effort should be made for the same rater to perform 
all HAM-D assessments for an individual subject. An assessment timeframe of 7 days will be 
used on Day 1 and ‘Since Last Visit’ will be used for all other visits. 
The 17-item HAM-D will be used to rate the severity of depression in 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.  
In addition to the primary efficacy endpoint of change from baseline in HAM-D total score, 
several secondary efficacy endpoints will be derived for the HAM-D. Hamilton Rating Scale for 
Depression subscale scores will be calculated as the sum of the items comprising each subscale. 
Hamilton Rating Scale for Depression response will be defined as having a 50% or greater 
reduction from baseline in HAM-D total score. Hamilton Rating Scale for Depression remission 
will be defined as having a HAM-D total score of ≤7.  
11.1.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive 
episodes in subjects with mood disorders. It was designed as an adjunct to the HAM-D that 
would be more sensitive to the changes brought on by antidepressants and other forms of 
treatment than the Hamilton Scale.  
Higher MADRS scores indicate more severe depression, and each item yields a score of 0 to 6. 
The overall score ranges from 0 to 60 (Williams 2008). 
The MADRS total score will be calculated as the sum of the 10 individual item scores.  
11.1.3. 
Hamilton Anxiety Rating Scale (HAM-A) 
The 14-item HAM-A will be used to rate the severity of symptoms of anxiety (Williams 2013c; 
Williams 2013d). Each of the 14 items is defined by a series of symptoms, and measures both 
psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical 


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complaints related to anxiety). Scoring for HAM-A is calculated by assigning scores of 0 (not 
present) to 4 (very severe), with a total score range of 0 to 56, where <17 indicates mild severity, 
18 to 24, mild to moderate severity, and 25 to 30, moderate to severe severity. The HAM-A total 
score will be calculated as the sum of the 14 individual item scores. 
11.1.4. 
Clinical Global Impression (CGI) 
The CGI is a validated measure often utilized in clinical trials to allow clinicians to integrate 
several sources of information into a single rating of the subject’s condition. The CGI scale 
consists of 3 items. Only the first 2 items are being used in this study.  
The CGI-S uses a 7-point Likert scale to rate the severity of the subject’s illness at the time of 
assessment, relative to the clinician’s past experience with subjects who have the same diagnosis. 
Considering total clinical experience, a subject is assessed on severity of mental illness at the 
time of rating as 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately 
ill; 5=markedly ill; 6=severely ill; and 7=extremely ill (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 
“much improved.”  
11.1.5. 
Short Form-36 Version 2 (SF-36v2) 
The Medical Outcomes Study SF-36v2 is a 36-item measure of health status that has undergone 
validation in many different disease states (Ware 2007). The SF-36v2 covers eight health 
dimensions including four physical health status domains (physical functioning, role 
participation with physical health problems [role-physical], bodily pain, and general health) and 
four mental health status domains (vitality, social functioning, role participation with emotional 
health problems [role-emotional], and mental health). In addition, two summary scores, physical 
component summary and mental component summary, are produced by taking a weighted linear 
combination of the eight individual domains. The SF-36v2 is available with two recall periods: 
the standard recall period is 4 weeks and the acute recall period is 1 week. This study will use the 
acute version, which asks patients to respond to questions as they pertain to the past week. 
Higher SF-36v2 scores indicate a better state of health.  
11.1.6. 
Patient Health Questionnaire (PHQ-9) 
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 may 
complete questionnaires at baseline and at regular intervals thereafter. Scoring is based on 
responses to specific questions, as follows: 0=not at all; 1=several days; 2=more than half the 
days; and 3=nearly every day.  


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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. 
11.1.7. 
Insomnia Severity Index (ISI) 
The ISI is a validated questionnaire designed to assess the nature, severity, and impact of 
insomnia (Morin 2011). The ISI uses a 5-point Likert Scale to measure various aspects of 
insomnia severity (0 = none, 1 = mild, 2 = moderate; 3 = severe; 4 = very severe), satisfaction 
with current sleep pattern (0 = very satisfied, 1 = satisfied, 2 = neutral, 3 = dissatisfied, 4 = very 
dissatisfied), and various aspects of the impact of insomnia on daily functioning (0 = not at all, 
1 = a little, 2 = somewhat, 3 = much, 4 = very much). A total score of 0 to 7 = “no clinically 
significant insomnia,” 8 to 14 = subthreshold insomnia,” 15 to 21 = “clinical insomnia (moderate 
severity),” and 22 to 28 = “clinical insomnia (severe).”  
11.1.8. 
Core Consensus Sleep Diary 
The Core Consensus Sleep Diary collects subjective sleep parameters, including sleep onset 
latency, total sleep time, and wake after sleep onset, number of awakenings, and sleep quality. 
The take-home subject sleep diary assessment will be administered using an eDiary solution. The 
eDiary will be captured using either a provisioned smartphone device or bring-your-own-device 
solution, depending on the subject’s preference. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
All assessments will be conducted according to the schedule of assessments (Table 1). 
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 (ICD-10) should be recorded. 
The Massachusetts General Hospital Antidepressant Treatment Response Questionnaire 
(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. 
12.1.2. 
Weight and Height 
Height (Screening only) and weight will be measured and documented. 
12.1.3. 
Physical Examination 
Physical examinations assessing body systems (eg, head, eyes, ears, nose, and throat; heart; 
lungs; abdomen; and extremities), as well as cognitive and neurological examinations and mental 
status examinations will be conducted and documented. 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. 
New or worsening abnormalities that are judged to be clinically significant will be recorded as 
AEs, assessed according to Section 12.2.1.1. 
12.1.4. 
Vital Signs 
Vital signs comprise both supine and standing for systolic and diastolic blood pressure and heart 
rate measurements. Heart rate and blood pressure are to be collected in supine position after the 
subject has been resting for 5 minutes and then after approximately 3 minutes in the standing 
position. Respiratory rate and temperature are collected once, in either position. Vital signs will 
be documented. When vital signs are scheduled at the same time as blood draws, vital signs will 
be obtained first. 
Any abnormality in vital signs will be interpreted by the Investigator as abnormal, NCS or 
abnormal, CS in source documents. New or worsening abnormalities that are judged to be 
clinically significant will be recorded as AEs, assessed according to Section 12.2.1.1.  


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12.1.5. 
Electrocardiogram (ECG) 
Supine 12-lead ECGs will be performed in triplicate at all scheduled time points. The standard 
intervals (heart rate, PR, QRS, QT, and QTcF) as well as any rhythm abnormalities will be 
recorded.
 
 
12.1.6. 
Laboratory Assessments 
Samples will be collected in accordance with acceptable laboratory procedures detailed in the 
laboratory manual.   
The clinical laboratory tests to be performed are listed in Table 3. 
Table 3: 
Clinical Laboratory Tests 
Hematology  
Serum Chemistry 
Urinalysis 
Coagulation 
Red blood cell count 
Hemoglobin  
Hematocrit  
White blood cell count with 
differential  
Platelet count 
Red Blood Cell Indices 
(MCV, MCH, MCHC) 
Reflex to Red blood cell 
morphology if indices are 
abnormal 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
Total protein 
Creatinine 
Blood urea nitrogen 
Creatine kinase 
Gamma-glutamyl transferase 
Potassium 
Sodium 
Lactate dehydrogenase 
Glucose 
Chloride 
Bicarbonate 
Calcium 
Phosphorus 
Triglycerides 
Thyroid stimulating hormone 
(TSH) 
Reflex to free T3/T4 if TSH 
is abnormal  
pH 
Specific gravity 
Protein 
Glucose 
Red blood cell 
Nitrite 
Leukocyte 
esterase 
Ketones 
Bilirubin 
Urobilinogen 
Activated partial 
thromboplastin 
time 
Prothrombin time 
International 
normalized ratio 


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Table 3: 
Clinical Laboratory Tests (Continued) 
Diagnostic  
 
 
 
Serum 
Urine 
Breathalyzer 
 
Hepatitis B 
Hepatitis C 
Reflex HCV RNA 
HIV-1 and -2 
Female subjects that are not 
surgically sterile and do not 
meet the protocol-defined 
criteria for being post-
menopausal: serum hCG 
Female subjects, if 
menopause is suspected and 
not surgically sterile: FSH 
Drug screen including: 
amphetamines, barbiturates, 
benzodiazepines, 
cannabinoids, cocaine, 
opiates, phencyclidine 
Female subjects that are not 
surgically sterile and do not 
meet the protocol-defined 
criteria for being post-
menopausal: urine hCG  
Alcohol 
 
Abbreviations: FSH = follicle stimulating hormone; hCG = human chorionic gonadotropin; HCV = hepatitis C 
virus; HIV = human immunodeficiency virus 
The central laboratory will perform laboratory tests for hematology, serum chemistry, urinalysis, 
and coagulation. The results of laboratory tests will be returned to the Investigator, who is 
responsible for reviewing and filing these results. All laboratory safety data will be transferred 
electronically to Sage Therapeutics or designee in the format requested by Sage Therapeutics.  
Laboratory reports must be signed and dated by the Investigator or subinvestigator indicating 
that the report has been reviewed and any abnormalities have been assessed for clinical 
significance. Any abnormalities identified prior to first dose will require clear and complete 
documentation in the source documents as to the investigator’s assessment of not clinically 
significant before proceeding with randomization.  
All clinical laboratory test results outside the central laboratory’s reference range will be 
interpreted by the Investigator as abnormal, NCS; or abnormal, CS in source documents. New or 
worsening abnormalities that are judged to be clinically significant will be recorded as AEs, 
assessed according to Section 12.2.1.1. A clinically significant laboratory abnormality following 
subject randomization will be followed until the abnormality returns to an acceptable level or a 
satisfactory explanation has been obtained. 
A serum follicle stimulating hormone test will be conducted at Screening to confirm whether a 
female subject with ≥12 months of spontaneous amenorrhea meets the protocol-defined criteria 
for being post-menopausal (Section 8.1). 
 
 
 
 
 
 


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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 3). A breath test 
for alcohol will be performed. 
12.1.6.2. Pregnancy Screen 
For female subjects that are not surgically sterile and do not meet the protocol-defined criteria 
for being post-menopausal, a serum pregnancy test will be performed at Screening and a urine 
pregnancy test will be performed at all other scheduled timepoints thereafter, including the ET 
visit for subjects who prematurely discontinue. 
12.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011). This scale 
consists of a baseline evaluation that assesses the lifetime experience of the subject with suicidal 
ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last 
study visit. The C-SSRS includes ‘yes’ or ‘no’ responses for assessment of suicidal ideation and 
behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being 
the most severe).  
The “Baseline/Screening” C-SSRS form will be completed at screening (lifetime history and past 
24 months). The “Since Last Visit” C-SSRS form will be completed at all subsequent time 
points, as outlined in Table 1. 
12.1.8. 
Physician Withdrawal Checklist 
The PWC is based on the 35-item Penn Physician Withdrawal Checklist that was developed in 
the 1960s to measure benzodiazepine and benzodiazepine-like discontinuation symptoms. The 
PWC-20 is a shorter version of the Penn Physician Withdrawal Checklist based on the 20 items 
that provided the best differentiation from placebo in previous trials. The PWC-20 is made up of 
a list of 20 symptoms (eg, loss of appetite, nausea-vomiting, diarrhea, anxiety-nervousness, 
irritability, etc) that are rated on a scale of 0 (not present) to 3 (severe) (Rickels 2008). The 
PWC-20 will be used to monitor for the presence of potential withdrawal symptoms following 
discontinuation of SAGE-217. 


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12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Definition of Adverse Events 
12.2.1.1. Adverse Event (AE) 
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 treatment has been administered. 
A TEAE is an AE that occurs after the first administration of any study drug. The term study 
drug includes any Sage investigational product, a comparator, or a placebo administered in a 
clinical trial. 
Laboratory abnormalities and changes from baseline in vital signs, ECGs, and physical 
examinations are considered AEs if they result in discontinuation or interruption of study 
treatment, require therapeutic medical intervention, meet protocol specific criteria (if applicable) 
and/or if the Investigator considers them to be clinically significant. Laboratory values and vital 
signs that meet the criteria for an SAE should be reported in an expedited manner. Laboratory 
abnormalities and changes from baseline in vital signs, ECGs, 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. 
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 
subject with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
12.2.1.2. Serious Adverse Event (SAE) 
A serious adverse event is any untoward medical occurrence that at any dose: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
An SAE may also be any other medically important event that, in the opinion of the Investigator 
may jeopardize the subject or may require medical intervention to prevent one of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 


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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 within 24 hours of first awareness (Section 12.5). All SAEs 
should to be followed until the event resolved, the condition stabilized, was no longer considered 
clinically significant or the subject was lost to follow-up. Serious adverse events occurring after 
a subject’s final visit (including the last follow-up visit) should be reported to Sage or designee 
only if the Investigator considers the SAE to be related to study treatment.  
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.  
12.3. 
Relationship to Study Drug 
The Investigator must make the determination of relationship to the study drug for each adverse 
event (not related, possibly related or probably related). The Investigator should decide whether, 
in his or her medical judgment, there is a reasonable possibility that the event may have been 
caused by the investigational product. If no valid reason exists for suggesting a relationship, then 
the adverse event should be classified as “not related.” If there is any valid reason, even if 
undetermined, for suspecting a possible cause-and-effect relationship between the investigational 
product and the occurrence of the adverse event, then the adverse event should be considered at 
least “possibly related.”  
Table 4: 
Relationship to Study Drug 
Relationship 
Definition 
Not Related: 
No relationship between the experience and the administration of study drug; related to 
other etiologies such as concomitant medications or subject’s clinical state. 
Possibly Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug.  
The reaction might have been produced by the subject’s clinical state or other modes of 
therapy administered to the subject, but this is not known for sure. 
Probably Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug.  
The reaction cannot be reasonably explained by the known characteristics of the subject’s 
clinical state or other modes of therapy administered to the subject. 


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If the relationship between the adverse event/serious adverse event and the investigational 
product is determined to be “possible” or “probable”, the event will be considered related to the 
investigational product for the purposes of expedited regulatory reporting. 
12.4. 
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), 
resolution (date and time), intensity, causality, action taken, serious outcome (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 12.2.1.2. An AE of severe intensity 
may not be considered serious. 
If a female subject becomes pregnant during this study, pregnancy information must be collected 
and recorded on the Sage Therapeutics 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 male subject’s female partner who becomes pregnant while the male subject 
is participating in study. After obtaining the necessary signed informed consent from the 
pregnant female partner directly, the investigator will follow the same pregnancy reporting 
procedures specified for pregnant female subjects. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented even if the subject was 
discontinued from the study. If the pregnancy ends for any reason before the anticipated date, the 
investigator should notify the sponsor. 
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 or a complication relating to 
the pregnancy occurs (e.g., spontaneous abortion). If the outcome of the pregnancy meets the 
criteria for immediate classification as an SAE (i.e., postpartum complication, spontaneous 
abortion, stillbirth, neonatal death, or congenital anomaly/birth defects), the investigator should 
follow the procedures for reporting an SAE. 
12.5. 
Reporting Serious Adverse Events 
All SAEs must be reported to Sage, or designee, immediately. A written account of the SAE 
must be sent to Sage, or designee, within 24 hours of the first awareness of the event by the 
investigator and/or his staff. The Investigator must complete, sign and date the SAE report form, 


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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 
(CRF) and/or study file. 
Any SAEs discovered by the Investigator after the designated follow up time for the study, 
should be promptly reported to Sage, or designee, according to the timelines noted above.  
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 ethics committee 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. Ethics Committee 
(EC)/Institutional Review Boards (IRBs) will be notified of SAEs and/or SUSARs as required by 
local law. In addition, appropriate Sponsor Drug Safety and Pharmacovigilance personnel, or 
designee, will unblind SUSARs for the purpose of regulatory reporting. The Sponsor, or 
designee, will submit SUSARs (in blinded or unblinded fashion) to regulatory agencies 
according to local law. The Sponsor, or designee, will submit SUSARs to investigators in a 
blinded fashion. 
12.6. 
Emergency Identification of Study Drug 
During the study, 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 treatment received. Unless a subject is at 
immediate risk, the Investigator must make diligent attempts to contact Sage prior to unblinding 
the study treatment administered to a subject. Any request from the Investigator about the 
treatment administered to study subjects must be discussed with Sage. If the unblinding occurs 
without Sage’s knowledge, the Investigator must notify Sage as soon as possible and no later 
than the next business morning. All circumstances surrounding a premature unblinding must be 
clearly documented in the source records. Unless a subject is at immediate risk, any request for 
the unblinding of individual subjects must be made in writing to Sage and approved by the 
appropriate Sage personnel, according to standard operating procedures.  
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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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. 
When all subjects complete the Day 42 visit, the database will be locked, followed by treatment 
unblinding to the Sponsor and data analyses (site personnel and subjects will remain blinded). 
The extended follow-up period will continue as scheduled; the final database lock will occur 
when all subjects complete the extended follow-up period. 
13.1. 
Data Analysis Sets 
The Randomized set is defined as all subjects who are randomized. 
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 
HAM-D total score 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. No imputation process will be 
used to estimate missing data. A sensitivity analysis will be used to investigate the impact of 
missing data if ≥5% of subjects in any treatment group have missing data. 
13.3. 
General Considerations 
For the purpose of all safety and efficacy analyses where applicable, baseline is defined as the 
last measurement prior to the start of study drug administration.  
Continuous endpoints will be summarized with number (n), mean, standard deviation (SD), 
median, minimum, and maximum. In addition, change from baseline values will be calculated at 
each time point and summarized descriptively. For categorical endpoints, descriptive summaries 
will include counts and percentages.  
13.4. 
Demographics and Baseline Characteristics 
Demographic data (Section 12.1.1) and baseline characteristics, such as height, weight, and body 
mass index (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.  


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13.5. 
Efficacy Analyses 
Efficacy data will be summarized using appropriate descriptive statistics and other data 
presentation methods where applicable; subject listings will be provided for all efficacy data. 
Subjects will be analyzed according to randomized treatment.  
The estimand for the primary efficacy analysis is the mean change from baseline in HAM-D total 
score at Day 15. This will be analyzed using a mixed effects model for repeated measures 
(MMRM); the model will include treatment, baseline HAM-D total score, stratification factor, 
assessment time point, and time point-by-treatment as explanatory variables. All explanatory 
variables will be treated as fixed effects. All post-baseline time points will be included in the 
model. The main comparison will be between SAGE-217 and placebo at the 15-day time point. 
Model-based point estimates (ie, least squares [LS] means, 95% confidence intervals, and p-
values) will be reported where applicable. An unstructured covariance structure will be used to 
model the within-subject errors. 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. The sandwich estimator for the variance 
covariance matrix will be derived, using the EMPIRICAL option in the PROC MIXED statement 
in SAS. 
Similar to those methods described above for the primary endpoint, an MMRM will be used for 
the analysis of the change from baseline in other time points in HAM-D total score, MADRS 
total score, HAM-A total score, SF-36v2 score, PHQ-9 score, sleep diary endpoints (eg, sleep 
latency (SL), total sleep time (TST), wake after sleep onset (WASO)), ISI score and selected 
individual items and/or subscale scores in HAM-D for change from baseline.  
Generalized estimating equation (GEE) methods will be used for the analysis of HAM-D 
response (defined as ≥50% reduction from baseline in HAM-D total score) and HAM-D 
remission (defined as HAM-D total score of ≤7.0). GEE models will include terms for treatment, 
baseline score, stratification factor, assessment time point, and time point-by-treatment as 
explanatory variables. The comparison of interest will be the difference between SAGE-217 and 
matching placebo at the 15-day time point. Model-based point estimates (ie, odds ratios), 95% 
confidence intervals, and p-values will be reported.  
A GEE method will also be used for the analysis of CGI-I response including terms for 
treatment, baseline CGI-S score, stratification factor, assessment time point, and time point-by-
treatment as explanatory variables. 
 
13.6. 
Safety Analyses 
Safety and tolerability of study drug will be evaluated by incidence of AEs/SAEs, vital signs, 
clinical laboratory evaluations, and 12-lead ECG. Suicidality will be monitored by the C-SSRS. 
Potential withdrawal symptoms after discontinuation of SAGE-217 will be assessed using the 
PWC-20. Safety data will be listed by subject and summarized by treatment group. All safety 
summaries will be performed on the Safety Set. Where applicable, ranges of potentially clinical 
significant (PCS) values are provided in the SAP. 


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13.6.1. 
Adverse Events 
The analysis of AEs will be based on the concept of TEAEs. The incidence of TEAEs will be 
summarized overall and by Medical Dictionary for Regulatory Activities (MedDRA) Version 
18.1 or higher, System Organ Class (SOC), 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 (see Section 12.3).  
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).  
13.6.2. 
Clinical Laboratory Evaluations 
Results of clinical laboratory parameters in each scheduled visit and mean changes from baseline 
will be summarized in standard units. Normal range of each parameter is provided by the 
laboratory; shift from baseline to post-baseline values in abnormality of results will be provided. 
Potentially clinically significant values will be summarized by treatment. Any abnormal values 
deemed clinically significant by the investigator will be reported as an AE (see Section 12.2). 
Clinical laboratory results will be listed by subject and timing of collection. 
13.6.3. 
Physical Examinations 
The occurrence of a physical examination (Y/N) and the date performed will be listed by subject. 
Any clinically significant observation in physical examination will be reported as an AE (see 
Section 12.2). 
13.6.4. 
Vital Signs 
Results from each visit and mean changes from baseline in vital signs will be summarized by 
scheduled visit. Any abnormality deemed clinically significant by the investigator will be 
reported as an AE (see Section 12.2). Potentially clinically significant values will be summarized 
by treatment. Vital sign results will be listed by subject and timing of collection. 
13.6.5. 
12-Lead Electrocardiogram 
The following ECG parameters will be listed for each of the triplicate ECGs for each subject: 
heart rate, PR, QRS, QT, and QTcF; the derived mean of each parameter will also be listed. Any 
clinically significant abnormalities or changes in mean ECGs should be reported as an AE (see 
Section 12.2). Mean ECG data will be summarized by visit. Potentially clinically significant 
values of QTcF will be summarized by treatment. Electrocardiogram findings will be listed by 
subject and visit.  
13.6.6. 
Prior and Concomitant Medications 
Medications will be recorded at each study visit during the study and will be coded using World 
Health Organization-Drug dictionary (WHO-DD) September 2015, or later.  


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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 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.  
13.6.7. 
Columbia Suicide Severity Rating Scale 
Suicidality data collected on the C-SSRS at baseline and by visit during the Treatment Period 
will be summarized by treatment. Listings will include all data, including behavior type and/or 
category for Suicidal Ideation and Suicidal Behavior of the C-SSRS.  
13.6.8. 
Physician Withdrawal Checklist 
Potential withdrawal symptoms collected on the PWC-20 will be summarized by visit and 
treatment. Listings will include all data by subject. 
 
 
 
 
 
13.8. 
Determination of Sample Size 
Assuming a two-sided alpha level of 0.05, a sample size of 399 evaluable subjects would provide 
90% power to detect a placebo-adjusted treatment difference of approximately 4 points in the 
primary endpoint, change from baseline in HAM-D total score at Day 15, assuming SD of 
10 points. Assuming an 11% dropout rate and a 1:1:1 randomization ratio within each stratum 
(antidepressant use at baseline, yes or no), approximately 450 total randomized subjects will be 
required to obtain 399 evaluable subjects. Evaluable subjects are defined as those randomized 
subjects who receive study drug and have valid baseline and at least 1 post-baseline HAM-D 
assessment. Additional subjects may be randomized if the dropout rate is greater than 11%. 


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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 (or designee) will visit the investigational study site per Sage Standard Operating 
Procedures 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. 
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 


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investigator should contact Sage Therapeutics immediately if contacted by a regulatory agency 
about an inspection. 
14.3. 
Institutional Review Board (IRB) or Ethics Committee (EC) 
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 Practices 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 Informed Consent Form, 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 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 Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use and Good Clinical Practice 
guidelines, as well as all 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 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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19. 
LIST OF REFERENCES 
Busner J, Targum S. CGI-S. (2007a), as adapted from Kay, Stanley R, Positive and Negative 
Symptoms in Schizophrenia:Assessment and Research.  Clinical and Experimental Psychiatry, 
Monograph No. 5.  Brunner/Mazel, 1991.  Modified from Guy W. Clinical Global Impressions: 
In ECDEU Assessment Manual for Psychopharmacology. 1976; 218-22. Revised DHEW Pub. 
(ADM) Rockville, MD: National Institute for Mental Health.   
Busner J, Targum S. CGI-I.  (2007b), as adapted from Spearing, et al.  Psychiatry Research, 
1997;73:159-71.  Modified from Guy W. Clinical Global Impressions: In ECDEU Assessment 
Manual for Psychopharmacology. 1976; 218-22. Revised DHEW Pub. (ADM) Rockville, MD: 
National Institute for Mental Health.   
Conradi HJ, Ormel J, de Jonge P. Presence of individual (residual) symptoms during depressive 
episodes and periods of remission: a 3-year prospective study. Psychol Med. 2011 
Jun;41(6):1165-74. 
Drugan RC, Morrow AL, Weizman R, et al. Stress-induced behavioral depression in the rat is 
associated with a decrease in GABA receptor-mediated chloride ion flux and brain 
benzodiazepine receptor occupancy. Brain Res. 1989;487: 45–51. 
DSM-5.  Diagnostic and statistical manual of mental disorders (5th ed.).  American Psychiatric 
Association 2013.  Arlington, VA: American Psychiatric Publishing. 
Gerner RH, Hare TA. GABA in normal subjects and patients with depression, schizophrenia, 
mania, and anorexia nervosa. Am J Psychiatry. 1981;138:1098–101. 
Greenberg PE, Fournier AA, Sisitsky T, Pike CT, Kessler RC. The economic burden of adults 
with major depressive disorder in the United States (2005 and 2010). J Clin Psychiatry. 2015 
Feb;76(2):155-62. 
Honig A, Bartlett JR, Bouras N, Bridges PK. Amino acid levels in depression: a preliminary 
investigation. J Psychiatr Res. 1988; 22:159–64. 
Luscher B, Shen Q, Sahir N. The GABAergic deficit hypothesis of major depressive disorder. 
Mol Psychiatry. 2011;16(4):383-406. 
Maguire J, Mody I. GABA(A)R plasticity during pregnancy: Relevance to postpartum 
depression. Neuron. 2008;59(2);207-13.   
Maguire J, Ferando I, Simonsen C, Mody I. Excitability changes related to GABAA receptor 
plasticity during pregnancy. J Neurosci. 2009;29(30):9592-601.   
Mann JJ, Oguendo MA, Watson KT, et al. Anxiety in major depression and cerebrospinal fluid 
free gamma-aminobutyric acid. Depress Anxiety. 2014;31(10):814-21. 
  


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Morin CM, Belleville G, Bélanger L, Ivers H. The Insomnia Severity Index: Psychometric 
Indicators to Detect Insomnia Cases and Evaluate Treatment Response. Sleep. 2011;34(5):601-
608. 
Olfson M, Marcus SC, Shaffer D. Antidepressant drug therapy and suicide in severely depressed 
children and adults: A case-control study. Archives of general psychiatry. 2006:63(8);865-872. 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The Columbia-
Suicide Severity Rating Scale: initial validity and internal consistency findings from three 
multisite studies with adolescents and adults. Am J Psychiatry. 2011 Dec;168(12):1266-77. 
Rickels K, Garcia-Espana F, Mandos LA, Case GW. Physician Withdrawal Checklist (PWC-20). 
J Clin Psychopharmacol. 2008;28(4):447-451. 
Romera I, Pérez V, Ciudad A, et al. Residual symptoms and functioning in depression, does the 
type of residual symptom matter? A post-hoc analysis. BMC Psychiatry. 2013 Feb 11;13:51. 
Rudolph U, Knoflach F. Beyond classical benzodiazepines: novel therapeutic potential of 
GABAA receptor subtypes. Nat Rev Drug Discov. 2011 Jul 29;10(9):685-97. 
Schüle C, Nothdurfter C, Rupprecht R.  The role of allopregnanolone in depression and anxiety. 
Prog Neurobiol. 2014 Feb;113:79-87. 
Trivedi MH, Rush AJ, Wisniewski SR, et al. (STAR*D Study Team). Evaluation of outcomes 
with citalopram for depression using measurement-based care in STAR*D: implications for 
clinical practice. Am J Psychiatry. 2006 Jan;163(1):28-40. 
Ware JE Jr, Kosinski M, Bjorner JB, et al.  User's Manual for the SF-36v2 Health Survey.  2nd 
ed.  Lincoln, RI:  QualityMetric Incorporated; 2007. 
Williams JBW, Kobak KA. Development and reliability of a structured interview guide for the 
Montgomery-Asberg Depression Rating Scale (SIGMA). Br J Psychiatry. 2008;192:52-8. 
Williams JBW.  SIGH-D 24hr: V1.3 – 24 HR Version. 2013a. 
Williams JBW.  SIGH-D Past week:  Past Week Version. 2013b. 
Williams JBW.  SIGH-A 24hr: V1.3 – 24 HR Version. 2013c. 
Williams JBW.  SIGH-A Past week:  Past Week Version. 2013d. 
 


Protocol 217-MDD-301 Summary of Changes  
 
 
 
 
 
 
 
Sage Therapeutics 
Amendment #3, Version 4.0 
CONFIDENTIAL 
 
1 
Protocol 217-MDD-301 Amendment 3 
Date of Amendment: 07 March 2019 
A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study Evaluating 
the Efficacy of SAGE-217 in the Treatment of Adult Subjects with Major Depressive 
Disorder 
Rationale for Protocol Amendment 
The primary purpose for this protocol amendment is to extend the follow-up period (total of 
6 months). Additional changes are being implemented as outlined below: 
• 
Prohibit subjects from participating in night shift work for subject safety with evening dosing 
• 
Specify subjects receiving psychotherapy at Screening must have been receiving therapy on a 
regular schedule for at least 60 days prior to Day 1 and plan to continue the psychotherapy 
schedule through Day 42 
• 
Specify body mass index parameters that would be exclusionary or that would require further 
evaluation prior to admission to the study 
• 
Restrict only strong CYP3A inducers due to results from a drug-drug interaction study of 
SAGE-217 with CYP inducers 
• 
Exclude subjects who have been taking benzodiazepines, barbiturates, or GABAA modulators 
daily or near-daily for more than 1 year at Screening and exclude subjects taking any 
benzodiazepine or GABA modulator with a half-life of ≥48 hours (eg, diazepam) from 
60 days prior to Day 1 to avoid any confounding effects with SAGE-217 
• 
Exclude all atypical and typical antipsychotics 
• 
Exclude psychostimulants and opioids 
• 
Specify 2 database locks (the first after all subjects complete 4 weeks of follow-up and the 
final after all subjects complete the 6-month follow-up period) 
• 
Increase time required for subject to be standing before standing vital signs are taken 
• 
Remove pulse oximetry that was inadvertently listed in Section 12.1.4 Vital Signs 
• 
Specify additional clinical laboratory tests that the laboratory performs 
• 
Specify conduct for unresolved adverse events after the last scheduled visit 
• 
Update terminology and definition of the Efficacy Set (now Full Analysis Set) to specify that 
subjects in this set must have a valid baseline HAM-D score 
• 
Remove concomitant medication usage that was inadvertently listed in Section 13.6 Safety 
Analyses 
A detailed summary of changes is provided in Table 1Table 1. Corrections to typographical 
errors, punctuation, grammar, abbreviations, and formatting are not detailed individually, nor are 
administrative updates such as revising the document date, updating the document header and 
version number, and updating the table of contents. 


Protocol 217-MDD-301 Summary of Changes  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Amendment #3, Version 4.0 
CONFIDENTIAL 
 
2 
Table 1: 
Protocol Amendment 3 Detailed Summary of Changes 
The primary section of the protocol affected by the changes in Protocol Amendment 3 is indicated. The corresponding related text has 
been revised throughout the protocol. Deleted text is indicated by strikeout; added text is indicated by bold font. 
Purpose: Extend the follow-up period (total of 6 months) resulting in an additional 3 visits 
The primary change occurs in Section 7.1 Overall Study Design 
Changed text: 
This is a randomized, double-blind, parallel-group, placebo-controlled study in subjects with MDD (MADRS total score 
≥30). The study will consist of a Screening Period of up to 28 days, a 14-day Treatment Period, a 28-day follow-up 
period, and an extended follow-up period through Day 182 (6 months following the last dose)a 4-week Follow-up Period. 
Sections also affected by this change:  
• 
Synopsis, Planned Duration of Subject Participation 
• 
Synopsis, Study Description 
• 
Table 1 Schedule of Events 
• 
Synopsis and Section 8.1 Subject Inclusion Criteria #8, #9, #10, and #11 
• 
Synopsis and Section 8.2 Subject Exclusion Criteria #19 
• 
Section 8.3 Subject Withdrawal Criteria 
• 
Section 9.2.2 Prohibited Medications 
• 
Section 9.2.3 Other Restrictions 
Purpose: Prohibit subjects from participating in night shift work for subject safety with evening dosing 
The primary change occurs in Section 8.1 Subject Inclusion Criteria 
Changed text: 
4. Subject agrees to adhere to the study requirements, including not participating in night shift work.  
Sections also affected by this change:  
• 
Synopsis, Subject Inclusion Criteria 
• 
9.2.3 Other Restrictions 


Protocol 217-MDD-301 Summary of Changes  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Amendment #3, Version 4.0 
CONFIDENTIAL 
 
3 
Purpose: Specify subjects receiving psychotherapy at Screening must have been receiving therapy on a regular schedule for at least 60 days prior 
to Day 1 and plan to continue the psychotherapy schedule through Day 42 
The primary change occurs in Section 8.1 Subject Inclusion Criteria 
Added text: 
7. Subjects taking antidepressants psychotropic medications used to treat major depressive disorder (eg, antidepressants, 
atypical antipsychotics) must have been taking these medications at the same dose for at least 60 days prior to Day 1. 
Subjects receiving psychotherapy must have been receiving therapy on a regular schedule for at least 60 days prior to Day 
1. 
Sections also affected by this change:  
• 
Synopsis, Subject Inclusion Criteria 
• 
9.2.3 Other Restrictions 
Purpose: Specify body mass index parameters that would be exclusionary or that would require further evaluation prior to admission to the study 
The primary change occurs in Section 8.2 Subject Exclusion Criteria 
Added text: 
3. 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. A body mass index (BMI) ≤18 or ≥50 kg/m2 at Screening is 
exclusionary; 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, chronic obstructive pulmonary disease [COPD]), concomitant medications, and prior 
tolerability of sedating agents. 
Sections also affected by this change:  
• 
Synopsis, Subject Exclusion Criteria 


Protocol 217-MDD-301 Summary of Changes  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sage Therapeutics 
Amendment #3, Version 4.0 
CONFIDENTIAL 
 
4 
Purpose: Restrict only strong CYP3A inducers due to results from a drug-drug interaction study of SAGE-217 with CYP inducers 
The primary change occurs in Section 8.2 Subject Exclusion Criteria 
Changed text: 
17. Use of any strong CYP3A inducer, such as such as rifampin, carbamazepine, ritonavir, enzalutamide, 
mitotaneefavirenz, nevirapine, phenytoin, phenobarbital and or St John’s Wort, within 28 days prior to the first dose of 
study drug. 
Sections also affected by this change:  
• 
Synopsis, Subject Exclusion Criteria 
• 
Section 9.2.2 Prohibited Medications 
Purpose: Exclude subjects that have been taking benzodiazepines, barbiturates, or GABAA modulators daily or near-daily for more than 1 year at 
Screening and exclude subjects taking any benzodiazepine or GABA modulator with a half-life of ≥48 hours (eg, diazepam) from 60 days prior to 
Day 1 to avoid any confounding effects with SAGE-217 
The primary change occurs in Section 8.2 Subject Exclusion Criteria 
Changed text: 
20. Subject is taking benzodiazepines, barbiturates, or GABAA modulators/GABA-containing agents (eg, eszopiclone, 
zopiclone, zaleplon, and zolpidem) at Day -28, or has been using these agents daily or near-daily (≥4 times per week) for 
more than 1 year. Subject is taking any benzodiazepine or GABA modulator with a half-life of ≥48 hours (eg, diazepam) 
from 60 days prior to Day 1. 
Sections also affected by this change:  
• 
Synopsis, Subject Exclusion Criteria 
• 
Section 9.2.2 Prohibited Medications 


Protocol 217-MDD-301 Summary of Changes  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sage Therapeutics 
Amendment #3, Version 4.0 
CONFIDENTIAL 
 
5 
Purpose: Exclude all atypical and typical antipsychotics 
The primary change occurs in Section 8.2 Subject Exclusion Criteria 
Changed text: 
21. Subject is taking non-GABA anti-insomnia medications (eg melatonin, Benadryl [anti-histamines], trazodone, low 
dose quetiapine, mirtazapine, etc), or first or second generation (typical/atypical) antipsychotics at Day -14. 
Sections also affected by this change:  
• 
Synopsis, Subject Exclusion Criteria 
• 
Synopsis and Section 8.1 Subject Inclusion Criterion #7 
• 
Section 9.2.1 Prior and Concomitant Medications and/or Supplements 
• 
Section 9.2.2 Prohibited Medications 
Purpose: Exclude psychostimulants and opioids 
The primary change occurs in Section 8.2 Subject Exclusion Criteria 
Added text: 
25. Subject is taking psychostimulants (eg, methylphenidate, amphetamine) or opioids, regularly or as-needed, at Day -28. 
Sections also affected by this change:  
• 
Synopsis, Subject Exclusion Criteria 
• 
Section 9.2.2 Prohibited Medications 
Purpose: Specify 2 database locks (the first after all subjects complete 4 weeks of follow-up and the final after all subjects complete the 6-month 
follow-up period) 
The primary change occurs in Section 9.4 Randomization and Blinding 
Added text: 
The Sponsor will be unblinded following the first database lock when all subjects complete the Day 42 visit; site personnel 
and subjects will remain blinded throughout the extended follow-up until the final database lock when all subjects 
complete the Day 182 visit. 
Sections also affected by this change:  
• 
Synopsis, Statistical Methods 
• 
Section 13 Statistics 


Protocol 217-MDD-301 Summary of Changes  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sage Therapeutics 
Amendment #3, Version 4.0 
CONFIDENTIAL 
 
6 
Purpose: Increase time required for subject to be standing before standing vital signs are taken 
The primary change occurs in Section 12.1.4 Vital Signs 
Changed text: 
Vital signs comprise both supine and standing for systolic and diastolic blood pressure and heart rate measurements. Heart 
rate and blood pressure are to be collected in supine position after the subject has been resting for 5 minutes and then after 
approximately 31 minutes in the standing position. 
Sections also affected by this change:  
• 
Table 1 footnote ‘k’ 
Purpose: Remove pulse oximetry that was inadvertently listed in Section 12.1.4 Vital Signs 
The primary change occurs in Section 12.1.4 Vital Signs 
Removed text: 
Respiratory rate, pulse oximetry and temperature are collected once, in either position. 
Sections also affected by this change:  
• 
Not applicable 
Purpose: Specify additional clinical laboratory tests that the laboratory performs 
The primary change occurs in Table 3 Clinical Laboratory Tests 
Changed text: 
Added red blood cell indices to the hematology panel which will reflex to red blood cell morphology if the indices are 
abnormal. 
Added that the thyroid stimulation hormone (TSH) test in the serum chemistry panel will reflex to free T3/T4 if TSH is 
abnormal 
Sections also affected by this change:  
• 
Not applicable 


Protocol 217-MDD-301 Summary of Changes  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sage Therapeutics 
Amendment #3, Version 4.0 
CONFIDENTIAL 
 
7 
Purpose: Specify conduct for unresolved adverse events after the last scheduled visit 
The primary change occurs in 12.2.1.1 Adverse Event (AE) 
Added text: 
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 subject with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
Sections also affected by this change:  
• 
Not applicable 
Purpose: Update terminology and definition of the Efficacy Set (now Full Analysis Set) to specify that subjects in this set must have a valid 
baseline HAM-D score 
The primary change occurs in 13.1 Data Analysis Sets 
Changed text: 
The Efficacy Full Analysis Set is, defined as all randomized subjects in the Safety Set with a valid baseline HAM-D total 
score and at least 1 post-baseline HAM-D total score evaluation, will be used for analysis of efficacy data.  
Sections also affected by this change:  
• 
Synopsis, Analysis Sets 
Purpose: Remove concomitant medication usage that was inadvertently listed in Section 13.6 Safety Analyses 
The primary change occurs in 13.6 Safety Analyses 
Removed text: 
Safety and tolerability of study drug will be evaluated by incidence of adverse events/serious adverse events AEs/SAEs, 
concomitant medication usage, vital signs, clinical laboratory evaluations, and 12-lead ECG. 
Sections also affected by this change:  
• 
Synopsis, Safety Analysis 
 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-MDD-301 v5.0 
 
CONFIDENTIAL 
 
 
1 
 
1. 
TITLE PAGE 
 
A PHASE 3, MULTICENTER, DOUBLE-BLIND, 
RANDOMIZED, PLACEBO-CONTROLLED STUDY 
EVALUATING THE EFFICACY OF SAGE-217 IN THE 
TREATMENT OF ADULT SUBJECTS WITH MAJOR 
DEPRESSIVE DISORDER 
 
PROTOCOL NUMBER: 217-MDD-301 
 
Study Drug 
SAGE-217 
Clinical Phase 
Phase 3 
Sponsor 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 
Sponsor Contact 
Tel:
email:
Sponsor Medical Monitor 
MD, MBA 
Tel:
email:
Date of Original Protocol 
Version 1.0, 16 JUL 2018 
Date of Amendment 1 
Version 2.0, 25 SEP 2018 
Date of Amendment 2 
Version 3.0, 11 OCT 2018 
Date of Amendment 3 
Version 4.0, 07 March 2019 
Date of Amendment 4 
Version 5.0, 25 March 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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217-MDD-301 v5.0 
 
CONFIDENTIAL 
 
 
3 
 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for SAGE-217. I have read the 
217-MDD-301 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) 
 


Clinical Protocol 
 
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CONFIDENTIAL 
 
 
4 
 
2. 
SYNOPSIS 
Name of Sponsor/Company: 
Sage Therapeutics 
Name of Investigational Product: 
SAGE-217 Capsules 
Name of Active Ingredient: 
SAGE-217 
Title of Study: A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study 
Evaluating the Efficacy of SAGE-217 in the Treatment of Adult Subjects with Major Depressive 
Disorder 
Number of Sites and Study Location: Approximately 55 sites in the United States 
Phase of development: 3 
Planned Duration of Subject Participation: 
Up to 213 days (up to 28-day Screening Period, 14-day Double-blind Treatment Period, and up 
to 6 months (168 days) of Follow-up) 
Objectives: 
Primary:  
• 
To evaluate the efficacy of SAGE-217 in the treatment of major depressive disorder 
(MDD) compared to placebo. 
Secondary: 
• 
To evaluate the effect of SAGE-217 on sleep.  
• 
To assess patient-reported outcome (PRO) measures as they relate to health-related 
quality of life and depressive symptoms. 
Safety: 
• 
To evaluate the safety and tolerability of SAGE-217. 
 
 
 
  
 
 
Endpoints: 
Primary: 
• 
The primary efficacy endpoint is the change from baseline in the 17-item Hamilton 
Rating Scale for Depression (HAM-D) total score at Day 15. 
Secondary: 
• 
Change from baseline in the 17-item HAM-D total score at other timepoints 
• 
HAM-D response at Day 15 and all other time points, defined as a ≥50% reduction in 
HAM-D score from baseline  
• 
HAM-D remission at Day 15 and all other time points, defined as HAM-D total score 
≤7 
• 
Clinical Global Impression - Improvement (CGI-I) response at Day 15 and all other 


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CONFIDENTIAL 
 
 
5 
 
time points, defined as “much improved” or “very much improved”  
• 
Change from baseline in Clinical Global Impression - Severity (CGI-S) score at Day 15 
and all other time points 
• 
Change from baseline in Hamilton Anxiety Rating Scale (HAM-A) total score at Day 15 
and all other time points  
• 
Change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) 
total score at Day 15 and all other time points 
• 
Change from baseline in HAM-D subscale and individual item scores at all time points 
• 
Change in sleep at Day 15 and all other time points, as assessed by 
o Insomnia Severity Index (ISI) 
o Subjective sleep parameters collected with the Core Consensus Sleep Diary 
• 
Change from baseline in PRO measures of health-related quality of life, as assessed by 
responses to the 36-item Short Form survey version 2 (SF-36v2), and of depressive 
symptoms, as assessed by the 9-item Patient Health Questionnaire (PHQ-9) 
Safety Endpoints: 
• 
Incidence and severity of adverse events/serious adverse events  
• 
Changes from baseline in clinical laboratory measures, vital signs, and 
electrocardiograms (ECGs) 
• 
Suicidal ideation and behavior using the Columbia Suicide Severity Rating Scale 
(C-SSRS)  
• 
Potential withdrawal symptoms using the 20-item Physician Withdrawal Checklist 
(PWC-20) 
 
 
  
 
  
 
 
 
 
 
Study Description:  
This is a randomized, double-blind, parallel-group, placebo-controlled study in subjects with 
MDD (MADRS total score ≥32 and a HAM-D total score ≥22). Randomization will be stratified 
based on use of antidepressant treatment (current/stable or not treated/withdrawn ≥60 days) at 
baseline and carried out within each stratum in a 1:1:1 ratio to receive SAGE-217 20 mg, 
SAGE-217 30 mg, or matching placebo; subjects will be treated for 14 days beginning on Day 1.  
The study will consist of a Screening Period of up to 28 days, a 14-day Treatment Period, a 28-
day follow-up period, and an extended follow-up period through Day 182 (6 months following 
the last dose).  
The Screening Period begins with the signing of the informed consent form (ICF) at the 
Screening Visit; 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 


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CONFIDENTIAL 
 
 
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MADRS, HAM-D and CGI-S.  
Antidepressants are permitted provided subjects are on a stable dose for at least 60 days prior to 
Day 1 and agree to continue on the stable dose through the follow-up period (Day 42). Initiation 
of new antidepressants or any other medications that may potentially have an impact on efficacy 
or safety endpoints will not be allowed between screening and completion of the Day 42 
assessments.  
Eligible subjects will be stratified based on use of antidepressant treatment (current/stable or not 
treated/withdrawn ≥60 days) and randomized within each stratum to one of 3 treatment groups 
(SAGE-217 20 mg, SAGE-217 30 mg, or matching placebo) in a 1:1:1 ratio. Subjects will self-
administer a single dose of study drug once daily in the evening with food, on an outpatient 
basis, for 14 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 treatment and follow-up periods as outlined in Table 1. 
Subjects who cannot tolerate study drug will be discontinued from study drug and will receive 
treatment as clinically indicated. 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. Follow-up visits should take place as scheduled relative to the last dose of 
treatment (eg, if a subject’s last dose is on Day 13, their first follow-up visit (Visit 7,) should 
occur 4 days later). 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 both visits will be conducted. 
Number of Subjects (planned):  
Approximately 450 subjects will be randomized and dosed to obtain 399 evaluable subjects. 
Eligibility Criteria: 
Inclusion 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, including not participating in night 
shift work.  
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 a MADRS total score of ≥32 and a HAM-D total score ≥22 at screening and 
Day 1 (prior to dosing).  
7. Subjects taking antidepressants must have been taking these medications at the same 
dose for at least 60 days prior to Day 1. Subjects receiving psychotherapy must have 
been receiving therapy on a regular schedule for at least 60 days prior to Day 1. 
8. Subject is willing to delay start of other antidepressant or antianxiety medications and 
any new pharmacotherapy regimens, including as-needed benzodiazepine anxiolytics 


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7 
 
and sleep aids, until after completion of the Day 42 visit.  
9. Female subject agrees to use one of the following methods of contraception during the 
treatment period and for 30 days following the last dose of study drug, unless she is 
postmenopausal (defined as no menses for 12 months without an alternative medical 
cause and confirmed by follicle stimulating hormone [FSH] >40 mIU/mL), surgically 
sterile (hysterectomy or bilateral oophorectomy), or does not engage in sexual relations 
which  carry a risk of pregnancy: 
• 
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 
10. Male subject agrees to use an acceptable method of effective contraception during the 
treatment period 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. 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 #9 for acceptable 
contraception methods). 
11. Male subject is willing to abstain from sperm donation during the treatment period and 
for 5 days after receiving the last dose of the study drug. 
12. Subject agrees to refrain from drugs of abuse and alcohol for the duration of the study. 
Exclusion Criteria: 
1. Subject has attempted suicide associated with the current episode of MDD. 
2. Subject had onset of the current depressive episode during pregnancy or 4 weeks 
postpartum, or the subject has presented for screening during the 6-month postpartum 
period. 
3. 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. A body 
mass index (BMI) ≤18 or ≥50 kg/m2 at Screening is exclusionary; 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, chronic obstructive pulmonary disease [COPD]), 
concomitant medications, and 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 


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CONFIDENTIAL 
 
 
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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 within the current major depressive episode. 
6. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds.  
7. Subject has a positive pregnancy test at screening or on Day 1 prior to the start of study 
drug administration or, if she is breastfeeding at Screening or on Day 1 (prior to 
administration of study drug), she does not agree to temporarily cease giving breast milk 
to her child(ren) from just prior to receiving study drug on Day 1 until 7 days after the 
last dose of study drug.  
8. Subject has detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus 
(HCV) and positive HCV viral load, or human immunodeficiency virus (HIV) antibody 
at screening. 
9. Subject has a clinically significant abnormal 12-lead ECG at the screening or baseline 
visits. NOTE: mean QT interval calculated using the Fridericia method (QTcF) of 
>450 msec in males or >470 msec in females will be the basis for exclusion from the 
study.  
10. Subject has active psychosis per Investigator assessment.  
11. Subject has a medical history of seizures.  
12. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder.  
13. 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. 
14. Subject has had exposure to another investigational medication or device within 30 days 
prior to screening.  
15. Subject has previously participated in a SAGE-217 or a SAGE-547 (brexanolone) 
clinical trial.  
16. Use of any known strong inhibitors of cytochrome P450 (CYP)3A4 within 28 days or 
five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, or Seville 
oranges, or products containing these within 14 days prior to the first dose of study 
drug.  
17. Use of any strong CYP3A inducer, such as rifampin, carbamazepine, enzalutamide, 
mitotane, phenytoin, or St John’s Wort, within 28 days prior to the first dose of study 
drug. 
18. Subject has a positive drug and/or alcohol screen at screening or on Day 1 prior to 
dosing. 
19. Subject plans to undergo elective surgery before completion of the Day 42 visit. 
20. Subject is taking benzodiazepines, barbiturates, or GABAA modulators (eg, eszopiclone, 


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CONFIDENTIAL 
 
 
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zopiclone, zaleplon, and zolpidem) at Day -28, or has been using these agents daily or 
near-daily (≥4 times per week) for more than 1 year. Subject is taking any 
benzodiazepine or GABA modulator with a half-life of ≥48 hours (eg, diazepam) from 
60 days prior to Day 1. 
21. Subject is taking non-GABA anti-insomnia medications (eg melatonin, Benadryl [anti-
histamines], trazodone), or first or second generation (typical/atypical) antipsychotics at 
Day -14.  
22. 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. 
23. Subject has a history of sleep apnea. 
24. Subject has had gastric bypass surgery, has a gastric sleeve or lap band, or has had any 
related procedures that interfere with gastrointestinal transit. 
25. Subject is taking psychostimulants (eg, methylphenidate, amphetamine) or opioids, 
regularly or as-needed, at Day -28. 
Study Drug, 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: 
Placebo will be provided as hard gelatin capsules for oral administration containing only the 
excipients listed above for the active capsule.  
Duration of Treatment: 14 days 
Statistical methods: 
A detailed description of the analyses to be performed in the study will be provided in the 
Statistical Analysis Plan (SAP). The SAP will be finalized and approved prior to treatment 
unblinding.  
When all subjects complete the Day 42 visit, the database will be locked, followed by treatment 
unblinding to the Sponsor and data analyses (site personnel and subjects will remain blinded). 
The extended follow-up period will continue as scheduled; the final database lock will occur 
when all subjects complete the extended follow-up period. 
General Considerations 
For the purpose of all safety and efficacy analyses where applicable, baseline is defined as the 
last measurement prior to the start of study drug administration.  
Continuous endpoints will be summarized descriptively with n, mean, standard deviation, 
median, minimum, and maximum. In addition, change from baseline values will be calculated at 
each time point and summarized descriptively. For categorical endpoints, descriptive summaries 
will include counts and percentages.  
Analysis Sets 
The Randomized Set is defined as all subjects who are randomized. 


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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 HAM-D total score at least 1 post-baseline HAM-D total score.  
 
Determination of Sample Size 
Assuming a two-sided alpha level of 0.05, a sample size of 399 evaluable subjects would 
provide 90% power to detect a placebo-adjusted treatment difference of approximately 4 points 
in the primary endpoint, change from baseline in HAM-D total score at Day 15, assuming 
standard deviation (SD) of 10 points. Assuming a 11% dropout rate and a 1:1:1 randomization 
ratio within each stratum (antidepressant use at baseline, yes or no), approximately 450 total 
randomized subjects will be required to obtain 399 evaluable subjects. Evaluable subjects are 
defined as those randomized subjects who receive study drug and have valid baseline and at 
least 1 post-baseline HAM-D assessment. Additional subjects may be randomized if the dropout 
rate is greater than 11%. 
Analysis of Primary Endpoint 
The estimand for the primary efficacy analysis is the mean change from baseline in HAM-D 
total score at Day 15. This will be analyzed using a mixed effects model for repeated measures 
(MMRM); the model will include treatment, baseline HAM-D total score, stratification factor, 
assessment time point, and time point-by-treatment as explanatory variables. All explanatory 
variables will be treated as fixed effects. All post-baseline time points will be included in the 
model. The main comparison will be between SAGE-217 and placebo at the 15-day time point. 
Model-based point estimates (ie, least squares [LS] means, 95% confidence intervals, and p-
values) will be reported where applicable. An unstructured covariance structure will be used to 
model the within-subject errors. 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.  
Analysis of Secondary Endpoints 
Similar to those methods described above for the primary endpoint, an MMRM will be used for 
the analysis of the change from baseline in other time points in HAM-D total score, MADRS 
total score, HAM-A total score, SF-36v2 score, PHQ-9 score, sleep diary endpoints (eg, sleep 
latency (SL), total sleep time (TST), wake after sleep onset (WASO)), ISI score and selected 
individual items and/or subscale scores in HAM-D for change from baseline.  
Generalized estimating equation (GEE) methods will be used for the analysis of HAM-D 
response (defined as ≥50% reduction from baseline in HAM-D total score) and HAM-D 
remission (defined as HAM-D total score of ≤7.0). GEE models will include terms for 
treatment, baseline score, stratification factor, assessment time point, and time point-by-
treatment as explanatory variables. The comparison of interest will be the difference between 
SAGE-217 and matching placebo at the 15-day time point. Model-based point estimates (ie, 
odds ratios), 95% confidence intervals, and p-values will be reported.  
A GEE method will also be used for the analysis of CGI-I response including terms for 
treatment, baseline CGI-S score, stratification factor, assessment time point, and time point-by-
treatment as explanatory variables. 
 
 


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Safety Analysis 
Safety and tolerability of study drug will be evaluated by incidence of adverse events/serious 
adverse events, vital signs, clinical laboratory evaluations, and 12-lead ECG. Suicidality will be 
monitored by the C-SSRS. Potential withdrawal symptoms after discontinuation of SAGE-217 
will be assessed using the PWC-20. 
 
 
 
 


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Table 1: 
Schedule of Events 
Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
Follow-up Period 
Extended Follow-Up 
Visit Days 
D-28 to D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(+1d) 
and/or 
EOTa 
D18 
(±1d) 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
or 
ET 
D70, D126, D182 
(±7d) 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12, V13, V14 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Duplicate Subject Checkb 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
 
 
 
Serum FSH testc 
X 
 
 
 
 
 
 
 
 
 
 
 
SCID-5-CT 
X 
 
 
 
 
 
 
 
 
 
 
 
MGH ATRQ 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/Family History 
X 
 
 
 
 
 
 
 
 
 
 
 
Subject trainingd 
X 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examinatione 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Body Weight/Height 
X 
 
 
 
 
X (wt only) 
 
 
 
 
X (wt 
only) 
 
Clinical Laboratory 
Assessmentsf 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
Drug & Alcohol Screeng 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy Testh 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
 


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Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
Follow-up Period 
Extended Follow-Up 
Visit Days 
D-28 to D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(+1d) 
and/or 
EOTa 
D18 
(±1d) 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
or 
ET 
D70, D126, D182 
(±7d) 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12, V13, V14 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGl 
X 
X 
 
 
 
X 
 
 
 
 
X 
X (Day 182 only) 
C-SSRSm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAM-Dn, o 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MADRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
HAM-Ao 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
CGI-S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SF-36v2 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
PHQ-9 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
ISI 
 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
PWC-20 
 
X 
 
 
 
X 
X 
X 
 
 
 
 
Sleep diaryp 
X 
 
 
 
Study Drug Dispensation 
 
X 
 
X 
 
 
 
 
 
 
 
 
Study Drug Administration 
 
X (Day 1 through Day 14) 
 
 
 
 
 
 


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Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
Follow-up Period 
Extended Follow-Up 
Visit Days 
D-28 to D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(+1d) 
and/or 
EOTa 
D18 
(±1d) 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
or 
ET 
D70, D126, D182 
(±7d) 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12, V13, V14 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug 
Accountability/Return 
 
 
 
X 
 
X 
 
 
 
 
Xr 
 
Adverse Events/SAEss 
X 
Prior/Concomitant 
Medications/Procedurest 
X 
CGI-I = Clinical Global Impression – Improvement; CGI-S – Clinical Global Impression – Severity;
 C-
SSRS = Columbia Suicide Severity Rating Scale; D = day; EOT = end of treatment; ET = early termination; ECG = electrocardiogram; 
 
 FSH = follicle stimulating hormone; HAM-A = Hamilton Anxiety Rating Scale; HAM-D = Hamilton Rating Scale for Depression, 17-item; HIV = human 
immunodeficiency virus; ISI = Insomnia Severity Index; MADRS = Montgomery-Åsberg Depression Rating Scale; MGH ATRQ = Massachusetts General Hospital 
Antidepressant Treatment Response Questionnaire; PHQ-9 = 9-item Patient Health Questionnaire; PWC-20 = 20-item Physician Withdrawal Checklist; O = Optional; 
; SCID-5-CT = Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition Clinical Trials Version; SF-36v2 = 
36-item Short Form survey version 2; V = visit; wt = weight 
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. 
Follow-up visits should take place as scheduled relative to the last dose of treatment. 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 both visits will be conducted.  
b Subjects will be asked to authorize that their unique subject identifiers be entered into a registry (www.subjectregistry.com) with the intent of identifying subjects who may meet 
exclusion criteria for participation in another clinical study. 
c A serum follicle stimulating hormone test will be conducted at Screening for female subjects that are not surgically sterile to confirm whether a female subject with ≥12 months 
of spontaneous amenorrhea meets the protocol-defined criteria for being post-menopausal. 
d Subjects will be trained on use of software applications and devices necessary for the conduct of the study by site personnel. 
e A full physical examination will be conducted at Screening and abbreviated physical examinations will be conducted thereafter. A full physical examination includes assessment 
of body systems (eg, head, eye, ear, nose, and throat; heart; lungs; abdomen; and extremities). 
f Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. 
g Urine toxicology for selected drugs of abuse (as per the lab manual) and breath test for alcohol. 
h Serum pregnancy test at screening and urine pregnancy test thereafter for female subjects that are not surgically sterile and do not meet the protocol-defined criteria for being 
post-menopausal. 
 
 
 


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15 
 
k Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing). Heart rate and blood pressure to be collected in supine position at 
all scheduled time points after the subject has been resting for 5 minutes and then after approximately 3 minutes in the standing position. Vital signs may be repeated at the 
discretion of the Investigator as clinically indicated. 
l Triplicate ECGs will be collected. 
 
m The “Baseline/Screening” C-SSRS form will be completed at screening. The “Since Last Visit” C-SSRS form will be completed at any time of day at all subsequent time points. 
n The HAM-D is to be completed as early during the visit as possible. 
o The assessment timeframe for HAM-D scales will refer to the past 7 days (1 week) at Screening and “Since Last Visit” for all other visits. The assessment timeframe for HAM-A 
scale will refer to the past 7 days (1 week) at all visits. 
p Subjects are instructed to complete the Core Consensus Sleep Diary starting at least 7 days prior to Day 1 and then daily through Day 28. 
 
 
r To be performed at the ET visit only. 
s Adverse events will be collected starting at the time of informed consent and throughout the duration of the subject’s participation in the study. 
t Prior medications will be collected at Screening and concomitant medications and/or procedures will be collected at each subsequent visit. 
 


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3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF
FIGURES
1.
TITLE PAGE ................................................................................................................1 
2.
SYNOPSIS ...................................................................................................................4 
3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............16 
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................21 
5.
INTRODUCTION ......................................................................................................23 
5.1. 
Background of Major Depressive Disorder and Unmet Medical Need ......................23 
5.2. 
SAGE-217 ...................................................................................................................23 
5.3. 
Potential Risks and Benefits .......................................................................................24 
5.4. 
Dose Justification ........................................................................................................24 
6.
STUDY OBJECTIVES AND PURPOSE ..................................................................25 
6.1. 
Study Objective ..........................................................................................................25 
6.1.1. 
Primary Objective .......................................................................................................25 
6.1.2. 
Secondary Objective(s) ...............................................................................................25 
6.1.3. 
Safety Objective ..........................................................................................................25 
 
25 
6.2. 
Endpoints ....................................................................................................................25 
6.2.1. 
Primary Endpoint ........................................................................................................25 
6.2.2. 
Secondary Endpoint(s) ................................................................................................25 
6.2.3. 
Safety Endpoint(s) ......................................................................................................26 
 
26 
7.
INVESTIGATIONAL PLAN .....................................................................................27 
7.1. 
Overall Study Design ..................................................................................................27 
7.2. 
Number of Subjects ....................................................................................................27 
7.3. 
Treatment Assignment ................................................................................................27 
7.4. 
Dose Adjustment Criteria ...........................................................................................28 
7.5. 
Criteria for Study Termination ...................................................................................28 
8.
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................29 
8.1. 
Subject Inclusion Criteria ...........................................................................................29 
8.2. 
Subject Exclusion Criteria ..........................................................................................30 
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8.3. 
Subject Withdrawal Criteria .......................................................................................32 
8.3.1. 
Replacement of Subjects .............................................................................................32 
9.
TREATMENT OF SUBJECTS ..................................................................................33 
9.1. 
Study Drug ..................................................................................................................33 
9.2. 
Prior Medications, Concomitant Medications, and Restrictions ................................33 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................33 
9.2.2. 
Prohibited Medications ...............................................................................................33 
9.2.3. 
Other Restrictions .......................................................................................................34 
9.3. 
Treatment Adherence ..................................................................................................34 
9.4. 
Randomization and Blinding ......................................................................................35 
10.
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................36 
10.1. 
Description of Study Drug ..........................................................................................36 
10.2. 
Study Drug Packaging and Labeling ..........................................................................36 
10.3. 
Study Drug Storage .....................................................................................................36 
10.4. 
Study Drug Preparation ..............................................................................................36 
10.5. 
Study Drug Administration .........................................................................................36 
10.6. 
Study Drug Accountability .........................................................................................36 
10.7. 
Study Drug Handling and Disposal ............................................................................37 
11.
ASSESSMENT OF EFFICACY 
 .............................38 
11.1. 
Efficacy Assessments .................................................................................................38 
11.1.1. 
Hamilton Rating Scale for Depression (HAM-D) ......................................................38 
11.1.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) ........................................38 
11.1.3. 
Hamilton Anxiety Rating Scale (HAM-A) .................................................................38 
11.1.4. 
Clinical Global Impression (CGI) ..............................................................................39 
11.1.5. 
Short Form-36 Version 2 (SF-36v2) ...........................................................................39 
11.1.6. 
Patient Health Questionnaire (PHQ-9) .......................................................................39 
11.1.7. 
Insomnia Severity Index (ISI) ....................................................................................40 
11.1.8. 
Core Consensus Sleep Diary ......................................................................................40 
 
40 
 
40 
 
41 
 
41 
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41 
12.
ASSESSMENT OF SAFETY .....................................................................................42 
12.1. 
Safety Parameters .......................................................................................................42 
12.1.1. 
Demographic/Medical History ...................................................................................42 
12.1.2. 
Weight and Height ......................................................................................................42 
12.1.3. 
Physical Examination .................................................................................................42 
12.1.4. 
Vital Signs ..................................................................................................................42 
12.1.5. 
Electrocardiogram (ECG) ...........................................................................................43 
12.1.6. 
Laboratory Assessments .............................................................................................43 
12.1.6.1. 
Drugs of Abuse and Alcohol ......................................................................................45 
12.1.6.2. 
Pregnancy Screen ........................................................................................................45 
12.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................45 
12.1.8. 
Physician Withdrawal Checklist .................................................................................45 
12.2. 
Adverse and Serious Adverse Events .........................................................................46 
12.2.1. 
Definition of Adverse Events .....................................................................................46 
12.2.1.1. 
Adverse Event (AE) ....................................................................................................46 
12.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................46 
12.3. 
Relationship to Study Drug ........................................................................................47 
12.4. 
Recording Adverse Events .........................................................................................48 
12.5. 
Reporting Serious Adverse Events .............................................................................48 
12.6. 
Emergency Identification of Study Drug ....................................................................49 
13.
STATISTICS ..............................................................................................................50 
13.1. 
Data Analysis Sets ......................................................................................................50 
13.2. 
Handling of Missing Data ...........................................................................................50 
13.3. 
General Considerations ...............................................................................................50 
13.4. 
Demographics and Baseline Characteristics ...............................................................50 
13.5. 
Efficacy Analyses .......................................................................................................51 
13.6. 
Safety Analyses ..........................................................................................................51 
13.6.1. 
Adverse Events ...........................................................................................................52 
13.6.2. 
Clinical Laboratory Evaluations .................................................................................52 
13.6.3. 
Physical Examinations ................................................................................................52 
13.6.4. 
Vital Signs ..................................................................................................................52 
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13.6.5. 
12-Lead Electrocardiogram ........................................................................................52 
13.6.6. 
Prior and Concomitant Medications ...........................................................................52 
13.6.7. 
Columbia Suicide Severity Rating Scale ....................................................................53 
13.6.8. 
Physician Withdrawal Checklist .................................................................................53 
 
53 
13.8. 
Determination of Sample Size ....................................................................................53 
14.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................54 
14.1. 
Study Monitoring ........................................................................................................54 
14.2. 
Audits and Inspections ................................................................................................54 
14.3. 
Institutional Review Board (IRB) or Ethics Committee (EC) ....................................55 
15.
QUALITY CONTROL AND QUALITY ASSURANCE .........................................56 
16.
ETHICS ......................................................................................................................57 
16.1. 
Ethics Review .............................................................................................................57 
16.2. 
Ethical Conduct of the Study ......................................................................................57 
16.3. 
Written Informed Consent ..........................................................................................57 
17.
DATA HANDLING AND RECORDKEEPING .......................................................58 
17.1. 
Inspection of Records .................................................................................................58 
17.2. 
Retention of Records ..................................................................................................58 
18.
PUBLICATION POLICY ..........................................................................................59 
19.
LIST OF REFERENCES ............................................................................................60 
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LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................12 
Table 2: 
Abbreviations and specialist terms .............................................................................21 
Table 3: 
Clinical Laboratory Tests ...........................................................................................43 
Table 4: 
Relationship to Study Drug ........................................................................................47 
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4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and specialist terms 
Abbreviation or specialist term 
Explanation 
AE 
adverse event 
CGI-I 
Clinical Global Impression – Improvement 
CGI-S 
Clinical Global Impression – Severity 
CRF 
case report form 
CS 
clinically significant 
 
 
C-SSRS
Columbia Suicide Severity Rating Scale 
CYP 
cytochrome P450 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
end of treatment 
ET 
early termination 
 
 
FSH 
follicle stimulating hormone 
GABA 
γ-aminobutyric acid 
GEE 
generalized estimating equation 
HAM-A 
Hamilton Rating Scale for Anxiety 
HAM-D 
Hamilton Rating Scale for Depression 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ID 
identification 
IRB 
institutional review board 
IRT 
interactive response technology 
ISI 
Insomnia Severity Index 
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Table 2: 
Abbreviations and specialist terms (Continued) 
Abbreviation or specialist term 
Explanation 
MADRS 
Montgomery Åsberg Depression Rating Scale 
MDD 
major depressive disorder 
MGH ATRQ 
Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire 
MMRM 
mixed effects model for repeated measures 
NCS 
not clinically significant 
PCS 
Potentially clinically significant 
PHQ-9 
9-item Patient Health Questionnaire
PK 
pharmacokinetic 
PRO 
patient-reported outcome 
PWC-20 
20-item Physician Withdrawal Checklist
QTcF 
QT corrected according to Fridericia’s formula 
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 
SF-36v2 
36-item Short Form version 2
SUSAR 
suspected, unexpected, serious, adverse reactions 
TEAE 
treatment-emergent adverse event 
WHO 
World Health Organization 
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5. 
INTRODUCTION
5.1. 
Background of Major Depressive Disorder and Unmet Medical Need 
The World Health Organization (WHO) has identified depression as the leading cause of 
disability worldwide, and as a major contributor to the overall global burden of disease 
(http://www.who.int/mediacentre/factsheets/fs369/en/). Globally, depression has been estimated 
to affect over 300 million people. 
In the United States, the economic burden of depression, including workplace costs, direct costs 
and suicide-related costs, was estimated to be $210.5 billion in 2010 (Greenberg 2015). As per 
WHO statistics, over 800,000 people die due to suicide every year, and suicide is the second 
leading cause of death in 15- to 29-year-olds. The rate of US adults making a suicide attempt has 
increased (0.62% from 2004 to 2005 to 0.79% from 2012 to 2013), with a shift to more attempts 
among younger adults (42% to 50%, respectively) and among those with a depressive disorder 
(26% to 54%, respectively; Olfson 2017). 
In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), 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 (SSRIs), 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 (CSF) 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 
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and is generally expected to have good extravascular exposure. In exploratory in vitro receptor 
and ion channel assays and in vivo safety pharmacology studies, SAGE-217 was highly selective 
for GABAA receptors, and, consistent with the actions of other GABAA receptor potentiators 
(Rudolph 2011), exhibits potent anticonvulsant, anxiolytic, and sedative activity when 
administered in vivo. 
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 [HAM-A], 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 HAM-A. 
SAGE-217 has been generally well tolerated in clinical studies to date. The most common 
treatment-emergent adverse events (TEAEs) were sedation, somnolence, and dizziness. Most 
adverse events (AEs) were reported as mild or moderate in intensity. There have been no deaths 
and only one subject with essential tremor experienced a serious adverse event (SAE) of 
transient confusion leading to discontinuation of study drug. No other SAEs have been reported 
in any study of SAGE-217.  
Additional information on nonclinical and clinical data is provided in the Investigator’s 
Brochure.  
5.3. 
Potential Risks and Benefits 
Non-serious events of sedation, somnolence, and dizziness were the most commonly reported 
AEs with SAGE-217. Given the outcome of the Phase 2 study of SAGE-217 in subjects with 
MDD, the current significant unmet need in the treatment of depression, and a favorable benefit-
risk profile, further investigation of SAGE-217 in patients with MDD is justified. 
5.4. 
Dose Justification 
There will be 2 dose levels of SAGE-217 in this study in order to study dose ranging: 30 mg per 
day and 20 mg per day. The higher dose level of 30 mg per day is the maximum tolerated dose in 
the multiple ascending dose study of SAGE-217 in healthy subjects and is also the dose level that 
was effective and generally well tolerated in a Phase 2 study in subjects with MDD (217-MDD-
201). The lower dose of 20 mg per day will be studied in subjects with MDD for the first time in 
the current study and is anticipated to be well tolerated as it is lower than the maximum tolerated 
dose level. Due to sedation/somnolence observed in previous clinical trials when administered in 
the morning, and improved tolerability when given in the evening, both doses of 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 is to evaluate the efficacy of SAGE-217 in the treatment of MDD 
compared to placebo. 
6.1.2. 
Secondary Objective(s) 
Secondary objectives are: 
•
To evaluate the effect of SAGE-217 on sleep.
•
To assess patient-reported outcome (PRO) measures as they relate to health-related
quality of life and depressive symptoms.
6.1.3. 
Safety Objective 
The safety objective is to evaluate the safety and tolerability of SAGE-217. 
 
 
 
6.2. 
Endpoints
6.2.1. 
Primary Endpoint
The primary endpoint of this study is the change from baseline in the 17-item HAM-D total score 
at Day 15. 
6.2.2. 
Secondary Endpoint(s) 
•
Change from baseline in the 17-item HAM-D total score at other time points
•
HAM-D response at Day 15 and all other time points, defined as a ≥50% reduction in
HAM-D score from baseline
•
HAM-D remission at Day 15 and all other time points, defined as HAM-D total
score ≤7
•
CGI-I response at Day 15 and all other time points, defined as “much improved” or
“very much improved”
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•
Change from baseline in Clinical Global Impression - Severity (CGI-S) score at
Day 15 and all other time points
•
Change from baseline in HAM-A total score at Day 15 and all other time points
•
Change from baseline in the MADRS total score at Day 15 and all other time points
•
Change from baseline in HAM-D subscale and individual item scores at all time
points
•
Change in sleep at Day 15 and all other time points, as assessed by:
−
Insomnia Severity Index (ISI)
−
Subjective sleep parameters collected with the Core Consensus Sleep Diary
•
Change from baseline in PRO measures of health-related quality of life, as assessed
by responses to the 36-item Short Form survey version 2 (SF-36v2), and of
depressive symptoms, as assessed by the 9-item Patient Health Questionnaire (PHQ-
9)
6.2.3. 
Safety Endpoint(s)
•
Incidence and severity of adverse events/serious adverse events
•
Changes from baseline in clinical laboratory measures, vital signs, and
electrocardiograms (ECGs)
•
Suicidal ideation and behavior using the Columbia Suicide Severity Rating Scale
(C-SSRS)
•
Potential withdrawal symptoms using the 20-item Physician Withdrawal Checklist
(PWC-20)
 
 
 
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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design
This is a randomized, double-blind, parallel-group, placebo-controlled study in subjects with 
MDD (MADRS total score ≥32 and a HAM-D total score ≥22). The study will consist of a 
Screening Period of up to 28 days, a 14-day Treatment Period, a 28-day follow-up period, and an 
extended follow-up period through Day 182 (6 months following the last dose).  
The Screening Period begins with the signing of the informed consent form (ICF) at the 
Screening Visit; the ICF must be signed prior to beginning any screening activities. At the time 
of providing informed consent for the study, subjects will also be asked to authorize that their 
unique subject identifiers be entered into a registry (www.subjectregistry.com) with the intent of 
identifying subjects who may meet exclusion criteria due to participation in another clinical 
study (Section 8.2). 
The diagnosis of MDD must be made according to Structured Clinical Interview for Diagnostic 
and 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.  
Antidepressants are permitted provided subjects are on a stable dose for at least 60 days prior to 
Day 1 and agree to continue on the stable dose through the 28-day follow-up period (Day 42). 
Initiation of new antidepressants or any other medications that may potentially have an impact on 
efficacy or safety endpoints is prohibited between screening and completion of the Day 42 
assessments.  
Eligible subjects will be stratified based on use of antidepressant treatment (current/stable or not 
treated/withdrawn ≥60 days) and randomized within each stratum to one of 3 treatment groups 
(SAGE-217 20 mg, SAGE-217 30 mg, or matching placebo) in a 1:1:1 ratio. Subjects will self-
administer a single dose of study drug with food once daily in the evening on an outpatient basis, 
for 14 days. Dose reductions are not permitted. Study drug administration will be monitored via 
a clinical monitoring service (see Section 9.3). 
Subjects will return to the study center during the treatment and follow-up periods as outlined in 
Table 1. 
7.2. 
Number of Subjects 
Approximately 450 subjects will be randomized and dosed to obtain 399 evaluable subjects (see 
Section 13.8). 
7.3. 
Treatment Assignment 
Subjects will be randomly assigned to a treatment group on Day 1. Randomization will be 
stratified based on use of antidepressant treatment (current/stable or not treated/withdrawn 
≥60 days) at baseline and performed within each stratum in a 1:1:1 ratio to receive SAGE-217 
20 mg, SAGE-217 30 mg, or matching placebo. 
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7.4. 
Dose Adjustment Criteria 
Dose adjustments are not permitted in this study. Subjects who cannot tolerate study drug will be 
discontinued from study drug and will receive treatment as clinically indicated (see Section 8.3). 
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 
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, including not participating in night
shift work.
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 a MADRS total score of ≥32 and a HAM-D total score ≥22 at screening and
Day 1 (prior to dosing).
7. Subjects taking antidepressants must have been taking these medications at the same dose
for at least 60 days prior to Day 1. Subjects receiving psychotherapy must have been
receiving therapy on a regular schedule for at least 60 days prior to Day 1.
8. Subject is willing to delay start of other antidepressant or antianxiety medications and
any new pharmacotherapy regimens, including as-needed benzodiazepine anxiolytics and
sleep aids, until after completion of the Day 42 visit.
9. Female subject agrees to use one of the following methods of contraception during the
treatment period and for 30 days following the last dose of study drug, unless she is
postmenopausal (defined as no menses for 12 months without an alternative medical
cause and confirmed by follicle stimulating hormone [FSH] >40 mIU/mL), surgically
sterile (hysterectomy or bilateral oophorectomy), or does not engage in sexual relations
which carry a risk of pregnancy:
•
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.
10. Male subject agrees to use an acceptable method of effective contraception during the
treatment period 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. Acceptable
methods of effective contraception for males includes vasectomy, or a condom with
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spermicide used together with highly effective female contraception methods if the 
female partner is of child-bearing potential (see Inclusion Criteria #9 for acceptable 
contraception methods). 
11. Male subject is willing to abstain from sperm donation the treatment period and for 5
days after receiving the last dose of the study drug.
12. 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 had onset of the current depressive episode during pregnancy or 4 weeks
postpartum, or the subject has presented for screening during the 6-month postpartum
period.
3. 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. A body
mass index (BMI) ≤18 or ≥50 kg/m2 at Screening is exclusionary; 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, chronic obstructive pulmonary disease [COPD]),
concomitant medications, and 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 within the current major depressive episode.
6. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds.
7. Subject has a positive pregnancy test at screening or on Day 1 prior to the start of study
drug administration or, if she is breastfeeding at Screening or on Day 1 (prior to
administration of study drug), she does not agree to temporarily cease giving breast milk
to her child(ren) from just prior to receiving study drug on Day 1 until 7 days after the
last dose of study drug.
8. Subject has detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV)
and positive HCV viral load, or human immunodeficiency virus (HIV) antibody at
screening.
9. Subject has a clinically significant abnormal 12-lead ECG at the screening or baseline
visits. NOTE: mean QT interval calculated using the Fridericia method (QTcF) of
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10. Subject has active psychosis per Investigator assessment.
11. Subject has a medical history of seizures.
12. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective
disorder.
13. 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.
14. Subject has had exposure to another investigational medication or device within 30 days
prior to screening.
15. Subject has previously participated in a SAGE-217 or a SAGE-547 (brexanolone) clinical
trial.
16. Use of any known strong inhibitors of cytochrome P450 (CYP)3A4 within 28 days or
five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, or Seville
oranges, or products containing these within 14 days prior to the first dose of study drug.
17. Use of any strong CYP3A inducer, such as rifampin, carbamazepine, enzalutamide,
mitotane, phenytoin, or St John’s Wort, within 28 days prior to the first dose of study
drug.
18. Subject has a positive drug and/or alcohol screen at screening or on Day 1 prior to
dosing.
19. Subject plans to undergo elective surgery before completion of the Day 42 visit.
20. Subject is taking benzodiazepines, barbiturates, or GABAA modulators (eg, eszopiclone,
zopiclone, zaleplon, and zolpidem) at Day -28, or has been using these agents daily or
near-daily (≥4 times per week) for more than 1 year. Subject is taking any
benzodiazepine or GABA modulator with a half-life of ≥48 hours (eg, diazepam) from 60
days prior to Day 1.
21. Subject is taking non-GABA anti-insomnia medications (eg melatonin, Benadryl [anti-
histamines], trazodone), or first or second generation (typical/atypical) antipsychotics at
Day -14.
22. 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.
23. Subject has a history of sleep apnea.
24. Subject has had gastric bypass surgery, has a gastric sleeve or lap band, or has had any
related procedures that interfere with gastrointestinal transit.
25. Subject is taking psychostimulants (eg, methylphenidate, amphetamine) or opioids,
regularly or as-needed, at Day -28.
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8.3. 
Subject Withdrawal Criteria 
Subjects may withdraw from the study drug or terminate from the study at any time for any 
reason. 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 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.  
Subjects who discontinue study drug early should return to the site for an end of treatment (EOT) 
visit as soon as possible, preferably the day after treatment is discontinued. Follow-up visits 
should take place as scheduled relative to the last dose of treatment (eg, if a subject’s last dose is 
on Day 13, their first follow-up visit (Visit 7) should occur 4 days later). 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.  
A subject will be deemed lost to follow-up after attempts at contacting the subject have been 
unsuccessful. 
8.3.1. 
Replacement of Subjects 
Subjects will not be replaced. Additional subjects may be randomized if the drop-out rate is 
higher than anticipated (Section 13.8). 
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9. 
TREATMENT OF SUBJECTS 
9.1. 
Study Drug
Subjects will self-administer SAGE-217 (20 or 30 mg) or matching placebo orally once daily in 
the evening with food for 14 days.  
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 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.  
Antidepressants that have been taken at the same dose for at least 60 days prior to Day 1 are 
permitted if the subject intends to continue the stable dose through Day 42. 
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 
The following specific classes of medications are prohibited: 
•
Initiation of new psychotropic medications through the Day 42 visit
•
Initiation of new antidepressant therapy from 60 days prior to Day 1 through the Day
42 visit
•
Use of any benzodiazepines, barbiturates, GABAA modulators, GABA-containing
agents from Day -28 through the Day 42 visit (from Day -60 for benzodiazepine or
GABA modulators with a half-life of ≥48 hours)
•
Chronic or as-needed psychostimulants (eg, methylphenidate, amphetamine) or
opioids from Day -28 through the Day 42 visit
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•
First generation (typical) antipsychotics (eg, haloperidol, perphenazine) and second
generation (atypical) antipsychotics (eg, aripiprazole, quetiapine) from Day -14
through the Day 42 visit
•
Use of any non-GABA anti-insomnia medications (eg, melatonin, Benadryl [anti-
histamines], trazodone, low dose quetiapine, mirtazapine, etc) from Day -14 through
the Day 42 visit
•
Exposure to another investigational medication or device from 30 days prior to
Screening through the Day 42 visit
•
Any known strong inhibitors CYP3A4 from Day -28 or 5 half-lives prior to Day 1
(whichever is longer) through the treatment period
•
Use of any strong CYP3A inducer, such as rifampin, carbamazepine, enzalutamide,
mitotane, phenytoin, or St John’s Wort from Day -28 through the treatment period.
9.2.3. 
Other Restrictions
The consumption of grapefruit juice, grapefruit, or Seville oranges, or products containing these 
is prohibited throughout the treatment period. 
Consumption of alcohol or use of drugs of abuse is discouraged throughout the duration of the 
study. 
Female subjects who are lactating or actively breastfeeding must stop giving breast milk to the 
baby(ies) starting on Day 1 until 7 days after the last dose of study drug. 
Elective surgeries or procedures are prohibited through the Day 42 visit. 
Subjects must not participate in night shift work. 
Subjects receiving psychotherapy on a regular schedule for at least 60 days prior to Day 1 are 
permitted if the subject intends to continue the stable dose through the follow-up period 
(Day 42). 
9.3. 
Treatment Adherence 
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 10.4 and Table 1).  
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 
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 by dose level, as well as missed doses. 
In addition, the subject will be instructed to bring their dosing kit to the site as outlined in 
Table 1, at which time the Investigator or designee will be responsible for ensuring the kit 
contains sufficient doses for the duration of the treatment period.  
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All subjects should be reinstructed about the dosing requirement 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-compliance in the source documents. 
9.4. 
Randomization and Blinding 
This is a randomized double-blind, placebo-controlled study. Subjects who meet the entrance 
criteria will be randomized in a stratified manner based on use of antidepressant treatment 
(current/stable or not treated/withdrawn ≥60 days) at baseline; randomization will be done within 
each stratum in a 1:1:1 ratio to receive SAGE-217 20 mg, 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 (SAGE-217 20 mg, SAGE-217 30 mg, or placebo) will be based on the 
randomization schedule. The randomization schedules will be kept strictly confidential, 
accessible only to authorized personnel until the time of unblinding.  
The Sponsor will be unblinded following the first database lock when all subjects complete the 
Day 42 visit; site personnel and subjects will remain blinded throughout the extended follow-up 
until the final database lock when all subjects complete the Day 182 visit. 
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 (see Section 12.6 for 
more details related to unblinding).  
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10.
STUDY DRUG MATERIALS AND MANAGEMENT
10.1. 
Description of Study Drug
SAGE-217 is available as hard gelatin capsules containing a white to off-white powder. In 
addition to the specified amount of SAGE-217 Drug Substance, active SAGE-217 Capsules 
contain croscarmellose sodium, mannitol, silicified microcrystalline cellulose (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 Practices/Good Clinical Practices guidelines will 
be prepared by the Sponsor. 
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 is to be administered orally once daily in the evening with food. Practical options 
include taking SAGE-217 within 1 hour of dinner or taking SAGE-217 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. 
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The designated site staff will dispense the supplied subject-specific kits to subjects at the planned 
dispensation visit intervals outlined in Table 1.  
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 randomize the 
eligible subject into the study 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. 
At the subsequent study drug-dispensing visit, 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 this visit must be 
recorded.  
If dispensing errors or discrepancies are discovered by site staff or sponsor’s designee, the 
Sponsor must be notified immediately. 
The 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.
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11.
ASSESSMENT OF EFFICACY 
All assessments will be conducted according to the schedule of assessments (Table 1). 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 (HAM-D) 
The primary outcome measure is the change from baseline in 17-item HAM-D total score at the 
end of the Treatment Period (Day 15). Every effort should be made for the same rater to perform 
all HAM-D assessments for an individual subject. An assessment timeframe of 7 days will be 
used at Screening, and ‘Since Last Visit’ will be used for all other visits. 
The 17-item HAM-D will be used to rate the severity of depression in 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. 
In addition to the primary efficacy endpoint of change from baseline in HAM-D total score, 
several secondary efficacy endpoints will be derived for the HAM-D. Hamilton Rating Scale for 
Depression subscale scores will be calculated as the sum of the items comprising each subscale. 
Hamilton Rating Scale for Depression response will be defined as having a 50% or greater 
reduction from baseline in HAM-D total score. Hamilton Rating Scale for Depression remission 
will be defined as having a HAM-D total score of ≤7.  
11.1.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive 
episodes in subjects with mood disorders. It was designed as an adjunct to the HAM-D that 
would be more sensitive to the changes brought on by antidepressants and other forms of 
treatment than the Hamilton Scale.  
Higher MADRS scores indicate more severe depression, and each item yields a score of 0 to 6. 
The overall score ranges from 0 to 60 (Williams 2008). 
The MADRS total score will be calculated as the sum of the 10 individual item scores.  
11.1.3. 
Hamilton Anxiety Rating Scale (HAM-A) 
The 14-item HAM-A will be used to rate the severity of symptoms of anxiety (Williams 2013c; 
Williams 2013d). Each of the 14 items is defined by a series of symptoms, and measures both 
psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical 
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complaints related to anxiety). Scoring for HAM-A is calculated by assigning scores of 0 (not 
present) to 4 (very severe), with a total score range of 0 to 56, where <17 indicates mild severity, 
18 to 24, mild to moderate severity, and 25 to 30, moderate to severe severity. The HAM-A total 
score will be calculated as the sum of the 14 individual item scores. 
11.1.4. 
Clinical Global Impression (CGI) 
The CGI is a validated measure often utilized in clinical trials to allow clinicians to integrate 
several sources of information into a single rating of the subject’s condition. The CGI scale 
consists of 3 items. Only the first 2 items are being used in this study.  
The CGI-S uses a 7-point Likert scale to rate the severity of the subject’s illness at the time of 
assessment, relative to the clinician’s past experience with subjects who have the same diagnosis. 
Considering total clinical experience, a subject is assessed on severity of mental illness at the 
time of rating as 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately 
ill; 5=markedly ill; 6=severely ill; and 7=extremely ill (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 
“much improved.”  
11.1.5. 
Short Form-36 Version 2 (SF-36v2) 
The Medical Outcomes Study SF-36v2 is a 36-item measure of health status that has undergone 
validation in many different disease states (Ware 2007). The SF-36v2 covers eight health 
dimensions including four physical health status domains (physical functioning, role 
participation with physical health problems [role-physical], bodily pain, and general health) and 
four mental health status domains (vitality, social functioning, role participation with emotional 
health problems [role-emotional], and mental health). In addition, two summary scores, physical 
component summary and mental component summary, are produced by taking a weighted linear 
combination of the eight individual domains. The SF-36v2 is available with two recall periods: 
the standard recall period is 4 weeks and the acute recall period is 1 week. This study will use the 
acute version, which asks patients to respond to questions as they pertain to the past week. 
Higher SF-36v2 scores indicate a better state of health.  
11.1.6. 
Patient Health Questionnaire (PHQ-9) 
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 may 
complete questionnaires at baseline and at regular intervals thereafter. Scoring is based on 
responses to specific questions, as follows: 0=not at all; 1=several days; 2=more than half the 
days; and 3=nearly every day.  
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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. 
11.1.7. 
Insomnia Severity Index (ISI) 
The ISI is a validated questionnaire designed to assess the nature, severity, and impact of 
insomnia (Morin 2011). The ISI uses a 5-point Likert Scale to measure various aspects of 
insomnia severity (0 = none, 1 = mild, 2 = moderate; 3 = severe; 4 = very severe), satisfaction 
with current sleep pattern (0 = very satisfied, 1 = satisfied, 2 = neutral, 3 = dissatisfied, 4 = very 
dissatisfied), and various aspects of the impact of insomnia on daily functioning (0 = not at all, 
1 = a little, 2 = somewhat, 3 = much, 4 = very much). A total score of 0 to 7 = “no clinically 
significant insomnia,” 8 to 14 = subthreshold insomnia,” 15 to 21 = “clinical insomnia (moderate 
severity),” and 22 to 28 = “clinical insomnia (severe).”  
11.1.8. 
Core Consensus Sleep Diary 
The Core Consensus Sleep Diary collects subjective sleep parameters, including sleep onset 
latency, total sleep time, and wake after sleep onset, number of awakenings, and sleep quality. 
The take-home subject sleep diary assessment will be administered using an eDiary solution. The 
eDiary will be captured using either a provisioned smartphone device or bring-your-own-device 
solution, depending on the subject’s preference. 
 
 
 
 
 
 
 
 
 
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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters
All assessments will be conducted according to the schedule of assessments (Table 1). 
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 (ICD-10) should be recorded. 
The Massachusetts General Hospital Antidepressant Treatment Response Questionnaire 
(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. 
12.1.2. 
Weight and Height 
Height (Screening only) and weight will be measured and documented. 
12.1.3. 
Physical Examination 
Physical examinations assessing body systems (eg, head, eyes, ears, nose, and throat; heart; 
lungs; abdomen; and extremities), as well as cognitive and neurological examinations and mental 
status examinations will be conducted and documented. 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. 
New or worsening abnormalities that are judged to be clinically significant will be recorded as 
AEs, assessed according to Section 12.2.1.1. 
12.1.4. 
Vital Signs 
Vital signs comprise both supine and standing for systolic and diastolic blood pressure and heart 
rate measurements. Heart rate and blood pressure are to be collected in supine position after the 
subject has been resting for 5 minutes and then after approximately 3 minutes in the standing 
position. Respiratory rate and temperature are collected once, in either position. Vital signs will 
be documented. When vital signs are scheduled at the same time as blood draws, vital signs will 
be obtained first. 
Any abnormality in vital signs will be interpreted by the Investigator as abnormal, NCS or 
abnormal, CS in source documents. New or worsening abnormalities that are judged to be 
clinically significant will be recorded as AEs, assessed according to Section 12.2.1.1.  
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12.1.5. 
Electrocardiogram (ECG) 
Supine 12-lead ECGs will be performed in triplicate at all scheduled time points. The standard 
intervals (heart rate, PR, QRS, QT, and QTcF) as well as any rhythm abnormalities will be 
recorded.
 
 
12.1.6. 
Laboratory Assessments 
Samples will be collected in accordance with acceptable laboratory procedures detailed in the 
laboratory manual.   
The clinical laboratory tests to be performed are listed in Table 3. 
Table 3: 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Coagulation 
Red blood cell count 
Hemoglobin  
Hematocrit  
White blood cell count with 
differential 
Platelet count 
Red Blood Cell Indices 
(MCV, MCH, MCHC) 
Reflex to Red blood cell 
morphology if indices are 
abnormal 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
Total protein 
Creatinine 
Blood urea nitrogen 
Creatine kinase 
Gamma-glutamyl transferase 
Potassium 
Sodium 
Lactate dehydrogenase 
Glucose 
Chloride 
Bicarbonate 
Calcium 
Phosphorus 
Triglycerides 
Thyroid stimulating hormone 
(TSH) 
Reflex to free T3/T4 if TSH 
is abnormal  
pH 
Specific gravity 
Protein 
Glucose 
Red blood cell 
Nitrite 
Leukocyte 
esterase 
Ketones 
Bilirubin 
Urobilinogen 
Activated partial 
thromboplastin 
time 
Prothrombin time 
International 
normalized ratio 
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Table 3: 
Clinical Laboratory Tests (Continued) 
Diagnostic 
Serum 
Urine 
Breathalyzer 
Hepatitis B 
Hepatitis C 
Reflex HCV RNA 
HIV-1 and -2 
Female subjects that are not 
surgically sterile and do not 
meet the protocol-defined 
criteria for being post-
menopausal: serum hCG 
Female subjects, if 
menopause is suspected and 
not surgically sterile: FSH 
Drug screen including: 
amphetamines, barbiturates, 
benzodiazepines, 
cannabinoids, cocaine, 
opiates, phencyclidine 
Female subjects that are not 
surgically sterile and do not 
meet the protocol-defined 
criteria for being post-
menopausal: urine hCG  
Alcohol 
Abbreviations: FSH = follicle stimulating hormone; hCG = human chorionic gonadotropin; HCV = hepatitis C 
virus; HIV = human immunodeficiency virus 
The central laboratory will perform laboratory tests for hematology, serum chemistry, urinalysis, 
and coagulation. The results of laboratory tests will be returned to the Investigator, who is 
responsible for reviewing and filing these results. All laboratory safety data will be transferred 
electronically to Sage Therapeutics or designee in the format requested by Sage Therapeutics.  
Laboratory reports must be signed and dated by the Investigator or subinvestigator indicating 
that the report has been reviewed and any abnormalities have been assessed for clinical 
significance. Any abnormalities identified prior to first dose will require clear and complete 
documentation in the source documents as to the investigator’s assessment of not clinically 
significant before proceeding with randomization.  
All clinical laboratory test results outside the central laboratory’s reference range will be 
interpreted by the Investigator as abnormal, NCS; or abnormal, CS in source documents. New or 
worsening abnormalities that are judged to be clinically significant will be recorded as AEs, 
assessed according to Section 12.2.1.1. A clinically significant laboratory abnormality following 
subject randomization will be followed until the abnormality returns to an acceptable level or a 
satisfactory explanation has been obtained. 
A serum follicle stimulating hormone test will be conducted at Screening to confirm whether a 
female subject with ≥12 months of spontaneous amenorrhea meets the protocol-defined criteria 
for being post-menopausal (Section 8.1). 
 
 
 
 
 
 
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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 3). A breath test 
for alcohol will be performed. 
12.1.6.2. Pregnancy Screen 
For female subjects that are not surgically sterile and do not meet the protocol-defined criteria 
for being post-menopausal, a serum pregnancy test will be performed at Screening and a urine 
pregnancy test will be performed at all other scheduled timepoints thereafter, including the ET 
visit for subjects who prematurely discontinue. 
12.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011). This scale 
consists of a baseline evaluation that assesses the lifetime experience of the subject with suicidal 
ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last 
study visit. The C-SSRS includes ‘yes’ or ‘no’ responses for assessment of suicidal ideation and 
behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being 
the most severe).  
The “Baseline/Screening” C-SSRS form will be completed at screening (lifetime history and past 
24 months). The “Since Last Visit” C-SSRS form will be completed at all subsequent time 
points, as outlined in Table 1. 
12.1.8. 
Physician Withdrawal Checklist 
The PWC is based on the 35-item Penn Physician Withdrawal Checklist that was developed in 
the 1960s to measure benzodiazepine and benzodiazepine-like discontinuation symptoms. The 
PWC-20 is a shorter version of the Penn Physician Withdrawal Checklist based on the 20 items 
that provided the best differentiation from placebo in previous trials. The PWC-20 is made up of 
a list of 20 symptoms (eg, loss of appetite, nausea-vomiting, diarrhea, anxiety-nervousness, 
irritability, etc) that are rated on a scale of 0 (not present) to 3 (severe) (Rickels 2008). The 
PWC-20 will be used to monitor for the presence of potential withdrawal symptoms following 
discontinuation of SAGE-217. 
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12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Definition of Adverse Events 
12.2.1.1. Adverse Event (AE) 
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 treatment has been administered. 
A TEAE is an AE that occurs after the first administration of any study drug. The term study 
drug includes any Sage investigational product, a comparator, or a placebo administered in a 
clinical trial. 
Laboratory abnormalities and changes from baseline in vital signs, ECGs, and physical 
examinations are considered AEs if they result in discontinuation or interruption of study 
treatment, require therapeutic medical intervention, meet protocol specific criteria (if applicable) 
and/or if the Investigator considers them to be clinically significant. Laboratory values and vital 
signs that meet the criteria for an SAE should be reported in an expedited manner. Laboratory 
abnormalities and changes from baseline in vital signs, ECGs, 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. 
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 
subject with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
12.2.1.2. Serious Adverse Event (SAE) 
A serious adverse event is any untoward medical occurrence that at any dose: 
•
Results in death
•
Is immediately life-threatening
•
Requires in-patient hospitalization or prolongation of existing hospitalization
•
Results in persistent or significant disability or incapacity
•
Results in a congenital abnormality or birth defect
An SAE may also be any other medically important event that, in the opinion of the Investigator 
may jeopardize the subject or may require medical intervention to prevent one of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 
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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 within 24 hours of first awareness (Section 12.5). All SAEs 
should to be followed until the event resolved, the condition stabilized, was no longer considered 
clinically significant or the subject was lost to follow-up. Serious adverse events occurring after 
a subject’s final visit (including the last follow-up visit) should be reported to Sage or designee 
only if the Investigator considers the SAE to be related to study treatment.  
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.
12.3. 
Relationship to Study Drug 
The Investigator must make the determination of relationship to the study drug for each adverse 
event (not related, possibly related or probably related). The Investigator should decide whether, 
in his or her medical judgment, there is a reasonable possibility that the event may have been 
caused by the investigational product. If no valid reason exists for suggesting a relationship, then 
the adverse event should be classified as “not related.” If there is any valid reason, even if 
undetermined, for suspecting a possible cause-and-effect relationship between the investigational 
product and the occurrence of the adverse event, then the adverse event should be considered at 
least “possibly related.”  
Table 4: 
Relationship to Study Drug 
Relationship 
Definition 
Not Related: 
No relationship between the experience and the administration of study drug; related to 
other etiologies such as concomitant medications or subject’s clinical state. 
Possibly Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug.  
The reaction might have been produced by the subject’s clinical state or other modes of 
therapy administered to the subject, but this is not known for sure. 
Probably Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug.  
The reaction cannot be reasonably explained by the known characteristics of the subject’s 
clinical state or other modes of therapy administered to the subject. 
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If the relationship between the adverse event/serious adverse event and the investigational 
product is determined to be “possible” or “probable”, the event will be considered related to the 
investigational product for the purposes of expedited regulatory reporting. 
12.4. 
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), 
resolution (date and time), intensity, causality, action taken, serious outcome (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 12.2.1.2. An AE of severe intensity 
may not be considered serious. 
If a female subject becomes pregnant during this study, pregnancy information must be collected 
and recorded on the Sage Therapeutics 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 male subject’s female partner who becomes pregnant while the male subject 
is participating in study. After obtaining the necessary signed informed consent from the 
pregnant female partner directly, the investigator will follow the same pregnancy reporting 
procedures specified for pregnant female subjects. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented even if the subject was 
discontinued from the study. If the pregnancy ends for any reason before the anticipated date, the 
investigator should notify the sponsor. 
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 or a complication relating to 
the pregnancy occurs (e.g., spontaneous abortion). If the outcome of the pregnancy meets the 
criteria for immediate classification as an SAE (i.e., postpartum complication, spontaneous 
abortion, stillbirth, neonatal death, or congenital anomaly/birth defects), the investigator should 
follow the procedures for reporting an SAE. 
12.5. 
Reporting Serious Adverse Events 
All SAEs must be reported to Sage, or designee, immediately. A written account of the SAE 
must be sent to Sage, or designee, within 24 hours of the first awareness of the event by the 
investigator and/or his staff. The Investigator must complete, sign and date the SAE report form, 
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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 
(CRF) and/or study file. 
Any SAEs discovered by the Investigator after the designated follow up time for the study, 
should be promptly reported to Sage, or designee, according to the timelines noted above.  
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 ethics committee 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. Ethics Committee 
(EC)/Institutional Review Boards (IRBs) will be notified of SAEs and/or SUSARs as required by 
local law. In addition, appropriate Sponsor Drug Safety and Pharmacovigilance personnel, or 
designee, will unblind SUSARs for the purpose of regulatory reporting. The Sponsor, or 
designee, will submit SUSARs (in blinded or unblinded fashion) to regulatory agencies 
according to local law. The Sponsor, or designee, will submit SUSARs to investigators in a 
blinded fashion. 
12.6. 
Emergency Identification of Study Drug 
During the study, 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 treatment received. Unless a subject is at 
immediate risk, the Investigator must make diligent attempts to contact Sage prior to unblinding 
the study treatment administered to a subject. Any request from the Investigator about the 
treatment administered to study subjects must be discussed with Sage. If the unblinding occurs 
without Sage’s knowledge, the Investigator must notify Sage as soon as possible and no later 
than the next business morning. All circumstances surrounding a premature unblinding must be 
clearly documented in the source records. Unless a subject is at immediate risk, any request for 
the unblinding of individual subjects must be made in writing to Sage and approved by the 
appropriate Sage personnel, according to standard operating procedures.  
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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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. 
When all subjects complete the Day 42 visit, the database will be locked, followed by treatment 
unblinding to the Sponsor and data analyses (site personnel and subjects will remain blinded). 
The extended follow-up period will continue as scheduled; the final database lock will occur 
when all subjects complete the extended follow-up period. 
13.1. 
Data Analysis Sets 
The Randomized set is defined as all subjects who are randomized. 
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 
HAM-D total score 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. No imputation process will be 
used to estimate missing data. A sensitivity analysis will be used to investigate the impact of 
missing data if ≥5% of subjects in any treatment group have missing data. 
13.3. 
General Considerations 
For the purpose of all safety and efficacy analyses where applicable, baseline is defined as the 
last measurement prior to the start of study drug administration.  
Continuous endpoints will be summarized with number (n), mean, standard deviation (SD), 
median, minimum, and maximum. In addition, change from baseline values will be calculated at 
each time point and summarized descriptively. For categorical endpoints, descriptive summaries 
will include counts and percentages.  
13.4. 
Demographics and Baseline Characteristics 
Demographic data (Section 12.1.1) and baseline characteristics, such as height, weight, and body 
mass index (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. 
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13.5. 
Efficacy Analyses 
Efficacy data will be summarized using appropriate descriptive statistics and other data 
presentation methods where applicable; subject listings will be provided for all efficacy data. 
Subjects will be analyzed according to randomized treatment.  
The estimand for the primary efficacy analysis is the mean change from baseline in HAM-D total 
score at Day 15. This will be analyzed using a mixed effects model for repeated measures 
(MMRM); the model will include treatment, baseline HAM-D total score, stratification factor, 
assessment time point, and time point-by-treatment as explanatory variables. All explanatory 
variables will be treated as fixed effects. All post-baseline time points will be included in the 
model. The main comparison will be between SAGE-217 and placebo at the 15-day time point. 
Model-based point estimates (ie, least squares [LS] means, 95% confidence intervals, and p-
values) will be reported where applicable. An unstructured covariance structure will be used to 
model the within-subject errors. 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. The sandwich estimator for the variance 
covariance matrix will be derived, using the EMPIRICAL option in the PROC MIXED statement 
in SAS. 
Similar to those methods described above for the primary endpoint, an MMRM will be used for 
the analysis of the change from baseline in other time points in HAM-D total score, MADRS 
total score, HAM-A total score, SF-36v2 score, PHQ-9 score, sleep diary endpoints (eg, sleep 
latency (SL), total sleep time (TST), wake after sleep onset (WASO)), ISI score and selected 
individual items and/or subscale scores in HAM-D for change from baseline.  
Generalized estimating equation (GEE) methods will be used for the analysis of HAM-D 
response (defined as ≥50% reduction from baseline in HAM-D total score) and HAM-D 
remission (defined as HAM-D total score of ≤7.0). GEE models will include terms for treatment, 
baseline score, stratification factor, assessment time point, and time point-by-treatment as 
explanatory variables. The comparison of interest will be the difference between SAGE-217 and 
matching placebo at the 15-day time point. Model-based point estimates (ie, odds ratios), 95% 
confidence intervals, and p-values will be reported.  
A GEE method will also be used for the analysis of CGI-I response including terms for 
treatment, baseline CGI-S score, stratification factor, assessment time point, and time point-by-
treatment as explanatory variables. 
 
13.6. 
Safety Analyses 
Safety and tolerability of study drug will be evaluated by incidence of AEs/SAEs, vital signs, 
clinical laboratory evaluations, and 12-lead ECG. Suicidality will be monitored by the C-SSRS. 
Potential withdrawal symptoms after discontinuation of SAGE-217 will be assessed using the 
PWC-20. Safety data will be listed by subject and summarized by treatment group. All safety 
summaries will be performed on the Safety Set. Where applicable, ranges of potentially clinical 
significant (PCS) values are provided in the SAP. 
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13.6.1. 
Adverse Events 
The analysis of AEs will be based on the concept of TEAEs. The incidence of TEAEs will be 
summarized overall and by Medical Dictionary for Regulatory Activities (MedDRA) Version 
18.1 or higher, System Organ Class (SOC), 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 (see Section 12.3).  
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).  
13.6.2. 
Clinical Laboratory Evaluations 
Results of clinical laboratory parameters in each scheduled visit and mean changes from baseline 
will be summarized in standard units. Normal range of each parameter is provided by the 
laboratory; shift from baseline to post-baseline values in abnormality of results will be provided. 
Potentially clinically significant values will be summarized by treatment. Any abnormal values 
deemed clinically significant by the investigator will be reported as an AE (see Section 12.2). 
Clinical laboratory results will be listed by subject and timing of collection. 
13.6.3. 
Physical Examinations 
The occurrence of a physical examination (Y/N) and the date performed will be listed by subject. 
Any clinically significant observation in physical examination will be reported as an AE (see 
Section 12.2). 
13.6.4. 
Vital Signs 
Results from each visit and mean changes from baseline in vital signs will be summarized by 
scheduled visit. Any abnormality deemed clinically significant by the investigator will be 
reported as an AE (see Section 12.2). Potentially clinically significant values will be summarized 
by treatment. Vital sign results will be listed by subject and timing of collection. 
13.6.5. 
12-Lead Electrocardiogram 
The following ECG parameters will be listed for each of the triplicate ECGs for each subject: 
heart rate, PR, QRS, QT, and QTcF; the derived mean of each parameter will also be listed. Any 
clinically significant abnormalities or changes in mean ECGs should be reported as an AE (see 
Section 12.2). Mean ECG data will be summarized by visit. Potentially clinically significant 
values of QTcF will be summarized by treatment. Electrocardiogram findings will be listed by 
subject and visit.  
13.6.6. 
Prior and Concomitant Medications 
Medications will be recorded at each study visit during the study and will be coded using World 
Health Organization-Drug dictionary (WHO-DD) September 2015, or later.  
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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 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.  
13.6.7. 
Columbia Suicide Severity Rating Scale 
Suicidality data collected on the C-SSRS at baseline and by visit during the Treatment Period 
will be summarized by treatment. Listings will include all data, including behavior type and/or 
category for Suicidal Ideation and Suicidal Behavior of the C-SSRS.  
13.6.8. 
Physician Withdrawal Checklist 
Potential withdrawal symptoms collected on the PWC-20 will be summarized by visit and 
treatment. Listings will include all data by subject. 
 
 
 
 
 
13.8. 
Determination of Sample Size 
Assuming a two-sided alpha level of 0.05, a sample size of 399 evaluable subjects would provide 
90% power to detect a placebo-adjusted treatment difference of approximately 4 points in the 
primary endpoint, change from baseline in HAM-D total score at Day 15, assuming SD of 
10 points. Assuming an 11% dropout rate and a 1:1:1 randomization ratio within each stratum 
(antidepressant use at baseline, yes or no), approximately 450 total randomized subjects will be 
required to obtain 399 evaluable subjects. Evaluable subjects are defined as those randomized 
subjects who receive study drug and have valid baseline and at least 1 post-baseline HAM-D 
assessment. Additional subjects may be randomized if the dropout rate is greater than 11%. 
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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 (or designee) will visit the investigational study site per Sage Standard Operating 
Procedures 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.
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 
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investigator should contact Sage Therapeutics immediately if contacted by a regulatory agency 
about an inspection. 
14.3. 
Institutional Review Board (IRB) or Ethics Committee (EC) 
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 Practices 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 Informed Consent Form, 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 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 Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use and Good Clinical Practice 
guidelines, as well as all 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 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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19. 
LIST OF REFERENCES
Busner J, Targum S. CGI-S. (2007a), as adapted from Kay, Stanley R, Positive and Negative 
Symptoms in Schizophrenia:Assessment and Research.  Clinical and Experimental Psychiatry, 
Monograph No. 5.  Brunner/Mazel, 1991.  Modified from Guy W. Clinical Global Impressions: 
In ECDEU Assessment Manual for Psychopharmacology. 1976; 218-22. Revised DHEW Pub. 
(ADM) Rockville, MD: National Institute for Mental Health.   
Busner J, Targum S. CGI-I.  (2007b), as adapted from Spearing, et al.  Psychiatry Research, 
1997;73:159-71.  Modified from Guy W. Clinical Global Impressions: In ECDEU Assessment 
Manual for Psychopharmacology. 1976; 218-22. Revised DHEW Pub. (ADM) Rockville, MD: 
National Institute for Mental Health.   
Conradi HJ, Ormel J, de Jonge P. Presence of individual (residual) symptoms during depressive 
episodes and periods of remission: a 3-year prospective study. Psychol Med. 2011 
Jun;41(6):1165-74. 
Drugan RC, Morrow AL, Weizman R, et al. Stress-induced behavioral depression in the rat is 
associated with a decrease in GABA receptor-mediated chloride ion flux and brain 
benzodiazepine receptor occupancy. Brain Res. 1989;487: 45–51. 
DSM-5.  Diagnostic and statistical manual of mental disorders (5th ed.).  American Psychiatric 
Association 2013.  Arlington, VA: American Psychiatric Publishing. 
Gerner RH, Hare TA. GABA in normal subjects and patients with depression, schizophrenia, 
mania, and anorexia nervosa. Am J Psychiatry. 1981;138:1098–101. 
Greenberg PE, Fournier AA, Sisitsky T, Pike CT, Kessler RC. The economic burden of adults 
with major depressive disorder in the United States (2005 and 2010). J Clin Psychiatry. 2015 
Feb;76(2):155-62. 
Honig A, Bartlett JR, Bouras N, Bridges PK. Amino acid levels in depression: a preliminary 
investigation. J Psychiatr Res. 1988; 22:159–64. 
Luscher B, Shen Q, Sahir N. The GABAergic deficit hypothesis of major depressive disorder. 
Mol Psychiatry. 2011;16(4):383-406. 
Maguire J, Mody I. GABA(A)R plasticity during pregnancy: Relevance to postpartum 
depression. Neuron. 2008;59(2);207-13.   
Maguire J, Ferando I, Simonsen C, Mody I. Excitability changes related to GABAA receptor 
plasticity during pregnancy. J Neurosci. 2009;29(30):9592-601.   
Mann JJ, Oguendo MA, Watson KT, et al. Anxiety in major depression and cerebrospinal fluid 
free gamma-aminobutyric acid. Depress Anxiety. 2014;31(10):814-21. 
  
60


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CONFIDENTIAL 
Morin CM, Belleville G, Bélanger L, Ivers H. The Insomnia Severity Index: Psychometric 
Indicators to Detect Insomnia Cases and Evaluate Treatment Response. Sleep. 2011;34(5):601-
608. 
Olfson M, Marcus SC, Shaffer D. Antidepressant drug therapy and suicide in severely depressed 
children and adults: A case-control study. Archives of general psychiatry. 2006:63(8);865-872. 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The Columbia-
Suicide Severity Rating Scale: initial validity and internal consistency findings from three 
multisite studies with adolescents and adults. Am J Psychiatry. 2011 Dec;168(12):1266-77. 
Rickels K, Garcia-Espana F, Mandos LA, Case GW. Physician Withdrawal Checklist (PWC-20). 
J Clin Psychopharmacol. 2008;28(4):447-451. 
Romera I, Pérez V, Ciudad A, et al. Residual symptoms and functioning in depression, does the 
type of residual symptom matter? A post-hoc analysis. BMC Psychiatry. 2013 Feb 11;13:51. 
Rudolph U, Knoflach F. Beyond classical benzodiazepines: novel therapeutic potential of 
GABAA receptor subtypes. Nat Rev Drug Discov. 2011 Jul 29;10(9):685-97. 
Schüle C, Nothdurfter C, Rupprecht R.  The role of allopregnanolone in depression and anxiety. 
Prog Neurobiol. 2014 Feb;113:79-87. 
Trivedi MH, Rush AJ, Wisniewski SR, et al. (STAR*D Study Team). Evaluation of outcomes 
with citalopram for depression using measurement-based care in STAR*D: implications for 
clinical practice. Am J Psychiatry. 2006 Jan;163(1):28-40. 
Ware JE Jr, Kosinski M, Bjorner JB, et al.  User's Manual for the SF-36v2 Health Survey.  2nd 
ed.  Lincoln, RI:  QualityMetric Incorporated; 2007. 
Williams JBW, Kobak KA. Development and reliability of a structured interview guide for the 
Montgomery-Asberg Depression Rating Scale (SIGMA). Br J Psychiatry. 2008;192:52-8. 
Williams JBW.  SIGH-D 24hr: V1.3 – 24 HR Version. 2013a. 
Williams JBW.  SIGH-D Past week:  Past Week Version. 2013b. 
Williams JBW.  SIGH-A 24hr: V1.3 – 24 HR Version. 2013c. 
Williams JBW.  SIGH-A Past week:  Past Week Version. 2013d. 
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Protocol 217-MDD-301 Summary of Changes  
 
 
 
 
 
 
 
Sage Therapeutics 
Amendment #4, Version 5.0 
CONFIDENTIAL 
 
1 
Protocol 217-MDD-301 Amendment 4 
Date of Amendment: 25 March 2019 
A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study Evaluating 
the Efficacy of SAGE-217 in the Treatment of Adult Subjects with Major Depressive 
Disorder 
Rationale for Protocol Amendment 
The purpose for this protocol amendment is to increase the Montgomery-Åsberg Depression 
Rating Scale (MADRS) score required for entry into the study and include a minimum total 
score for the 17-item Hamilton Rating Scale for Depression (HAM-D) required for entry into the 
study. These changes are a result of a blinded data review during which it was discovered that a 
substantial number of subjects have entered the study with Day 1 HAM-D scores <22, with some 
as low as 13, which do not correlate with the intended severity of depression to be treated in this 
study.  
A detailed summary of changes is provided in Table 1. Corrections to typographical errors, 
punctuation, grammar, abbreviations, and formatting are not detailed individually, nor are 
administrative updates such as revising the document date, updating the document header and 
version number, and updating the table of contents. 


Protocol 217-MDD-301 Summary of Changes  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sage Therapeutics 
Amendment #4, Version 5.0 
CONFIDENTIAL 
 
2 
Table 1: 
Protocol Amendment 4 Detailed Summary of Changes 
The primary section of the protocol affected by the changes in Protocol Amendment 4 is indicated. The corresponding related text has 
been revised throughout the protocol. Deleted text is indicated by strikeout; added text is indicated by bold font. 
Purpose: Increase the MADRS score required for entry into the study and include a minimum HAM-D total score required for entry into the study 
in order to ensure enrollement of subjects with the intended severity of depression. 
The primary change occurs in Section 8.1 Subject Inclusion Criteria (#6) 
Changed text: 
6. Subject has a MADRS total score of ≥320 and a HAM-D total score ≥22 at screening and Day 1 (prior to dosing). 
Sections also affected by the change: 
• 
Synopsis, Study Description 
• 
Synopsis, Inclusion Criteria 
• 
Table 1 Schedule of Events 
• 
Table 1 footnote ‘o’ 
• 
Section 7.1 Overall Study Design 
• 
Section 11.1.1 Hamilton Rating Scale for Depression (HAM-D) 
 









SAP_001.pdf: 
Official Title: 
NCT Number: 
A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study 
Evaluating the Efficacy of SAGE-217 in the Treatment of Adult Subjects With 
Major Depressive Disorder
NCT03672175
Document Date: 
SAP Version 2.0: 12 November 2019


Clinical Study Report 
217-MDD-301A
16.1 Study Information 
1 
9.
STATISTICAL ANALYSIS PLAN
The original statistical analysis plan (SAP) was modified once. SAP Version 2 (12 November 
2019) is provided. 


  
 
 
 
 
SAGE THERAPEUTICS INCORPORATED  
Statistical Analysis Plan 
Methods 
Protocol Number 217-MDD-301 
 
 STUDY TITLE: A PHASE 3, MULTICENTER, DOUBLE-BLIND, 
RANDOMIZED, PLACEBO-CONTROLLED STUDY EVALUATING THE 
EFFICACY OF SAGE-217 IN THE TREATMENT OF ADULT SUBJECTS WITH 
MAJOR DEPRESSIVE DISORDER 
Author of SAP: 
 
Version: Version 2.0 
Version Date of SAP: 12 November 2019 
Sponsor: Sage Therapeutics, Inc. 
   215 First Street 
                              Cambridge, Massachusetts 02142 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written consent of 
Sage Therapeutics Incorporated is strictly prohibited except to the extent required under applicable laws or regulations.  
Persons to whom the information is disclosed must be informed that the information is confidential and may not be further 
disclosed by them. 
 
 
 
 
 
 
 
 
 




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1 
TABLE OF CONTENTS 
1 
Table of Contents ............................................................................................................. 3 
2 
List of Abbreviations ....................................................................................................... 5 
3 
Introduction...................................................................................................................... 7 
4 
Study Objectives .............................................................................................................. 7 
4.1 
Primary Objective ....................................................................................................... 7 
4.2 
Secondary Objective ................................................................................................... 7 
4.3 
Safety Objective ......................................................................................................... 7 
 
 7 
5 
Study Endpoints ............................................................................................................... 7 
5.1 
Efficacy Endpoints ..................................................................................................... 7 
5.2 
Safety Endpoints ......................................................................................................... 8 
 
 8 
6 
Study Design ..................................................................................................................... 8 
6.1 
Overall Design ............................................................................................................ 8 
6.2 
Sample Size and Power .............................................................................................. 9 
6.3 
Randomization ............................................................................................................ 9 
6.4 
Blinding and Unblinding .......................................................................................... 10 
7 
Modifications .................................................................................................................. 10 
7.1 
Modifications to the Approved Clinical Study Protocol .......................................... 10 
7.2 
Modifications to the Approved Statistical Analysis Plan ......................................... 10 
7.3 
Modifications to the Approved DMC Charter .......................................................... 10 
8 
Analysis Sets ................................................................................................................... 10 
8.1 
Randomized Set ........................................................................................................ 10 
8.2 
Safety Set .................................................................................................................. 10 
8.3 
Full Analysis Set ....................................................................................................... 11 
8.4 
Modified Full Analysis Set ....................................................................................... 11 
 
 11 
8.6 
Per Protocol Set ........................................................................................................ 11 
9 
Statistical Analysis ......................................................................................................... 11 
9.1 
General Considerations ............................................................................................ 11 
9.1.1 
Study Day Definition ........................................................................................ 12 
9.1.2 
Missing Data ..................................................................................................... 12 
9.2 
Background Characteristics ...................................................................................... 12 
9.2.1 
Subject Disposition ........................................................................................... 12 
9.2.2 
Protocol Deviations .......................................................................................... 13 
9.2.3 
Demographics and Baseline Characteristics ..................................................... 13 
9.2.4 Medical/Surgical History ....................................................................................... 14 
9.2.5 Prior and Concomitant Medications / Concomitant Procedures ............................ 15 
9.2.6 Study Drug Exposure ............................................................................................. 16 
9.2.7 Study Drug Adherence ........................................................................................... 17 
9.3 
Efficacy Analysis ...................................................................................................... 17 
9.3.1 
Definition of Efficacy Variables ....................................................................... 17 
9.3.1.1 
Hamilton Rating Scale for Depression (HAM-D) ..................................... 17 


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9.3.1.2 
Clinical Global Impression – Improvement (CGI-I) .................................. 18 
9.3.1.3 
Clinical Global Impression – Severity (CGI-S) ......................................... 18 
9.3.1.4 
Hamilton Anxiety Rating Scale (HAM-A) ................................................ 19 
9.3.1.5 
Montgomery-Åsberg Depression Rating Scale (MADRS) ........................ 19 
9.3.1.6 
Insomnia Severity Index (ISI) .................................................................... 19 
9.3.1.7 
Core Consensus Sleep Diary ...................................................................... 19 
9.3.1.8 
Short Form-36 Version 2 (SF-36v2) .......................................................... 21 
9.3.1.9 
Patient Health Questionnaire (PHQ-9)....................................................... 21 
9.3.2 
Visit Windows .................................................................................................. 21 
9.3.3 
Analysis of Efficacy Variable(s) ...................................................................... 22 
9.3.3.1 
Mixed Effects Model for Repeated Measures ............................................ 24 
9.3.3.2 
Generalized estimating equation (GEE) models ........................................ 25 
9.3.3.3 
Sensitivity Analysis .................................................................................... 26 
9.3.3.4 
Analysis of Time to First HAM-D Response/Remission ........................... 27 
9.3.3.5 
Multiplicity Adjustment versus Key Secondary Endpoints ....................... 27 
9.4 
Safety Analysis ......................................................................................................... 28 
9.4.1 
Adverse Events ................................................................................................. 29 
9.4.2 
Clinical Laboratory ........................................................................................... 31 
9.4.3 
Vital Signs ........................................................................................................ 34 
9.4.4 
Electrocardiogram ............................................................................................ 34 
9.4.5 
Physical Examination ....................................................................................... 35 
9.4.6 
Columbia Suicide Severity Rating Scale (C-SSRS) ......................................... 35 
9.4.7 
Physician Withdrawal Checklist (PWC) .......................................................... 36 
 
 36 
36 
36 
37 
37 
10 Summary of Interim and DMC Analyses .................................................................... 37 
11 References ....................................................................................................................... 37 
12 List of Appendices.......................................................................................................... 39 
12.1 Appendix A: Schedule of Assessments .................................................................... 39 
12.2 Appendix B: Details of Statistical Methodology ...................................................... 43 
12.3 Appendix C: Handling of Missing Dates ................................................................. 44 
12.3.1 
Adverse Events ................................................................................................. 44 
12.3.2 Dates in Disease History (Dates of diagnosis, current episode, first episode) .... 45 
12.3.3 
Prior and Concomitant Medications ................................................................. 45 
12.4 Appendix D: List of Displays ................................................................................... 45 
 
 


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2 
LIST OF ABBREVIATIONS 
Abbreviation or specialist term 
Explanation 
AE 
adverse event 
AR 
Autoregressive 
ATC 
anatomical therapeutic chemical 
BMI 
body mass index 
BYOD 
bring-your-own-device 
CGI-I 
Clinical Global Impression scale for improvement 
CGI-S 
Clinical Global Impression scale for severity 
  
  
CS 
Clinical significant 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DSM-5  
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition  
ECG 
Electrocardiogram 
eCRF  
electronic case report form  
EOT 
end of treatment 
ET 
early termination 
FAS 
Full Analysis Set 
 
 
FSH  
follicle stimulating hormone  
GEE  
generalized estimating equation  
HAM-A  
Hamilton Rating Scale for Anxiety  
HAM-D 
Hamilton Depression Rating Scale 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
IRT 
interactive response technology  
ISI 
Insomnia Severity Index 
LFT 
Liver Function Tests 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MCS 
mental component summary 
MDD 
major depressive disorder 
mFAS 
Modified Full Analysis Set 
MGH ATRQ 
Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire 
MMRM  
mixed effects model for repeated measures  
MedDRA 
Medical Dictionary for Regulatory Activities 
PCS 
Potentially clinically significant  
PCSC 
potentially clinically significant change 
PHQ-9 
Patient health Questionnaire 
 
 
PRO 
patient-reported outcome 
PT 
preferred term 
PWC-20 
20-item Physician Withdrawal Checklist  


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Abbreviation or specialist term 
Explanation 
QTcF 
QT corrected according to Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCID-5-CT 
Structured Clinical Interview for Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition for clinical trials 
SD 
standard deviation 
SE 
standard error 
SF-36 
36-item Short Form survey 
SI 
International System of Units 
sNAW 
subjective number of awakenings 
SOC 
System Organ Class 
sSL 
subjective sleep latency 
sTST 
subjective total sleep time 
sWASO 
subjective wake after sleep onset 
TEAE 
treatment-emergent adverse event 
UN 
Unstructured 
WHO-DD 
World Health Organization – Drug Dictionary 
 






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within each stratum in a 1:1:1 ratio to receive SAGE-217 20 mg, SAGE-217 30 mg, or matching 
placebo; subjects will be treated for 14 days beginning on Day 1. 
The study will consist of a Screening Period of up to 28 days, a 14-day Treatment Period, and up to 6 
months (168 days) of Follow-up.  
The Screening Period begins with the signing of the informed consent form (ICF) at the Screening 
Visit; 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. 
Antidepressants are permitted provided subjects are on a stable dose for at least 60 days prior to Day 
1 and agree to continue on the stable dose through the follow-up period (Day 42). Initiation of new 
antidepressants or any other medications that may potentially have an impact on efficacy or safety 
endpoints will not be allowed between screening and completion of the Day 42 assessments.  
Eligible subjects will be stratified based on use of antidepressant treatment (current/stable or not 
treated/withdrawn ≥60 days) and randomized within each stratum to one of 3 treatment groups 
(SAGE-217 20 mg, SAGE-217 30 mg, or matching placebo) in a 1:1:1 ratio. Subjects will self-
administer a single dose of study drug once daily in the evening with food, on an outpatient basis, for 
14 days. Subjects will return to the study center during the treatment and follow-up periods as 
outlined Appendix A.  
Dose reductions are not permitted. Subjects who cannot tolerate study drug will be discontinued from 
study drug and will receive treatment as clinically indicated. 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. Follow-up visits should take place every 7 days after the last dose of 
treatment for 4 follow-up visits. 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 assessments scheduled for both visits will be conducted, without repetition 
of any assessment 
6.2 
Sample Size and Power 
Assuming a two-sided alpha level of 0.05, a sample size of 399 evaluable subjects would provide 
90% power to detect a placebo-adjusted treatment difference of approximately 4 points in the primary 
endpoint, change from baseline in HAM-D total score at Day 15, assuming standard deviation (SD) of 
10 points. Assuming an 11% dropout rate and a 1:1:1 randomization ratio within each stratum 
(antidepressant use at baseline, yes or no), approximately 450 total randomized subjects will be 
required to obtain 399 evaluable subjects. Evaluable subjects are defined as those randomized 
subjects who receive study drug and have valid baseline and at least 1 post-baseline HAM-D 
assessment. Additional subjects may be randomized if the dropout rate is greater than 11%.  
6.3 
Randomization 
This is a randomized, double-blind, placebo-controlled study. Subjects who meet the eligibility 
criteria will be randomized in a stratified manner based on use of antidepressant treatment 
(current/stable or not treated/withdrawn ≥60 days) at baseline; randomization will be done within 
each stratum in a 1:1:1 ratio to receive SAGE-217 20 mg, SAGE-217 30 mg, or matched placebo.  






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if the time of an assessment is not collected, the assessment on Day 1 is assumed to be prior to dosing 
if the protocol mentions that this assessment needs to be before dosing or it is collected as “pre-
dose”.  
9.1.1 
Study Day Definition 
It is to be noted that the study drug is administered in the evening with food.  The assessments at the 
clinic on Day 1 are hence before the first dose of study drug. 
Study day will be defined as follows:  
• 
The day of subject receiving the first dose of study drug is designated as Day 1. 
• 
For visit days after Day 1, study day = visit date – Day 1 date + 1. 
• 
For visit days prior to Day 1, study day = visit date – Day 1 date.  Thus, study days for 
screening visit are negative numbers.  There is no “Day 0”. 
9.1.2 
Missing Data 
All subjects will be used in the analyses, as per the analysis populations, using all non-missing data 
available.  Efficacy analyses will use sensitivity analyses to assess the impact of missing data. Safety 
analyses will not impute missing data.  Imputation of missing data in scoring of questionnaires is 
discussed in respective sections below.  Handling of missing or incomplete dates have been discussed 
in Section 12.3, Appendix C. 
9.2 
Background Characteristics  
All displays in this section will be presented under the treatment arms of placebo, SAGE-217 20mg, 
SAGE-217 30mg, SAGE-217 (20mg or 30mg) and Overall. 
9.2.1 
Subject Disposition 
The analyses of subject disposition will use all subjects who provided written inform consent to the 
study. 
The summaries of subject disposition will include the number of subjects who were screened, who 
were randomized, who received study drug, the number and percentage of subjects who completed 
the study, who are ongoing in the study (applicable only for the Day 42 Database Lock), who 
prematurely withdrew from the study, primary reasons for not completing the study, who completed 
treatment, who discontinued treatment prematurely, and primary reasons for discontinuing treatment. 
Study completion summary and treatment completion summary will be based on subjects who 
received study drug (Safety Set).  Percentages will be calculated based on Safety Set. These data will 
be provided by randomized treatment groups. If a subject is rescreened because the subject has been a 
screen failure the first time, the status of the subject will be determined from the second screening. In 
the count of screened subjects, this subject will be counted only once.   
A completer for the study is defined as one who completed the last follow up visit and is derived from 
the study conclusion CRF page with the completion question answered Yes. Note that in earlier 
versions of the protocol, this will be the completion of Day 42 while for later versions of the protocol 
this will be the completion of Day 182. 
A subject is marked as completing the treatment if the prematurely discontinued question in the 
treatment discontinuation CRF page is answered No. 
The number and percentage of subjects in each analysis set will be provided, using Safety Set as the 
denominator.  Using Randomized Set, the reason for not being included in other analysis sets will be 
summarized. 


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The summary of subject disposition will also be provided using Modified Full Analysis Set. 
A separate data listing will be provided for all subjects who prematurely discontinued treatment or 
prematurely withdrew from the study with reasons, number of days on study drug, etc., using Safety 
Set. 
9.2.2 Protocol Deviations 
Protocol deviations identified during site monitoring will be captured on eCRF and categorized by the 
study team as major and minor deviations, without any unblinding information.  Protocol deviations, 
including but not limited to the use of prohibited medications, may be identified by blinded data 
review; these will be included in the list and categorized similarly.  The major deviations are further 
categorized as major-efficacy, major-safety and major-GCP deviations.  The major deviations will be 
summarized by type and by actual treatment received using Safety Set.  The minor deviations will be 
included in the listing.  
The deviations identified as major deviations will be reviewed by the study team prior to database 
lock in a blinded fashion to determine subjects in FAS to be excluded from the Per Protocol Set.  In 
addition, Per Protocol Set will also exclude FAS subject satisfying any of the following conditions: 
1. Study Drug Adherence (defined in Section 9.2.7) < 75% or less than 11 doses consumed 
2. Inappropriate drug consumption (typically due to incorrect kit dispensation): if the subject 
consumed at any time during the study any study drug that the subject is not randomized to  
The above criteria will be included in the major protocol deviation listing.  In addition, a listing of 
inappropriate study drug consumption will be provided, which will include number of inappropriate 
doses consumed. Any violation of inclusion/exclusion criteria will be presented in a data listing using 
Randomized Set. 
9.2.3 
Demographics and Baseline Characteristics 
The following analyses will use the Safety Set (using actual treatment received), the FAS and mFAS 
(using randomized treatment). 
Demographic data (age, race, gender, ethnicity, employment status, highest education level, 
marital/civil status) and baseline characteristics, such as height, weight, and body mass index (BMI), 
will be summarized by treatment group (randomized for FAS and actual for Safety Set) and pooled 
treatment groups. Highest education level will be categorized in the summary tables as follows: 
Less than or equal to12th grade, no diploma 
12th grade diploma or GED 
Some college but no degree 
Associate degree 
Bachelor’s degree 
Master’s degree 
Professional degree 
Doctoral degree 
Baseline subgroups will be summarized for the following categories (for definition of antidepressant, 
see Section 9.2.5): 
• 
Race (Black or African American, White, Other) 
•   Gender (Female, Male) 
• 
Age (18-24, 25-50, 51-65 years) 


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• 
Baseline antidepressant use (Yes, No) 
• 
BMI (≤18.4, 18.5-24.9, 25-29.9, ≥30 kg/m2) 
•  Baseline HAM-D total score (<22, >=22 but <25, >=25) 
A separate listing for subjects who were randomized under incorrect stratification of anti-depressant 
use at baseline will be provided.  The correct use is determined from concomitant medication records 
with Anatomic Therapeutic Classification (ATC) level 3 = N06A, comparing the start/end dates of 
the medication versus the date of first dose of study drug.  The stratum for randomization is 
determined from the eCRF entry of what was entered in IRT system during randomization.  
Diagnostic labs are part of screening. A data listing using the Safety set will be provided. The 
following diagnostic screening test results will be included in this listing. 
Diagnostic  
 
 
Serum 
Urine 
Breathalyzer 
Hepatitis B 
Drug screen: including 
amphetamines, barbiturates, 
benzodiazepines, cannabinoids, 
cocaine, opiates, phencyclidine 
Alcohol 
Hepatitis C 
Female subjects that are not 
surgically sterile and do not meet 
the protocol-defined criteria for 
being post-menopausal: urine hCG 
 
Reflex HCV RNA 
 
 
HIV-1 and -2 
 
 
Female subjects that are not 
surgically sterile and do not meet 
the protocol-defined criteria for 
being post-menopausal: serum hCG 
 
 
Female Subjects, if menopause is 
suspected and not surgically sterile: 
FSH 
 
 
Abbreviations: FSH=follicle stimulating hormone; hCG=human chorionic gonadotropin; HCV = 
hepatitis C virus; HIV = human immunodeficiency virus 
 
9.2.4 Medical/Surgical History 
The following analyses will use the Safety Set.  
The history related to MDD (date of initial diagnosis of MDD, antidepressant usage, information of 
depressive episodes, etc.) will be collected.  Years since initial diagnosis of MDD, anti-depressant 
usage, and information of depressive episodes will be summarized. Years since initial diagnosis of 
MDD, days since start of current episode and years since start of first episode will be calculated 
using:   First dose date of the study drug – date of interest. For imputation of incomplete dates in 
medical history, please see Section 12.3.3. 


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Medical/surgical history collected at screening will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA), Version 21.0 or higher. Medical/surgical history data will be 
summarized by system organ class (SOC) and preferred term (PT). A summary of medical/surgical 
history that are ongoing at the time of screening will be provided separately.   
Subject history of psychiatric disorders and family psychiatric history will be summarized.   
 
9.2.5 Prior and Concomitant Medications / Concomitant Procedures 
The following analyses will use the Safety Set. 
All medications taken and procedures undergone during the study will be recorded; in addition, 
psychotropic medications taken within 6 months prior to screening, and non-psychotropic 
medications taken within 30 days prior to screening will also be collected.  Psychotropic and non-
psychotropic medications are collected on separate CRF pages.  All medications will be coded using 
World Health Organization-Drug dictionary (WHO-DD) March 2018 or later. 
Medications will be presented according to whether they are being taken prior to and/or during the 
study (concomitant).  Prior medications are defined as those taken prior to the initiation of the start of 
study drug.  Concomitant medications are defined as those with a start date on or after the first dose 
of study drug or those with a start date before the first dose of study drug that are ongoing or with a 
stop date on or after the first dose of study drug.  If medication dates are incomplete and it is not clear 
whether the medication was concomitant, it will be assumed concomitant.  For imputation of missing 
concomitant medication dates, please refer to Appendix C, Section 12.3.  Note that it is possible for a 
medication to be both ‘prior’ and ‘concomitant’. 
Concomitant medications will be further divided by usage period as follows (if time is missing, the 
date will be used for this algorithm):  
• 
On-treatment concomitant medications are those that have been used any time from start of 
first dose to the last dose of study drug. 
• 
 Post-treatment concomitant medications are those that have been started after the last dose of 
study drug. 
Prior and concomitant non-psychotropic medication use will be summarized by anatomical 
therapeutic chemical (ATC) level 1 and Standard Medication Name. Similar summary tables will be 
provided for psychotropic medications. The differentiation of non-psychotropic versus psychotropic 
medications are based on which CRF page the medication is collected on.  Separate but similar 
summaries will be provided for concomitant medication use for on-treatment and post-treatment 
periods as defined above. 
In addition, for prior and concomitant psychotropic medication separate summaries will be provided 
by ATC level 1 and ATC level 4. 
Antidepressants that have been taken at the same dose for at least 60 days prior to the first dose of 
study drug are permitted if the subject intends to continue the stable dose through the follow-up 
period (Day 42). Initiation of new antidepressants or any other medications that may potentially have 
an impact on efficacy or safety endpoints is prohibited from at least the screening visit and through 
completion of the Day 42 assessments. Anti-depressant medications are identified by ATC3 level 
code of N06A.  A summary of anti-depressant use at baseline and any change in these medications 
post-baseline (including the follow up period) will be provided. 


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Atypical antipsychotics will be identified by dictionary code of ATC level 3 equal to N05A, and will 
be listed separately.  These medications are prohibited at entry in the Protocol Amendment 4 and 
beyond, but was permitted in earlier protocol versions as long as as these are taken in stable dose for 
at least 60 days prior to the first dose of study drug and through Day 42. These medications will 
include, but not limited to: 
Aripiprazole  
Asenapine  
Brexpiprazole 
Cariprazine 
Clozapine  
Iloperidone  
Lurasidone 
Olanzapine  
Paliperidone  
Pimavanserin 
Quetiapine  
Risperidone Ziprasidone  
Concomitant procedures are recorded on a separate eCRF page; this will be presented in a listing by 
subject, and will not be summarized. The study day for the end date of the procedure will be 
provided, when a complete end date is available.  
Prohibited medications are reviewed by the the medical monitor in the study team on an ongoing 
basis in blinded fashion; any medication identified as prohibited medication intake is captured in the 
protocol deviations list.   
9.2.6 Study Drug Exposure 
The following analyses will use the Safety Set. 
Total drug exposure (in mg) is defined as the total study drug in mg for SAGE-217 that was taken 
during the study.  Total drug exposure for subjects randomized to placebo is zero, unless the subject 
has taken SAGE-217 by mistake, in which case the total exposure comes from SAGE-217 exposure.  
If the patient skips the dose on any of the days, the dose taken is 0 mg.   
Total exposure duration to study drug (in days) is defined as: Date of last dose – date of first dose + 1. 
Note that this does not exclude days when the dose has been missed. 
Percent of the planned exposure received is defined as the total drug exposure, divided by planned 
exposure, times 100.  For subjects who complete the treatment period, planned exposure is 14 days of 
treatment planned, times X mg for subjects randomized to SAGE-217, where X=30 for subjects 
randomized to 30mg, and X=20 for subjects randomized to 20mg. For subjects who discontinue the 
treatment early, the planned exposure is (Last dose date – First dose date + 1), times X mg for 
subjects randomized to SAGE-217.  For subjects randomized to placebo, this measure is not 
applicable. 
Total drug exposure, total exposure duration and percent of the planned exposure received will be 
summarized descriptively.  Number and percentage of subjects with less than 11 doses consumed will 
be provided. 


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9.2.7 Study Drug Adherence 
The following analyses will use the Full Analysis Set as well as mFAS separately. Study drug 
adherence (%) is defined as the number of capsules taken, divided by the number of capsules planned 
to be taken, times 100.   
The schedule of study drug is one capsule per day, so the number of days planned for study drug 
intake is the same as the number of capsules planned to be taken.  The number of planned days for 
study drug intake is defined as follows: 
1.   If the subject discontinues treatment within Day 2 and Day 14 (both inclusive), the planned 
number of days is the last dose day of study drug.  
2.   If the subject does not discontinue treatment, the planned number of days is 14.  
Study drug adherence will be summarized descriptively.  Number and percentage of subjects with 
study drug adherence in categories - <75%, 75-100%, >100% - will be provided.   
9.3 
Efficacy Analysis  
9.3.1 
Definition of Efficacy Variables 
The efficacy variables are defined as follows: 
9.3.1.1 
 Hamilton Rating Scale for Depression (HAM-D) 
The 17-item HAM-D will be used to rate the severity of depression in subjects already diagnosed as 
depressed.  HAM-D is collected during the clinic visit on Days 1, 3, 8, 12, 15, 18, 21, 28, 35, 42, 70, 
126, 182 .The 17-item HAM-D comprises of individual ratings related to the following symptoms: 
depressed mood (sadness, hopeless, helpless, worthless), feelings of guilt, suicide, insomnia (early, 
middle, late), work and activities, retardation (slowness of thought and speech; impaired ability to 
concentrate; decreased motor activity), agitation, anxiety (psychic and somatic), somatic symptoms 
(gastrointestinal and general), genital symptoms, hypochondriasis, loss of weight, and insight.  Each 
item is scored in a range of 0 to 2 or 0 to 4, with higher scores indicating a greater degree of 
depression.  The score for each item will be summed to compute a total score, which ranges from 0 to 
52.  If more than 3 individual items are missing a response, the HAM-D total score will not be 
calculated and will be left as missing.  If less than or equal to 3 individual item scores are missing, the 
missing item scores will be imputed by the mean of all other available item scores, or the maximum 
possible values for the missing responses, whichever is smaller, to calculate the HAM-D total score.   
Four HAM-D subscale scores will be calculated will be calculated as the sum of the individual rating 
scores related to each subscale, divided by the total possible score within the subscale, multiplied by 
100, and rounded to a whole number.  If more than one item is missing or HAM-D total score is 
missing, the subscale score is left as missing; if one item on a particular subscale is missing, but has 
been imputed for the calculation of total score, the imputed value from total score calculation will be 
used in subscale score calculation for that item.  Following table describes the subscale score 
calculation: 
 
HAM-D Subscales 
Items 
Calculation 
Core 
Depressed mood 
Feeling of guilt 
Suicide 
Work and activities 
Retardation 
Sum of the 5-item responses/20 x 100.   
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 


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calculate HAM-D total score to 
calculate the subscale.  
Anxiety 
Anxiety psychic 
Anxiety somatic 
Somatic symptoms gastrointestinal 
Somatic symptoms general 
Hypochondriasis 
Loss weight 
Sum of the 6-item responses/18 x 100.   
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale.  
Bech-6 
Depressed mood 
Feeling of guilt 
Work and activities 
Retardation 
Anxiety psychic 
Somatic symptoms general 
Sum of the 6-item responses/22 x 100.   
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale.  
Maier 
Depressed mood 
Feeling of guilt 
Work and activities 
Retardation 
Agitation 
Anxiety psychic 
Sum of the 6-item responses/24 x 100.   
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale.  
HAM-D response will be defined as having a 50% or greater reduction from baseline in HAM-D total 
score; only subjects who have a non-missing total score of HAM-D at baseline as well as the visit will 
be considered in HAM-D response evaluations.  HAM-D remission will be defined as having a 
HAM-D total score of ≤7; if HAM-D total score is missing, remission will not be defined. For a 
sensitivity analysis the worst-case scenario imputation will be used, i.e. missing values for HAM-D 
response (remission) will be considered as “No response” (“No remission”). 
9.3.1.2 
 Clinical Global Impression – Improvement (CGI-I) 
The Clinical Global Impression - Improvement (CGI-I) employs a 7-point Likert scale to measure the 
overall improvement in the subject’s condition post-treatment. The Investigator will rate the subject’s 
total improvement. Response choices include: 0=not assessed, 1=very much improved, 2=much 
improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, and 7=very 
much worse. The CGI-I is only rated at post-treatment assessments on Days 3, 8, 12, 15, 18, 21, 28, 
35, 42, 70, 126, 182. By definition, all CGI-I assessments are evaluated against baseline conditions. 
CGI-I response will be defined as having a CGI-I score of “very much improved” or “much 
improved.” Missing CGI-I at the visit will not be evaluated for response. 
9.3.1.3 
 Clinical Global Impression – Severity (CGI-S) 
The Clinical Global Impression - Severity (CGI-S) uses a 7-point Likert scale to rate the severity of 
the subject’s illness at the time of assessment, relative to the clinician’s past experience with subjects 
who have the same diagnosis. Considering total clinical experience, a subject is assessed on severity 
of mental illness at the time of rating as 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly 
ill; 4=moderately ill; 5=markedly ill; 6=severely ill; and 7=extremely ill.  CGI-S is collected at 
Screening day, Days 1, 3, 8, 12, 15, 18, 21, 28, 35, 42, 70, 126, and 182. 


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9.3.1.4 
Hamilton Anxiety Rating Scale (HAM-A) 
The 14-item HAM-A will be used to rate the severity of symptoms of anxiety. HAM-A is collected 
during the clinic visit at Days 1, 8, 15, 18, 28, 42.  Each of the 14 items is defined by a series of 
symptoms, and measures both psychic anxiety (mental agitation and psychological distress) and 
somatic anxiety (physical complaints related to anxiety). Scoring for HAM-A is calculated by 
assigning scores of 0 (not present) to 4 (very severe), with a total score range of 0 to 56, where <17 
indicates mild severity, 18 to 24, mild to moderate severity, and 25 to 30, moderate to severe severity. 
The HAM-A total score will be calculated as the sum of the 14 individual item scores. If more than 3 
individual items are missing a response, the HAM-A total score will not be calculated and will be left 
as missing.  If less than or equal to 3 individual item scores are missing, the missing item scores will 
be imputed by the mean of all other available item scores, or the maximum possible values for the 
missing responses, whichever is smaller, to calculate the HAM-A total score.   
9.3.1.5 
 Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive 
episodes in subjects with mood disorders.  MADRS is collected at Screening, during the clinic visit 
on Days 1, 3, 8, 12, 15, 18, 21, 28, 35, and 42. 
Each MADRS item ranges from 0 to 6; higher MADRS scores indicate more severe depression.  The 
MADRS total score will be calculated as the sum of the 10 individual item scores, which ranges from 
0 to 60.  If more than two individual items are missing, the MADRS total score will not be calculated 
and will be left as missing.  If less than or equal to two individual item scores are missing, the missing 
item scores will be imputed by the mean of all other available item scores, or the maximum possible 
values for the missing responses, whichever is smaller, to calculate the MADRS total score.  
MADRS response will be defined as having a 50% or greater reduction from baseline in MADRS 
total score; only subjects who have a non-missing total score of MADRS at baseline as well as the 
visit will be considered in MADRS response evaluations.  MADRS remission will be defined as 
having a MADRS total score of ≤10; if MADRS total score is missing, remission will not be defined. 
9.3.1.6 
 Insomnia Severity Index (ISI) 
The ISI is a validated, 7-item questionnaire designed to assess the nature, severity, and impact of 
insomnia.  It is collected during the clinic visit on Days 1, 8, 15, 18, 21, 28, 42, 70, 126, and 182.  The 
ISI uses a 5-point Likert Scale to measure various aspects of insomnia severity (0 = none, 1 = mild, 2 
= moderate; 3 = severe; 4 = very severe), satisfaction with current sleep pattern (0 = very satisfied, 1 
= satisfied, 2 = moderately satisfied, 3 = dissatisfied, 4 = very dissatisfied), and various aspects of the 
impact of insomnia on daily functioning (0 = not at all, 1 = a little, 2 = somewhat, 3 = much, 4 = very 
much).  The total score is derived as the sum of item scores.  If more than 1 individual item is 
missing, the ISI total score will not be calculated and will be left as missing.  If 1 individual item 
score is missing, the missing item score will be imputed by the mean of all other available item scores 
to calculate the ISI total score. Total score is categorized as: 0 to 7 = “no clinically significant 
insomnia”, 8 to 14 = subthreshold insomnia”, 15 to 21 = “clinical insomnia (moderate severity) and 
22 to 28 = “clinical insomnia (severe).” Missing ISI total score will not be categorized. 
9.3.1.7 
Core Consensus Sleep Diary 
The take-home subject sleep diary assessment will be administered using an eDiary solution. The 
eDiary will be captured using either a provisioned smartphone device or bring-your-own-device 
(BYOD) solution, depending on the subject’s preference. The sleep diary will be collected at least 7 
days prior to Day 1 and then daily through Day 28. The sleep diary is to be completed each day in the 
morning, preferably in the morning after awakening from sleep, regarding the last night’s sleep. 


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Subjective sleep parameters will be derived for study days 8, 15, 21, 28 using the mean of non-
missing assessments between the previous visit day (exclusive) and the current visit day (inclusive). 
The baseline subjective sleep parameters will be calculated as the mean of 7 days immediately 
preceding day 1. In addition, Day 18 visit values will be calculated using the days after Day 15 visit 
until Day 18 visit, but this timepoint will only be displayed in summary and listing, not used for 
analysis model.   
Parameters to be analyzed are as follows: 
sTST (in minutes) = Total sleep time = Time of final awakening -  (Time when tried to sleep + time 
taken to fall asleep) – time of being awake after sleep onset 
sSL (in minutes) = Sleep Latency  
sWASO (in minutes) = Wake after Sleep Onset = sWASO 
sNAW = Number of awakenings = sNAW 
sSQ = Sleep Quality  
The date/time stamp on the day’s entry is compared to clinic visit date to identify records that go into 
the calculation of a visit assessment.  In case of duplicate assessment on the same day, the first 
assessment will be counted toward the mean, but all assessments will be listed.  The times entered in 
the diary by the subject, e.g. time when went to bed, time when tried to fall asleep, etc. need to be 
associated with a date in order to make meaningful comparisons or to be used in calculations.  The 
following algorithm will be followed for this purpose: If Time to Bed is AM, then all time questions 
are associated with stamped date.  If Time to Bed is PM and Time out of Bed is PM, then all time 
questions are associated with date one day before the stamped date.  Otherwise, when Time to Bed is 
PM, all times in diary marked as PM are associated with day before the stamped date, and all times in 
diary marked as AM are associated with stamped date. 
Since the data is subject-entered and not monitored, a record may be invalid when it fails to 
make logical sense, particularly in calculation of sTTB or sTST, A record is considered 
invalid if either of the following holds true (use date/time combination to do these 
comparisons): 
1. Any of the eight response or date stamp is missing. 
2. sTST > sTTB (Total time in bed, in minutes, calculated as Time out of bed – Time to 
bed) 
3. sTST < 0 
4. sTTB <= 0 
5. Time to bed > Time when tried to sleep  
6. Time to bed > Time of final awakening  
7. Time when tried to sleep > Time of final awakening 
8. Time tried to sleep > Time out of bed  
9. Time of final awakening > Time out of bed 
An invalid record will be dropped from analysis of sTST, but not from the analysis of other 
sleep diary endpoints.  The sleep diary data will not be windowed. 
 
Sleep quality (sSQ) response will be defined as having a sSQ score of “very good” or “good.”  
Missing sSQ at the visit will not be evaluated for response. 
 


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9.3.1.8 
 Short Form-36 Version 2 (SF-36v2) 
The Medical Outcomes Study Short Form-36 version 2 (SF-36v2) is a 36-item measure of health 
status that has undergone validation in many different disease states.  This is collected during the 
clinical visits at Screening, on Days 1, 8, 15, 28, 42, 70, 126, and 182. 
The SF-36 covers 8 health dimensions including 4 physical health status domains (physical 
functioning, role participation with physical health problems [role-physical], bodily pain, and general 
health) and 4 mental health status domains (vitality, social functioning, role participation with 
emotional health problems [role-emotional], and mental health).  In addition, two component 
summary scores, physical component summary and mental component summary (MCS), are 
produced by taking a weighted linear combination of the 8 individual domains. There is also an 
Utility Index score (Release 2) that is available in SF-36 scale. Higher scores indicate a better state of 
health. 
The scoring of this questionnaire is proprietary to Optum Incorporated; it involves using current 
norms of relevant populations.  The raw data will be provided to Optum, and they will return the 
validated, quality-checked derived scores for each subject at each assessment, which will be used for 
analyses. 
9.3.1.9 
Patient Health Questionnaire (PHQ-9)  
The PHQ-9 is a 9-item subject-rated depressive symptom severity scale. It is collected during the 
clinic visit on Days 1, 8, 15, 21, 42, 70, 126, and 182. Scoring is based on responses to specific 
questions, as follows: 0=not at all; 1=several days; 2=more than half the days; and 3=nearly every 
day.  
The PHQ-9 total score will be calculated as the sum of the 9 individual item scores. If more than 1 
individual item is missing, the PHQ-9 total score will not be calculated and will be left as missing.  If 
1 individual item score is missing, the missing item score will be imputed by the mean of all other 
available item scores to calculate the PHQ-9 total score. The PHQ-9 total score will be categorized as 
follows: 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. 
9.3.2 
Visit Windows 
The scheduled visits will not be windowed and will be used at nominal visit value for analysis 
purposes.  The unscheduled, end-of-treatment (EOT) and early termination (ET) visit will be mapped 
to a scheduled visit for analysis.  For unscheduled visits that happens on or before EOT visit date 
(including EOT visit) will be mapped using the date of collection/assessment and Day 1 first dose 
date as a basis to determine study day and then study day will be mapped to the intended visit 
according to the visit windows specified in the table below. Unscheduled visits after EOT visit date, 
including ET visit, will be windowed using relative days since last dose date; the mapping will follow 
the table below.  In order to accommodate as much data as possible into analysis, these windows have 
been widened compared to protocol-specified operational window, to have no gap between them; 
these windows are used for analysis purposes only.  Note that Day 18 data will not be windowed; it 
will be presented in summaries as nominal visit values, and will not be included in the modeling or in 
figures. 
Once analysis visit windows are assigned, all visits, including scheduled visits, unscheduled visits, 
and EOT/ET visits will be eligible for being flagged as the “analyzed record” within the analysis 
window; a subject’s individual analysis visit window could potentially contain more than 1 visit.  In 
the event of multiple visits falling within an analysis window or in case of a tie, the following rules 
will be used in sequence to determine the “analyzed record” for the analysis visit window: 


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•         If the data from the scheduled visit is available, then the scheduled visit data will be used.  
•         If there is no data from the scheduled visit is available, the data closest to the scheduled 
study day for that window will be used.  
o If there is a tie between the data in the number of days before and after the 
scheduled day, the later data will be used.  
The summary by visit will use the “analyzed records” only – at most one per subject.  The data not 
flagged as the “analyzed record” will be included in listings. An unscheduled visit that does not fall 
under any analysis window (e.g. in case one is available after Day 182) will remain in the 
database,and will be included in the listings.   
Table 1 displays windows for efficacy analysis.  
Table 1: Visit Windows for Efficacy Analysis 
Scheduled Visit (+/1 window days) in 
protocol 
Target Study Day  
Study Day Window for Visit in 
Analysis 
Screening 
Day -1 
Days (-28) to (-1) 
First Dose 
Day 1 (pre-dose) 
Day 1 (pre-dose) 
Day 3 (±1 day) 
Day 3 
Day 2 - Day 5  
Day 8 (±1 day) 
Day 8 
Day 6 - Day 9  
Day 12 (±1 day) 
Day 12 
Day 10 - Day 13 
Day 15 (±1 day) 
Day 15 
Day 14 - Day 17 
Day 21 / last dose + 7 days (±1 day) 
Day 21 (last dose date + 7 
days) 
Day 18 - Day 23 (last dose date +4 
days, +9 days) 
Day 28 / last dose + 14 days (±3 day) 
Day 28 (last dose date + 14 
days) 
Day 24 - Day 31 (last dose date 
+10 days, +17 days) 
Day 35 / last dose + 21 days (±3 days) 
Day 35 (last dose date + 21 
days) 
Day 32 – Day 38 (last dose date 
+18 days, +24 days) 
Day 42 / last dose + 28 days (±3 days) 
Day 42 (last dose date + 28 
days) 
Day 39 – Day 45 (last dose date 
+25 days, +31 days) 
Day 70 / last dose + 56 days (± 7 days) 
Day 70 (last dose date + 56 
days) 
Day 60 – Day 80 (last dose date + 
46 days, +66 days) 
Day 126 / last dose + 112 days (± 7 days) 
Day 126 (last dose date + 
112 days) 
Day 116 – Day 136 (last dose date 
+ 102 days, + 122 days) 
Day 182 / last dose + 168 days (± 7 days) 
Day 182 (last dose date + 
168 days) 
Day 172 – Day 192 (last dose date 
+ 158 days, +178 days) 
Note: Parenthesized study day and study day window are for unscheduled visits, EOT and ET for 
subjects who have discontinued treatment prematurely and such visit date is >=4 days from the last 
dose of study drug intake (i.e. visit date – last dose date + 1 >4). 
9.3.3 
Analysis of Efficacy Variable(s) 
The modified FAS will be used for all efficacy summary tables, since this corresponds to the targeted 
patient population (see Section 7.1). Corresponding analysis in FAS will be provided for supportive 
purposes only. Subjects will be analyzed according to randomized treatment. 


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The following efficacy endpoints will be summarized descriptively by scheduled assessment time 
point:  
• 
HAM-D total score – observed, change from baseline, percent change from baseline 
• 
HAM-D subscale scores – observed, change from baseline, percent change from 
baseline 
• 
HAM-D individual item score -– observed, change from baseline  
• 
HAM-D response – missing response not accounted 
• 
HAM-D response – missing response counted as No response 
• 
HAM-D remission – missing remission not accounted 
• 
HAM-D remission – missing remission counted as No remission 
• 
CGI-I score -observed  
• 
CGI-I response  
• 
CGI-S score – observed and change from baseline 
• 
HAM-A total score – observed, change from baseline, percent change from baseline 
• 
HAM-A individual item score -– observed, change from baseline  
• 
MADRS total score – observed, change from baseline, percent change from baseline 
• 
MADRS individual item score – observed, change from baseline 
• 
MADRS response – missing response not accounted 
• 
MADRS remission – missing remission not accounted 
• 
ISI total score– observed (including categories), change from baseline (including any 
shift from baseline in categories)  
• 
Sleep endpoints (eg, subjective sleep latency (sSL), subjective total sleep time 
(sTST), subjective wake after sleep onset (sWASO) – observed, change from 
baseline, percent change from baseline 
• 
SF-36v2 domain/component score– observed, change from baseline, percent change 
from baseline  
In addition to the three randomized treatment arms in the study, the SF-36 data will 
also be summarized for SAGE-217 irrespective of dose (20mg and 30mg dose arms 
combined in one). 
• 
PHQ-9 score – observed (including categories), change from baseline (including any 
shift from baseline in categories)  
• 
PWC-20 – observed, change from baseline  
The HAM-D change from baseline in total score, response and remission will also be presented by the 
following subgroups: 
• 
Antidepressant use at baseline: yes, no 
• 
Age group: 18-24, 25-50, 51-65 years 


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• 
Gender: Male, Female  
• 
Race: White, Black or African American, Other 
• 
BMI (≤18.4, 18.5-24.9, 25-29.9, ≥30 kg/m2) 
• 
Baseline HAM-D total score: <22, >=22 but <25, >=25 
In addition, post-baseline percentage improvement in HAM-D total score will be presented in 
histogram over scheduled visits by treatment group under the following categories: < 0% (worsened), 
>= 0% but < 25%, >=25% but < 50%, >= 50% but <75%, >=75%. Post baseline HAM-D remission 
will also be presented in histogram with HAM-D total score over time: <=7, >7 but <=15, >15.  
Supporting data will be presented in summary tables. 
Bar charts over scheduled visits by treatment for HAM-D response, HAM-D remission and CGI-I 
response will be provided. 
As part of supportive analyses, the HAM-D total scores, MADRS total scores, HAM-D response and 
HAM-D remission will be summarized for Per Protocol Set as well as FAS separately. Line plots, 
histograms and bar charts will be provided for FAS when applicable. 
9.3.3.1 
Mixed Effects Model for Repeated Measures 
The estimand for the primary efficacy analysis is defined as follows: 
1)   The target population is adult subjects with a diagnosis of major depressive disorder and 
within a current depressive episode of moderate severity (HAM-D total score >=22). 
2)   The variable of interest is the change from baseline in HAM-D total score at Day 15. 
3)   The population summary level deals with the difference between SAGE-217 and placebo 
treatments in mean change from baseline in HAM-D total score at Day 15. 
4)   The intercurrent events could be: 
a.   the premature discontinuation of treatment for any reason, thus not having a Day 15 
HAM-D total score available.  This will be dealt by a sensitivity analysis using 
multiple imputation technique as described below.   
b.  Certain medications including, but not limited to, new antidepressants or 
benzodiazepines are prohibited in the protocol until Day 42 follow-up; however, the 
treatment policy strategy dictates that the results following these prohibited 
medication use will not be manipulated, but will rather be used ‘as is’ in analysis.  
Please note that the protocol does not specify any rescue process, hence there is no 
rescue medication.   
Data from SAGE-217 30mg group versus placebo group will be analyzed using a mixed effects 
model for repeated measures (MMRM); the model will include treatment (SAGE-217 30 mg, SAGE-
217 20 mg or placebo), baseline HAM-D total score, anti-depressant use at baseline (Yes or No), 
assessment time point (excluding Day 18), and time point-by-treatment as explanatory variables. All 
explanatory variables will be treated as fixed effects. All post-baseline time points will be included in 
the model, except Day 18. The main comparison will be between SAGE-217 and placebo at the 15-
day time point. Model-based point estimates i.e., least squares [LS] mean, is used as the test statistic 
and will be reported where applicable along with 95% confidence intervals, and p-values. An 
unstructured (UN) 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. The sandwich estimator for the variance covariance matrix will be derived, using the 


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EMPIRICAL option in the PROC MIXED statement in SAS. The p-value will be interpreted at 5% 
level of significance. 
If the comparison of SAGE-217 30mg versus placebo is significant at 0.05 level, other hypotheses 
testing will proceed with multiplicity adjustment, as described in Section 9.3.3.5. 
Similar to those methods described above for the primary endpoint, a MMRM will be used for the 
analysis of the change from baseline in other time points in HAM-D total score, all time points in 
HAM-D subscale scores (Core Subscale score, Anxiety Subscale score, Bech-6 Subscale score and 
Maier Subscale score), HAM-D individual item scores, CGI-S score, HAM-A total score, MADRS 
total score, MADRS individual item scores, ISI score,  sleep endpoints (eg, sleep onset latency (sSL), 
total sleep time (sTST), wake after sleep onset (sWASO). Number of awakenings (sNAW)), SF-36v2 
Domain/Component Score, and PHQ-9 total score.  The explanatory variable of baseline value will 
use the respective parameters being analyzed.  The analyses will also be provided for change from 
baseline in HAM-D total score within each baseline subgroup level separately. 
For each model, the comparison of interest will be between SAGE-217 and matching placebo at the 
15-day time point, with 30mg comparison followed by 20mg comparison, according to the 
multiplicity adjustment, as described in Section 9.3.3.5. However, model-based point estimates (i.e., 
LS means), 95% confidence intervals, and p-values will be reported for all time points. 
Line plot of model-based LS Mean and standard error (SE) over time will be prepared for change 
from baseline in HAM-D total score, HAM-D subscale scores, CGI-S score, HAM-A total score, 
MADRS total score, ISI score, sleep endpoints (total sleep time (sTST), sleep latency (sSL), wake 
after sleep onset (sWASO), number of awakenings (sNAW), and PHQ-9 score. Forest plot for 
subgroup analysis for change from baseline in HAM-D total score at Day 15 – LS means, confidence 
interval – will be provided. In addition, a Forest plot for individual items in HAM-D and for 
subscales of HAM-D will also be provided.  For SF-36, LS means of change from baseline at Day 15 
will be provided in bar chart for each domain/component.  
Summary of HAM-D total score along with model-based estimates and line plot will be provided for 
Per Protocol Set as well as for FAS as a supportive analysis for the primary endpoint. 
9.3.3.2 
  Generalized estimating equation (GEE) models 
Generalized estimating equation (GEE) methods will be used for the analysis of HAM-D response 
and HAM-D remission. GEE models will include terms for treatment (SAGE-217 30mg, SAGE-217 
20mg, Placebo), baseline HAM-D score, antidepressant use at baseline (Yes or No), assessment time 
point, and time point-by-treatment as explanatory variables. The comparison of interest will be the 
difference between SAGE-217 and matching placebo at the 15-day time point – 30mg comparison, 
followed by 20mg comparison, according to the multiplicity adjustment, as described in Section 
9.3.3.5. Model-based point estimates (i.e., odds ratios), 95% confidence intervals, and p-values will 
be reported.  
A GEE method will also be used for the analysis of MADRS response and remission including terms 
for treatment, baseline MADRS score, antidepressant use at baseline, assessment time point, and time 
point-by-treatment as explanatory variables. 
A GEE method will also be used for the analysis of CGI-I response including terms for treatment, 
baseline CGI-S score, antidepressant use at baseline, assessment time point, and time point-by-
treatment as explanatory variables.   
A GEE model will be used for analysis of sleep quality (sSQ) response including terms for treatment, 
baseline sSQ, antidepressant use at baseline, assessment time point, and time point-by-treatment as 
explanatory variables.  


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9.3.3.3 
Sensitivity Analysis 
A sensitivity analysis will be used to investigate the impact of missing data if ≥ 5% of subjects have 
missing data in primary efficacy endpoint assessment (i.e., HAM-D total score at Day 15).   
Imputation based on study withdrawal reason will be used.  The missing change from baseline in 
HAM-D total scores will be imputed using multiple imputation methods. The MMRM model will use 
the imputed dataset (all observed and imputed values included) to estimate the treatment difference.  
The modified FAS will be used for sensitivity analyses, with FAS as supportive analyses.  Sample 
SAS codes for MI imputation is provided in Section 12.2, Appendix B. 
Imputation distribution: 
The imputation distribution for the missing change from baseline in HAM-D total score at each 
timepoint will be assumed to have a normal distribution.  All randomized subjects will be classified as 
non-missing category, missing category 1, or missing category 2, based on the following rules: 
• 
Non-missing category: Subject with non-missing change from baseline in HAM-D total score 
at Day X 
• 
Missing category 1: Subject discontinued due to adverse events, physician decision, protocol 
deviation, non-compliance with study drug, , sponsor decision  or other, and is missing 
change from baseline in HAM-D total score at Day X 
• 
Missing category 2: Subject discontinued due to pregnancy, lost to follow-up, subject 
decision, withdrawal by subject, and is missing change from baseline in HAM-D total score 
at Day X, or subject completed study but is missing change from baseline in HAM-D total 
score at Day X 
Imputation algorithm: 
Missing values of change from baseline in HAM-D total score will be imputed separately within each 
treatment group using the following missing reason based algorithm: 
• 
Missing category 1: randomly draw a sample from the normal distribution N(µ, σ2), where µ 
is the mean of the non-missing change from baseline in HAM-D total score for placebo group 
for Day X, and σ2 is the sample variance estimated using the non-missing change.  This 
represents a conservative approach since higher values of change from baseline represents 
worse outcome, and placebo is supposed to provide a higher value. 
• 
Missing category 2: randomly draw a sample from the normal distribution N(µ, σ2), where µ 
is the mean of the non-missing change from baseline in HAM-D total score for subjects 
within the same treatment group at Day X, and σ2 is the sample variance estimated using the 
non-missing change. 
Analysis model: 
The complete MI method is described below: 
• 
Impute missing values using the normal distribution specified in the above algorithm to form 
a complete dataset (imputed dataset).  After imputation, all FAS subjects will have non-
missing change from baseline in HAM-D total score at all scheduled assessment time points. 
• 
Repeat the process K (K=20) times, using the procedure described above to form K imputed 
complete datasets. 
• 
Fit the MMRM model including treatment, baseline antidepressant use, and baseline HAM-D 
total score, to each imputed dataset, to estimate the treatment effect and its variance. 
• 
Combine the results from the K imputed datasets using the SAS procedure MIANALYZE, to 
derive the MI estimator. 
We fit the analysis model (MMRM model specified before) to the kth completed dataset, 
denoting the estimate of the treatment difference θ by θk from the kth completed dataset, and 


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denoting the corresponding estimate of the variance Vk. The MI estimator of θ, 
, is the 
average of the K individual estimators: 
 
The estimated variance of 
 is a combination of the between- and within-imputation 
variability as follows: 
 
where 
is the within-imputation variability and 
is the 
between-imputation variance. 
It has been shown that the statistic 
 
has an approximate t distribution where 
. 
9.3.3.4 
Analysis of Time to First HAM-D Response/Remission 
Using the modified FAS, Kaplan-Meier (KM) survival curve will be provided for time to first HAM-
D response; the median time to first response will be estimated from KM analysis. A subject will be 
censored at the subject’s last day of HAM-D evaluation in the database if the subject did not have a 
response.  Similar analysis will be done for first HAM-D remission.  
These analyses will be provided on FAS for supportive purposes only. 
9.3.3.5 
Multiplicity Adjustment versus Key Secondary Endpoints 
Multiplicity adjustment to statistical testing of hypotheses of secondary endpoints are done through 
dividing the alpha of 0.05 for primary testing into 30mg and 20mg in 80% and 20%, then proceeding 
sequentially with pre-identified key secondary endpoints.  Figure 1 below explains the strategy.  A 
secondary endpoint not included below is not adjusted for multiplicity, and hence will be interpreted 
with nominal p-value.   
Figure 1: Multiplicity Adjustment Strategy for Testing Key Secondary Endpoints 
 


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9.4 
Safety Analysis 
The primary objective is to evaluate the safety and tolerability of SAGE-217 as assessed by the 
incidence and severity of adverse events; changes from baseline in clinical laboratory measures, vital 
signs, and ECGs; and suicidal ideation and behavior using the C-SSRS. Potential withdrawal 
symptoms after discontinuation of SAGE-217 will be assessed using the PWC-20. Safety analyses 
will be conducted using the Safety Set, unless specified otherwise. The data will be presented by the 
actual treatment received rather than the treatment to which the subject has been randomized; for 
definition of actual treatment assignment, please see Section 9.1.  In addition to the three treatment 
arms in the study, the safety data will also be presented for SAGE-217 irrespective of dose (20mg and 
30mg dose arms combined in one). 
The safety endpoints evaluated at scheduled visits are taken as done in nominal visit, without any 
windowing.  If a value is available for a nominal scheduled visit, that value will be used in summary 
by visit.  Unscheduled visits, EOT and ET visits will be windowed using the same window days 
outlined in Table 1 for efficacy endpoints.  If scheduled visit value is not available, a value from the 
specific visit window will be included in summary, the choice of the record following the same rule 
as described in Section 9.3.2. 
Last value on treatment and Last value on study will be included in the summaries whenever 
indicated in the relevant sections below.  Last value on treatment is defined as the last post-baseline 
value between first dose of study drug (exclusive) and up to last dose of study drug + 7 days 
(inclusive).  Last value on study is defined as the last post-baseline value after the first dose of study 
drug. 
The safety endpoints and variables considered in the summary tables for this study are summarized in 
Table 2.  
Table 2: Safety endpoints and variables in the summary tables 
Safety 
Evaluation 
Incidence 
Observed 
Value 
Change from 
Baseline 
Abnormality/Clinical 
Significance (CS) 
Potentially Clinical 
Significance (PCS) 


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Safety 
Evaluation 
Incidence 
Observed 
Value 
Change from 
Baseline 
Abnormality/Clinical 
Significance (CS) 
Potentially Clinical 
Significance (PCS) 
AEs 
X 
 
 
 
 
Labs 
 
X 
X  
Z 
X 
ECGs 
 
X 
X 
Z 
X 
Vital Signs 
 
X 
X  
 
X 
C-SSRS 
X 
X 
X 
 
 
PWC-20 
 
X 
X 
 
 
Note: PCS criteria are outlined in sections 9.4.2-9.4.4 
X = to be summarized in tables 
Z = to be presented in listings only 
9.4.1 
Adverse Events 
Adverse events (AEs) are collected starting at the time of informed consent and throughout the 
duration of the subject’s participation in the study.  A treatment-emergent adverse event (TEAE) is 
defined as an adverse event with onset after the start of study drug. The TEAEs will be further 
categorized by the phase of occurrence as follows: 
Adverse events are assigned an AE period based on the onset date/time.  AE periods are defined as 
follows: 
• 
Pre-treatment AE: AE onset date before first study drug dosing date 
• 
TEAE: AE onset date/time on or after first study drug dose date/time (If an AE start date 
same as study drug first dose date, but no time either in AE start or treatment start, then 
consider this AE to be in treatment period TEAE.)   
• 
Treatment Period AE: AE onset date/time on or after first study drug dose date/time and on or 
before study drug last dose date + 1 day (Note that time does not matter for the end of this 
period.) 
• 
Follow-up period TEAE: AE onset date after study drug last dose date +1 day and on or 
before study drug last dose date + 28 days (Typically, Day 16 through Day 42 – time does not 
matter) 
• 
Extended Follow-up Period TEAE: AE onset date after study drug last dose date + 28 days  
• 
Double-blind Period TEAE: All AEs that are flagged as either Treatment Period or Follow-up 
Period TEAE 
If the date of an adverse event is incomplete and an unambiguous determination could not be made 
with respect to its onset time versus the first dose of study drug and/or last dose of study drug, the 
adverse event will be assumed to be a TEAE and a treatment period AE.  For imputation of missing 
AE dates, please refer to Appendix C, Section 12.3.1.  
All adverse events will be coded using MedDRA version 21.0 or higher.  
An overview summary table of TEAEs will present the number and percentage of subjects as well as 
the number of events for the following: 
o TEAE Double-Blind Period TEAE 
Treatment Period TEAE 
Follow-up Period TEAE 


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o Extended Follow-Up Period TEAE 
• 
TEAEs by maximum severity (severe>moderate>mild) 
o Double-Blind Period TEAE 
Treatment Period TEAE 
Follow-up Period TEAE 
o Extended Follow-Up Period TEAE 
• 
TEAE leading to discontinuation of study drug 
• 
TEAE leading to withdrawal from the study 
o Double-Blind Period TEAE 
Treatment Period TEAE 
Follow-up Period TEAE 
o Extended Follow-Up Period TEAE 
• 
Serious Adverse Event (SAE) 
o Double-Blind Period Serious AE 
Treatment Period Serious AE 
Follow-up Period Serious AE 
o Extended Follow-Up Period TEAE 
• 
Death 
o Double-Blind Period  
Treatment Period  
Follow-up Period 
o Extended Follow-Up 
 
Incidence of TEAEs in following categories will be provided by SOC and PT.  A subject is counted 
only once under each SOC and PT in case of multiple occurrences of the same AE. These tables will 
be sorted by decreasing frequency in SAGE-217 30mg+20mg group, then in 30mg group, then in 
20mg group, then in placebo group, then alphabetically.  
• 
TEAE 
• 
Double-Blind period TEAE 
• 
Treatment Period TEAE 
• 
Follow-up Period TEAE 
• 
Extended Follow-up Period TEAE 
• 
Double-Blind Period TEAEs by maximum Severity 
• 
Double-Blind Period TEAEs by relationship  


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• 
Serious TEAEs 
• 
Double-Blind Period Serious TEAEs 
• 
Treatment Period Serious TEAE 
• 
Follow-up Period Serious TEAE 
• 
Extended Follow-up Period Serious TEAE 
• 
Treatment Period TEAEs leading to discontinuation of study drug 
• 
TEAEs leading to withdrawal from the study  
• 
Double-Blind Period TEAEs leading to withdrawal from the study 
Listing of AEs with onset prior to first dose of study drug will be provided.  All listings on TEAEs 
will provide the period designation for each AE.   
A summary of most common study period TEAE just by preferred term where the incidence is more 
than 2% in any treatment group will be provided, sorted by decreasing frequency first by SAGE-217 
30mg+20mg group, then by 30mg, then by 20mg, then by placebo, then alphabetically.  
For maximum severity, subjects will be counted only once within each SOC and PT at the maximum 
severity in the following order: severe> moderate> mild; an AE with missing severity will be omitted 
from severity presentation.  For relationship to study drug, ‘related’ is defined as relationship being 
“possible” or “probable” or missing. A subject will be counted only once within each SOC and PT at 
the strongest relationship to study drug in the following order: related > not related. The incidences 
will be presented by descending frequency of SOC and then, within a SOC, by descending frequency 
of PT based on the subject count, and in alphabetical order of PT if the incidence within a PT is a tie.  
Adverse events with onset before the first dose of study drug will be provided in a separate listing.  
Separate data listing for deaths and non-fatal SAEs will be provided. 
In addition, double-blind period TEAE summary by SOC/PT will also be presented by the following 
subgroups: 
• 
Anti-depressant use at baseline: yes, no 
• 
Age group: 18-24, 25-50, 51-65 years 
• 
Gender: Male, Female  
• 
Race: White, Black or African American, Other 
• 
BMI (≤18.4, 18.5-24.9, 25-29.9, ≥30 kg/m2) 
• 
Baseline HAM-D total score: <22, >=22 but <25, >=25 
9.4.2 
Clinical Laboratory 
The clinical laboratory tests to be performed for monitoring of safety are listed in Table 3.  They are 
collected on screening day, days 1, 8, 15, 21, 28, 42, 70, 126, 182. 
Table 1: 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Coagulation 
Red blood cell count 
Hemoglobin  
Hematocrit  
Alanine aminotransferase  
Albumin  
Alkaline phosphatase  
pH  
Specific gravity  
Protein  
Activated partial 
 Thromboplastin 
  time  


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White blood cell count  
   with differential  
Platelet count 
Red Blood Cell Indices 
(MCV, MCH, MCHC)  
Reflex to Red blood cell 
morphology if indices are 
abnormal 
Aspartate aminotransferase  
Total bilirubin  
Direct bilirubin  
Indirect bilirubin  
Total protein  
Creatinine  
Blood urea nitrogen  
Creatine kinase  
Gamma-glutamyl transferase  
Potassium  
Sodium  
Lactate dehydrogenase  
Glucose  
Chloride  
Bicarbonate  
Calcium  
Phosphorus  
Triglycerides  
Thyroid stimulating hormone 
(TSH) 
Reflex to free T3/T4 if TSH is 
abnormal 
Glucose  
Red blood cell  
Nitrite  
Leukocyte 
esterase  
Ketones  
Bilirubin  
Urobilinogen  
Prothrombin time  
International 
  normalized ratio  
 
All parameters will be converted to consistent units according to the International System of Units 
(SI) before presentation. 
For the laboratory results that is “< or = x”, where x is a number as collected in the data, the numeric 
part of the result will be used in the calculation in the summary tables. The same is true if the result is 
presented as BLQ and a LLOQ value is provided – LLOQ value will be used for calculation in the 
summary tables. The actual results as collected will be displayed in the listings. 
Summary tables on lab parameters will include descriptive statistics for the observed values and 
changes from baseline by scheduled assessment timepoint in routine parameters in hematology, serum 
chemistry, coagulation and quantitative urinalysis test results.  It will also include the summary of last 
post-baseline values on treatment and on study.  The parameter values, which are produced only if 
another parameter is abnormal, will be included in data listings, but not summarized. 
If a normal range is provided for the parameter, out-of-range values will be flagged as low or high, 
where applicable, in the subject data listings.  A shift table for these parameters from baseline to each 
scheduled assessment time point will be provided.  This table will also include the shift from normal 
at baseline to high or low at any time during treatment (on or after first dose, on or before last dose + 
1 day), any time post-baseline during the study (on or after first dose) and at the end of study (i.e. the 
last available value in the database). Qualitative urinalysis parameters will be summarized 
descriptively.  
The number and percentage of subjects with PCS values will be provided in separate displays in 
hematology, serum chemistry, liver function tests and urinalysis tests provided for such occurrence 
any time post-baseline (irrespective of whether it happens in scheduled or unscheduled assessments). 
Potentially clinically significant values will be identified for specific laboratory parameters as 
outlined in the following table. 


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Laboratory  
Parameter 
Gender 
Units 
Criteria for PCS Values (Observed values) 
 
 
 
High  
Low  
Hematology 
 
 
 
 
Hemoglobin                     
Male 
g/L  
>185  
<115 
 
Female 
g/L  
>170 
<100 
Hematocrit    
Male 
Fraction of 1 
>0.55  
<0.385  
 
Female 
Fraction of 1 
>0.49 
<0.345 
Platelet count  
 
10^9/L  
>600 
<125 
White blood cell 
 
10^9/L  
>15  
<2.5  
Basophils  
 
10^9/L  
>0.5 
NA 
Eosinophils 
 
10^9/L  
>1.5 
NA 
Neutrophils  
 
10^9/L  
NA  
<1.5  
Lymphocytes  
 
10^9/L  
>6.0  
<0.5  
Monocytes  
 
10^9/L  
>1.4 
NA 
 
 
 
 
 
Serum Chemistry 
 
 
 
 
Albumin  
 
g/L  
>70  
<28  
Blood urea nitrogen  
 
mmol/L 
>10.71 
NA 
Calcium 
 
mmol/L 
>2.75 
<2.0 
Chloride 
 
mmol/L 
>120 
<90 
Creatinine 
 
mmol/L 
>3xULN or >3x Baseline 
 
Gamma Glutamyl 
Transferase  
 
 
>3xULN 
 
Glucose 
 
mmol/L 
>13.9 
<2.8 
Sodium  
 
mmol/L  
>150 
<132  
Potassium  
 
mmol/L  
>5.4  
<3.3  
Protein  
 
g/L 
 
<45 
Bicarbonate  
 
mmol/L  
>34  
<18  
Chloride  
 
mmol/L  
>120  
<90  
Phosphorus  
 
mmol/L 
>1.94 
<0.61 
Liver Function Tests 
(LFT) 
 
 
 
 
Bilirubin  
 
μmol/L  
>2xULN  
NA  
Aspartate 
Aminotransferase  
 
U/L  
>3xULN  
NA  
Alanine 
Aminotransferase  
 
U/L  
>3xULN  
NA  
Alkaline Phosphatase  
 
U/L  
>1.5xULN  
NA  
Liver function tests will be monitored closely for potentially clinically significant values, and will be 
summarized for occurrence any time post-baseline for the following parameters for these PCS 
threshold (for condition involving more than one parameters, the results need to be from the same 
timepoint): 
Alanine Aminotransferase: >3xULN, >5xULN, >10xULN 
Aspartate Aminotransferase: >3xULN, >5xULN, >10xULN 
Alanine Aminotransferase or Aspartate Aminotransferase: >3xULN, >5xULN, >10xULN 
Alkaline Phosphatase: >1.5xULN, >2xULN 
Total Bilirubin: >1.5xULN, >2xULN 
Total Bilirubin > 2xULN AND (Alanine Aminotransferase or Aspartate Aminotransferase >3xULN) 


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Total Bilirubin >2xULN AND Alkaline Phosphatase >2xULN AND (Alanine Aminotransferase or 
Aspartate Aminotransferase >3xULN) 
Any lab results considered clinically significant by the investigator will be captured as adverse events, 
hence will show up in AE displays. 
Pregnancy test results will be listed but not summarized.  
9.4.3 
Vital Signs 
Vitals for the following parameters - respiratory rate (breaths/minute), oral temperature (degrees C), 
supine heart rate (beats/minute), supine systolic blood pressure (mmHg), supine diastolic blood 
pressure (mmHg), standing heart rate (beats/minute), standing systolic blood pressure (mmHg), 
standing diastolic blood pressure (mmHg), – are collected at screening, days 1, 3, 8, 12, 15, 18, 21, 
28, 35, 42, 70, 126, and 182. Descriptive summaries of observed values and changes from baseline 
will be provided for vital sign parameters - by scheduled assessment time point.  It will also include 
the summary of last values on treatment and on study assessments. Additionally, the number and 
percentage of subjects with PCS and PCSC values will be summarized for such occurrence any time 
post-baseline. Potentially clinically significant values will be identified for vital sign parameters as 
outlined in the following table. 
Vital Sign 
Units 
Criteria for PCS Values 
(Observed values) 
Criteria for PCSC values 
(Change from Baseline 
values) 
 
 
High  
Low  
Increase  
Decrease  
Heart rate (supine and standing) 
Beats/min  
>120  
<40  
NA 
NA 
Systolic Blood Pressure (supine 
and standing)  
mmHg  
>180 
<90  
≥30 
≥30 
Diastolic Blood pressure 
(supine and standing)  
mmHg  
>110 
<50  
≥20 
≥20  
Supine - Standing Systolic 
Blood Pressure 
mmHg 
≥20 
 
 
 
Supine – Standing Diastolic 
Blood Pressure 
mmHg 
≥10 
 
 
 
Orthostatic hypotension: supine 
– standing SBP and DBP 
mmHg 
SBP >= 20 and 
DBP >= 10 
 
 
 
 
mmHg 
SBP >= 20 or 
DBP >= 10 
 
 
 
The orthostatic vital sign - the change from supine to standing (Supine – Standing) in heart rate, 
systolic and diastolic blood pressure – will be summarized by scheduled assessment timepoint. 
Any vital signs results considered clinically significant by the investigator will be captured as adverse 
events, hence will show up in AE displays. 
9.4.4 
Electrocardiogram 
Supine 12-lead ECGs will be performed in triplicate, and are collected on screening, days 1, 15, 42, 
and 182. The following ECG parameters will be listed for each subject: heart rate (beats per minute), 
PR (msec), QRS (msec), QT (msec), and QTcF (msec).     
The average of the triplicate values will be used in the summary, including baseline ECG values.  The 
observed value at each time point and change from baseline at each post-baseline scheduled time 
point will be summarized. This summary will also include the last values on treatment and on study.  


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Each ECG is evaluated as ‘normal’, ‘abnormal, not clinically significant’ and ‘abnormal, clinically 
significant’; the number and percentage of subjects with at least one of the triplicate values in the 
categories of ‘abnormal, clinically significant’ and ‘abnormal, not clinically significant’ will be 
provided at baseline and each post-baseline scheduled assessment time point. 
Additionally, the number and percentage of subjects with PCS and potentially clinically significant 
change (PCSC) values will be summarized for such occurrence any time post-baseline.  Potentially 
clinically significant values will be identified for ECG parameters as outlined in the following table.  
This analysis includes triplicate values individually, and is not based on average value.  In addition, 
the maximum value of QTcF if within any of the PCS criteria will be summarized. 
ECG 
Units 
Criteria for PCS Values (Observed values) 
Criteria for PCSC values 
(Change from Baseline) 
 
 
High  
Low  
Increase  
Decrease  
QTcF 
Interval 
msec  
>450 but <=480 
>480 but <=500 
>500 
NA  
>=30 to 60 
>60 
 
NA  
9.4.5 
Physical Examination  
Physical examination is scheduled on screening, day 1 and 42. Only clinically significant 
abnormalities are captured in the database – for post-baseline observations, these will be reported as 
adverse events, hence these will be included in AE displays; for pre-baseline observations, these will 
be reported as medical history, hence these will be included in Medical History displays.  The dates of 
physical examination will be listed to confirm that the examination was done.  
9.4.6 
Columbia Suicide Severity Rating Scale (C-SSRS) 
Suicidality data collected on the C-SSRS is collected during the clinical visits at Screening, Days 1, 3, 
8, 12, 15, 21, 28, 35, and 42.  The C-SSRS includes ‘yes’ or ‘no’ responses for assessment of suicidal 
ideation and behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 
5 being the most severe).  The subject’s non-suicidal self-injurious behaviors is also assessed 
separately as part of C-SSRS. The “Baseline/Screening” C-SSRS form will be completed at screening 
(lifetime history and past 24 months). The “Since Last Visit” C-SSRS form will be completed at all 
subsequent time points.  
 
The assessments for suicidal ideation is ranked as follows with 5 being the worst: 
1. Wish to be dead 
2. Non-specific active suicidal thoughts 
3. Active suicidal ideation with any methods 
4. Active suicidal ideation with some intent 
5. Active suicidal ideation with specific plan 
The assessments for suicidal behavior is ranked as follows with 5 being the worst: 
1. Preparatory acts or behavior 
2. Aborted attempt 
3. Interrupted attempt 
4. Actual attempt (non-fatal) 
5. Completed suicide 
Suicidal behavior is considered worse than suicidal ideation.   
 
Baseline for each question is defined as the worst of the assessments done before the first dose of 
study drug, excluding the lifetime version.  This will typically include the ‘past 24-month ‘version 


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from screening and ‘since last visit version’ from Day 1, as well as any unscheduled visits done 
before the first dose of study drug; any Yes will make the baseline value as Yes. 
 
The number and percentage of subjects with at least one response of ‘Yes’ to any C-SSRS suicidal 
ideation or suicidal behavior item, as well as for Subject’s non-suicidal self-injurious behavior, will 
be summarized first by visit, then separately for baseline and any time post-baseline.  
Summary of shift from baseline in C-SSRS suicidal ideation and suicidal behavior will be presented 
for the following categories (no suicidal ideation/behavior, suicidal ideation, suicidal behavior) for 
each scheduled assessment time point.  If the answer to all 5 assessments in suicidal ideation and all 5 
assessments in suicidal behavior is ‘No’ then the category for the table is considered as ‘No suicidal 
ideation/behavior’.  If any of the assessments in suicidal behavior is Yes, the category is considered 
as ‘Suicidal behavior’.  If any of the assessments in suicidal ideation is Yes but all assessments in 
suicidal behavior is No, the category is considered as ‘Suicidal ideation’. 
In addition, a summary of shift in suicidal ideation from baseline maximum rank score for any time 
post-baseline maximum rank score will be presented.  Maximum score 0 refers to all No for all 
assessments in the desired period for all 5 questions on suicidal ideation.    
9.4.7 
Physician Withdrawal Checklist (PWC) 
The PWC-20 will be used to monitor for the presence of potential withdrawal symptoms following 
discontinuation of SAGE-217 
The PWC-20 is made up of a list of 20 symptoms (eg, loss of appetite, nausea-vomiting, diarrhea, 
anxiety-nervousness, irritability, etc.) that are rated on a scale of 0 (not present) to 3 (severe. The total 
score is calculated as the sum of 20 responses and ranges from 0 to 60.  If more than 2 individual 
items are missing, the PWC total score will not be calculated and will be left as missing.  If less than 
or equal to 2 individual item scores are missing, the missing item scores will be imputed by the mean 
of all other available item scores or the maximum possible values for the missing responses, 
whichever is smaller, to calculate the PWC total score.  A higher total score indicates a greater degree 
withdrawal symptoms. 
The observed and change from baseline will be summarized for PWC total score. 


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10 SUMMARY OF INTERIM AND DMC ANALYSES 
Not applicable 
11 REFERENCES 
Draft clinical study protocol, version 5.0, 25 March 2019, Company: Sage Therapeutics Inc. 




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12 LIST OF APPENDICES 
12.1 Appendix A: Schedule of Assessments 
Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
Follow-up Period 
Extended Follow-up 
Visit Days 
D-28 to D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(±1d) 
and/or 
EOTa 
D18 
(±1d) 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
or 
ET 
D70, D146, D182 
(±7d) 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
 
V7 
V8 
V9 
V10 
V11 
V12, V13, V14 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Duplicate Subject Checkb 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
 
 
 
Serum FSH testc 
X 
 
 
 
 
 
 
 
 
 
 
 
SCID-5-CT 
X 
 
 
 
 
 
 
 
 
 
 
 
MGH ATRQ 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/Family History 
X 
 
 
 
 
 
 
 
 
 
 
 
Subject trainingd 
X 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examinatione 
X 
X 
 
 
 
 
 
 
 
 
X 
 
Body Weight/Height 
X 
 
 
 
 
X (wt 
only) 
 
 
 
 
X (wt 
only) 
 
Clinical Laboratory 
Assessmentsf 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
Drug & Alcohol Screeng 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
Follow-up Period 
Extended Follow-up 
Visit Days 
D-28 to D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(±1d) 
and/or 
EOTa 
D18 
(±1d) 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
or 
ET 
D70, D146, D182 
(±7d) 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
 
V7 
V8 
V9 
V10 
V11 
V12, V13, V14 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testh 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGl 
X 
X 
 
 
 
X 
 
 
 
 
X 
X (Day 182 only) 
C-SSRSm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAM-Dn, o 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MADRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
HAM-Ao 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
CGI-S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SF-36v2 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
PHQ-9 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
ISI 
 
X 
 
X 
 
X 
X 
X 
X 
 
X 
X 
PWC-20 
 
X 
 
 
 
X 
X 
X 
 
 
 
 


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Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
Follow-up Period 
Extended Follow-up 
Visit Days 
D-28 to D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(±1d) 
and/or 
EOTa 
D18 
(±1d) 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
or 
ET 
D70, D146, D182 
(±7d) 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
 
V7 
V8 
V9 
V10 
V11 
V12, V13, V14 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
Sleep diaryp 
X 
 
 
 
Study Drug Dispensation 
 
X 
 
X 
 
 
 
 
 
 
 
 
Study Drug Administration 
 
X (Day 1 through Day 14) 
 
 
 
 
 
 
Study Drug 
Accountability/Return 
 
 
 
X 
 
X 
 
 
 
 
Xr 
 
Adverse Events/SAEss 
X 
Prior/Concomitant 
Medications/Procedurest 
X 
CGI-I = Clinical Global Impression – Improvement; CGI-S – Clinical Global Impression – Severity;
C-SSRS = Columbia Suicide Severity Rating Scale; D = day; EOT = end of treatment; ET = early termination; ECG = electrocardiogram; 
 FSH = follicle stimulating hormone; HAM-A = Hamilton Anxiety Rating Scale; HAM-D = Hamilton Rating Scale for Depression, 17-item; HIV = human 
immunodeficiency virus; ISI = Insomnia Severity Index; MADRS = Montgomery-Åsberg Depression Rating Scale; MGH ATRQ = Massachusetts General Hospital 
Antidepressant Treatment Response Questionnaire; PHQ-9 = 9-item Patient Health Questionnaire; PWC-20 = 20-item Physician Withdrawal Checklist; O = Optional; 
  
 SCID-5-CT = Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition Clinical Trials Version; SF-36v2 = 36-
item Short Form survey version 2; V = visit; wt = weight 
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. 
Follow-up visits should take place every 7 days after the last dose of treatment for a total of 4 follow-up visits. 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 both visits will be conducted.  
b Subjects will be asked to authorize that their unique subject identifiers be entered into a registry (www.subjectregistry.com) with the intent of identifying subjects who may 
meet exclusion criteria for participation in another clinical study. 
c A serum follicle stimulating hormone test will be conducted at Screening for female subjects that are not surgically sterile to confirm whether a female subject with ≥12 
months of spontaneous amenorrhea meets the protocol-defined criteria for being post-menopausal. 
d Subjects will be trained on use of software applications and devices necessary for the conduct of the study by site personnel. 


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e A full physical examination will be conducted at Screening and abbreviated physical examinations will be conducted thereafter. A full physical examination includes 
assessment of body systems (eg, head, eye, ear, nose, and throat; heart; lungs; abdomen; and extremities). 
f Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. 
g Urine toxicology for selected drugs of abuse (as per the lab manual) and breath test for alcohol. 
h Serum pregnancy test at screening and urine pregnancy test thereafter for female subjects that are not surgically sterile and do not meet the protocol-defined criteria for 
being post-menopausal. 
 
 
 
k Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing). Heart rate and blood pressure to be collected in supine 
position at all scheduled time points after the subject has been resting for 5 minutes and then after 1 minute in the standing position. Vital signs may be repeated at the 
discretion of the Investigator as clinically indicated. 
l Triplicate ECGs will be collected. 
 
m The “Baseline/Screening” C-SSRS form will be completed at screening. The “Since Last Visit” C-SSRS form will be completed at any time of day at all subsequent time 
points. 
n The HAM-D is to be completed as early during the visit as possible. 
o The assessment timeframe for HAM-D scales will refer to the past 7 days (1 week) at Screening and “Since Last Visit” for all other visits. The assessment timeframe for 
HAM-A scale will refer to the past 7 days (1 week) at all visits. 
p Subjects are instructed to complete the Core Consensus Sleep Diary starting at least 7 days prior to Day 1 and then daily through Day 28. 
 
 
r To be performed at the ET visit only. 
s Adverse events will be collected starting at the time of informed consent and throughout the duration of the subject’s participation in the study. 
t Prior medications will be collected at Screening and concomitant medications and/or procedures will be collected at each subsequent visit. 
 


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12.2 Appendix B: Details of Statistical Methodology 
Sample SAS code for Mixed Effects Model for Repeated Measures (MMRM): 
ods output lsmeans=estimates diffs=diffs; 
proc mixed data=&data; 
class trtpn avisitn usubjid antidep; 
model chg=base trtpn avisitn trtpn*avisitn antidep / ddfm=kr s; 
repeated avisitn / subject=usubjid type=un;  
**If type=un does not converge, use type=TOEP; 
lsmeans trtpn*avisitn /diff=all cl alpha=0.05; 
** assuming the Placebo is A, SAGE-217 20 mg is B, SAG-271 30 mg is C 
run;  
Sample SAS code for Generalized Estimating Equation (GEE): 
proc genmod data=&data; 
class usubjid trtpn antidep avisitn; 
model aval=base trtpn avisitn trtpn*avisitn antidep /dist=bin link=logit; 
repeated subject=usubjid / type=un; * if convergence not met, use type=exch; 
lsmeans trtpn*avisitn / diff exp cl; 
run;  
 
Sample SAS code for Multiple Imputation (MI): 
** Missing category 1, trtp=A represent the PLACEBO group 
proc mi data=in seed=xxxx nimpute=20 round=. . . . 1 1 1 1 1 1 1 1 1 1 1 1 1 out= fcs_reg1; 
class trtp strata; 
FCS reg; 
mnar model (day3 day8 day 12 day15 day18 day21 day28 day42/ modelobs= (trtp='A')); 
var strata base day3 day8 day12 day15 day18 day21 day28 day35 day42; 
run; 
** Missing category 2 
 


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proc mi data=&data seed=xxxx nimpute=20 round=. . . . 1 1 1 1 1 1 1 1 1 1 1 1 1 out=fcs_reg2; 
class trtp strata; 
fcs nbiter=20 reg (base Day3 Day8  Day12 day15 day18 day21 day28 day35 day42/details); 
var trtp strata base Day3 Day8  Day12 day15 day18 day21 day28 day35 day42; 
run;  
12.3 Appendix C: Handling of Missing Dates 
Dates missing the day or both the day and month of the year will adhere to the following conventions in order to classify TEAEs and to 
classify prior and concomitant medications.  
In general, listings will present the actual partial or missing values rather than the imputed values that may be used in derivation. In instances 
where imputed values will be presented, imputed values will be flagged.  
12.3.1 Adverse Events 
If the AE start date is completely missing, do not impute a date but consider it as TEAE, unless the AE end date is before the 
initiation of treatment, in which case the AE will be considered prior. 
For partial AE start dates: 
•When the year is known, but the month and day is unknown, then: 
o If the year matches the year of first dose date and the end date (if present) is after first dose date, or AE is ongoing, then impute 
as the month and day of the first dose date + 1 day. 
o If the year of AE onset < year of initiation of the treatment, then the month and day will be set to December 31st.  
o If the year of AE onset > the year of initiation of treatment, then the month and day will be set to January 1st. 
 
•If the year and month are known, but the day is unknown, then: 
o If the year of AE onset = the year of initiation of the treatment and: 
 the month of AE onset = the month of initiation of the treatment, then the day will be set to the day of initiation of the 
treatment. 
 the month of AE onset < the month of initiation of the treatment, then the day will be set to the last day of month. 
 if the month of AE onset > the month of initiation of the treatment, then the day will be set to the 1st day of month. 
o If the year of AE onset < the year of initiation of the treatment, then the day will be set to the last day of month. 


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o If the year of AE onset > the year of initiation of the treatment, then the day will be set to the 1st day of month. 
If the imputed AE onset date is after the AE stop date, then the onset date will be set to the stop date. 
 
•When the year and day are present and the month is missing, treat it as if the day is missing, and only year is present.  Follow the 
imputation rules for “year is known, but the month and day is unknown”. 
•When the year is missing, but the month and/or day is known, treat this date as missing; do not impute. 
12.3.2 Dates in Disease History (Dates of diagnosis, current episode, first episode) 
o If the year is present and the month and day are missing, then the month and day will be set to January 1. 
o If the year and day are present and the month is missing, then the month will be set to January. 
o If the year and month are present and the day is missing, then the day will be set to the 1st day of month 
12.3.3 Prior and Concomitant Medications 
For the partial start date of medication: 
o If the year is present and the month and day are missing, then the month and day will be set to January 1. 
o If the year and day are present and the month is missing, then the month will be set to January. 
o If the year and month are present and the day is missing, then the day will be set to the 1st day of month. 
o If the imputed start date of medication is after the non-imputed end date of medication, then the start date will be set to the end date 
of medication. 
For the partial end date of medication: 
o If the year is present and the month and day are missing, then the month and day will be set to December 31. 
o If the year and day are present and the month is missing, then the month will be set to December. If the year and month are present 
and the day is missing, then the day will be set to the last day of the month. 
o If the year and day are present and the month is missing, then treat it as if the day is also missing.  Set the month and day to be 
December 31.   
 
12.4 Appendix D: List of Displays 
Tables 
Table Number 
Title 
Analysis Set 
Table 14.1.1.1 
Summary of Subject Disposition 
All Subjects 


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Table Number 
Title 
Analysis Set 
Table 14.1.1.2 
Summary of Subject Disposition 
Modified Full Analysis Set 
Table 14.1.2.1 
Summary of Major Protocol Deviations 
Safety Set 
Table 14.1.2.2 
Reasons for Exclusion from Analysis Sets 
Randomized Set 
Table 14.1.3.1.1 
Summary of Demographics and Baseline Characteristics 
Safety Set 
Table 14.1.3.1.2 
Summary of Demographics and Baseline Characteristics 
Full Analysis Set 
Table 14.1.3.1.3 
Summary of Demographics and Baseline Characteristics 
Modified Full Analysis Set 
Table 14.1.3.1.4 
Summary of Baseline Subgroups 
Safety Set 
Table 14.1.3.1.5 
Summary of Baseline Subgroups 
Full Analysis Set 
Table 14.1.3.1.6 
Summary of Baseline Subgroups 
Modified Full Analysis Set 
Table 14.1.3.2.1 
Summary of Disease History 
Safety Set 
Table 14.1.3.3.1 
Summary of Medical and Surgical History 
Safety Set 
Table 14.1.3.3.2 
Summary of Medical and Surgical History ongoing at Screening 
Safety Set 
Table 14.1.3.3.3 
Summary of Subject History of Psychiatric Disorder 
Safety Set 
Table 14.1.3.3.4 
Summary of Family History of Psychiatric Disorder 
Safety Set 
Table 14.1.4.1 
Summary of Prior Non-Psychotropic Medications 
Safety Set 
Table 14.1.4.2 
Summary of Concomitant Non-Psychotropic Medications 
Safety Set 
Table 14.1.4.3 
Summary of On-treatment Non-Psychotropic Medications  
Safety Set 
Table 14.1.4.4 
Summary of Post-treatment Non-Psychotropic Medications 
Safety Set 
Table 14.1.4.5.1 
Summary of Prior Psychotropic Medications 
Safety Set 
Table 14.1.4.5.2 
Summary of Prior Psychotropic Medications by ATC Level 4 
Safety Set 
Table 14.1.4.6.1 
Summary of Concomitant Psychotropic Medications 
Safety Set 
Table 14.1.4.6.2 
Summary of Concomitant Psychotropic Medications by ATC Level 4 
Safety Set 
Table 14.1.4.7 
Summary of On-treatment Psychotropic Medications 
Safety Set 
Table 14.1.4.8 
Summary of Post-treatment Psychotropic Medications 
Safety Set 
Table 14.1.4.9 
Summary of Use of Concomitant Antidepressant Medications 
Safety Set 
Table 14.1.4.10 
Summary of Study Drug Exposure  
Safety Set 
Table 14.1.4.11 
Summary of Study Drug Adherence 
Full Analysis Set 
Table 14.1.4.12 
Summary of Study Drug Adherence 
Modified Full Analysis Set 
Table 14.2.1.1.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Study 
Visit 
Full Analysis Set 
Table 14.2.1.1.2 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Total 
Score, Change from Baseline by Study Visit 
Full Analysis Set 


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Table Number 
Title 
Analysis Set 
Table 14.2.1.1.3 
Model-based Sensitivity Analysis on Hamilton Rating Scale for Depression (HAM-
D) Total Score, Change from Baseline at Day 15 
Full Analysis Set 
Table 14.2.1.1.4 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Study 
Visit 
Per Protocol Set 
Table 14.2.1.1.5 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Total 
Score, Change from Baseline by Study Visit 
Per Protocol Set 
Table 14.2.1.1.6 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Study 
Visit 
Modified Full Analysis Set 
Table 14.2.1.1.7 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Total 
Score, Change from Baseline by Study Visit 
Modified Full Analysis Set 
Table 14.2.1.1.8 
Model-based Sensitivity Analysis on Hamilton Rating Scale for Depression (HAM-
D) Total Score, Change from Baseline at Day 15 
Modified Full Analysis Set 
Table 14.2.2.1.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Subscale Scores by 
Study Visit 
Full Analysis Set 
Table 14.2.2.1.2 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Core 
Subscale Score, Change from Baseline by Study Visit 
Full Analysis Set 
Table 14.2.2.1.3 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Anxiety 
Subscale Score, Change from Baseline by Study Visit 
Full Analysis Set 
Table 14.2.2.1.4 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Bech-6 
Subscale Score, Change from Baseline by Study Visit 
Full Analysis Set 
Table 14.2.2.1.5 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Maier 
Subscale Score, Change from Baseline by Study Visit 
Full Analysis Set 
Table 14.2.2.1.6 
Summary of Hamilton Rating Scale for Depression (HAM-D) Subscale Scores by 
Study Visit 
Modified Full Analysis Set 
Table 14.2.2.1.7 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Core 
Subscale Score, Change from Baseline by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.1.8 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Anxiety 
Subscale Score, Change from Baseline by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.1.9 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Bech-6 
Subscale Score, Change from Baseline by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.1.10 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Maier 
Subscale Score, Change from Baseline by Study Visit 
Modified Full Analysis Set 


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Table Number 
Title 
Analysis Set 
Table 14.2.2.2.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Individual Item Score 
by Study Visit 
Full Analysis Set 
Table 14.2.2.2.2 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) 
Individual Item Score, Change from Baseline by Study Visit 
Full Analysis Set 
Table 14.2.2.2.3 
Summary of Hamilton Rating Scale for Depression (HAM-D) Individual Item Score 
by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.2.4 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) 
Individual Item Score, Change from Baseline by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.3.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Response by Study 
Visit 
Full Analysis Set 
Table 14.2.2.3.2.1 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Response 
by Study Visit 
Full Analysis Set 
Table 14.2.2.3.2.2 
Sensitivity Analysis: Summary of Hamilton Rating Scale for Depression (HAM-D) 
Response by Study Visit  
Full Analysis Set 
Table 14.2.2.3.2.3 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score – Percent 
Improvement – by Study Visit 
Full Analysis Set 
Table 14.2.2.3.2.4 
Summary of Time to First Hamilton Rating Scale for Depression (HAM-D) 
Response – Kaplan-Meier Analysis 
Full Analysis Set 
Table 14.2.2.3.3.1 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Response 
by Study Visit 
Per Protocol Set 
Table 14.2.2.3.3.2 
Summary of Hamilton Rating Scale for Depression (HAM-D) Response by Study 
Visit 
Modified Full Analysis Set 
Table 14.2.2.3.3.3 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Response 
by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.3.3.4 
Sensitivity Analysis: Summary of Hamilton Rating Scale for Depression (HAM-D) 
Response by Study Visit  
Modified Full Analysis Set 
Table 14.2.2.3.3.5 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score – Percent 
Improvement – by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.3.3.6 
Summary of Time to First Hamilton Rating Scale for Depression (HAM-D) 
Response – Kaplan-Meier Analysis 
Modified Full Analysis Set 
Table 14.2.2.3.4 
Summary of Hamilton Rating Scale for Depression (HAM-D) Remission by Study 
Visit 
Full Analysis Set 


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Table Number 
Title 
Analysis Set 
Table 14.2.2.3.5.1 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) 
Remission by Study Visit 
Full Analysis Set 
Table 14.2.2.3.5.2 
Sensitivity Analysis: Summary of Hamilton Rating Scale for Depression (HAM-D) 
Remission by Study Visit 
Full Analysis Set 
Table 14.2.2.3.5.3 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score in 
Categories, by Study Visit 
Full Analysis Set 
Table 14.2.2.3.5.4 
Summary of Time to First Hamilton Rating Scale for Depression (HAM-D) 
Remission – Kaplan-Meier Analysis 
Full Analysis Set 
Table 14.2.2.3.5.5 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) 
Remission by Study Visit 
Per Protocol Set 
Table 14.2.2.3.5.6 
Summary of Hamilton Rating Scale for Depression (HAM-D) Remission by Study 
Visit 
Modified Full Analysis Set 
Table 14.2.2.3.5.7 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) 
Remission by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.3.5.8 
Sensitivity Analysis: Summary of Hamilton Rating Scale for Depression (HAM-D) 
Remission by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.3.5.9 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score in 
Categories, by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.3.5.10 
Summary of Time to First Hamilton Rating Scale for Depression (HAM-D) 
Remission – Kaplan-Meier Analysis 
Modified Full Analysis Set 
Table 14.2.2.4.1 
Summary of HAM-D Total Score by Study Visit and Antidepressant Use at 
Baseline 
Full Analysis Set 
Table 14.2.2.4.2 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Total 
Score by Study Visit and Antidepressant Use at Baseline 
Full Analysis Set 
Table 14.2.2.4.3 
Summary of HAM-D Total Score by Study Visit and Age Group 
Full Analysis Set 
Table 14.2.2.4.4 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Total 
Score by Study Visit and Age Group  
Full Analysis Set 
Table 14.2.2.4.5 
Summary of HAM-D Total Score by Study Visit and Gender 
Full Analysis Set 
Table 14.2.2.4.6 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Total 
Score by Study Visit and Gender 
Full Analysis Set 
Table 14.2.2.4.7 
Summary of HAM-D Total Score by Study Visit and Race Group 
Full Analysis Set 
Table 14.2.2.4.8 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Total 
Score by Study Visit and Race Group 
Full Analysis Set 


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Table Number 
Title 
Analysis Set 
Table 14.2.2.4.9 
Summary of HAM-D Total Score by Study Visit and BMI Group 
Full Analysis Set 
Table 14.2.2.4.10 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Total 
Score by Study Visit and BMI Group 
Full Analysis Set 
Table 14.2.2.4.11 
Summary of HAM-D Total Score by Study Visit and Baseline HAM-D Total Score 
Category 
Full Analysis Set 
Table 14.2.2.4.12 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Total 
Score by Study Visit and Baseline HAM-D Total Score Category 
Full Analysis Set 
Table 14.2.2.4.13 
Summary of HAM-D Total Score by Study Visit and Antidepressant Use at 
Baseline 
Modified Full Analysis Set 
Table 14.2.2.4.14 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Total 
Score by Study Visit and Antidepressant Use at Baseline 
Modified Full Analysis Set 
Table 14.2.2.4.15 
Summary of HAM-D Total Score by Study Visit and Age Group 
Modified Full Analysis Set 
Table 14.2.2.4.16 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Total 
Score by Study Visit and Age Group  
Modified Full Analysis Set 
Table 14.2.2.4.17 
Summary of HAM-D Total Score by Study Visit and Gender 
Modified Full Analysis Set 
Table 14.2.2.4.18 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Total 
Score by Study Visit and Gender 
Modified Full Analysis Set 
Table 14.2.2.4.19 
Summary of HAM-D Total Score by Study Visit and Race Group 
Modified Full Analysis Set 
Table 14.2.2.4.20 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Total 
Score by Study Visit and Race Group 
Modified Full Analysis Set 
Table 14.2.2.4.21 
Summary of HAM-D Total Score by Study Visit and BMI Group 
Modified Full Analysis Set 
Table 14.2.2.4.22 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Total 
Score by Study Visit and BMI Group 
Modified Full Analysis Set 
Table 14.2.2.4.23 
Summary of HAM-D Total Score by Study Visit and Baseline HAM-D Total Score 
Category 
Modified Full Analysis Set 
Table 14.2.2.4.24 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Total 
Score by Study Visit and Baseline HAM-D Total Score Category 
Modified Full Analysis Set 
Table 14.2.2.5.1 
Summary of Clinical Global Impression – Improvement (CGI-I) by Study Visit 
Full Analysis Set 
Table 14.2.2.5.2 
Summary of Clinical Global Impression – Improvement (CGI-I) Response by Study 
Visit 
Full Analysis Set 
Table 14.2.2.5.3 
Model-based Results on Clinical Global Impression – Improvement (CGI-I) 
Response by Study Visit 
Full Analysis Set 
Table 14.2.2.5.4 
Summary of Clinical Global Impression – Severity (CGI-S) by Study Visit 
Full Analysis Set 


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Table Number 
Title 
Analysis Set 
Table 14.2.2.5.5 
Model-based Results on Clinical Global Impression – Severity (CGI-S), Change 
from Baseline by Study Visit 
Full Analysis Set 
Table 14.2.2.5.6 
Summary of Clinical Global Impression – Improvement (CGI-I) by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.5.7 
Summary of Clinical Global Impression – Improvement (CGI-I) Response by Study 
Visit 
Modified Full Analysis Set 
Table 14.2.2.5.8 
Model-based Results on Clinical Global Impression – Improvement (CGI-I) 
Response by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.5.9 
Summary of Clinical Global Impression – Severity (CGI-S) by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.5.10 
Model-based Results on Clinical Global Impression – Severity (CGI-S), Change 
from Baseline by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.6.1 
Summary of Hamilton Rating Scale for Anxiety (HAM-A) Total Score by Visit 
Full Analysis Set 
Table 14.2.2.6.2 
Model-based Results on Hamilton Rating Scale for Depression (HAM-A) Total 
Score, Change from Baseline by Study Visit 
Full Analysis Set 
Table 14.2.2.6.3 
Summary of Hamilton Rating Scale for Anxiety (HAM-A) Individual Item Score by 
Study Visit 
Full Analysis Set 
Table 14.2.2.6.4 
Summary of Hamilton Rating Scale for Anxiety (HAM-A) Total Score by Visit 
Modified Full Analysis Set 
Table 14.2.2.6.5 
Model-based Results on Hamilton Rating Scale for Depression (HAM-A) Total 
Score, Change from Baseline by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.6.6 
Summary of Hamilton Rating Scale for Anxiety (HAM-A) Individual Item Score by 
Study Visit 
Modified Full Analysis Set 
Table 14.2.2.7.1 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Total Score 
by Study Visit 
Full Analysis Set 
Table 14.2.2.7.2 
Model-based Results on Montgomery-Asberg Depression Rating Scale (MADRS) 
Total Score, Change from Baseline by Study Visit 
Full Analysis Set 
Table 14.2.2.7.3 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Individual 
Item Score by Study Visit 
Full Analysis Set 
Table 14.2.2.7.3.1 
Model-based Results on Montgomery-Asberg Depression Rating Scale (MADRS) 
Individual Item Score, Change from Baseline 
Full Analysis Set 
Table 14.2.2.7.4 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Total Score 
by Study Visit 
Per Protocol Set 
Table 14.2.2.7.5.1 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Total Score 
by Study Visit 
Modified Full Analysis Set 


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Table Number 
Title 
Analysis Set 
Table 14.2.2.7.5.2 
Model-based Results on Montgomery-Asberg Depression Rating Scale (MADRS) 
Total Score, Change from Baseline by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.7.5.3 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Individual 
Item Score by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.7.5.4 
Model-based Results on Montgomery-Asberg Depression Rating Scale (MADRS) 
Individual Item Score, Change from Baseline 
Modified Full Analysis Set 
Table 14.2.2.7.6 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Response by 
Study Visit 
Full Analysis Set 
Table 14.2.2.7.7 
Model-based Results on Montgomery-Asberg Depression Rating Scale (MADRS) 
Response by Study Visit 
Full Analysis Set 
Table 14.2.2.7.8 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Remission 
by Study Visit 
Full Analysis Set 
Table 14.2.2.7.9 
Model-based Results on Montgomery-Asberg Depression Rating Scale (MADRS) 
Remission by Study Visit 
Full Analysis Set 
Table 14.2.2.7.10 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Response by 
Study Visit 
Modified Full Analysis Set 
Table 14.2.2.7.11 
Model-based Results on Montgomery-Asberg Depression Rating Scale (MADRS) 
Response by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.7.12 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Remission 
by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.7.13 
Model-based Results on Montgomery-Asberg Depression Rating Scale (MADRS) 
Remission by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.8.1 
Summary of Insomnia Severity Index (ISI) Total Score by Study Visit 
Full Analysis Set 
Table 14.2.2.8.2 
Model-based Results on Insomnia Severity Index (ISI) Total Score, Change from 
Baseline by Study Visit 
Full Analysis Set 
Table 14.2.2.8.3 
Summary of Insomnia Severity Index (ISI) Total Score by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.8.4 
Model-based Results on Insomnia Severity Index (ISI) Total Score, Change from 
Baseline by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.9.1 
Summary of Core Consensus Sleep Diary by Study Visit 
Full Analysis Set 
Table 14.2.2.9.2 
Model-based Results on Subjective Sleep Latency (sSL) , Change from Baseline by 
Study Visit 
Full Analysis Set 
Table 14.2.2.9.3 
Model-based Results on Subjective Wake after Sleep Onset (sWASO) , Change 
from Baseline by Study Visit 
Full Analysis Set 


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Table Number 
Title 
Analysis Set 
Table 14.2.2.9.4 
Model-based Results on Subjective Number of Awakenings (sNAW) , Change from 
Baseline by Study Visit 
Full Analysis Set 
Table 14.2.2.9.5 
Model-based Results on Subjective Total Sleep Time (sTST) , Change from 
Baseline by Study Visit 
Full Analysis Set 
Table 14.2.2.9.6 
Model-based Results on Subjective Sleep Quality (sSQ) Response by Study Visit 
Full Analysis Set 
Table 14.2.2.9.7 
Summary of Core Consensus Sleep Diary by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.9.8 
Model-based Results on Subjective Sleep Latency (sSL) , Change from Baseline by 
Study Visit 
Modified Full Analysis Set 
Table 14.2.2.9.9 
Model-based Results on Subjective Wake after Sleep Onset (sWASO) , Change 
from Baseline by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.9.10 
Model-based Results on Subjective Number of Awakenings (sNAW) , Change from 
Baseline by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.9.11 
Model-based Results on Subjective Total Sleep Time (sTST) , Change from 
Baseline by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.9.12 
Model-based Results on Subjective Sleep Quality (sSQ) Response by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.10.1 
Summary of Short Form-36 Version 2 (SF-36v2) Domain/Component Score by 
Study Visit 
Full Analysis Set 
Table 14.2.2.10.2 
Model-based Results on Short Form-36 Version 2 (SF-36v2) Physical Functioning 
Domain Score, Change from Baseline by Study Visit 
Full Analysis Set 
Table 14.2.2.10.3 
Model-based Results on Short Form-36 Version 2 (SF-36v2) Role-physical Domain 
Score, Change from Baseline by Study Visit 
Full Analysis Set 
Table 14.2.2.10.4 
Model-based Results on Short Form-36 Version 2 (SF-36v2) Bodily Pain Domain 
Score, Change from Baseline by Study Visit 
Full Analysis Set 
Table 14.2.2.10.5 
Model-based Results on Short Form-36 Version 2 (SF-36v2) General Health 
Domain Score, Change from Baseline by Study Visit 
Full Analysis Set 
Table 14.2.2.10.6 
Model-based Results on Short Form-36 Version 2 (SF-36v2) Vitality Domain 
Score, Change from Baseline by Study Visit 
Full Analysis Set 
Table 14.2.2.10.7 
Model-based Results on Short Form-36 Version 2 (SF-36v2) Social Functioning 
Domain Score, Change from Baseline by Study Visit 
Full Analysis Set 
Table 14.2.2.10.8 
Model-based Results on Short Form-36 Version 2 (SF-36v2) Role-emotional 
Domain Score, Change from Baseline by Study Visit 
Full Analysis Set 
Table 14.2.2.10.9 
Model-based Results on Short Form-36 Version 2 (SF-36v2) Mental Health 
Domain Score, Change from Baseline by Study Visit 
Full Analysis Set 


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Table Number 
Title 
Analysis Set 
Table 14.2.2.10.10 
Model-based Results on Short Form-36 Version 2 (SF-36v2) Physical Component 
Summary Score, Change from Baseline by Study Visit 
Full Analysis Set 
Table 14.2.2.10.11 
Model-based Results on Short Form-36 Version 2 (SF-36v2) Mental Component 
Summary Score, Change from Baseline by Study Visit 
Full Analysis Set 
Table 14.2.2.10.12 
Model-based Results on Short Form-36 Version 2 (SF-36v2) Utility Score (Release 
2), Change from Baseline by Study Visit 
Full Analysis Set 
Table 14.2.2.10.13 
Summary of Short Form-36 Version 2 (SF-36v2) Domain/Component Score by 
Study Visit 
Modified Full Analysis Set 
Table 14.2.2.10.14 
Model-based Results on Short Form-36 Version 2 (SF-36v2) Physical Functioning 
Domain Score, Change from Baseline by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.10.15 
Model-based Results on Short Form-36 Version 2 (SF-36v2) Role-physical Domain 
Score, Change from Baseline by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.10.16 
Model-based Results on Short Form-36 Version 2 (SF-36v2) Bodily Pain Domain 
Score, Change from Baseline by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.10.17 
Model-based Results on Short Form-36 Version 2 (SF-36v2) General Health 
Domain Score, Change from Baseline by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.10.18 
Model-based Results on Short Form-36 Version 2 (SF-36v2) Vitality Domain 
Score, Change from Baseline by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.10.19 
Model-based Results on Short Form-36 Version 2 (SF-36v2) Social Functioning 
Domain Score, Change from Baseline by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.10.20 
Model-based Results on Short Form-36 Version 2 (SF-36v2) Role-emotional 
Domain Score, Change from Baseline by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.10.21 
Model-based Results on Short Form-36 Version 2 (SF-36v2) Mental Health 
Domain Score, Change from Baseline by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.10.22 
Model-based Results on Short Form-36 Version 2 (SF-36v2) Physical Component 
Summary Score, Change from Baseline by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.10.23 
Model-based Results on Short Form-36 Version 2 (SF-36v2) Mental Component 
Summary Score, Change from Baseline by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.10.24 
Model-based Results on Short Form-36 Version 2 (SF-36v2) Utility Score (Release 
2), Change from Baseline by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.11.1 
Summary of Patient Health Questionnaire (PHQ-9) Total Score by Study Visit 
Full Analysis Set 
Table 14.2.2.11.2 
Model-based Results on Patient Health Questionnaire (PHQ-9) Total Score, Change 
from Baseline by Study Visit 
Full Analysis Set 


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Table Number 
Title 
Analysis Set 
Table 14.2.2.11.3 
Summary of Patient Health Questionnaire (PHQ-9) Total Score by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.11.4 
Model-based Results on Patient Health Questionnaire (PHQ-9) Total Score, Change 
from Baseline by Study Visit 
Modified Full Analysis Set 
Table 14.3.1.1 
Overview of Treatment-Emergent Adverse Events 
Safety Set 
Table 14.3.1.2 
Summary of Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
Safety Set 
Table 14.3.1.3 
Summary of Double-Blind Period Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.4 
Summary of Treatment Period Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.5 
Summary of Follow-up Period Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.6 
Summary of Extended Follow-up Period Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.7 
Summary of Double-Blind Period Treatment-Emergent Adverse Events by System 
Organ Class, Preferred Term, and Use of Antidepressant at Baseline 
Safety Set 
Table 14.3.1.8 
Summary of Double-Blind Period Treatment-Emergent Adverse Events by System 
Organ Class, Preferred Term, and Age Group 
Safety Set 
Table 14.3.1.9 
Summary of Double-Blind Period Treatment-Emergent Adverse Events by System 
Organ Class, Preferred Term, and Gender 
Safety Set 
Table 14.3.1.10 
Summary of Double-Blind Period Treatment-Emergent Adverse Events by System 
Organ Class, Preferred Term, and Race Group 
Safety Set 
Table 14.3.1.10.1 
Summary of Double-Blind Period Treatment-Emergent Adverse Events by System 
Organ Class, Preferred Term, and BMI Group 
Safety Set 
Table 14.3.1.10.2 
Summary of Double-Blind Period Treatment-Emergent Adverse Events by System 
Organ Class, Preferred Term, and Baseline HAM-D Total Score 
Safety Set 
Table 14.3.1.11 
Summary of Double-Blind Period Treatment-Emergent Adverse Events by System 
Organ Class, Preferred Term, and Maximum Severity 
Safety Set 
Table 14.3.1.12 
Summary of Double-Blind Period Treatment-Emergent Adverse Events by System 
Organ Class, Preferred Term, and Relationship to Study Drug 
Safety Set 
Table 14.3.1.13 
Summary of Treatment Period Treatment-Emergent Adverse Events Leading to 
Discontinuation of Study Drug by System Organ Class and Preferred Term 
Safety Set 


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Table Number 
Title 
Analysis Set 
Table 14.3.1.14 
Summary of Treatment-Emergent Adverse Events Leading to Withdrawal from the 
Study by System Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.15 
Summary of Double-Blind Period Treatment-Emergent Adverse Events Leading to 
Withdrawal from the Study by System Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.16 
Summary of Treatment-Emergent Serious Adverse Events by System Organ Class 
and Preferred Term 
Safety Set 
Table 14.3.1.17 
Summary of Double-Blind Period Treatment-Emergent Serious Adverse Events by 
System Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.18 
Summary of Treatment Period Treatment-Emergent Serious Adverse Events by 
System Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.19 
Summary of Follow-up Period Treatment-Emergent Serious Adverse Events by 
System Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.20 
Summary of Extended Follow-up Period Treatment-Emergent Serious Adverse 
Events by System Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.21 
Summary of Most Common (>5%) Double-Blind Period Treatment-Emergent 
Adverse Events by Preferred Term 
Safety Set 
Table 14.3.4.1.1.1 
Summary of Serum Chemistry Results by Study Visit 
Safety Set 
Table 14.3.4.1.1.2 
Summary of Shift in Serum Chemistry Results during the Study 
Safety Set 
Table 14.3.4.1.1.3 
Summary of Potentially Clinically Significant Liver Function Tests at Any Time 
Post-Baseline 
Safety Set 
Table 14.3.4.1.1.4 
Summary of Potentially Clinically Significant Serum Chemistry (excluding LFT) at 
Any Time Post-Baseline 
Safety Set 
Table 14.3.4.1.2.1 
Summary of Hematology Results by Study Visit 
Safety Set 
Table 14.3.4.1.2.2 
Summary of Shift in Hematology Results during the Study 
Safety Set 
Table 14.3.4.1.2.3 
Summary of Potentially Clinically Significant Hematology Results Any Time Post-
Baseline 
Safety Set 
Table 14.3.4.1.3.1 
Summary of Urinalysis Results by Study Visit – Quantitative Results 
Safety Set 
Table 14.3.4.1.3.2 
Summary of Urinalysis by Study Visit – Qualitative Results 
Safety Set 
Table 14.3.4.1.4.1 
Summary of Coagulation Results by Study Visit  
Safety Set 
Table 14.3.4.2.1 
Summary of Vital Signs by Study Visit 
Safety Set 
Table 14.3.4.2.2 
Summary of Potentially Clinically Significant Vital Signs Any Time Post-Baseline 
Safety Set 
Table 14.3.4.2.3 
Summary of Orthostatic Changes (Supine minus Standing in Vital Signs by Study 
Visit 
Safety Set 


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Table Number 
Title 
Analysis Set 
Table 14.3.4.3.1 
Summary of ECG data by Study Visit 
Safety Set 
Table 14.3.4.3.2 
Summary of Abnormal ECG by Study Visit 
Safety Set 
Table 14.3.4.3.3 
Summary of Potentially Clinically Significant QTcF in ECG Data Any Time Post-
Baseline 
Safety Set 
Table 14.3.4.4.1 
Summary of Columbia Suicide Rating Scale (C-SSRS) Suicidal Ideation and 
Suicidal Behavior by Study Visit and Treatment Group 
Safety Set 
Table 14.3.4.4.2 
Summary of Columbia-Suicide Severity Rating Scale (C-SSRS) on Suicidal 
Ideation and Suicidal Behavior Data 
Safety Set 
Table 14.3.4.4.3.1 
Summary of Shift from Baseline in Columbia-Suicide Severity Rating Scale (C-
SSRS) Suicidal Ideation and Suicidal Behavior by Study Visit 
Safety Set 
Table 14.3.4.4.3.2 
Summary of Shift from Baseline in C0SSRS Maximum Severity Score in Suicidal 
Ideation at Any Time Post-Baseline 
Safety Set 
Table 14.3.4.4.4 
Summary of Physical Withdrawal Checklist (PWC) Total Scores by Study Visit 
Safety Set 
 
Figures 
Figure Number 
Title 
Analysis Set 
Figure 14.2.2.1.2.1 
 Line Plot of  LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score Over Time by Treatment Group 
Full Analysis Set 


Statistical Analysis Plan Methods 12 November 2019 Version 2.0 
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Figure Number 
Title 
Analysis Set 
Figure 14.2.2.1.4.1 
Line Plot of  LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Core Subscale Score Over Time by Treatment Group 
Full Analysis Set 
Figure 14.2.2.1.5.1 
Line Plot of  LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Anxiety Subscale Score Over Time by Treatment Group 
Full Analysis Set 
Figure 14.2.2.1.6.1 
Line Plot of  LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Bech-6 Subscale Score Over Time by Treatment Group 
Full Analysis Set 
Figure 14.2.2.1.7.1 
Line Plot of  LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Maier Subscale Score Over Time by Treatment Group 
Full Analysis Set 
Figure 14.2.2.1.9.1 
Line Plot of  LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score Over Time by Treatment Group 
Per Protocol Set 
Figure 14.2.2.1.9.2 
Line Plot of  LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score Over Time by Treatment Group 
Modified Full Analysis Set 
Figure 14.2.2.1.9.3 
Line Plot of  LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Core Subscale Score Over Time by Treatment Group 
Modified Full Analysis Set 
Figure 14.2.2.1.9.4 
Line Plot of  LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Anxiety Subscale Score Over Time by Treatment Group 
Modified Full Analysis Set 
Figure 14.2.2.1.9.5 
Line Plot of  LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Bech-6 Subscale Score Over Time by Treatment Group 
Modified Full Analysis Set 
Figure 14.2.2.1.9.6 
Line Plot of  LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Maier Subscale Score Over Time by Treatment Group 
Modified Full Analysis Set 
Figure 14.2.2.1.9.7 
Line Plot of  LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score Over Time by Treatment Group and 
Antidepressant Use at Baseline 
Modified Full Analysis Set 
Figure 14.2.2.1.9.8 
Line Plot of  LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score Over Time by Treatment Group and Age Group 
Modified Full Analysis Set 
Figure 14.2.2.1.9.9 
Line Plot of  LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score Over Time by Treatment Group and Sex 
Modified Full Analysis Set 
Figure 14.2.2.1.9.10 
Line Plot of  LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score Over Time by Treatment Group and Race Group 
Modified Full Analysis Set 
Figure 14.2.2.1.9.11 
Line Plot of  LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score Over Time by Treatment Group and BMI Group 
Modified Full Analysis Set 


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Figure Number 
Title 
Analysis Set 
Figure 14.2.2.1.9.12 
Line Plot of  LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score Over Time by Treatment Group and Baseline 
HAM-D Total Score 
Modified Full Analysis Set 
Figure 14.2.2.1.10.1 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Total Score, 
Response over Time  
Full Analysis Set 
Figure 14.2.2.1.10.2 
Histogram of Hamilton Rating Scale for Depression (HAM-D) Percentage 
Improvement over Time 
Full Analysis Set 
Figure 14.2.2.1.10.3 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Total Score, 
Remission over Time by Treatment Group 
Full Analysis Set 
Figure 14.2.2.1.10.3.1 
Histogram of Hamilton Rating Scale for Depression (HAM-D) Total Score over 
Time 
Full Analysis Set 
Figure 14.2.2.1.10.4 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Total Score, 
Response over Time  
Modified Full Analysis Set 
Figure 14.2.2.1.10.5 
Histogram of Hamilton Rating Scale for Depression (HAM-D) Percentage 
Improvement over Time 
Modified Full Analysis Set 
Figure 14.2.2.1.10.6 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Total Score, 
Remission over Time by Treatment Group 
Modified Full Analysis Set 
Figure 14.2.2.1.10.6.1 
Histogram of Hamilton Rating Scale for Depression (HAM-D) Total Score over 
Time 
Modified Full Analysis Set 
Figure 14.2.2.1.11.1 
Forest Plot of Change from Baseline at Day 15 in Hamilton Rating Scale for 
Depression (HAM-D) Total Score for Subgroups 
Full Analysis Set 
Figure 14.2.2.1.11.2 
Forest Plot of Change from Baseline at Day 15 in Hamilton Rating Scale for 
Depression (HAM-D) Total Score for Subscales of HAM-D 
Full Analysis Set 
Figure 14.2.2.1.11.3 
Forest Plot of Change from Baseline at Day 15 in Hamilton Rating Scale for 
Depression (HAM-D) Total Score for Individual Items of HAM-D Scale 
Full Analysis Set 
Figure 14.2.2.1.11.4 
Forest Plot of Change from Baseline at Day 15 in Hamilton Rating Scale for 
Depression (HAM-D) Total Score for Subgroups 
Modified Full Analysis Set 
Figure 14.2.2.1.11.5 
Forest Plot of Change from Baseline at Day 15 in Hamilton Rating Scale for 
Depression (HAM-D) Total Score for Subscales of HAM-D 
Modified Full Analysis Set 
Figure 14.2.2.1.11.6 
Forest Plot of Change from Baseline at Day 15 in Hamilton Rating Scale for 
Depression (HAM-D) Total Score for Individual Items of HAM-D Scale 
Modified Full Analysis Set 
Figure 14.2.2.5.2.1 
Bar Chart of CGI-I Response over Time by Treatment Group 
Full Analysis Set 


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Figure Number 
Title 
Analysis Set 
Figure 14.2.2.5.5.1 
Line Plot of LS Mean (±SE) Change from Baseline in CGI-S over Time by 
Treatment Group 
Full Analysis Set 
Figure 14.2.2.5.7.1 
Bar Chart of CGI-I Response over Time by Treatment Group 
Modified Full Analysis Set 
Figure 14.2.2.5.10.1 
Line Plot of LS Mean (±SE) Change from Baseline in CGI-S over Time by 
Treatment Group 
Modified Full Analysis Set 
Figure 14.2.2.6.2.1 
Line Plot of  LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Anxiety (HAM-A) Total Score Over Time by Treatment Group 
Full Analysis Set 
Figure 14.2.2.6.2.2 
Line Plot of  LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Anxiety (HAM-A) Total Score Over Time by Treatment Group 
Modified Full Analysis Set 
Figure 14.2.2.7.2.1 
Line Plot of  LS Mean (±SE) Change from Baseline in Montgomery-Asberg 
Depression Rating Scale (MADRS) Total Score Over Time by Treatment Group 
Full Analysis Set 
Figure 14.2.2.7.2.2 
Line Plot of  LS Mean (±SE) Change from Baseline in Montgomery-Asberg 
Depression Rating Scale (MADRS) Total Score Over Time by Treatment Group 
Modified Full Analysis Set 
Figure 14.2.2.8.2.1 
Line Plot of  LS Mean (±SE) Change from Baseline in Insomnia Severity Index 
(ISI) Total Score Over Time by Treatment Group 
Full Analysis Set 
Figure 14.2.2.8.2.2 
Line Plot of  LS Mean (±SE) Change from Baseline in Insomnia Severity Index 
(ISI) Total Score Over Time by Treatment Group 
Modified Full Analysis Set 
Figure 14.2.2.9.2.1 
Line Plot of  LS Mean (±SE) Change from Baseline in Subjective Sleep Latency 
(sSL) Total Score Over Time by Treatment Group 
Full Analysis Set 
Figure 14.2.2.9.3.1 
Line Plot of  LS Mean (±SE) Change from Baseline in Subjective Total Sleep Time 
(sTST) Total Score Over Time by Treatment Group 
Full Analysis Set 
Figure 14.2.2.9.4.1 
Line Plot of  LS Mean (±SE) Change from Baseline in Subjective Wake after Sleep 
Onset (sWASO) Total Score Over Time by Treatment Group 
Full Analysis Set 
Figure 14.2.2.9.5.1 
Line Plot of  LS Mean (±SE) Change from Baseline in Subjective Number of 
Awakenings (sNAW) Total Score Over Time by Treatment Group 
Full Analysis Set 
Figure 14.2.2.9.6.1 
Line Plot of  LS Mean (±SE) Change from Baseline in Subjective Sleep Latency 
(sSL) Total Score Over Time by Treatment Group 
Modified Full Analysis Set 
Figure 14.2.2.9.7.1 
Line Plot of  LS Mean (±SE) Change from Baseline in Subjective Total Sleep Time 
(sTST) Total Score Over Time by Treatment Group 
Modified Full Analysis Set 
Figure 14.2.2.9.8.1 
Line Plot of  LS Mean (±SE) Change from Baseline in Subjective Wake after Sleep 
Onset (sWASO) Total Score Over Time by Treatment Group 
Modified Full Analysis Set 
Figure 14.2.2.9.9.1 
Line Plot of  LS Mean (±SE) Change from Baseline in Subjective Number of 
Awakenings (sNAW) Over Time by Treatment Group 
Modified Full Analysis Set 


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Figure Number 
Title 
Analysis Set 
Figure 14.2.2.10.2.1 
Bar Chart of LS Mean (±SE) Change from Baseline in Short Form-36 Version 2 
(SF-36v2) at Day 15 by Domain/Component and Treatment Group 
Full Analysis Set 
Figure 14.2.2.10.2.2 
Bar Chart of LS Mean (±SE) Change from Baseline in Short Form-36 Version 2 
(SF-36v2) at Day 15 by Domain/Component and Treatment Group 
Modified Full Analysis Set 
Figure 14.2.2.11.2 
Model-based LS Mean (±SE) Change from Baseline in Patient Health 
Questionnaire (PHQ-9) Total Score Over Time by Treatment Group 
Full Analysis Set 
Figure 14.2.2.11.3 
Model-based LS Mean (±SE) Change from Baseline in Patient Health 
Questionnaire (PHQ-9) Total Score Over Time by Treatment Group 
Modified Full Analysis Set 
 
Listings 
Listing Number 
Title 
Analysis Set 
Listing 16.2.1.1 
Subject Disposition 
All Subjects 
Listing 16.2.1.2 
Premature Discontinuation from Study Drug and/or Withdrawal from the Study 
Safety Set 
Listing 16.2.2.1 
Protocol Deviations 
Safety Set 
Listing 16.2.2.2 
Inappropriate Study Drug Consumption 
Safety Set 
Listing 16.2.3.1 
Inclusion/Exclusion Criteria Violations 
Randomized Set 
Listing 16.2.4.1 
Demographics 
Safety Set 
Listing 16.2.4.2 
Baseline Characteristics 
Safety Set 
Listing 16.2.4.2.1 
Incorrect Stratification related to Antidepressant Use at Baseline 
Safety Set 
Listing 16.2.4.2.2 
Diagnostic Laboratory Results 
Safety Set 
Listing 16.2.4.3.1 
Medical and Surgical History 
Safety Set 
Listing 16.2.4.3.2 
Disease History 
Safety Set 
Listing 16.2.4.3.3 
Subject History of Psychiatric Disorder 
Safety Set 
Listing 16.2.4.3.4 
Family History of Psychiatric Disorder 
Safety Set 
Listing 16.2.4.4.1 
Prior and Concomitant Psychotropic Medications 
Safety Set 
Listing 16.2.4.4.2 
Prior and Concomitant Non-Psychotropic Medications 
Safety Set 
Listing 16.2.4.4.3 
Listing of Use of Antidepressant during the Study 
Safety Set 
Listing 16.2.4.4.4 
Listing of Use of Atypical Antipsychotics during the Study 
Safety Set 
Listing 16.2.4.4.5 
Concomitant Procedures 
Safety Set 
Listing 16.2.5.1 
Study Drug Administration 
Safety Set 
Listing 16.2.5.2 
Study Drug Exposure 
Safety Set 


Statistical Analysis Plan Methods 12 November 2019 Version 2.0 
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Listing Number 
Title 
Analysis Set 
Listing 16.2.5.3 
Study Drug Adherence 
Safety Set 
Listing 16.2.6.1 
Hamilton Rating Scale for Depression (HAM-D) 
Full Analysis Set 
Listing 16.2.6.2.1 
Clinical Global Impression (CGI) – Improvement 
Full Analysis Set 
Listing 16.2.6.2.2 
Clinical Global Impression (CGI) – Severity 
Full Analysis Set 
Listing 16.2.6.2.3 
Hamilton Anxiety Rating Scale (HAM-A) 
Full Analysis Set 
Listing 16.2.6.2.4 
Montgomery-Asberg Depression Rating Scale (MADRS) 
Full Analysis Set 
Listing 16.2.6.2.5 
Insomnia Severity Index (ISI) 
Full Analysis Set 
Listing 16.2.6.2.6 
Core Consensus Sleep Diary 
Full Analysis Set 
Listing 16.2.6.2.7.1 
Short-Form 36 (SF-36) Individual Item Scores 
Full Analysis Set 
Listing 16.2.6.2.7.2 
Short-Form 36 (SF-36) Domain/Component Scores 
Full Analysis Set 
Listing 16.2.6.2.8 
Patient Health Questionnaire (PHQ-9) 
Full Analysis Set 
Listing 16.2.7.1 
Treatment-Emergent Adverse Events 
Safety Set 
Listing 16.2.7.2 
Non-fatal Serious Adverse Events 
Safety Set 
Listing 16.2.7.3 
Adverse Events Leading to Death 
Safety Set 
Listing 16.2.7.4 
Adverse Events with Onset Prior to First Dose of Study Drug 
Safety Set 
Listing 16.2.7.5 
Adverse Events leading to Premature Discontinuation of Study Drug 
Safety Set 
Listing 16.2.7.6 
Adverse Events leading to Premature Withdrawal from the Study 
Safety Set 
Listing 16.2.8.1.1 
Serum Chemistry Data (excluding Liver Function Tests) 
Safety Set 
Listing 16.2.8.1.1.1 
Potentially Clinically Significant Serum Chemistry Values (excluding Liver Function 
Tests) 
Safety Set 
Listing 16.2.8.1.2 
Serum Chemistry Data, Liver Function Tests  
Safety Set 
Listing 16.2.8.1.3 
Hematology Data 
Safety Set 
Listing 16.2.8.1.4 
Urinalysis Data 
Safety Set 
Listing 16.2.8.1.5 
Coagulation Data 
Safety Set 
Listing 16.2.8.1.6 
Pregnancy Test 
Safety Set 
Listing 16.2.8.2 
Vital Signs 
Safety Set 
Listing 16.2.8.3 
Electrocardiogram (ECG) Data 
Safety Set 
Listing 16.2.8.4 
Physical Examination 
Safety Set 
Listing 16.2.8.5.4.1 
Columbia-Suicide Severity Rating Scale (C-SSRS) – Suicidal Ideation 
Safety Set 
Listing 16.2.8.5.4.2 
Columbia-Suicide Severity Rating Scale (C-SSRS) – Suicidal Behavior 
Safety Set 
Listing 16.2.8.6 
Physician Withdrawal Checklist (PWC) 
Safety Set 


Statistical Analysis Plan Methods 12 November 2019 Version 2.0 
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Listing Number 
Title 
Analysis Set