Conditions: Depressive Disorder, Major
Keywords: Depression Depressive disorder SAGE-217
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 543
Healthy volunteers: no

Brief summary:
The purpose of this study to evaluate the efficacy of SAGE-217 in the treatment of participants with 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, once daily at approximately 8 PM with fat-containing food for 14 days. arm 2: Participants self-administered SAGE-217 50 mg capsules, once daily at approximately 8 PM with fat-containing food for 14 days. Participants who could not tolerate 50 mg received 40 mg for the remainder of the treatment period as per discretion of investigator.

Interventions: intervention 1: SAGE-217 intervention 2: Placebo
Intervention descriptions: intervention 1: SAGE-217 oral capsules. intervention 2: SAGE-217 matched-placebo oral 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
Major Depressive Disorder
NCT Number: 
NCT04442490
Document Dates:
Protocol Version 6.0: 02 March 2020
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 B
16.1 Study Information 
1 
1.
PROTOCOL AND PROTOCOL AMENDMENTS
The original protocol (Version 6) was amended 2 times.  Links to each version of the protocol 
are provided below. 
Protocol Versions 
Amendment 5, Version 6, 02 March 2020  
Summary of Changes from Amendment 5, 02 March 2020 
Amendment 6, Version 7, 14 September 2020 
Summary of Changes from Amendment 6, 14 September 2020 
Amendment 7, Version 8, 14 December 2020 
Summary of Changes from Amendment 7, 14 December 2020 
Administrative Letters 
Administrative Letter #4, 14 October 2020 


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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 
Date of Amendment 5 
Version 5.0, 25 March 2019 
Version 6.0, 02 March 2020 
 
Confidentiality Statement 
The confidential information in this document is provided to you as an Investigator or consultant for review by you, 
your staff, and the applicable Institutional Review Board/Independent Ethics Committee. Your acceptance of this 
document constitutes agreement that you will not disclose the information contained herein to others without written 
authorization from Sage Therapeutics, Inc. 


02 MAR 2020




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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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PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Syneos Health Medical 
Monitor  
, MD   
   
Email: 
 
Office: 
 
Cell:  
 
Sage Study Physician 
, MD, MBA 
  
Email: 
 
Tel: 
 
24-Hour Serious 
Adverse Event 
Reporting 
IQVIA Lifecycle Safety 
Email: Sage.Safety@iqvia.com  
Telephone 
Fax 
 
 
+1 855-564-2229 
+1 855-638-1674 
Product Complaint 
Reporting 
Sage Therapeutics, Inc. 
Email: productcomplaints@sagerx.com  
Tel: +1 833-554-7243 
 


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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: Part A: Approximately 55 sites in the United States 
Part B: Approximately 40 sites in the United States 
Phase of development: 3 
Planned Duration of Subject Participation: 
Part A: 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) 
Part B: up to 70 days (up to 28-day Screening Period, 14-day Double-blind Treatment Period, and 
a 28-day double-blind Follow-up Period) 
Objectives: 
Primary:  
• 
To evaluate the efficacy of SAGE-217 in the treatment of major depressive disorder 
(MDD) compared to placebo. 
Secondary: 
• 
Part A only: 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. 
Part A - 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  


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• 
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”  
• 
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) 
Part B - Key Secondary: 
• 
CGI-S at Day 15 
• 
HAM-D total score at Day 3, Day 28, and Day 42 
Part B – Other Secondary: 
• 
HAM-D response at Day 15 and Day 42 
• 
HAM-D remission at Day 15 and Day 42 
• 
CGI-I response, defined as “much improved” or “very much improved”, at Day 15 
• 
MADRS total score at Day 15 
• 
HAM-A total score at Day 15 
• 
Time to first HAM-D response 
• 
Change from baseline in PRO measures of health-related quality of life, as assessed by 
responses to SF-36v2, and of depressive symptoms, as assessed by the 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) 
 
 
  
 
  
 
 


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Study Description:  
This is a randomized, double-blind, parallel-group, placebo-controlled study in subjects with 
MDD. This study will be conducted in 2 parts – Part A and Part B. Part B will commence after 
all subjects in Part A have completed the Day 42 visit. Parts A and B will enroll unique subjects. 
For both study parts, 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. Each 
study part is described below. 
Part A 
Part A 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. 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. 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 2. 
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. 
Part B 
Part B will consist of a Screening Period of up to 28 days, a 14-day double-blind Treatment 
Period, and a 28-day follow-up period. Part B of the study may run concurrently with the 
extended follow-up period in Part A. 
The Screening Period begins with the signing of the ICF at the Screening Visit; the ICF must be 
signed prior to beginning any screening activities. Subjects will undergo preliminary screening 


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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 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 2 treatment groups 
(SAGE-217 50 mg or matching placebo) in a 1:1 ratio. Subjects will self-administer study drug 
once daily at approximately 8 PM with fat-containing food (eg, within 1 hour of an evening 
meal which contains fat, or with a fat-containing snack), on an outpatient basis, for 14 days. 
Subjects will return to the study center during the treatment and follow-up periods as outlined in 
Table 3.  
During the treatment period, subjects will be able to receive study drug as long as there are no 
dose limiting safety/tolerability concerns. Subjects who cannot tolerate 50 mg will receive 
40 mg for the remainder of the treatment period. At the discretion of the Investigator, subjects 
who cannot tolerate the 40-mg dose may be discontinued from study drug.  
Subjects who discontinue treatment early should return to the site for an 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 ET visit. If necessary, 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 EOT visit assessments should be 
conducted in addition to an abbreviated physical exam. 
Number of Subjects (planned):  
Part A: approximately 450 subjects will be randomized and dosed to obtain 399 evaluable 
subjects. 
Part B: approximately 240 subjects will be randomized and dosed to obtain 216 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 64 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.  


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6. For Part A, subject has a MADRS total score of ≥32 and a HAM-D total score ≥22 at 
screening and Day 1 (prior to dosing). For Part B, subject has a HAM-D total score 
≥24 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 who have stopped taking 
antidepressants within 60 days must have stopped for longer than 5 half-lives of the 
antidepressant 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 or 
without 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 is currently at significant risk of suicide, as judged by the Investigator, or 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. 


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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. For 
Part A, 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. For Part B, a BMI 
≤18 or ≥45 kg/m2 is exclusionary; a BMI of 40 to 44.9 kg/m2, inclusive, at Screening is 
subject to a broader evaluation of medical comorbidities as described above.  
4. 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.  
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.  


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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. 
SAGE-217 Dosage and Mode of Administration:  
SAGE-217 is available as hard gelatin capsules for oral administration. Available dose strengths 
are: 
• 
Part A: a 30-mg or 20-mg dose 
• 
Part B: a 50-mg dose, with the option to reduce to 40 mg for intolerable AEs  
Reference Therapy, Dosage, and Mode of Administration: 
Placebo will be provided as hard gelatin capsules for oral administration.  
Duration of Treatment: 14 days 


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Statistical methods: 
A detailed description of the statistical analyses to be performed in the study will be provided in 
the Statistical Analysis Plan (SAP). Separate SAPs will be generated for each part of the study. 
The SAP for each study part will be finalized and approved prior to treatment unblinding of each 
respective part.  
For Part A, 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. 
Part B will not include an extended follow-up period, and the database lock will occur at the end 
of the study after all subjects have completed the Day 42 visit. 
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.  
 
Determination of Sample Size 
For Part A, 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%. 
For Part B, assuming a two-sided alpha level of 0.05, a sample size of 216 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 a standard deviation (SD) of 9 points. Assuming a 10% dropout rate and a 1:1 
randomization ratio within each stratum (antidepressant use at baseline, yes or no), 
approximately 240 total randomized subjects will be required to obtain 216 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.  
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, 


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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 in Part A 
only (eg, sleep latency (SL), total sleep time (TST), wake after sleep onset (WASO)), ISI score 
in Part A only, 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 
will be assessed using the PWC-20. 
 
 
 
 
 


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Table 2: 
Schedule of Events (Part A) 
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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217-MDD-301 v6.0 
 
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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) 
 
 
 
 
 
 


Clinical Protocol 
 
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217-MDD-301 v6.0 
 
CONFIDENTIAL 
 
 
16 
 
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. When ECGs and 
 collection occur on the same day, the 12-lead ECGs will be performed 
 sample collection. 
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 during the extended follow-up period 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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Table 3: 
Schedule of Events (Part B) 
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 
EOT a 
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 Participant Check b 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
 
 
Serum FSH test c 
X 
 
 
 
 
 
 
 
 
 
 
SCID-5-CT 
X 
 
 
 
 
 
 
 
 
 
 
MGH ATRQ 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Family History 
X 
 
 
 
 
 
 
 
 
 
 
Subject training d 
X 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Physical Examination e 
X 
X 
 
 
 
 
 
 
 
 
X 
Body Weight/Height 
X 
 
 
 
 
X 
(weight 
only) 
 
 
 
 
X 
(weight 
only) 
Clinical Laboratory 
Assessments f 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
Drug & Alcohol Screen g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test h 
X 
X 
 
 
 
X 
 
 
X 
 
X 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-MDD-301 v6.0 
 
CONFIDENTIAL 
 
 
19 
 
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 
EOT a 
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 
 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs k 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
12-Lead ECG l 
X 
X 
 
 
 
X 
 
 
 
 
X 
C-SSRS m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAM-D n, o 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
MADRS 
 
X 
 
X 
 
X 
 
 
X 
 
X 
HAM-A o 
 
X 
 
X 
 
X 
 
 
X 
 
X 
CGI-S 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
SF-36v2 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
PHQ-9 
 
X 
 
X 
 
X 
 
 
X 
 
X 
PWC-20 
 
X 
 
 
 
X 
X 
X 
 
 
 
Study Drug Dispensation 
 
X 
 
X 
 
 
 
 
 
 
 
Study Drug Administration 
 
X (Day 1 through Day 14) 
 
 
 
 
 
Study Drug 
Accountability/Return 
 
 
 
X 
 
X 
 
 
 
 
X q 


Clinical Protocol 
 
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217-MDD-301 v6.0 
 
CONFIDENTIAL 
 
 
20 
 
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 
EOT a 
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 
 
Adverse Events/SAEs r 
X 
Prior/Concomitant 
Medications/Procedures s 
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; 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. 
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. If 
necessary, 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 EOT 
visit assessments should be conducted in addition to an abbreviated physical exam.  
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 participants 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). An abbreviated physical exam includes a brief medical history followed by 
targeted physical exam. 
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 who 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 participant has been resting for 5 minutes and then after approximately 3 minutes in the standing position. Vital signs may be repeated at the 
discretion of the Investigator as clinically indicated. 
l Triplicate ECGs will be collected. When ECGs 
 collection occur on the same day, the 12-lead ECGs will be performed 
 sample collection. 


Clinical Protocol 
 
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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 
scales will refer to the past 7 days (1 week) at all visits. 
q To be performed at the ET visit only. 
r Adverse events will be collected starting at the time of informed consent and throughout the duration of the subject’s participation in the study. 
s Prior medications will be collected at Screening and concomitant medications and/or procedures will be collected at each subsequent visit. 


Clinical Protocol 
 
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217-MDD-301 v6.0 
 
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22 
 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
1. 
TITLE PAGE ................................................................................................................1 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................4 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............22 
LIST OF TABLES .........................................................................................................................26 
LIST OF FIGURES .......................................................................................................................26 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................27 
5. 
INTRODUCTION ......................................................................................................29 
5.1. 
Background of Major Depressive Disorder and Unmet Medical Need ......................29 
5.2. 
SAGE-217 ...................................................................................................................29 
5.3. 
Potential Risks and Benefits .......................................................................................30 
5.4. 
Dose Justification ........................................................................................................30 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................36 
6.1. 
Study Objective ..........................................................................................................36 
6.1.1. 
Primary Objective .......................................................................................................36 
6.1.2. 
Secondary Objective(s) ...............................................................................................36 
6.1.3. 
Safety Objective ..........................................................................................................36 
 
36 
6.2. 
Endpoints ....................................................................................................................36 
6.2.1. 
Primary Endpoint ........................................................................................................36 
6.2.2. 
Part A - Secondary Endpoints .....................................................................................36 
6.2.3. 
Part B – Key Secondary Endpoints ............................................................................37 
6.2.4. 
Part B – Other Secondary Endpoints ..........................................................................37 
6.2.5. 
Safety Endpoints .........................................................................................................37 
 
37 
7. 
INVESTIGATIONAL PLAN .....................................................................................39 
7.1. 
Overall Study Design ..................................................................................................39 
7.2. 
Number of Subjects ....................................................................................................40 


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7.3. 
Treatment Assignment ................................................................................................40 
7.4. 
Dose Adjustment Criteria ...........................................................................................41 
7.5. 
Criteria for Study Termination ...................................................................................41 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................42 
8.1. 
Subject Inclusion Criteria ...........................................................................................42 
8.2. 
Subject Exclusion Criteria ..........................................................................................43 
8.3. 
Subject Withdrawal Criteria .......................................................................................45 
8.3.1. 
Replacement of Subjects .............................................................................................46 
9. 
TREATMENT OF SUBJECTS ..................................................................................47 
9.1. 
Study Drug ..................................................................................................................47 
9.2. 
Prior Medications, Concomitant Medications, and Restrictions ................................47 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................47 
9.2.2. 
Prohibited Medications ...............................................................................................47 
9.2.3. 
Other Restrictions .......................................................................................................48 
9.3. 
Treatment Adherence ..................................................................................................48 
9.4. 
Randomization and Blinding ......................................................................................49 
9.4.1. 
Emergency Identification of Study Drug ....................................................................49 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................51 
10.1. 
Description of Study Drug ..........................................................................................51 
10.2. 
Study Drug Packaging and Labeling ..........................................................................51 
10.3. 
Study Drug Storage .....................................................................................................51 
10.4. 
Study Drug Preparation ..............................................................................................51 
10.5. 
Study Drug Administration .........................................................................................51 
10.6. 
Study Drug Accountability .........................................................................................52 
10.7. 
Study Drug Handling and Disposal ............................................................................52 
10.8. 
Product Complaints ....................................................................................................53 
11. 
ASSESSMENT OF EFFICACY 
 .............................54 
11.1. 
Efficacy Assessments .................................................................................................54 
11.1.1. 
Hamilton Rating Scale for Depression (HAM-D) ......................................................54 
11.1.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) ........................................54 
11.1.3. 
Hamilton Anxiety Rating Scale (HAM-A) .................................................................54 
11.1.4. 
Clinical Global Impression (CGI) ..............................................................................55 


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11.1.5. 
Short Form-36 Version 2 (SF-36v2) ...........................................................................55 
11.1.6. 
Patient Health Questionnaire (PHQ-9) .......................................................................55 
11.1.7. 
Insomnia Severity Index (ISI; Part A Only) ...............................................................56 
11.1.8. 
Core Consensus Sleep Diary (Part A Only) ...............................................................56 
 
56 
 
 
57 
 
57 
 
57 
 
57 
12. 
ASSESSMENT OF SAFETY .....................................................................................58 
12.1. 
Safety Parameters .......................................................................................................58 
12.1.1. 
Demographic/Medical History ...................................................................................58 
12.1.2. 
Weight and Height ......................................................................................................58 
12.1.3. 
Physical Examination .................................................................................................58 
12.1.4. 
Vital Signs ..................................................................................................................58 
12.1.5. 
Electrocardiogram (ECG) ...........................................................................................59 
12.1.6. 
Laboratory Assessments .............................................................................................59 
12.1.6.1. 
Drugs of Abuse and Alcohol ......................................................................................61 
12.1.6.2. 
Pregnancy Screen ........................................................................................................61 
12.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................61 
12.1.8. 
Physician Withdrawal Checklist .................................................................................61 
12.2. 
Adverse and Serious Adverse Events .........................................................................62 
12.2.1. 
Definition of Adverse Events .....................................................................................62 
12.2.1.1. 
Adverse Event (AE) ....................................................................................................62 
12.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................62 
12.3. 
Relationship to Study Drug ........................................................................................63 
12.4. 
Recording Adverse Events .........................................................................................64 
12.5. 
Reporting Serious Adverse Events .............................................................................64 
12.6. 
Overdose .....................................................................................................................65 
13. 
STATISTICS ..............................................................................................................66 
13.1. 
Data Analysis Sets ......................................................................................................66 
13.2. 
Handling of Missing Data ...........................................................................................66 


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13.3. 
General Considerations ...............................................................................................66 
13.4. 
Demographics and Baseline Characteristics ...............................................................66 
13.5. 
Efficacy Analyses .......................................................................................................67 
13.6. 
Safety Analyses ..........................................................................................................67 
13.6.1. 
Adverse Events ...........................................................................................................68 
13.6.2. 
Clinical Laboratory Evaluations .................................................................................68 
13.6.3. 
Physical Examinations ................................................................................................68 
13.6.4. 
Vital Signs ..................................................................................................................68 
13.6.5. 
12-Lead Electrocardiogram ........................................................................................68 
13.6.6. 
Prior and Concomitant Medications ...........................................................................69 
13.6.7. 
Columbia Suicide Severity Rating Scale ....................................................................69 
13.6.8. 
Physician Withdrawal Checklist .................................................................................69 
 
69 
13.8. 
Determination of Sample Size ....................................................................................69 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................71 
14.1. 
Study Monitoring ........................................................................................................71 
14.2. 
Audits and Inspections ................................................................................................71 
14.3. 
Institutional Review Board (IRB) or Ethics Committee (EC) ....................................72 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................73 
16. 
ETHICS ......................................................................................................................74 
16.1. 
Ethics Review .............................................................................................................74 
16.2. 
Ethical Conduct of the Study ......................................................................................74 
16.3. 
Written Informed Consent ..........................................................................................74 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................75 
17.1. 
Inspection of Records .................................................................................................75 
17.2. 
Retention of Records ..................................................................................................75 
18. 
PUBLICATION POLICY ..........................................................................................76 
19. 
LIST OF REFERENCES ............................................................................................77 
 


Clinical Protocol 
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26 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Schedule of Events (Part A) .......................................................................................14 
Table 3: 
Schedule of Events (Part B) ........................................................................................18 
Table 4: 
Abbreviations and specialist terms .............................................................................27 
Table 5: 
Clinical Laboratory Tests ...........................................................................................59 
Table 6: 
Relationship to Study Drug ........................................................................................63 
LIST OF FIGURES 
Figure 1: 
Predicted SAGE-217 concentrations (Cavg and Cmax) following dosing of 30 
to 50 mg daily .............................................................................................................32 
Figure 2: 
Total score change on Day 15 (Studies 217-MDD-201B, 217-PPD-201, 
Part A of the current study) ........................................................................................33 
Figure 3: 
Predicted incidence of sedation or somnolence by dose ............................................34 


Clinical Protocol 
 
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27 
 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 4: 
Abbreviations and specialist terms 
Abbreviation or specialist term 
Explanation 
ADR 
adverse drug reaction 
AE 
adverse event 
AUC 
area under the curve 
Cavg 
average plasma concentration 
CGI-I 
Clinical Global Impression – Improvement 
CGI-S 
Clinical Global Impression – Severity 
Cmax  
maximum plasma concentration 
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  


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Abbreviation or specialist term 
Explanation 
IRB 
institutional review board 
IRT 
interactive response technology 
ISI 
Insomnia Severity Index 
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 
MTD 
maximum tolerated dose 
NCS 
not clinically significant 
NOAEL 
no-observed-adverse-effect-level 
OS 
oral solution 
PCS 
Potentially clinically significant 
PHQ-9 
9-item Patient Health Questionnaire 
 
 
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 
This study is being conducted in 2 parts – Part A and Part B. Unless otherwise specified, text in 
the following sections applies to both study parts.  
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 suicide attempts in adults 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 mirtazapine 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). 
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 
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. 
Unlike other neurotropic medications that target GABAA receptors, SAGE-217 is an allosteric 
modulator of both synaptic as well as extrasynaptic GABAA receptors (Martinez Botella 2017). 


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As such, SAGE-217 may represent a therapeutic advantage in the treatment of depressive 
disorders by resetting the GABAergic imbalance in depression by affecting both phasic and tonic 
inhibition. 
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 (Gunduz-Bruce 2019). 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. The most common adverse 
events (AEs) associated with SAGE-217 are somnolence, dizziness, and sedation; most AEs 
were reported as mild or moderate in intensity. Refer to the Investigator’s Brochure for a detailed 
description of the chemistry, pharmacology, efficacy, and safety of SAGE-217.  
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 
Part A 
There will be 2 dose levels of SAGE-217 in Part A 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 
(MTD) for the oral solution formulation 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 
Part A. 
Part B 
To date, the current capsule utilized in clinical studies is not associated with an MTD. Initial 
MTD assessments were performed using SAGE-217 in an oral solution (OS) at steady-state in 
healthy subjects, which provided an MTD with a Cmax of 125 ng/mL at 30 mg OS. While re-
identification of the MTD using the capsule formulations was not conducted, steady-state 30 mg 


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capsules provide a model-derived Cmax approximately 50% lower (64 ng/mL) than the 
concentration associated with the MTD of 30 mg OS (125 ng/mL).  
Studies 217-MDD-201 and 217-PPD-201, employing 30 mg capsules administered each evening 
for 14 days, demonstrated significant reduction in symptoms of depression, anxiety and 
insomnia. The safety profile in these studies is consistent with the GABAA neurosteroid 
mechanism, including adverse drug reactions (ADRs) of somnolence, sedation, and dizziness at 
rates of 4 to 15%; the majority with mild intensity. Phase 3 studies in a broader patient 
population demonstrate activity of SAGE-217 associated with improvement in depressive 
symptoms, however, both the efficacy and safety findings support investigation of a higher dose, 
with predictable ADRs expected to be within an acceptable range. 
Preliminary data through Day 42 of the double-blind period in Part A of this study demonstrated 
significant anti-depressant effects compared to placebo at Day 3, 8, and 12 but not Day 15 
(primary endpoint) for the 30 mg dose. The 20 mg dose did not separate from placebo at any 
timepoint. The rates of expected ADRs of somnolence, sedation and dizziness in the 30 mg arm 
were each less than 10%; rates of discontinuation for AEs were lower with SAGE-217 30 mg 
(2.1%) than with placebo (3.2%). No clinically relevant changes in vital signs, laboratories, 
electrocardiogram measures, or suicidal thinking were observed in either Part A of the current 
study or across the full SAGE-217 program, now with over 2000 subjects exposed to treatment. 
In addition, approximately 112 additional subjects have received blinded study drug (SAGE-217 
or placebo) in ongoing blinded clinical studies. Relevant results from Part A of this study are 
available in the SAGE-217 Investigator’s Brochure.  
Direct and modeled data from completed studies to date (including efficacy studies 
217-MDD-201 and 217-PPD-201) in addition to Part A (through Day 42 of the double-blind 
period) of the current study, have been used to assess and predict the efficacy and safety 
outcomes at SAGE-217 concentrations expected with higher doses of SAGE-217 capsules (eg, 
40 and 50 mg).  
Direct safety data come from more than 140 subjects exposed to concentrations of SAGE-217 
which are higher than those achieved with a 30-mg capsule daily dose, primarily in the clinical 
pharmacology program. No serious adverse events were reported in association with any of these 
higher exposures. Consistent with the pharmacological action of SAGE-217 at the GABAA 
receptor, reports of somnolence, dizziness and sedation were increased at increased plasma 
concentrations. Results from a clinically-complete study which evaluated the effects of 
SAGE-217 on driving performance (Study 217-CLP-113), in which subjects (n=59) were 
exposed to 4 days of 30 mg capsules, followed by a single dose of 60 mg capsules administered 
the evening prior to a driving simulation test, are illustrative. During treatment with 30 mg 
capsules daily (Day 1 to 4), the rates of somnolence, and dizziness were 8.5%, and 13.6%, 
respectively. After a single dose of 60 mg on Day 5, the rates of somnolence and dizziness 
increased to 13.8% and 22.4%, respectively. For these ADRs, the events were mild or moderate 
in intensity, and no discontinuations due to the adverse events occurred. No events of sedation 
were reported but could be reflected as events of fatigue which were reported at a rate of 3.4% 
with 30 mg (Day 1 to 4) and 13.8% after a dose of 60 mg on Day 5. In addition, in this study, 
while there was an increase in incidence of somnolence, dizziness and fatigue at 60 mg, there 
was not an increase in the severity of events. Additional data from Study 217-CLP-113 are 
provided in the Investigator’s Brochure. 


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Direct evidence related to efficacy and safety outcomes following administration of SAGE-217 
capsules at doses above 30 mg is further provided by results from a Phase 1, placebo-controlled 
study in healthy subjects using a 5-hour phase advance model of insomnia (Study 
217-EXM-101). Administration of single doses of SAGE-217 up to 45 mg improved sleep 
efficiency, duration, maintenance and sleep quality compared with placebo. Evening 
administration of SAGE-217 was generally well tolerated, with an acceptable safety and 
tolerability profile. All reported TEAEs were mild and all resolved. Additional data from Study 
217-EXM-101 are provided in the Investigator’s Brochure. 
Using exposure-response models developed for both efficacy and safety outcomes, the 
benefit-risk profile of SAGE-217 at doses of 40 or 50 mg capsules is expected to be acceptable. 
In Figure 1, the predicted concentrations of SAGE-217 following doses of 30, 40 or 50 mg 
capsules once daily are shown relative to two important concentration markers: Cavg as a marker 
for efficacy, identified based on pharmacodynamic biomarker modeling and clinical 
effectiveness (40 ng/mL) and Cmax as a marker for safety, associated with the MTD of the oral 
solution (125 ng/mL).  
Figure 1: 
Predicted SAGE-217 concentrations (Cavg and Cmax) following dosing of 30 to 
50 mg daily 
 
Dashed vertical lines represent target concentrations for efficacy (Cavg >40 ng/mL) and safety (Cmax<125 ng/mL). 
Percentage next to dashed lines indicate the percentages with Cavg>40 ng/mL or with Cmax>124 ng.   
The selection of 50 mg dosed daily was based first on efficacy, enabling the largest number of 
subjects to achieve a steady-state Cavg over 40 ng/mL. Figure 1 shows a dose of 50 mg will allow 
>90% subjects to maintain the target Cavg yet remain within the range of acceptable tolerability. 
With respect to Cmax, less than 1 in 5 (19%) subjects at the 50 mg dose level are expected to 
exceed a Cmax over 125 ng/mL, a level observed in Phase 1 studies which utilized oral solution 
and which was associated with a greater rate of sedation events.  
Increased granularity of the exposure-efficacy relationship is provided in Figure 2. Across 
Studies 217-MDD-201B, 217-PPD-201, and Part A of the current study, increased 
concentrations of SAGE-217 were associated with a larger reduction in depressive symptoms 
(Figure 2). Based on linear regression modeling, effect sizes for HAM-D were dose dependent, 
with a 50 mg dose administered once daily for 14 days predicted to provide greater therapeutic 


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benefit compared to daily doses of 40 and 30 mg. Based on preliminary results from Part A of 
this study, a dose of 30 mg may be considered the minimally effective dose.  
Figure 2: 
Total score change on Day 15 (Studies 217-MDD-201B, 217-PPD-201, Part A 
of the current study) 
 
 
Solid blue line= linear regression line; shaded area=95% CI around the regression; horizontal dashed line=mean 
placebo response; Vertical dashed lines from left to right are average concentrations for 20 mg capsules 
217-MDD-301 Part A, 30 mg capsules 217-MDD-301 Part A, 30 mg capsules 217-MDD-201B; 30 mg capsules 
217-PPD-201  
Exposure-response modeling for safety quantified the relationship between maximum plasma 
concentration (Cmax) and safety from studies 217-MDD-201, 217-PPD-201, and Part A of the 
current study. The safety endpoint for modeling was selected as the incidence of sedation or 
somnolence during SAGE-217 treatment, as they represent on-target effects at the GABAA 
receptor and are the most commonly occurring adverse events with SAGE-217 when considering 
all doses and formulations. Logistic regression modeling indicated higher Cmax values were 
associated with an increased incidence of sedation or somnolence across mild, moderate and 
severe intensities. Based on this observed relationship, the predicted incidence rates of sedation 
or somnolence were simulated at SAGE-217 doses of 30, 40 or 50 mg administered once daily 
(Figure 3). 


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Figure 3: 
Predicted incidence of sedation or somnolence by dose 
 
Circle and solid line=point estimate and 95% prediction interval. Percentage on the right of bar=absolute percentage 
of patients with sedation or somnolence during treatment with SAGE-217; percentage in parenthesis=difference in 
percentage from placebo. 
While Figure 3 indicates an increasing incidence of sedation or somnolence with a higher dose 
the rates of such events across all levels of severity are expected to be approximately 20 to 25%, 
consistent with safety outcomes associated with some currently available anti-depressants. As 
with usual clinical practice, subjects will have the option to dose reduce to 40 mg at any time 
should a lack of tolerability develop. As a reflection of the model accuracy, the cohort in 
CLP-113 exposed to 30 mg daily for 4 days, followed by a single-dose of 60 mg achieved a 
mean plasma concentration of 97 ng/mL at 8.5 hours after dosing, suggesting the Cmax 
experienced by these subjects approached or exceeded 125 ng/mL and was higher than the 
predicted Cmax of 106 ng/mL for a 50 mg dose (data on file).  
Safety margins have been calculated using the NOAELs from the 6-month rat and 9-month dog 
general toxicology studies (most conservative approach) and predicted steady-state exposures in 
humans following daily administration of 30, 40, or 50 mg SAGE-217 capsules. At present, 
mean steady-state exposures in humans following daily administration of 30 mg SAGE-217 
capsules following a high fat meal (most conservative; Cmax = 64 ng/mL; AUC = 936 ng⸱hr/mL) 
maintain safety margins of approximately 5x to 8x in rat (Cmax or AUC) and 6x in dog (Cmax or 
AUC) relative to the NOAEL in the respective species. While these margins are expectedly 
reduced with higher SAGE-217 concentrations, they remain approximately 3x to 5x in rat and 4x 
in dog (Cmax or AUC) to predicted plasma exposures for a 50 mg capsule administered once 
daily). 
Sedation, an extension of the pharmacologic mechanism of SAGE-217, was the primary 
dose-limiting effect in toxicity studies in rats and dogs. In dogs, the toxicologic ‘effect dose’ 
levels of 2.5 mg/kg/day (9-month study, episodic dosing study) or 2 mg/kg/day (3-month study) 
associated with a low incidence of convulsion and/or early mortality during or following the 
dosing phase, were associated with exposures 7- to 11-fold above clinically relevant Cmax 
following administration of 30 mg capsules. Similar margin calculations for adverse effect levels 
in dogs to potential higher SAGE-217 dose levels (40 or 50 mg/day) remain at or above 4.5x for 
both Cmax and AUC. All non-clinical findings are provided in the SAGE-217 Investigator’s 
Brochure. The totality of the nonclinical safety data supports the use of SAGE-217 for the 


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treatment of patients at the higher clinical dose regimen, particularly in the context of the current 
safety database of greater than 2000 subjects exposed to SAGE-217 treatment.  
In summary, preliminary results through Day 42 of the double-blind period in Part A of this 
study support the need for higher steady-state concentrations of SAGE-217 to allow subjects to 
experience maximum anti-depressant, anti-anxiety, and anti-insomnia benefits. Doses of 
SAGE-217 40 and 50 mg will be utilized in this trial, as well as all other ongoing trials with 
SAGE-217, under the 14-day regimen of an initial evening dose of 50 mg with reduction to 
40 mg as needed based on tolerability. These higher doses of SAGE-217 are expected to exhibit 
a favorable benefit-risk profile in the context of 30 mg now being identified as a minimally 
effective dose. While higher rates of ADRs may be anticipated, SAGE-217 is expected to 
maintain an acceptable tolerability profile, based on a current safety database of greater than 
2000 subjects exposed to SAGE-217 treatment across different doses/concentrations. In addition, 
higher doses offer the potential for improved therapeutic benefit over the short 14-day treatment 
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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: 
• Part A only: 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. 
Part A - Secondary Endpoints 
• 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 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. 
Part B – Key Secondary Endpoints 
• CGI-S at Day 15 
• HAM-D total score at Day 3, Day 28, and Day 42 
6.2.4. 
Part B – Other Secondary Endpoints 
• HAM-D response at Day 15 and Day 42 
• HAM-D remission at Day 15 and Day 42 
• CGI-I response, defined as “much improved” or “very much improved”, at Day 15 
• MADRS total score at Day 15 
• HAM-A total score at Day 15 
• Time to first HAM-D response 
• Change from baseline in PRO measures of health-related quality of life, as assessed 
by responses to the SF-36v2, and of depressive symptoms as assessed by the PHQ-9 
6.2.5. 
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) 
 
 
 


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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. This study will be conducted in 2 parts – Part A and Part B. Bart B will commence after 
all subjects in Part A have completed the Day 42 visit. Part A and Part B will enroll unique 
subjects. For both study parts, 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. Each study part is described below. 
Part A 
Part A 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). 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 2. 
Part B 
Part B will consist of a Screening Period of up to 28 days, a 14-day Treatment Period, and a 
28-day double-blind follow-up period. Part B of the study may run concurrently with the 
extended follow-up period in Part A. 
The Screening Period begins with the signing of the 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 


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exclusion criteria due to participation in another clinical study (Section 8.2). 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 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 2 treatment groups 
(SAGE-217 50 mg or matching placebo) in a 1:1 ratio. Subjects will self-administer study drug 
once daily at approximately 8 PM with fat-containing food (eg, within 1 hour of an evening meal 
which contains fat or with a fat-containing snack), on an outpatient basis, for 14 days. See 
Section 10.5 for examples of fat-containing snacks. Subjects will return to the study center 
during the treatment and follow-up periods as outlined in Table 3.  
During the treatment period, subjects will be able to receive study drug as long as there are no 
dose limiting safety/tolerability concerns. Subjects who cannot tolerate 50 mg will receive 40 mg 
for the remainder of the treatment period. At the discretion of the Investigator, subjects who 
cannot tolerate the 40-mg dose may be discontinued from study drug.  
Subjects who discontinue treatment early should return to the site for an 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 ET visit. The EOT and ET visits 
can be on the same day if a subject discontinues study drug and decides to terminate the study on 
the same day during a clinic visit; in this case, all EOT visit assessments should be conducted in 
addition to an abbreviated physical exam.  
7.2. 
Number of Subjects 
In Part A, approximately 450 subjects will be randomized and dosed to obtain 399 evaluable 
subjects (see Section 13.8). In Part B, approximately 240 subjects will be randomized and dosed 
to obtain 216 evaluable subjects. 
7.3. 
Treatment Assignment 
For both study parts, subjects will be randomly assigned to a treatment group on Day 1 and will 
be stratified based on use of antidepressant treatment (current/stable or not treated/withdrawn 
≥60 days) at baseline. In Part A, randomization will be performed within each stratum in a 1:1:1 
ratio to receive SAGE-217 20 mg, SAGE-217 30 mg, or matching placebo. In Part B, 
randomization will be performed within each stratum in a 1:1 ratio to receive SAGE-217 50 mg 
or matching placebo.  


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7.4. 
Dose Adjustment Criteria 
In Part A, dose adjustments are not permitted and subjects who cannot tolerate study drug will be 
discontinued from study drug and will receive treatment as clinically indicated (see Section 8.3). 
During the treatment period in Part B, subjects will be able to receive study drug as long as there 
are no dose limiting safety/tolerability concerns. Subjects who cannot tolerate 50 mg will receive 
40 mg for the remainder of the treatment period. At the discretion of the Investigator, subjects 
who cannot tolerate the 40-mg dose may be discontinued from study drug (refer to Section 8.3 
for procedures for early study drug discontinuation). If dose adjustment is deemed necessary by 
the Investigator at any time during the treatment period, the subject will return to the site to 
return any remaining study drug and for the adjusted dose to be dispensed. 
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 64 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. For Part A, subject has a MADRS total score of ≥32 and a HAM-D total score ≥22 at 
screening and Day 1 (prior to dosing). For Part B, subject has a HAM-D total score ≥24 
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 who have stopped taking antidepressants 
within 60 days must have stopped for longer than 5 half-lives of the antidepressant 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 


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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 or 
without 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 is currently at significant risk of suicide, as judged by the Investigator, or 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. For Part 
A, 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. For Part B, a BMI ≤18 
or ≥45 kg/m2 is exclusionary; a BMI of 40 to 44.9 kg/m2, inclusive, at Screening is 
subject to a broader evaluation of medical comorbidities as described above. 
4. 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 
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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 
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. 


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25. Subject is taking psychostimulants (eg, methylphenidate, amphetamine) or opioids, 
regularly or as-needed, at Day -28. 
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, including suicidality, at the discretion of the 
Investigator  
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 may withdraw the subject from the 
study at his/her discretion. 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.  
In Part A, 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.  
In Part B, subjects who discontinue study drug early should return to the site for an 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. If necessary, 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 EOT visit 
assessments should be conducted in addition to an abbreviated physical exam. 


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For both study parts, 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 
In Part A, subjects will self-administer SAGE-217 (20 or 30 mg) or matching placebo orally 
once daily in the evening with food for 14 days.  
In Part B, subjects will self-administer SAGE-217 (50 mg or 40 mg [for dose adjustments only 
as permitted as described in Section 7.4]) or matching placebo orally once daily at approximately 
8 PM with food for 14 days. The 50-mg and 40-mg doses will be administered as 2 capsules per 
dose (50 mg, administered as one 30 mg-capsule and one 20-mg capsule, and 40-mg, 
administered as two 20-mg capsules). Placebo will also be administered as 2 capsules to 
maintain the blind.  
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 
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• Chronic or as-needed psychostimulants (eg, methylphenidate, amphetamine) or 
opioids from Day -28 through the Day 42 visit 
• First generation (typical) antipsychotics (eg, haloperidol, perphenazine) and second 
generation (atypical) antipsychotics (eg, aripiprazole, quetiapine) from Day -14 
through the Day 42 visit 
• Use of any non-GABA anti-insomnia medications (eg, 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 who are feeling sedated, somnolent, and/or dizzy are to refrain from driving or engaging 
in any activity requiring alertness. 
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 10.5,  Table 2, and Table 3).  
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 


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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 2 and Table 3, at which time the Investigator or designee will be responsible for ensuring 
the kit contains sufficient doses for the duration of the treatment period.  
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. For both study parts, 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.  
In Part A, 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. In Part B, randomization will be done within 
each stratum in a 1:1 ratio to receive SAGE-217 50 mg or matched placebo.  
In both study parts, subjects, clinicians, and the study team will be blinded to treatment 
allocation. Randomization will be performed centrally via an interactive response technology 
(IRT) system. Randomization schedules will be generated by an independent statistician. The 
allocation to treatment group will be based on the randomization schedule. The randomization 
schedules will be kept strictly confidential, accessible only to authorized personnel until the time 
of unblinding.  
In Part A, 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 Part B, the Sponsor, site personnel and subjects will remain blinded until the database lock 
when all subjects complete the Day 42 visit. 
9.4.1. 
Emergency Identification of Study Drug 
During the study, the blind is to be broken only when the safety of a subject is at risk and the 
treatment plan is dependent on the study treatment received. Unless a subject is at immediate 
risk, the Investigator should make diligent attempts to contact Sage prior to unblinding the study 
treatment administered to a subject. Requests from the Investigator about the treatment 
administered to study subjects should be discussed with the Sage Medical Monitor. If the 
unblinding occurs without Sage’s knowledge, the Investigator must notify Sage within 24 hours 
of breaking the blind. All circumstances surrounding a premature unblinding must be clearly 
documented in the source records.   
In all cases where the 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 


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eCRF. At the of withdrawal from the study/stopping participation, if possible, an EOT and/or ET 
visit should be conducted.  
If a subject or study personnel become unblinded to treatment, the subject will be excluded from 
the Full Analysis Set, as detailed further in the statistical analysis plan. 


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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. 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. For Part A, each unit dose consists of 
1 capsule. For Part B, each unit dose consists of 2 capsules (see Section 9.1). 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 
In Part A, 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.  
In Part B, SAGE-217 is to be administered orally once daily at approximately 8 PM with 
fat-containing food (eg, within 1 hour of an evening meal which contains fat, or with a 
fat-containing snack). Examples of fat-containing snacks include nuts, peanut butter, avocado, 
eggs, and cheese.  
In both study parts, 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. 


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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 2 and Table 3.  
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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10.8. 
Product Complaints 
A product complaint is any written, electronic, or verbal expression of dissatisfaction regarding 
the identity, quality, reliability, safety, purity, potency, effectiveness or performance (applicable 
for approved marketed products) of a drug product after it is released for distribution. In the 
course of conduct of the study, study personnel may become aware of a product complaint 
associated with the use of a Sage product. Personnel shall notify Sage within 24 hours by 
forwarding the product complaint information via the contact information listed in Table 1. 
Where possible, personnel should segregate any product, materials, or packaging associated with 
the product complaint. 


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11. 
ASSESSMENT OF EFFICACY 
 
All assessments will be conducted according to the schedule of assessments (Table 2 and 
Table 3). 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 past 7 days 
(1 week) will be used at Screening and during the extended Follow-up Period (Part A only), 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; Part A Only) 
The ISI will be assessed in Part A only. 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 (Part A Only) 
The Core Consensus Sleep Diary will be assessed in Part A only. This instrument 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 2 and 
Table 3). 
12.1.1. 
Demographic/Medical History 
Demographic characteristics (age, race, gender, ethnicity, employment status, highest education 
level, marital/civil status) and a full medical history, including: family psychiatric history, 
generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, persistent 
depressive disorder, postpartum depression, substance use disorder, alcohol use disorder, major 
depressive disorder with seasonal pattern, major depressive disorder with psychotic features, 
premenstrual dysphoric disorder, major depressive disorder with atypical features, schizophrenia; 
or schizoaffective disorder will be documented. The diagnosis of MDD will be determined using 
the SCID-5-CT. If available, the disease code associated with the diagnosis of MDD based on 
the 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. An abbreviated physical exam includes a 
brief medical history followed by a targeted physical exam. 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 


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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.  
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. When ECG 
 sample collection occur during the same visit, the ECGs will be 
conducted first. 
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 5. 
Table 5: 
Clinical Laboratory Tests 
Hematology  
Serum Chemistry 
Urinalysis 
Coagulation 
Red blood cell count 
Hemoglobin  
Hematocrit 
White blood cell count with 
differential  
Platelet count 
Red Blood Cell Indices 
(MCV, MCH, MCHC) 
Reflex to Red blood cell 
morphology if indices are 
abnormal 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
Total protein 
Creatinine 
Blood urea nitrogen 
Creatine kinase 
Gamma-glutamyl transferase 
Potassium 
Sodium 
Lactate dehydrogenase 
Glucose 
Chloride 
Bicarbonate 
Calcium 
Phosphorus 
Triglycerides 
pH 
Specific gravity 
Protein 
Glucose 
Red blood cell 
Nitrite 
Leukocyte 
esterase 
Ketones 
Bilirubin 
Urobilinogen 
Activated partial 
thromboplastin 
time 
Prothrombin time 
International 
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Thyroid stimulating hormone 
(TSH) 
Reflex to free T3/T4 if 
TSH is abnormal  
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 5). 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 2 and Table 3). 
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 6: 
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. Any complication during 
pregnancy  (eg, anemia, infections, pre-eclampsia) should be reported as an AE/SAE. If the 
outcome of the pregnancy meets the criteria for immediate classification as an SAE (ie, 
spontaneous abortion, stillbirth, neonatal death, 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. 
Overdose 
An overdose is defined as more than 2 capsules of study drug taken by a subject in an 18-hour 
period or more than 4 capsules taken by a subject in a 36-hour period. Overdoses, regardless of 
presence of associated clinical manifestation(s) (eg, headache, abnormal laboratory value) will 
be considered an AE and recorded as such on the eCRF. Any clinical manifestation(s) of 
overdose must also be recorded as an AE on the eCRF. In addition, all overdoses must be 
recorded on an Overdose form and sent to Sage or designee within 24 hours of the site becoming 
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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. Separate SAPs will be generated for each part of the study. The SAP for 
each study part will be finalized and approved prior to treatment unblinding of each respective 
part. 
In Part A, 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. Data from Part A may be 
analyzed and reported following final database lock and before Part B is complete. For Part B, 
the final database lock will occur when all subjects complete the study; treatment unblinding and 
analyses will follow the database lock. 
Separate clinical study reports will be produced for each part of the study. 
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.  


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Medical/family history will be listed by subject.  
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 in Part A 
only (eg, sleep latency (SL), total sleep time (TST), wake after sleep onset (WASO)), ISI score 
in Part A only, 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 


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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 
clinically significant (PCS) values are provided in the SAP. 
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.  


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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 
For Part A, 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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For Part B, assuming a two-sided alpha level of 0.05, a sample size of 216 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 a standard deviation (SD) of 9 points. Assuming a 10% dropout rate and a 
1:1 randomization ratio within each stratum (antidepressant use at baseline, yes or no), 
approximately 240 total randomized subjects will be required to obtain 216 evaluable subjects. 
Evaluable subjects are defined as those randomized subjects who receive study drug and have a 
valid baseline and at least 1 postbaseline HAM-D assessment. 


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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. 
DSM-5.  Diagnostic and statistical manual of mental disorders (5th ed.).  American Psychiatric 
Association 2013.  Arlington, VA: American Psychiatric Publishing. 
Greenberg PE, Fournier AA, Sisitsky T, Pike CT, Kessler RC. The economic burden of adults 
with major depressive disorder in the United States (2005 and 2010). J Clin Psychiatry. 2015 
Feb;76(2):155-62. 
Gunduz-Bruce H, Silber C, Kaul I, et al. Trial of SAGE-217 in Patients with Major Depressive 
Disorder. N Engl J Med. 2019; 381:903-911. 
Martinez Botella G, Salituro FG, Harrison BL, et al. Neuroactive steroids. 2. 3α-hydroxy-3β-
methyl-21-(4-cyano-1H-pyrazol-1’-yl)-19-nor-5β-pregnan-20-one (SAGE-217): A clinical next 
generation neuroactive steroid positive allosteric modulator of the (γ-aminobutyric acid) A 
receptor. J Med Chem 2017;28;60(18):7810-19. 
 
   
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. 


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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. 
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. 
 


217-MDD-301 Summary of Changes  
 
 
 
 
Sage Therapeutics 
Protocol Version 6.0, Amendment 5 
 
1 
Protocol 217-MDD-301, Amendment 5  
Date of Amendment: 02 March 2020  
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 add a new study part (Part B) to evaluate 
a 50-mg dose (to align with changes to the dose level applied to other active clinical studies of 
SAGE-217), for further evaluation of the safety and efficacy of SAGE-217. Associated changes 
to the Part B-specific study objectives and endpoints, subject eligibility criteria, planned number 
of subjects, schedule of assessments, study drug dose and administration, and dose justification 
based on the addition of Part B have been incorporated.  
Other changes implemented with this amendment include the following: 
• Background information was changed to update the SAGE-217 mechanism of action to 
reflect current data 
• Safety information presented in the introduction was simplified with reference to the 
SAGE-217 Investigator’s Brochure for detailed safety information 
• Clarified that the decision to withdraw a subject from the study is solely at the discretion 
of the investigator 
• Added a restriction for subjects feeling sedated, somnolent, or dizzy to refrain from 
driving or engaging in other activities requiring alertness 
• Added an overdose section 
• Clarified AEs/SAEs related to pregnancy 
• Edited the description of the study drug to pertain to autofill formulation only 
• Emergency identification of the study drug was moved to the randomization and blinding 
section for improved organization 
• Clarified timing of dose administration and dosing instructions for subjects in Part B 
Separately, for interstudy consistency, other minor updates have been made to align with 
changes applied in other SAGE-217 studies.  
Other minor administrative changes have been made, including changes identified in 
administrative letters dated 19 August 2019 and 29 August 2019, as well as inclusion of 
emergency contact information and product complaint reporting information.   
A detailed summary of changes is provided in Table 1. Updated references, protocol signatories, 
and corrections to typographical errors, punctuation, grammar, abbreviations, and formatting are 
not detailed. 


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Protocol Version 6.0, Amendment 5 
 
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Table 1: 
Protocol Amendment 5 Detailed Summary of Changes  
The primary section of the protocol affected by the changes in Protocol Amendment 5 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: Revise the overall study design to include a new study part (Part B) designed to evaluate a 50-mg dose. Clarify that the 
study will be conducted in 2 parts. 
The primary change occurs in Section 7.1 Overall Study Design.  
Now reads:  
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). This study will be conducted in 2 parts – Part A and Part B. Bart B will commence 
after all subjects in Part A have completed the Day 42 visit. Part A and Part B will enroll unique subjects. For both study 
parts, 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. Each study part is described below. 
Part A 
Part A 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). Subjects will undergo preliminary screening 
procedures at the Screening Visit to determine eligibility, including completion of the MADRS, HAM-D, and CGI-S. 
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 


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Protocol Version 6.0, Amendment 5 
 
3 
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 2. 
Part B 
Part B will consist of a Screening Period of up to 28 days, a 14-day Treatment Period, and a 28-day double-blind follow-up 
period. Part B of the study may run concurrently with the extended follow-up period in Part A. 
The Screening Period begins with the signing of the 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). 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 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 2 treatment groups (SAGE-217 50 mg or matching placebo) in a 1:1 ratio. 
Subjects will self-administer study drug once daily at approximately 8 PM with fat-containing food (eg, within 1 hour of an 
evening meal which contains fat or with a fat-containing snack), on an outpatient basis, for 14 days. See Section 10.5 for 
examples of fat-containing snacks. Subjects will return to the study center during the treatment and follow-up periods as 
outlined in Table 3.  
During the treatment period, subjects will be able to receive study drug as long as there are no dose limiting safety/tolerability 
concerns. Subjects who cannot tolerate 50 mg will receive 40 mg for the remainder of the treatment period. At the discretion 
of the Investigator, subjects who cannot tolerate the 40-mg dose may be discontinued from study drug.  
Subjects who discontinue treatment early should return to the site for an 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 ET visit. The EOT and ET visits can be on the same 


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Protocol Version 6.0, Amendment 5 
 
4 
day if a subject discontinues study drug and decides to terminate the study on the same day during a clinic visit; in this case, 
all EOT visit assessments should be conducted in addition to an abbreviated physical exam. 
Sections also affected by this change:  
• 
Synopsis  
• 
Section 5 Introduction 
• 
Section 6 Objectives and Purpose 
• 
Section 7 Investigational Plan 
• 
Section 8 Selection and Withdrawal Criteria 
• 
Section 9 Treatment of Subjects 
• 
Section 10 Study Drug Materials and Management 
• 
Section 11 Assessment of Efficacy 
 
• 
Section 13 Statistics 
 
Purpose: Update objectives and endpoints to identify those that pertain to Part A only, identify key secondary endpoints for Part B; 
secondary endpoints related to sleep (Insomnia Severity Index and subjective sleep parameters collected with the Core Consensus 
Sleep Diary), 
 will not be evaluated in 
Part B 
The primary change occurs in Section 6 Objectives and Purpose. 
Now reads: 
6.1.2. Secondary Objective(s) 
Secondary objectives are: 
• Part A only: To evaluate the effect of SAGE-217 on sleep.  
 
 
 


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Protocol Version 6.0, Amendment 5 
 
5 
 
 
 
6.2.2 Part A - Secondary Endpoints 
6.2.3 Part B – Key Secondary Endpoints 
• CGI-S at Day 15 
• HAM-D total score at Day 3, Day 28, and Day 42 
6.2.4 Part B – Other Secondary Endpoints 
• HAM-D response at Day 15 and Day 42 
• HAM-D remission at Day 15 and Day 42 
• CGI-I response, defined as “much improved” or “very much improved”, at Day 15 
• MADRS total score at Day 15 
• HAM-A total score at Day 15 
• Time to first HAM-D response 
• Change from baseline in PRO measures of health-related quality of life, as assessed by responses to the SF-36v2, 
and of depressive symptoms as assessed by the PHQ-9 
 
 
 
 
 
 
 
 
 
Sections also affected by this change:  
• 
Synopsis 
• 
Section 11 Assessment of Efficacy 
 


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Protocol Version 6.0, Amendment 5 
 
6 
 
Purpose: Update the number of subjects to reflect the addition of Part B 
The primary change occurs in Section 7.2 Number of Subjects  
Now reads:  
In Part A, aApproximately 450 subjects will be randomized and dosed to obtain 399 evaluable subjects (see Section 13.8). In Part B, 
approximately 240 subjects will be randomized and dosed to obtain 216 evaluable subjects. 
Sections also affected by this change:   
• 
Synopsis  
 
Purpose: Update randomization and blinding to include the randomization and blinding plan for Part B. 
The primary change occurs in Section 9.4 Randomization and Blinding  
Now reads:  
This is a randomized double-blind, placebo-controlled study. For both study parts, Ssubjects 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.  
In Part A, 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. In Part B, randomization will be done within each stratum in a 1:1 ratio to receive SAGE-217 50 mg or 
matched placebo.  
In both study parts, Ssubjects, 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 Part A, Tthe 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. 


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Protocol Version 6.0, Amendment 5 
 
7 
In exceptional circumstances and for the safety of the study subject, the Investigator may request unblinding of and individual 
subject’s treatment in the study via the IRT (see Section for more details related to unblinding). 
In Part B, the Sponsor, site personnel and subjects will remain blinded until the database lock when all subjects complete the 
Day 42 visit. 
Sections also affected by this change:  
• 
7.3 Treatment Assignment 
• 
Synopsis  
 
Purpose: Add dose justification language to support the SAGE-217 50-mg dose. Clarify that the MTD of 30 mg was determined using 
the oral solution formulation.  
The primary change occurs in Section 5.4 Dose Justification 
Now reads:  
Part A 
There will be 2 dose levels of SAGE-217 in Part A 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 (MTD) for the oral solution formulation 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 Part A. 
Part B 
To date, the current capsule utilized in clinical studies is not associated with an MTD. Initial MTD assessments were 
performed using SAGE-217 in an oral solution (OS) at steady-state in healthy subjects, which provided an MTD with a Cmax of 
125 ng/mL at 30 mg OS. While re-identification of the MTD using the capsule formulations was not conducted, steady-state 30 
mg capsules provide a model-derived Cmax approximately 50% lower (64 ng/mL) than the concentration associated with the 
MTD of 30 mg OS (125 ng/mL).  


217-MDD-301 Summary of Changes  
 
 
 
 
 
 
 
 
 
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Protocol Version 6.0, Amendment 5 
 
8 
Studies 217-MDD-201 and 217-PPD-201, employing 30 mg capsules administered each evening for 14 days, demonstrated 
significant reduction in symptoms of depression, anxiety and insomnia. The safety profile in these studies is consistent with the 
GABAA neurosteroid mechanism, including adverse drug reactions (ADRs) of somnolence, sedation, and dizziness at rates of 
4 to 15%; the majority with mild intensity. Phase 3 studies in a broader patient population demonstrate activity of SAGE-217 
associated with improvement in depressive symptoms, however, both the efficacy and safety findings support investigation of a 
higher dose, with predictable ADRs expected to be within an acceptable range. 
Preliminary data through Day 42 of the double-blind period in Part A of this study demonstrated significant anti-depressant 
effects compared to placebo at Day 3, 8, and 12 but not Day 15 (primary endpoint) for the 30 mg dose. The 20 mg dose did not 
separate from placebo at any timepoint. The rates of expected ADRs of somnolence, sedation and dizziness in the 30 mg arm 
were each less than 10%; rates of discontinuation for AEs were lower with SAGE-217 30 mg (2.1%) than with placebo (3.2%). 
No clinically relevant changes in vital signs, laboratories, electrocardiogram measures, or suicidal thinking were observed in 
either Part A of the current study or across the full SAGE-217 program, now with over 2000 subjects exposed to treatment. In 
addition, approximately 112 additional subjects have received blinded study drug (SAGE-217 or placebo) in ongoing blinded 
clinical studies. Relevant results from Part A of this study are available in the SAGE-217 Investigator’s Brochure.  
Direct and modeled data from completed studies to date (including efficacy studies 217-MDD-201 and 217-PPD-201) in 
addition to Part A (through Day 42 of the double-blind period) of the current study, have been used to assess and predict the 
efficacy and safety outcomes at SAGE-217 concentrations expected with higher doses of SAGE-217 capsules (eg, 40 and 
50 mg).  
Direct safety data come from more than 140 subjects exposed to concentrations of SAGE-217 which are higher than those 
achieved with a 30-mg capsule daily dose, primarily in the clinical pharmacology program. No serious adverse events were 
reported in association with any of these higher exposures. Consistent with the pharmacological action of SAGE-217 at the 
GABAA receptor, reports of somnolence, dizziness and sedation were increased at increased plasma concentrations. Results 
from a clinically-complete study which evaluated the effects of SAGE-217 on driving performance (Study 217-CLP-113), in 
which subjects (n=59) were exposed to 4 days of 30 mg capsules, followed by a single dose of 60 mg capsules administered the 
evening prior to a driving simulation test, are illustrative. During treatment with 30 mg capsules daily (Day 1 to 4), the rates of 
somnolence, and dizziness were 8.5%, and 13.6%, respectively. After a single dose of 60 mg on Day 5, the rates of somnolence 
and dizziness increased to 13.8% and 22.4%, respectively. For these ADRs, the events were mild or moderate in intensity, and 
no discontinuations due to the adverse events occurred. No events of sedation were reported but could be reflected as events of 
fatigue which were reported at a rate of 3.4% with 30 mg (Day 1 to 4) and 13.8% after a dose of 60 mg on Day 5. In addition, 
in this study, while there was an increase in incidence of somnolence, dizziness and fatigue at 60 mg, there was not an increase 
in the severity of events. Additional data from Study 217-CLP-113 are provided in the Investigator’s Brochure. 


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Protocol Version 6.0, Amendment 5 
 
9 
Direct evidence related to efficacy and safety outcomes following administration of SAGE-217 capsules at doses above 30 mg is 
further provided by results from a Phase 1, placebo-controlled study in healthy subjects using a 5-hour phase advance model 
of insomnia (Study 217-EXM-101). Administration of single doses of SAGE-217 up to 45 mg improved sleep efficiency, 
duration, maintenance and sleep quality compared with placebo. Evening administration of SAGE-217 was generally well 
tolerated, with an acceptable safety and tolerability profile. All reported TEAEs were mild and all resolved. Additional data 
from Study 217-EXM-101 are provided in the Investigator’s Brochure. 
Using exposure-response models developed for both efficacy and safety outcomes, the benefit-risk profile of SAGE-217 at 
doses of 40 or 50 mg capsules is expected to be acceptable. In Figure 1, the predicted concentrations of SAGE-217 following 
doses of 30, 40 or 50 mg capsules once daily are shown relative to two important concentration markers: Cavg as a marker for 
efficacy, identified based on pharmacodynamic biomarker modeling and clinical effectiveness (40 ng/mL) and Cmax as a 
marker for safety, associated with the MTD of the oral solution (125 ng/mL).  
Figure 1: Predicted SAGE-217 concentrations (Cavg and Cmax) following dosing of 30 to 50 mg daily 
------Figure 1 image------ 
The selection of 50 mg dosed daily was based first on efficacy, enabling the largest number of subjects to achieve a steady-state 
Cavg over 40 ng/mL. Figure 1 shows a dose of 50 mg will allow >90% subjects to maintain the target Cavg yet remain within the 
range of acceptable tolerability. With respect to Cmax, less than 1 in 5 (19%) subjects at the 50 mg dose level are expected to 
exceed a Cmax over 125 ng/mL, a level observed in Phase 1 studies which utilized oral solution and which was associated with a 
greater rate of sedation events.  
Increased granularity of the exposure-efficacy relationship is provided in Figure 2. Across Studies 217-MDD-201B, 217-PPD-
201, and Part A of the current study, increased concentrations of SAGE-217 were associated with a larger reduction in 
depressive symptoms (Figure 2). Based on linear regression modeling, effect sizes for HAM-D were dose dependent, with a 50 
mg dose administered once daily for 14 days predicted to provide greater therapeutic benefit compared to daily doses of 40 
and 30 mg. Based on preliminary results from Part A of this study, a dose of 30 mg may be considered the minimally effective 
dose.  
Figure 1: Total score change on Day 15 (Studies 217-MDD-201B, 217-PPD-201, Part A of the current study) 
------Figure 2 image------ 
Exposure-response modeling for safety quantified the relationship between maximum plasma concentration (Cmax) and safety 
from studies 217-MDD-201, 217-PPD-201, and Part A of the current study. The safety endpoint for modeling was selected as 
the incidence of sedation or somnolence during SAGE-217 treatment, as they represent on-target effects at the GABAA 


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Protocol Version 6.0, Amendment 5 
 
10 
receptor and are the most commonly occurring adverse events with SAGE-217 when considering all doses and formulations. 
Logistic regression modeling indicated higher Cmax values were associated with an increased incidence of sedation or 
somnolence across mild, moderate and severe intensities. Based on this observed relationship, the predicted incidence rates of 
sedation or somnolence were simulated at SAGE-217 doses of 30, 40 or 50 mg administered once daily (Figure 3). 
Figure 2: Predicted incidence of sedation or somnolence by dose 
------Figure 3 image------ 
While Figure 3 indicates an increasing incidence of sedation or somnolence with a higher dose the rates of such events across 
all levels of severity are expected to be approximately 20 to 25%, consistent with safety outcomes associated with some 
currently available anti-depressants. As with usual clinical practice, subjects will have the option to dose reduce to 40 mg at 
any time should a lack of tolerability develop. As a reflection of the model accuracy, the cohort in CLP-113 exposed to 30 mg 
daily for 4 days, followed by a single-dose of 60 mg achieved a mean plasma concentration of 97 ng/mL at 8.5 hours after 
dosing, suggesting the Cmax experienced by these subjects approached or exceeded 125 ng/mL and was higher than the 
predicted Cmax of 106 ng/mL for a 50 mg dose (data on file).  
Safety margins have been calculated using the NOAELs from the 6-month rat and 9-month dog general toxicology studies 
(most conservative approach) and predicted steady-state exposures in humans following daily administration of 30, 40, or 50 
mg SAGE-217 capsules. At present, mean steady-state exposures in humans following daily administration of 30 mg SAGE-
217 capsules following a high fat meal (most conservative; Cmax = 64 ng/mL; AUC = 936 ng⸱hr/mL) maintain safety margins of 
approximately 5x to 8x in rat (Cmax or AUC) and 6x in dog (Cmax or AUC) relative to the NOAEL in the respective species. 
While these margins are expectedly reduced with higher SAGE-217 concentrations, they remain approximately 3x to 5x in rat 
and 4x in dog (Cmax or AUC) to predicted plasma exposures for a 50 mg capsule administered once daily). 
Sedation, an extension of the pharmacologic mechanism of SAGE-217, was the primary dose-limiting effect in toxicity studies 
in rats and dogs. In dogs, the toxicologic ‘effect dose’ levels of 2.5 mg/kg/day (9-month study, episodic dosing study) or 2 
mg/kg/day (3-month study) associated with a low incidence of convulsion and/or early mortality during or following the dosing 
phase, were associated with exposures 7- to 11-fold above clinically relevant Cmax following administration of 30 mg capsules. 
Similar margin calculations for adverse effect levels in dogs to potential higher SAGE-217 dose levels (40 or 50 mg/day) 
remain at or above 4.5x for both Cmax and AUC. All non-clinical findings are provided in the SAGE-217 Investigator’s 
Brochure. The totality of the nonclinical safety data supports the use of SAGE-217 for the treatment of patients at the higher 
clinical dose regimen, particularly in the context of the current safety database of greater than 2000 subjects exposed to 
SAGE-217 treatment.  


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11 
In summary, preliminary results through Day 42 of the double-blind period in Part A of this study support the need for higher 
steady-state concentrations of SAGE-217 to allow subjects to experience maximum anti-depressant, anti-anxiety, and anti-
insomnia benefits. Doses of SAGE-217 40 and 50 mg will be utilized in this trial, as well as all other ongoing trials with SAGE-
217, under the 14-day regimen of an initial evening dose of 50 mg with reduction to 40 mg as needed based on tolerability. 
These higher doses of SAGE-217 are expected to exhibit a favorable benefit-risk profile in the context of 30 mg now being 
identified as a minimally effective dose. While higher rates of ADRs may be anticipated, SAGE-217 is expected to maintain an 
acceptable tolerability profile, based on a current safety database of greater than 2000 subjects exposed to SAGE-217 
treatment across different doses/concentrations. In addition, higher doses offer the potential for improved therapeutic benefit 
over the short 14-day treatment course.  
Sections also affected by this change: 
• 
Added Figures 1 to 3 
 
Purpose: Modify background information to align with current understanding of the mechanisms of action of SAGE-217 and update 
safety information to include a high-level summary with reference to the Investigator’s Brochure for more detailed safety information. 
The primary change occurs in Section 5 Introduction 
Now reads: 
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 


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12 
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 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. 
Unlike other neurotropic medications that target GABAA receptors, SAGE-217 is an allosteric modulator of both synaptic as 
well as extrasynaptic GABAA receptors (Martinez Botella 2017). As such, SAGE-217 may represent a therapeutic advantage in 
the treatment of depressive disorders by resetting the GABAergic imbalance in depression by affecting both phasic and tonic 
inhibition. 
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 (Gunduz-Bruce 2019). 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 adverse events associated with SAGE-
217 are somnolence, dizziness, and sedation; most adverse events were reported as mild or moderate in intensity. Refer to the 
Investigator’s Brochure for a detailed description of the chemistry, pharmacology, efficacy, and safety of SAGE-217. 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.  
Sections also affected by this change:  
• 
Not applicable 
 
Purpose: Modify dose adjustment criteria to indicate that dose reductions are permitted in Part B for subjects who cannot tolerate the 
50-mg dose.  


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Protocol Version 6.0, Amendment 5 
 
13 
The primary change occurs in Section 7.4 Dose Adjustment Criteria 
Now reads:  
 
In Part A, dDose adjustments are not permitted in this study and sSubjects who cannot tolerate study drug will be discontinued from 
study drug and will receive treatment as clinically indicated (see Section 8.3). 
During the treatment period in Part B, subjects will be able to receive study drug as long as there are no dose limiting 
safety/tolerability concerns. Subject who cannot tolerate 50 mg will receive 40 mg for the remainder of the treatment period. 
At the discretion of the Investigator, subjects who cannot tolerate the 40-mg dose may be discontinued from study drug (refer 
to Section 8.3 for procedures for early study drug discontinuation). If dose adjustment is deemed necessary by the Investigator 
at any time during the treatment period, the subject will return to the site to return any remaining study drug and for the 
adjusted dose to be dispensed. 
Sections also affected by this change:  
• 
Synopsis 
• 
Section 5.4 Dose Justification 
• 
Section 7.1 Overall Study Design 
• 
Section 9.1 Study Drug 
 
Purpose: Add product complaint reporting information.   
The primary change occurs in added Section 10.8 Product Complaints.  
Now reads:  
A product complaint is any written, electronic, or verbal expression of dissatisfaction regarding the identity, quality, 
reliability, safety, purity, potency, effectiveness, or performance (applicable for approved marketed products) of a drug 
product after it is released for distribution.  
In the course of conduct of the study, study personnel may become aware of a product complaint associated with the use of a 
Sage product. Personnel shall notify Sage within 24 hours by forwarding the product complaint information via the contact 
information listed in Table 1. Where possible, personnel should segregate any product, materials, or packaging associated with 
the product complaint.  


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Protocol Version 6.0, Amendment 5 
 
14 
Sections also affected by this change:  
• 
Added Table 1 Emergency Contact Information 
 
Purpose: Revise subject withdrawal criteria to indicate that the decision to withdraw a subject from the study is solely at the 
discretion of the Investigator 
The primary change occurs in Section 8.3 Subject Withdrawal Criteria 
Now reads: 
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, including suicidality, 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 may withdraw the subject 
from the study at his/her discretion.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.  
Sections also affected by this change:  
• 
Not applicable 


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15 
 
Purpose: Update subject inclusion criteria to: 1) modify the upper age limit to 64 years, inclusive for subjects in Part B to conform 
with the accepted definition of non-elderly subjects; 2) allow subjects with higher HAM-D score to be eligible for Part B; 3) clarify 
that if subjects have stopped taking antidepressants within 60 days of Day 1, they must also have stopped taking them for longer than 
5 half-lives to ensure full wash-out prior to study start; 4) lower the upper BMI limit for subjects in Part B to 45 kg/m2; and 5) specify 
that use of condoms with or without spermicide is an acceptable method of contraception. 
The primary change occurs in Section 8.1 Subject Inclusion Criteria 
Now reads: 
2. Subject is a male or female between 18 and 654 years of age, inclusive. 
6. For Part A, sSubject has a MADRS total score of ≥32 and a HAM-D total score ≥22 at screening and Day 1 (prior to dosing). For 
Part B, subject has a HAM-D total score ≥24 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 who have stopped taking antidepressants within 60 days must have stopped for longer than 5 half-lives of the 
antidepressant 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. Subjects receiving psychotherapy must have been receiving therapy on a regular schedule for at least 
60 days prior to Day 1. 
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 or without 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: Clarify the exclusion criterion of suicide risk. Lower the upper BMI limit for subjects in Part B to 45kg/m2.  
The primary change occurs in Section 8.2 Subject Exclusion Criteria 


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Protocol Version 6.0, Amendment 5 
 
16 
Now reads:  
1. Subject is currently at significant risk of suicide, as judged by the Investigator, or has attempted suicide associated with the 
current episode of MDD. 
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. For Part A, aA 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. For Part B, a 
BMI ≤18 or ≥45 kg/m2 is exclusionary; a BMI of 40 to 44.9 kg/m2, inclusive, at Screening is subject to a broader evaluation 
of medical comorbidities as described above. 
Sections also affected by this change:  
• 
Synopsis 
Purpose: Update description of study drug to delete information pertaining to the profill formulation, which is not being used in this 
study.  
The primary change occurs in Section 10.1 Description of Study Drug 
Now reads:  
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.  
Sections also affected by this change:  
• 
Synopsis 


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17 
Purpose: Update description of study drug to delete information pertaining to the profill formulation, which is not being used in this 
study.  
The primary change occurs in Section 10.1 Description of Study Drug 
Now reads:  
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.  
Sections also affected by this change:  
• 
Synopsis 
Purpose: Update study drug information to include the dose-specific information for Part B.  
The primary change occurs in Section 9.1 Study Drug 
Now reads:  
In Part A, Ssubjects will self-administer SAGE-217 (20 or 30 mg) or matching placebo orally once daily in the evening with food for 
14 days.  
In Part B, subjects will self-administer SAGE-217 (50 mg or 40 mg [for dose adjustments only as permitted as described in 
Section 7.4]) or matching placebo orally once daily at approximately 8 PM with food for 14 days. The 50-mg and 40-mg doses 
will be administered as 2 capsules per dose (50 mg, administered as one 30 mg-capsule and one 20-mg capsule, and 40-mg, 
administered as two 20-mg capsules). Placebo will also be administered as 2 capsules to maintain the blind.  
Sections also affected by this change:  
• 
Section 10.2 Study Drug Packaging and Labeling 
• 
Synopsis 
Purpose: Add a section to define overdose and procedures in the event of overdose. 


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18 
The primary change is a new Section 12.6 Overdose 
Now reads:  
An overdose is defined as more than 2 capsules of study drug taken by a subject in an 18-hour period or more than 4 capsules 
taken by a subject in a 36-hour period. Overdoses, regardless of presence of associated clinical manifestation(s) (eg, headache, 
abnormal laboratory value) will be considered an AE and recorded as such on the eCRF. Any clinical manifestation(s) of 
overdose must also be recorded as an AE on the eCRF. In addition, all overdoses must be recorded on an Overdose form and 
sent to Sage or designee within 24 hours of the site becoming aware of the overdose.  
Sections also affected by this change:  
• 
Not applicable 
Purpose: Specify procedures for subjects who discontinue study drug early during Part B. 
The primary change occurs in Section 8.3 Subject Withdrawal Criteria 
Now reads:  
In Part B, subjects who discontinue study drug early should return to the site for an EOT visit as soon as possible, preferably 
the day after treatment is discontinued, and an ET visit should be conducted 7 days later. If necessary, 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 EOT visit assessments should be conducted in addition to an abbreviated physical exam. 
For both study parts, aA subject will be deemed lost to follow-up after attempts at contacting the subject have been unsuccessful. 
Sections also affected by this change:  
• 
Synopsis 
• 
Section 7.1 Overall Study Design 
Purpose: Specify that separate SAPs and clinical study reports will be generated for each study. Additionally, data from Part A may 
be analyzed and reported following final database lock and before Part B is complete. 
The primary change occurs in Section 13 Statistics 


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Now reads: 
A separate statistical analysis plan (SAP) will provide a detailed description of the analyses to be performed in the study. Separate 
SAPs will be generated for each part of the study. The SAP for each study part will be finalized and approved prior to treatment 
unblinding of each respective part. 
In Part A, wWhen 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. Data from Part A may be 
analyzed and reported following final database lock and before Part B is complete. For Part B, the final database lock will 
occur when all subjects complete the study; treatment unblinding and analyses will follow the database lock. 
Separate clinical study reports will be produced for each part of the study. 
Sections also affected by this change:  
• 
Synopsis 
Purpose: Update determination of sample size to include Part B. 
The primary change occurs in Section 13.8 Determination of Sample Size 
Now reads: 
For Part A, Aassuming 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%. 
For Part B, assuming a two-sided alpha level of 0.05, a sample size of 216 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 a standard deviation (SD) of 9 points. Assuming a 10% dropout rate and a 1:1 
randomization ratio within each stratum (antidepressant use at baseline, yes or no), approximately 240 total randomized 


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20 
subjects will be required to obtain 216 evaluable subjects. Evaluable subjects are defined as those randomized subjects who 
receive study drug and have a valid baseline and at least 1 postbaseline HAM-D assessment. 
Sections also affected by this change:  
• 
Synopsis 
Purpose: Clarify pregnancy-related AEs/SAEs 
The primary change occurs in Section 12.4 Recording Adverse Events 
Now reads: 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that a study drug may have interfered with the effectiveness of 
a contraceptive medication. Any complication or a complication relating to the during pregnancy occurs (e.g., anemia, infections, 
pre-eclampsiaspontaneous abortion) should be reported as an AE/SAE. 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 
 
 
 
 
 
 
  
 
 


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21 
 
 
 
  
 
 
Purpose: Update assessment of efficacy section to modify assessments that pertain only to Part A 
The primary change occurs in Section 11 Assessment of Efficacy 
 
Now reads: 
11.1.7     Insomnia Severity Index (ISI; Part A Only)  
The ISI will be assessed in Part A only. The ISI is a validated questionnaire designed to assess the nature, severity, and impact of 
insomnia (Morin 2011).  
11.1.8     Core Consensus Sleep Diary (Part A Only) 
The Core Consensus Sleep Diary will be assessed in Part A only. This instrument collects subjective sleep parameters, including 
sleep onset latency, total sleep time, and wake after sleep onset, number of awakenings, and sleep quality.  
     
 
 
 
  
     
 
 
 
 
  
Sections also affected by this change:  


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22 
• 
Not applicable 
Purpose: Modify efficacy analysis to indicate the Part A-specific endpoints 
The primary change occurs in Section 13.5 Efficacy Analysis  
Now reads: 
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 in Part A only (eg, sleep latency (SL), total sleep time (TST), wake after sleep onset (WASO)), ISI score in Part A 
only, and selected individual items and/or subscale scores in HAM-D for change from baseline.  
Sections also affected by this change:  
• 
Synopsis 
Purpose: Include a restriction for subjects feeling sedated, somnolent, or dizzy to refrain from driving or engaging in other activities 
requiring alertness. 
The primary change occurs in Section 9.2.3 Other Restrictions 
Now reads: 
Subjects who are feeling sedated, somnolent, and/or dizzy are to refrain from driving or engaging in any activity requiring 
alertness. 
Sections also affected by this change:  
• 
Not applicable 
Purpose: Specify that for Part B, in the event of a dose reduction, an unscheduled 
 sample should be collected, if possible, prior to 
the dose adjustment. 


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23 
 
 
 
 
 
Sections also affected by this change:  
• 
Schedule of Events (Part B) footnote p 
 
Purpose: Add definition of an abbreviated physical exam 
The primary change occurs in Section 12.1.3 Physical Examination 
Now reads: 
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. An abbreviated 
physical exam includes a brief medical history followed by a targeted physical exam. 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. 
Sections also affected by this change:  
• 
Schedule of Events (Part B) footnote e 
 
Purpose: Add specific psychiatric diagnoses that are documented as part of medical history.  
The primary change occurs in Section 12.1.1 Demographic/Medical History 
Now reads: 
Demographic characteristics (age, race, gender, ethnicity, employment status, highest education level, marital/civil status) and a full 
medical history, including: family psychiatric history, generalized anxiety disorder, obsessive-compulsive disorder, panic 


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24 
disorder, persistent depressive disorder, postpartum depression, substance use disorder, alcohol use disorder, major 
depressive disorder with seasonal pattern, major depressive disorder with psychotic features, premenstrual dysphoric 
disorder, major depressive disorder with atypical features, schizophrenia, or schizoaffective disorder will be documented. The 
diagnosis of MDD will be determined using the SCID-5-CT. If available, the disease code associated with the diagnosis of MDD 
based on the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) should be 
recorded. 
Sections also affected by this change:  
• 
Not applicable 
Purpose: In accordance with Administrative Letter #2, dated 15 August 2019, specify that for the extended follow-up period, an 
assessment timeframe of past 7 days should be used for the HAM-D questionnaire. 
The primary change occurs in Section 11.1.1 Hamilton Rating Scale for Depression (HAM-D) 
Now reads: 
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 past 7 days (1 week) will be used at Screening and during the extended Follow-up Period (Part A only), and ‘Since 
Last Visit’ will be used for all other visits. 
Sections also affected by this change:  
• 
Schedule of Events (Part A) footnote o 
Purpose: Correct typographical errors, punctuation, grammar, abbreviations, formatting and updated references list. 
These changes are not listed individually. 
 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-MDD-301 v7.0 
 
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 MAR 2019 
Date of Amendment 4 
Date of Amendment 5 
Version 5.0, 25 MAR 2019 
Version 6.0, 02 MAR 2020 
Date of Amendment 6 
Version 7.0, 14 SEP 2020 
 
Confidentiality Statement 
The confidential information in this document is provided to you as an Investigator or consultant for review by you, 
your staff, and the applicable Institutional Review Board/Independent Ethics Committee. Your acceptance of this 
document constitutes agreement that you will not disclose the information contained herein to others without written 
authorization from Sage Therapeutics, Inc. 


Clinical Protocol 
 
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217-MDD-301 v7.0 
 
CONFIDENTIAL 
 
 
2 
 
SPONSOR APPROVAL 
Protocol Number: 
217-MDD-301 
Study Drug: 
SAGE-217 
Study Phase: 
Phase 3 
Sponsor: 
Sage Therapeutics, Inc. 
Protocol Date: 
Version 7.0, 14 September 2020 
Sponsor Approval 
 
__
_________________________ ___________________________ 
, MD, MBA 
Date 
 
Sage Therapeutics 
 
__
________________________________ ___________________________ 
, MBBS (MD) 
Date 
 
Sage Therapeutics 
 
__
____________________________________ ___________________________ 
, RAC 
Date 
 
Sage Therapeutics 
 
_______________________________________________ ___________________________ 
 
Date 
 
Sage Therapeutics 
 
__
__________________________________ ___________________________ 
, PhD 
Date 
 
Sage Therapeutics 
 
__
_______________________________ ___________________________ 
 
Date 
 
Sage Therapeutics 
DocuSign Envelope ID: A35A0B09-6DF4-4986-BD35-8851C5746D31
9/15/2020
9/15/2020
9/15/2020
9/15/2020
9/15/2020
9/15/2020


Clinical Protocol 
 
Sage Therapeutics, Inc. 
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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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217-MDD-301 v7.0 
 
CONFIDENTIAL 
 
 
4 
 
PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Syneos Health Medical 
Monitor  
, MD   
   
Email: 
 
Office: 
 
Cell:  
 
Sage Study Physician 
, MD, MBA 
  
Email: 
 
Tel: 
 
24-Hour Serious 
Adverse Event 
Reporting 
IQVIA Lifecycle Safety 
Email: Sage.Safety@iqvia.com  
Telephone 
Fax 
 
 
+1 855-564-2229 
+1 855-638-1674 
Product Complaint 
Reporting 
Sage Therapeutics, Inc. 
Email: productcomplaints@sagerx.com  
Tel: +1 833-554-7243 
 


Clinical Protocol 
 
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217-MDD-301 v7.0 
 
CONFIDENTIAL 
 
 
5 
 
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: Part A: Approximately 55 sites in the United States 
Part B: Approximately 40 sites in the United States 
Phase of development: 3 
Planned Duration of Subject Participation: 
Part A: 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) 
Part B: up to 70 days (up to 28-day Screening Period, 14-day Double-blind Treatment Period, and 
a 28-day double-blind Follow-up Period) 
Objectives: 
Primary:  
• 
To evaluate the efficacy of SAGE-217 in the treatment of major depressive disorder 
(MDD) compared to placebo. 
Secondary: 
• 
Part A only: 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. 
Part A - 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  


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CONFIDENTIAL 
 
 
6 
 
• 
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”  
• 
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) 
Part B - Key Secondary: 
• 
Change from baseline in CGI-S at Day 15 
• 
Change from baseline in HAM-D total score at Day 8, Day 3, and Day 42 
Part B – Other Secondary: 
• 
HAM-D response at Day 15 and Day 42 
• 
HAM-D remission at Day 15 and Day 42 
• 
CGI-I response, defined as “much improved” or “very much improved”, at Day 15 
• 
Change from baseline in MADRS total score at Day 15 
• 
Change from baseline in HAM-A total score at Day 15 
• 
Time to first HAM-D response 
• 
Change from baseline in PRO measures of health-related quality of life, as assessed by 
responses to SF-36v2, and of depressive symptoms, as assessed by the 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) 
 
 
  
 
  
 
 


Clinical Protocol 
 
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CONFIDENTIAL 
 
 
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Study Description:  
This is a randomized, double-blind, parallel-group, placebo-controlled study in subjects with 
MDD. This study will be conducted in 2 parts – Part A and Part B. Part B will commence after 
all subjects in Part A have completed the Day 42 visit. Parts A and B will enroll unique subjects. 
For both study parts, 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. Each 
study part is described below. 
Part A 
Part A 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. 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. 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 2. 
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. 
Part B 
Part B will consist of a Screening Period of up to 28 days, a 14-day double-blind Treatment 
Period, and a 28-day follow-up period. Part B of the study may run concurrently with the 
extended follow-up period in Part A. 
The Screening Period begins with the signing of the ICF at the Screening Visit; the ICF must be 
signed prior to beginning any screening activities. Subjects will undergo preliminary screening 


Clinical Protocol 
 
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CONFIDENTIAL 
 
 
8 
 
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 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 2 treatment groups 
(SAGE-217 50 mg or matching placebo) in a 1:1 ratio. Subjects will self-administer study drug 
once daily at approximately 8 PM with fat-containing food (eg, within 1 hour of an evening 
meal which contains fat, or with a fat-containing snack), on an outpatient basis, for 14 days. 
Subjects will return to the study center during the treatment and follow-up periods as outlined in 
Table 3.  
During the treatment period, subjects will be able to receive study drug as long as there are no 
dose limiting safety/tolerability concerns. Subjects who cannot tolerate 50 mg will receive 
40 mg for the remainder of the treatment period. At the discretion of the Investigator, subjects 
who cannot tolerate the 40-mg dose may be discontinued from study drug.  
Subjects who discontinue treatment early should return to the site for an 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 ET visit. If necessary, 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 EOT visit assessments should be 
conducted in addition to an abbreviated physical exam. 
Number of Subjects (planned):  
Part A: approximately 450 subjects will be randomized and dosed to obtain 399 evaluable 
subjects. 
Part B: approximately 370 subjects will be randomized and dosed to obtain sufficient evaluable 
subjects for all analyses. 
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 64 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.  


Clinical Protocol 
 
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CONFIDENTIAL 
 
 
9 
 
6. For Part A, subject has a MADRS total score of ≥32 and a HAM-D total score ≥22 at 
screening and Day 1 (prior to dosing). For Part B, subject has a HAM-D total score 
≥24 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 who have stopped taking 
antidepressants within 60 days must have stopped for longer than 5 half-lives of the 
antidepressant 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 or 
without 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 is currently at significant risk of suicide, as judged by the Investigator, or 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. 


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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. For 
Part A, 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. For Part B, a BMI 
≤18 or ≥45 kg/m2 is exclusionary; a BMI of 40 to 44.9 kg/m2, inclusive, at Screening is 
subject to a broader evaluation of medical comorbidities as described above.  
4. 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.  
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.  


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CONFIDENTIAL 
 
 
11 
 
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. 
SAGE-217 Dosage and Mode of Administration:  
SAGE-217 is available as hard gelatin capsules for oral administration. Available dose strengths 
are: 
• 
Part A: a 30-mg or 20-mg dose 
• 
Part B: a 50-mg dose, with the option to reduce to 40 mg for intolerable AEs  
Reference Therapy, Dosage, and Mode of Administration: 
Placebo will be provided as hard gelatin capsules for oral administration.  
Duration of Treatment: 14 days 


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Statistical methods: 
A detailed description of the statistical analyses to be performed in the study will be provided in 
the Statistical Analysis Plan (SAP). Separate SAPs will be generated for each part of the study. 
The SAP for each study part will be finalized and approved prior to treatment unblinding of each 
respective part.  
For Part A, 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. 
Part B will not include an extended follow-up period, and the database lock will occur at the end 
of the study after all subjects have completed the Day 42 visit. 
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.  
 
Determination of Sample Size 
For Part A, 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%. 
For Part B, assuming a two-sided alpha level of 0.05, a sample size of 216 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 a standard deviation (SD) of 9 points. Assuming a 10% dropout rate and a 1:1 
randomization ratio within each stratum (antidepressant use at baseline, yes or no), 
approximately 240 total randomized subjects will be required to obtain 216 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. To ensure sufficient power for 
subgroup analyses, approximately 370 subjects will be randomized for Part B (see SAP for 
details). 
 


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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, 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 in Part A 
only (eg, sleep latency (SL), total sleep time (TST), wake after sleep onset (WASO)), ISI score 
in Part A only, 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 
will be assessed using the PWC-20. 
 
 
 
 
 


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Table 2: 
Schedule of Events (Part A) 
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 
 
 
 
 
 
 
 
 
 
 
 


Clinical Protocol 
 
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217-MDD-301 v7.0 
 
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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) 
 
 
 
 
 
 


Clinical Protocol 
 
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217-MDD-301 v7.0 
 
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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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217-MDD-301 v7.0 
 
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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. When ECGs 
 sample collection occur on the same day, the 12-lead ECGs will be performed 
 sample collection. 
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 during the extended follow-up period 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. 
 


Clinical Protocol 
 
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217-MDD-301 v7.0 
 
CONFIDENTIAL 
 
 
 
18 
 
Table 3: 
Schedule of Events (Part B) 
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 
EOT a 
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 Participant Check b 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
 
 
Serum FSH test c 
X 
 
 
 
 
 
 
 
 
 
 
SCID-5-CT 
X 
 
 
 
 
 
 
 
 
 
 
MGH ATRQ 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Family Historyd 
X 
 
 
 
 
 
 
 
 
 
 
Subject training e 
X 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Physical Examination f 
X 
X 
 
 
 
 
 
 
 
 
X 
Body Weight/Height 
X 
 
 
 
 
X 
(weight 
only) 
 
 
 
 
X 
(weight 
only) 
Clinical Laboratory 
Assessments g 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
Drug & Alcohol Screen h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-MDD-301 v7.0 
 
CONFIDENTIAL 
 
 
 
19 
 
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 
EOT a 
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 
 
Pregnancy Test i 
X 
X 
 
 
 
X 
 
 
X 
 
X 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs l 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
12-Lead ECG m 
X 
X 
 
 
 
X 
 
 
 
 
X 
C-SSRS n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAM-D o, p 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
MADRS 
 
X 
 
X 
 
X 
 
 
X 
 
X 
HAM-A o 
 
X 
 
X 
 
X 
 
 
X 
 
X 
CGI-S 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
SF-36v2 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
PHQ-9 
 
X 
 
X 
 
X 
 
 
X 
 
X 
PWC-20 
 
X 
 
 
 
X 
X 
X 
 
 
 
Study Drug Dispensation 
 
X 
 
X 
 
 
 
 
 
 
 
Study Drug Administration 
 
X (Day 1 through Day 14) 
 
 
 
 
 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-MDD-301 v7.0 
 
CONFIDENTIAL 
 
 
 
20 
 
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 
EOT a 
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 
 
Study Drug 
Accountability/Return 
 
 
 
X 
 
X 
 
 
 
 
X q 
Adverse Events/SAEsd, r 
X 
Prior/Concomitant 
Medications/Proceduresd, s 
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; 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. 
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. If 
necessary, 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 EOT 
visit assessments should be conducted in addition to an abbreviated physical exam.  
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 participants 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 Information regarding diagnosis, isolation, and/or hospitalization due to COVID-19 will be documented as part of Medical History, AE collection, and prior/concomitant 
medication/procedure collection at Screening and throughout the study. 
e Subjects will be trained on use of software applications and devices necessary for the conduct of the study by site personnel. 
f A full physical examination will be conducted at Screening and abbreviated physical examinations will be conducted thereafter. A full physical examination includes assessment 
of body systems (eg, head, eye, ear, nose, and throat; heart; lungs; abdomen; and extremities). An abbreviated physical exam includes a brief medical history followed by 
targeted physical exam. 
g Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. 
h Urine toxicology for selected drugs of abuse (as per the lab manual) and breath test for alcohol. 
i Serum pregnancy test at screening and urine pregnancy test thereafter for female subjects who are not surgically sterile and do not meet the protocol-defined criteria for being 
post-menopausal. 


Clinical Protocol 
 
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217-MDD-301 v7.0 
 
CONFIDENTIAL 
 
 
 
21 
 
 
l Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing). Heart rate and blood pressure to be collected in supine position at 
all scheduled time points after the participant has been resting for 5 minutes and then after approximately 3 minutes in the standing position. Vital signs may be repeated at the 
discretion of the Investigator as clinically indicated. 
m Triplicate ECGs will be collected. When ECGs 
 sample collection occur on the same day, the 12-lead ECGs will be performed 
 sample collection. 
n 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. 
o The HAM-D is to be completed as early during the visit as possible. 
p The assessment timeframe for HAM-D scales will refer to the past 7 days (1 week) at Screening and “Since Last Visit” for all other visits. The assessment timeframe for HAM-A 
scales will refer to the past 7 days (1 week) at all visits. 
 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. 
 


Clinical Protocol 
 
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217-MDD-301 v7.0 
 
CONFIDENTIAL 
 
 
22 
 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
1. 
TITLE PAGE ................................................................................................................1 
SPONSOR APPROVAL .................................................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................4 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............22 
LIST OF TABLES .........................................................................................................................26 
LIST OF FIGURES .......................................................................................................................26 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................27 
5. 
INTRODUCTION ......................................................................................................29 
5.1. 
Background of Major Depressive Disorder and Unmet Medical Need ......................29 
5.2. 
SAGE-217 ...................................................................................................................29 
5.3. 
Potential Risks and Benefits .......................................................................................30 
5.4. 
Dose Justification ........................................................................................................30 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................36 
6.1. 
Study Objective ..........................................................................................................36 
6.1.1. 
Primary Objective .......................................................................................................36 
6.1.2. 
Secondary Objective(s) ...............................................................................................36 
6.1.3. 
Safety Objective ..........................................................................................................36 
 
36 
6.2. 
Endpoints ....................................................................................................................36 
6.2.1. 
Primary Endpoint ........................................................................................................36 
6.2.2. 
Part A - Secondary Endpoints .....................................................................................36 
6.2.3. 
Part B – Key Secondary Endpoints ............................................................................37 
6.2.4. 
Part B – Other Secondary Endpoints ..........................................................................37 
6.2.5. 
Safety Endpoints .........................................................................................................37 
 
.37 
7. 
INVESTIGATIONAL PLAN .....................................................................................39 
7.1. 
Overall Study Design ..................................................................................................39 


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7.2. 
Number of Subjects ....................................................................................................40 
7.3. 
Treatment Assignment ................................................................................................40 
7.4. 
Dose Adjustment Criteria ...........................................................................................41 
7.5. 
Criteria for Study Termination ...................................................................................41 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................42 
8.1. 
Subject Inclusion Criteria ...........................................................................................42 
8.2. 
Subject Exclusion Criteria ..........................................................................................43 
8.3. 
Subject Withdrawal Criteria .......................................................................................45 
8.3.1. 
Replacement of Subjects .............................................................................................46 
9. 
TREATMENT OF SUBJECTS ..................................................................................47 
9.1. 
Study Drug ..................................................................................................................47 
9.2. 
Prior Medications, Concomitant Medications, and Restrictions ................................47 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................47 
9.2.2. 
Prohibited Medications ...............................................................................................47 
9.2.3. 
Other Restrictions .......................................................................................................48 
9.3. 
Treatment Adherence ..................................................................................................48 
9.4. 
Randomization and Blinding ......................................................................................49 
9.4.1. 
Emergency Identification of Study Drug ....................................................................49 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................51 
10.1. 
Description of Study Drug ..........................................................................................51 
10.2. 
Study Drug Packaging and Labeling ..........................................................................51 
10.3. 
Study Drug Storage .....................................................................................................51 
10.4. 
Study Drug Preparation ..............................................................................................51 
10.5. 
Study Drug Administration .........................................................................................51 
10.6. 
Study Drug Accountability .........................................................................................52 
10.7. 
Study Drug Handling and Disposal ............................................................................52 
10.8. 
Product Complaints ....................................................................................................53 
11. 
ASSESSMENT OF EFFICACY 
 .............................54 
11.1. 
Efficacy Assessments .................................................................................................54 
11.1.1. 
Hamilton Rating Scale for Depression (HAM-D) ......................................................54 
11.1.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) ........................................54 
11.1.3. 
Hamilton Anxiety Rating Scale (HAM-A) .................................................................54 


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11.1.4. 
Clinical Global Impression (CGI) ..............................................................................55 
11.1.5. 
Short Form-36 Version 2 (SF-36v2) ...........................................................................55 
11.1.6. 
Patient Health Questionnaire (PHQ-9) .......................................................................55 
11.1.7. 
Insomnia Severity Index (ISI; Part A Only) ...............................................................56 
11.1.8. 
Core Consensus Sleep Diary (Part A Only) ...............................................................56 
 
56 
 
 
56 
 
57 
 
57 
 
57 
12. 
ASSESSMENT OF SAFETY .....................................................................................58 
12.1. 
Safety Parameters .......................................................................................................58 
12.1.1. 
Demographic/Medical History ...................................................................................58 
12.1.2. 
COVID-19 Questions .................................................................................................58 
12.1.3. 
Weight and Height ......................................................................................................58 
12.1.4. 
Physical Examination .................................................................................................59 
12.1.5. 
Vital Signs ..................................................................................................................59 
12.1.6. 
Electrocardiogram (ECG) ...........................................................................................59 
12.1.7. 
Laboratory Assessments .............................................................................................59 
12.1.7.1. 
Drugs of Abuse and Alcohol ......................................................................................61 
12.1.7.2. 
Pregnancy Screen ........................................................................................................61 
12.1.8. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................61 
12.1.9. 
Physician Withdrawal Checklist .................................................................................62 
12.2. 
Adverse and Serious Adverse Events .........................................................................62 
12.2.1. 
Definition of Adverse Events .....................................................................................62 
12.2.1.1. 
Adverse Event (AE) ....................................................................................................62 
12.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................63 
12.3. 
Relationship to Study Drug ........................................................................................63 
12.4. 
Recording Adverse Events .........................................................................................64 
12.5. 
Reporting Serious Adverse Events .............................................................................65 
12.6. 
Overdose .....................................................................................................................65 
13. 
STATISTICS ..............................................................................................................67 


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13.1. 
Data Analysis Sets ......................................................................................................67 
13.2. 
Handling of Missing Data ...........................................................................................67 
13.3. 
General Considerations ...............................................................................................67 
13.4. 
Demographics and Baseline Characteristics ...............................................................67 
13.5. 
Efficacy Analyses .......................................................................................................68 
13.6. 
Safety Analyses ..........................................................................................................68 
13.6.1. 
Adverse Events ...........................................................................................................69 
13.6.2. 
Clinical Laboratory Evaluations .................................................................................69 
13.6.3. 
Physical Examinations ................................................................................................69 
13.6.4. 
Vital Signs ..................................................................................................................69 
13.6.5. 
12-Lead Electrocardiogram ........................................................................................69 
13.6.6. 
Prior and Concomitant Medications ...........................................................................70 
13.6.7. 
Columbia Suicide Severity Rating Scale ....................................................................70 
13.6.8. 
Physician Withdrawal Checklist .................................................................................70 
 
70 
13.8. 
Determination of Sample Size ....................................................................................70 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................72 
14.1. 
Study Monitoring ........................................................................................................72 
14.2. 
Audits and Inspections ................................................................................................72 
14.3. 
Institutional Review Board (IRB) or Ethics Committee (EC) ....................................73 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................74 
16. 
ETHICS ......................................................................................................................75 
16.1. 
Ethics Review .............................................................................................................75 
16.2. 
Ethical Conduct of the Study ......................................................................................75 
16.3. 
Written Informed Consent ..........................................................................................75 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................76 
17.1. 
Inspection of Records .................................................................................................76 
17.2. 
Retention of Records ..................................................................................................76 
18. 
PUBLICATION POLICY ..........................................................................................77 
19. 
LIST OF REFERENCES ............................................................................................78 
 


Clinical Protocol 
 
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26 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Schedule of Events (Part A) .......................................................................................14 
Table 3: 
Schedule of Events (Part B) ........................................................................................18 
Table 4: 
Abbreviations and specialist terms .............................................................................27 
Table 5: 
Clinical Laboratory Tests ...........................................................................................59 
Table 6: 
Relationship to Study Drug ........................................................................................64 
 
LIST OF FIGURES 
Figure 1: 
Predicted SAGE-217 concentrations (Cavg and Cmax) following dosing of 30 
to 50 mg daily .............................................................................................................32 
Figure 2: 
Total score change on Day 15 (Studies 217-MDD-201B, 217-PPD-201, 
Part A of the current study) ........................................................................................33 
Figure 3: 
Predicted incidence of sedation or somnolence by dose ............................................34 
 
 


Clinical Protocol 
 
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217-MDD-301 v7.0 
 
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27 
 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 4: 
Abbreviations and specialist terms 
Abbreviation or specialist term 
Explanation 
ADR 
adverse drug reaction 
AE 
adverse event 
AUC 
area under the curve 
Cavg 
average plasma concentration 
CGI-I 
Clinical Global Impression – Improvement 
CGI-S 
Clinical Global Impression – Severity 
Cmax  
maximum plasma concentration 
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  


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Abbreviation or specialist term 
Explanation 
IRB 
institutional review board 
IRT 
interactive response technology 
ISI 
Insomnia Severity Index 
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 
MTD 
maximum tolerated dose 
NCS 
not clinically significant 
NOAEL 
no-observed-adverse-effect-level 
OS 
oral solution 
PCS 
Potentially clinically significant 
PHQ-9 
9-item Patient Health Questionnaire 
 
 
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 
This study is being conducted in 2 parts – Part A and Part B. Unless otherwise specified, text in 
the following sections applies to both study parts.  
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 suicide attempts in adults 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 mirtazapine 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). 
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 
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. 
Unlike other neurotropic medications that target GABAA receptors, SAGE-217 is an allosteric 
modulator of both synaptic as well as extrasynaptic GABAA receptors (Martinez Botella 2017). 


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As such, SAGE-217 may represent a therapeutic advantage in the treatment of depressive 
disorders by resetting the GABAergic imbalance in depression by affecting both phasic and tonic 
inhibition. 
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 (Gunduz-Bruce 2019). 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. The most common adverse 
events (AEs) associated with SAGE-217 are somnolence, dizziness, and sedation; most AEs 
were reported as mild or moderate in intensity. Refer to the Investigator’s Brochure for a detailed 
description of the chemistry, pharmacology, efficacy, and safety of SAGE-217.  
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 
Part A 
There will be 2 dose levels of SAGE-217 in Part A 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 
(MTD) for the oral solution formulation 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 
Part A. 
Part B 
To date, the current capsule utilized in clinical studies is not associated with an MTD. Initial 
MTD assessments were performed using SAGE-217 in an oral solution (OS) at steady-state in 
healthy subjects, which provided an MTD with a Cmax of 125 ng/mL at 30 mg OS. While re-
identification of the MTD using the capsule formulations was not conducted, steady-state 30 mg 


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capsules provide a model-derived Cmax approximately 50% lower (64 ng/mL) than the 
concentration associated with the MTD of 30 mg OS (125 ng/mL).  
Studies 217-MDD-201 and 217-PPD-201, employing 30 mg capsules administered each evening 
for 14 days, demonstrated significant reduction in symptoms of depression, anxiety and 
insomnia. The safety profile in these studies is consistent with the GABAA neurosteroid 
mechanism, including adverse drug reactions (ADRs) of somnolence, sedation, and dizziness at 
rates of 4 to 15%; the majority with mild intensity. Phase 3 studies in a broader patient 
population demonstrate activity of SAGE-217 associated with improvement in depressive 
symptoms, however, both the efficacy and safety findings support investigation of a higher dose, 
with predictable ADRs expected to be within an acceptable range. 
Preliminary data through Day 42 of the double-blind period in Part A of this study demonstrated 
significant anti-depressant effects compared to placebo at Day 3, 8, and 12 but not Day 15 
(primary endpoint) for the 30 mg dose. The 20 mg dose did not separate from placebo at any 
timepoint. The rates of expected ADRs of somnolence, sedation and dizziness in the 30 mg arm 
were each less than 10%; rates of discontinuation for AEs were lower with SAGE-217 30 mg 
(2.1%) than with placebo (3.2%). No clinically relevant changes in vital signs, laboratories, 
electrocardiogram measures, or suicidal thinking were observed in either Part A of the current 
study or across the full SAGE-217 program, now with over 2000 subjects exposed to treatment. 
In addition, approximately 112 additional subjects have received blinded study drug (SAGE-217 
or placebo) in ongoing blinded clinical studies. Relevant results from Part A of this study are 
available in the SAGE-217 Investigator’s Brochure.  
Direct and modeled data from completed studies to date (including efficacy studies 
217-MDD-201 and 217-PPD-201) in addition to Part A (through Day 42 of the double-blind 
period) of the current study, have been used to assess and predict the efficacy and safety 
outcomes at SAGE-217 concentrations expected with higher doses of SAGE-217 capsules (eg, 
40 and 50 mg).  
Direct safety data come from more than 140 subjects exposed to concentrations of SAGE-217 
which are higher than those achieved with a 30-mg capsule daily dose, primarily in the clinical 
pharmacology program. No serious adverse events were reported in association with any of these 
higher exposures. Consistent with the pharmacological action of SAGE-217 at the GABAA 
receptor, reports of somnolence, dizziness and sedation were increased at increased plasma 
concentrations. Results from a clinically-complete study which evaluated the effects of 
SAGE-217 on driving performance (Study 217-CLP-113), in which subjects (n=59) were 
exposed to 4 days of 30 mg capsules, followed by a single dose of 60 mg capsules administered 
the evening prior to a driving simulation test, are illustrative. During treatment with 30 mg 
capsules daily (Day 1 to 4), the rates of somnolence, and dizziness were 8.5%, and 13.6%, 
respectively. After a single dose of 60 mg on Day 5, the rates of somnolence and dizziness 
increased to 13.8% and 22.4%, respectively. For these ADRs, the events were mild or moderate 
in intensity, and no discontinuations due to the adverse events occurred. No events of sedation 
were reported but could be reflected as events of fatigue which were reported at a rate of 3.4% 
with 30 mg (Day 1 to 4) and 13.8% after a dose of 60 mg on Day 5. In addition, in this study, 
while there was an increase in incidence of somnolence, dizziness and fatigue at 60 mg, there 
was not an increase in the severity of events. Additional data from Study 217-CLP-113 are 
provided in the Investigator’s Brochure. 


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Direct evidence related to efficacy and safety outcomes following administration of SAGE-217 
capsules at doses above 30 mg is further provided by results from a Phase 1, placebo-controlled 
study in healthy subjects using a 5-hour phase advance model of insomnia (Study 
217-EXM-101). Administration of single doses of SAGE-217 up to 45 mg improved sleep 
efficiency, duration, maintenance and sleep quality compared with placebo. Evening 
administration of SAGE-217 was generally well tolerated, with an acceptable safety and 
tolerability profile. All reported TEAEs were mild and all resolved. Additional data from Study 
217-EXM-101 are provided in the Investigator’s Brochure. 
Using exposure-response models developed for both efficacy and safety outcomes, the 
benefit-risk profile of SAGE-217 at doses of 40 or 50 mg capsules is expected to be acceptable. 
In Figure 1, the predicted concentrations of SAGE-217 following doses of 30, 40 or 50 mg 
capsules once daily are shown relative to two important concentration markers: Cavg as a marker 
for efficacy, identified based on pharmacodynamic biomarker modeling and clinical 
effectiveness (40 ng/mL) and Cmax as a marker for safety, associated with the MTD of the oral 
solution (125 ng/mL).  
Figure 1: 
Predicted SAGE-217 concentrations (Cavg and Cmax) following dosing of 30 to 
50 mg daily 
 
Dashed vertical lines represent target concentrations for efficacy (Cavg >40 ng/mL) and safety (Cmax<125 ng/mL). 
Percentage next to dashed lines indicate the percentages with Cavg>40 ng/mL or with Cmax>124 ng.   
The selection of 50 mg dosed daily was based first on efficacy, enabling the largest number of 
subjects to achieve a steady-state Cavg over 40 ng/mL. Figure 1 shows a dose of 50 mg will allow 
>90% subjects to maintain the target Cavg yet remain within the range of acceptable tolerability. 
With respect to Cmax, less than 1 in 5 (19%) subjects at the 50 mg dose level are expected to 
exceed a Cmax over 125 ng/mL, a level observed in Phase 1 studies which utilized oral solution 
and which was associated with a greater rate of sedation events.  
Increased granularity of the exposure-efficacy relationship is provided in Figure 2. Across 
Studies 217-MDD-201B, 217-PPD-201, and Part A of the current study, increased 
concentrations of SAGE-217 were associated with a larger reduction in depressive symptoms 
(Figure 2). Based on linear regression modeling, effect sizes for HAM-D were dose dependent, 
with a 50 mg dose administered once daily for 14 days predicted to provide greater therapeutic 


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benefit compared to daily doses of 40 and 30 mg. Based on preliminary results from Part A of 
this study, a dose of 30 mg may be considered the minimally effective dose.  
Figure 2: 
Total score change on Day 15 (Studies 217-MDD-201B, 217-PPD-201, Part A 
of the current study) 
 
 
Solid blue line= linear regression line; shaded area=95% CI around the regression; horizontal dashed line=mean 
placebo response; Vertical dashed lines from left to right are average concentrations for 20 mg capsules 
217-MDD-301 Part A, 30 mg capsules 217-MDD-301 Part A, 30 mg capsules 217-MDD-201B; 30 mg capsules 
217-PPD-201  
Exposure-response modeling for safety quantified the relationship between maximum plasma 
concentration (Cmax) and safety from studies 217-MDD-201, 217-PPD-201, and Part A of the 
current study. The safety endpoint for modeling was selected as the incidence of sedation or 
somnolence during SAGE-217 treatment, as they represent on-target effects at the GABAA 
receptor and are the most commonly occurring adverse events with SAGE-217 when considering 
all doses and formulations. Logistic regression modeling indicated higher Cmax values were 
associated with an increased incidence of sedation or somnolence across mild, moderate and 
severe intensities. Based on this observed relationship, the predicted incidence rates of sedation 
or somnolence were simulated at SAGE-217 doses of 30, 40 or 50 mg administered once daily 
(Figure 3). 


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Figure 3: 
Predicted incidence of sedation or somnolence by dose 
 
Circle and solid line=point estimate and 95% prediction interval. Percentage on the right of bar=absolute percentage 
of patients with sedation or somnolence during treatment with SAGE-217; percentage in parenthesis=difference in 
percentage from placebo. 
While Figure 3 indicates an increasing incidence of sedation or somnolence with a higher dose 
the rates of such events across all levels of severity are expected to be approximately 20 to 25%, 
consistent with safety outcomes associated with some currently available anti-depressants. As 
with usual clinical practice, subjects will have the option to dose reduce to 40 mg at any time 
should a lack of tolerability develop. As a reflection of the model accuracy, the cohort in 
CLP-113 exposed to 30 mg daily for 4 days, followed by a single-dose of 60 mg achieved a 
mean plasma concentration of 97 ng/mL at 8.5 hours after dosing, suggesting the Cmax 
experienced by these subjects approached or exceeded 125 ng/mL and was higher than the 
predicted Cmax of 106 ng/mL for a 50 mg dose (data on file).  
Safety margins have been calculated using the NOAELs from the 6-month rat and 9-month dog 
general toxicology studies (most conservative approach) and predicted steady-state exposures in 
humans following daily administration of 30, 40, or 50 mg SAGE-217 capsules. At present, 
mean steady-state exposures in humans following daily administration of 30 mg SAGE-217 
capsules following a high fat meal (most conservative; Cmax = 64 ng/mL; AUC = 936 ng⸱hr/mL) 
maintain safety margins of approximately 5x to 8x in rat (Cmax or AUC) and 6x in dog (Cmax or 
AUC) relative to the NOAEL in the respective species. While these margins are expectedly 
reduced with higher SAGE-217 concentrations, they remain approximately 3x to 5x in rat and 4x 
in dog (Cmax or AUC) to predicted plasma exposures for a 50 mg capsule administered once 
daily). 
Sedation, an extension of the pharmacologic mechanism of SAGE-217, was the primary 
dose-limiting effect in toxicity studies in rats and dogs. In dogs, the toxicologic ‘effect dose’ 
levels of 2.5 mg/kg/day (9-month study, episodic dosing study) or 2 mg/kg/day (3-month study) 
associated with a low incidence of convulsion and/or early mortality during or following the 
dosing phase, were associated with exposures 7- to 11-fold above clinically relevant Cmax 
following administration of 30 mg capsules. Similar margin calculations for adverse effect levels 
in dogs to potential higher SAGE-217 dose levels (40 or 50 mg/day) remain at or above 4.5x for 
both Cmax and AUC. All non-clinical findings are provided in the SAGE-217 Investigator’s 
Brochure. The totality of the nonclinical safety data supports the use of SAGE-217 for the 


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treatment of patients at the higher clinical dose regimen, particularly in the context of the current 
safety database of greater than 2000 subjects exposed to SAGE-217 treatment.  
In summary, preliminary results through Day 42 of the double-blind period in Part A of this 
study support the need for higher steady-state concentrations of SAGE-217 to allow subjects to 
experience maximum anti-depressant, anti-anxiety, and anti-insomnia benefits. Doses of 
SAGE-217 40 and 50 mg will be utilized in this trial, as well as all other ongoing trials with 
SAGE-217, under the 14-day regimen of an initial evening dose of 50 mg with reduction to 
40 mg as needed based on tolerability. These higher doses of SAGE-217 are expected to exhibit 
a favorable benefit-risk profile in the context of 30 mg now being identified as a minimally 
effective dose. While higher rates of ADRs may be anticipated, SAGE-217 is expected to 
maintain an acceptable tolerability profile, based on a current safety database of greater than 
2000 subjects exposed to SAGE-217 treatment across different doses/concentrations. In addition, 
higher doses offer the potential for improved therapeutic benefit over the short 14-day treatment 
course.  


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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: 
• Part A only: 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. 
Part A - Secondary Endpoints 
• 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 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. 
Part B – Key Secondary Endpoints 
• Change from baseline in CGI-S at Day 15 
• Change from baseline in HAM-D total score at Day 8, Day 3, and Day 42 
6.2.4. 
Part B – Other Secondary Endpoints 
• HAM-D response at Day 15 and Day 42 
• HAM-D remission at Day 15 and Day 42 
• CGI-I response, defined as “much improved” or “very much improved”, at Day 15 
• Change from baseline in MADRS total score at Day 15 
• Change from baseline in HAM-A total score at Day 15 
• Time to first HAM-D response 
• Change from baseline in PRO measures of health-related quality of life, as assessed 
by responses to the SF-36v2, and of depressive symptoms as assessed by the PHQ-9 
6.2.5. 
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) 
 
 
 


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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. This study will be conducted in 2 parts – Part A and Part B. Bart B will commence after 
all subjects in Part A have completed the Day 42 visit. Part A and Part B will enroll unique 
subjects. For both study parts, 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. Each study part is described below. 
Part A 
Part A 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). 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 2. 
Part B 
Part B will consist of a Screening Period of up to 28 days, a 14-day Treatment Period, and a 
28-day double-blind follow-up period. Part B of the study may run concurrently with the 
extended follow-up period in Part A. 
The Screening Period begins with the signing of the 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 


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exclusion criteria due to participation in another clinical study (Section 8.2). 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 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 2 treatment groups 
(SAGE-217 50 mg or matching placebo) in a 1:1 ratio. Subjects will self-administer study drug 
once daily at approximately 8 PM with fat-containing food (eg, within 1 hour of an evening meal 
which contains fat or with a fat-containing snack), on an outpatient basis, for 14 days. See 
Section 10.5 for examples of fat-containing snacks. Subjects will return to the study center 
during the treatment and follow-up periods as outlined in Table 3.  
During the treatment period, subjects will be able to receive study drug as long as there are no 
dose limiting safety/tolerability concerns. Subjects who cannot tolerate 50 mg will receive 40 mg 
for the remainder of the treatment period. At the discretion of the Investigator, subjects who 
cannot tolerate the 40-mg dose may be discontinued from study drug.  
Subjects who discontinue treatment early should return to the site for an 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 ET visit. The EOT and ET visits 
can be on the same day if a subject discontinues study drug and decides to terminate the study on 
the same day during a clinic visit; in this case, all EOT visit assessments should be conducted in 
addition to an abbreviated physical exam.  
7.2. 
Number of Subjects 
In Part A, approximately 450 subjects will be randomized and dosed to obtain 399 evaluable 
subjects (see Section 13.8). In Part B, approximately 370 subjects will be randomized and dosed 
to obtain sufficient evaluable subjects for all analyses. 
7.3. 
Treatment Assignment 
For both study parts, subjects will be randomly assigned to a treatment group on Day 1 and will 
be stratified based on use of antidepressant treatment (current/stable or not treated/withdrawn 
≥60 days) at baseline. In Part A, randomization will be performed within each stratum in a 1:1:1 
ratio to receive SAGE-217 20 mg, SAGE-217 30 mg, or matching placebo. In Part B, 
randomization will be performed within each stratum in a 1:1 ratio to receive SAGE-217 50 mg 
or matching placebo.  


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7.4. 
Dose Adjustment Criteria 
In Part A, dose adjustments are not permitted and subjects who cannot tolerate study drug will be 
discontinued from study drug and will receive treatment as clinically indicated (see Section 8.3). 
During the treatment period in Part B, subjects will be able to receive study drug as long as there 
are no dose limiting safety/tolerability concerns. Subjects who cannot tolerate 50 mg will receive 
40 mg for the remainder of the treatment period. At the discretion of the Investigator, subjects 
who cannot tolerate the 40-mg dose may be discontinued from study drug (refer to Section 8.3 
for procedures for early study drug discontinuation). If dose adjustment is deemed necessary by 
the Investigator at any time during the treatment period, the subject will return to the site to 
return any remaining study drug and for the adjusted dose to be dispensed. 
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 64 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. For Part A, subject has a MADRS total score of ≥32 and a HAM-D total score ≥22 at 
screening and Day 1 (prior to dosing). For Part B, subject has a HAM-D total score ≥24 
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 who have stopped taking antidepressants 
within 60 days must have stopped for longer than 5 half-lives of the antidepressant 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 


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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 or 
without 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 is currently at significant risk of suicide, as judged by the Investigator, or 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. For Part 
A, 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. For Part B, a BMI ≤18 
or ≥45 kg/m2 is exclusionary; a BMI of 40 to 44.9 kg/m2, inclusive, at Screening is 
subject to a broader evaluation of medical comorbidities as described above. 
4. 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 
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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 
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. 


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25. Subject is taking psychostimulants (eg, methylphenidate, amphetamine) or opioids, 
regularly or as-needed, at Day -28. 
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, including suicidality, at the discretion of the 
Investigator  
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 may withdraw the subject from the 
study at his/her discretion. 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.  
In Part A, 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.  
In Part B, subjects who discontinue study drug early should return to the site for an 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. If necessary, 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 EOT visit 
assessments should be conducted in addition to an abbreviated physical exam. 


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For both study parts, 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 
In Part A, subjects will self-administer SAGE-217 (20 or 30 mg) or matching placebo orally 
once daily in the evening with food for 14 days.  
In Part B, subjects will self-administer SAGE-217 (50 mg or 40 mg [for dose adjustments only 
as permitted as described in Section 7.4]) or matching placebo orally once daily at approximately 
8 PM with food for 14 days. The 50-mg and 40-mg doses will be administered as 2 capsules per 
dose (50 mg, administered as one 30 mg-capsule and one 20-mg capsule, and 40-mg, 
administered as two 20-mg capsules). Placebo will also be administered as 2 capsules to 
maintain the blind.  
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 
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• Chronic or as-needed psychostimulants (eg, methylphenidate, amphetamine) or 
opioids from Day -28 through the Day 42 visit 
• First generation (typical) antipsychotics (eg, haloperidol, perphenazine) and second 
generation (atypical) antipsychotics (eg, aripiprazole, quetiapine) from Day -14 
through the Day 42 visit 
• Use of any non-GABA anti-insomnia medications (eg, 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 who are feeling sedated, somnolent, and/or dizzy are to refrain from driving or engaging 
in any activity requiring alertness. 
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 10.5,  Table 2, and Table 3).  
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 


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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 2 and Table 3, at which time the Investigator or designee will be responsible for ensuring 
the kit contains sufficient doses for the duration of the treatment period.  
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. For both study parts, 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.  
In Part A, 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. In Part B, randomization will be done within 
each stratum in a 1:1 ratio to receive SAGE-217 50 mg or matched placebo.  
In both study parts, subjects, clinicians, and the study team will be blinded to treatment 
allocation. Randomization will be performed centrally via an interactive response technology 
(IRT) system. Randomization schedules will be generated by an independent statistician. The 
allocation to treatment group will be based on the randomization schedule. The randomization 
schedules will be kept strictly confidential, accessible only to authorized personnel until the time 
of unblinding.  
In Part A, 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 Part B, the Sponsor, site personnel and subjects will remain blinded until the database lock 
when all subjects complete the Day 42 visit. 
9.4.1. 
Emergency Identification of Study Drug 
During the study, the blind is to be broken only when the safety of a subject is at risk and the 
treatment plan is dependent on the study treatment received. Unless a subject is at immediate 
risk, the Investigator should make diligent attempts to contact Sage prior to unblinding the study 
treatment administered to a subject. Requests from the Investigator about the treatment 
administered to study subjects should be discussed with the Sage Medical Monitor. If the 
unblinding occurs without Sage’s knowledge, the Investigator must notify Sage within 24 hours 
of breaking the blind. All circumstances surrounding a premature unblinding must be clearly 
documented in the source records.   
In all cases where the 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 


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eCRF. At the of withdrawal from the study/stopping participation, if possible, an EOT and/or ET 
visit should be conducted.  
If a subject(s) or study personnel become unblinded to subject’s treatment assignment before 
database lock, the subject(s) will be excluded from the Per Protocol Set, but included in Full 
Analysis Set, as detailed further in the statistical analysis plan. 


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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. 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. For Part A, each unit dose consists of 
1 capsule. For Part B, each unit dose consists of 2 capsules (see Section 9.1). 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 
In Part A, 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.  
In Part B, SAGE-217 is to be administered orally once daily at approximately 8 PM with 
fat-containing food (eg, within 1 hour of an evening meal which contains fat, or with a 
fat-containing snack). Examples of fat-containing snacks include nuts, peanut butter, avocado, 
eggs, and cheese.  
In both study parts, 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. 


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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 2 and Table 3.  
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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10.8. 
Product Complaints 
A product complaint is any written, electronic, or verbal expression of dissatisfaction regarding 
the identity, quality, reliability, safety, purity, potency, effectiveness or performance (applicable 
for approved marketed products) of a drug product after it is released for distribution. In the 
course of conduct of the study, study personnel may become aware of a product complaint 
associated with the use of a Sage product. Personnel shall notify Sage within 24 hours by 
forwarding the product complaint information via the contact information listed in Table 1. 
Where possible, personnel should segregate any product, materials, or packaging associated with 
the product complaint. 


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11. 
ASSESSMENT OF EFFICACY 
 
All assessments will be conducted according to the schedule of assessments (Table 2 and 
Table 3). 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 past 7 days 
(1 week) will be used at Screening and during the extended Follow-up Period (Part A only), 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: 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; Part A Only) 
The ISI will be assessed in Part A only. 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 (Part A Only) 
The Core Consensus Sleep Diary will be assessed in Part A only. This instrument 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 2 and 
Table 3). 
12.1.1. 
Demographic/Medical History 
Demographic characteristics (age, race, gender, ethnicity, employment status, highest education 
level, marital/civil status) and a full medical history, including: family psychiatric history, 
generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic 
stress disorder, bipolar disorder, persistent depressive disorder, postpartum depression, substance 
use disorder, alcohol use disorder, major depressive disorder with seasonal pattern, major 
depressive disorder with psychotic features, premenstrual dysphoric disorder, major depressive 
disorder with atypical features, schizophrenia; or schizoaffective disorder will be documented. 
The diagnosis of MDD will be determined using the SCID-5-CT. If available, the disease code 
associated with the diagnosis of MDD based on the 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. 
COVID-19 Questions 
Information regarding diagnosis, isolation, and/or hospitalization due to COVID-19 will be 
documented as part of Medical History, AE collection, and prior/concomitant 
medication/procedure collection at Screening and throughout the study. 
Questions to be asked are as follows: 
• Were you diagnosed with COVID-19 by a healthcare professional? 
− If the answer is “no”, no further questions. 
− If the answer is “yes”, the following questions are asked: 
o 
Did you have a test?  If yes, was the result positive, negative or inconclusive? 
o 
Were you isolated?  If yes, what were the dates of isolation? 
o 
Were you hospitalized?  If yes, what were the dates of hospitalization? 
12.1.3. 
Weight and Height 
Height (Screening only) and weight will be measured and documented. 


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12.1.4. 
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. An abbreviated physical exam includes a 
brief medical history followed by a targeted physical exam. 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. 
12.1.5. 
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.  
12.1.6. 
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. When ECG 
 sample collection occur during the same visit, the ECGs will be 
conducted first. 
12.1.7. 
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 5. 
Table 5: 
Clinical Laboratory Tests 
Hematology  
Serum Chemistry 
Urinalysis 
Coagulation 
Red blood cell count 
Hemoglobin  
Hematocrit 
White blood cell count with 
differential  
Platelet count 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Total bilirubin 
Direct bilirubin 
pH 
Specific gravity 
Protein 
Glucose 
Red blood cell 
Nitrite 
Activated partial 
thromboplastin 
time 
Prothrombin time 
International 
normalized ratio 


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Red Blood Cell Indices 
(MCV, MCH, MCHC) 
Reflex to Red blood cell 
morphology if indices are 
abnormal 
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  
Leukocyte 
esterase 
Ketones 
Bilirubin 
Urobilinogen 
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 


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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). 
 
 
 
 
 
 
 
 
 
 
 
 
12.1.7.1. Drugs of Abuse and Alcohol 
Urine toxicology tests will be performed for selected drugs of abuse (see Table 5). A breath test 
for alcohol will be performed. 
12.1.7.2. 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. 
12.1.8. 
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 
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The “Baseline/Screening” C-SSRS form will be completed at screening (lifetime history and past 
24 months). The “Since Last Visit” C-SSRS form will be completed at all subsequent time 
points, as outlined in Table 2 and Table 3). 
12.1.9. 
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. 
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. 


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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 
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.”  


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Table 6: 
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. 
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 


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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. Any complication during 
pregnancy  (eg, anemia, infections, pre-eclampsia) should be reported as an AE/SAE. If the 
outcome of the pregnancy meets the criteria for immediate classification as an SAE (ie, 
spontaneous abortion, stillbirth, neonatal death, 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 
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. 
Overdose 
An overdose is defined as more than 2 capsules of study drug taken by a subject in an 18-hour 
period or more than 4 capsules taken by a subject in a 36-hour period.  
 
Overdoses, regardless of presence of associated clinical manifestation(s) (eg, headache, 
abnormal laboratory value) will be considered an AE and recorded as such on the eCRF. Any 
clinical manifestation(s) of overdose must also be recorded as an AE on the eCRF. In addition, 


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all overdoses must be recorded on an Overdose form and sent to Sage or designee within 
24 hours of the site becoming aware of the overdose.  
 


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13. 
STATISTICS 
A separate statistical analysis plan (SAP) will provide a detailed description of the analyses to be 
performed in the study. Separate SAPs will be generated for each part of the study. The SAP for 
each study part will be finalized and approved prior to treatment unblinding of each respective 
part. 
In Part A, 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. Data from Part A may be 
analyzed and reported following final database lock and before Part B is complete. For Part B, 
the final database lock will occur when all subjects complete the study; treatment unblinding and 
analyses will follow the database lock. 
Separate clinical study reports will be produced for each part of the study. 
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.  


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Medical/family history will be listed by subject.  
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, 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 diary endpoints in Part A 
only (eg, sleep latency (SL), total sleep time (TST), wake after sleep onset (WASO)), ISI score 
in Part A only, 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 


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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 
clinically significant (PCS) values are provided in the SAP. 
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.  


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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 
For Part A, 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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For Part B, assuming a two-sided alpha level of 0.05, a sample size of 216 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 a standard deviation (SD) of 9 points. Assuming a 10% dropout rate and a 
1:1 randomization ratio within each stratum (antidepressant use at baseline, yes or no), 
approximately 240 total randomized subjects will be required to obtain 216 evaluable subjects. 
Evaluable subjects are defined as those randomized subjects who receive study drug and have a 
valid baseline and at least 1 postbaseline HAM-D assessment. To ensure sufficient power for 
subgroup analyses, approximately 370 subjects will be randomized for Part B (see SAP for 
details). 


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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. 
DSM-5.  Diagnostic and statistical manual of mental disorders (5th ed.).  American Psychiatric 
Association 2013.  Arlington, VA: American Psychiatric Publishing. 
Greenberg PE, Fournier AA, Sisitsky T, Pike CT, Kessler RC. The economic burden of adults 
with major depressive disorder in the United States (2005 and 2010). J Clin Psychiatry. 2015 
Feb;76(2):155-62. 
Gunduz-Bruce H, Silber C, Kaul I, et al. Trial of SAGE-217 in Patients with Major Depressive 
Disorder. N Engl J Med. 2019; 381:903-911. 
Martinez Botella G, Salituro FG, Harrison BL, et al. Neuroactive steroids. 2. 3α-hydroxy-3β-
methyl-21-(4-cyano-1H-pyrazol-1’-yl)-19-nor-5β-pregnan-20-one (SAGE-217): A clinical next 
generation neuroactive steroid positive allosteric modulator of the (γ-aminobutyric acid) A 
receptor. J Med Chem 2017;28;60(18):7810-19. 
  
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. 


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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. 
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. 
 


217-MDD-301 Summary of Changes 
Sage Therapeutics 
Version 7, Amendment 6  
 
 
1 
Protocol 217-MDD-301, Amendment 6 
Date of Amendment: 14 September 2020 
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 increase the sample size of Part B from 
240 to 370 participants to ensure sufficient power for all subgroup analyses. Additional changes 
are outlined below: 
Objectives and Endpoints (Part B): 
• Revised timepoints for the key secondary endpoint, change from baseline in HAM-D 
total score, to coincide with those defined in the statistical analysis plan 
• Specified terminology of secondary endpoints 
 
Schedule of Assessments (Part B): 
• Added COVID-19 questions 
 
Statistical Analysis: 
• Revised to specify that, in the event of unblinding of a subject’s treatment assignment 
before database lock, the subject will be excluded from the Per Protocol Set, to 
coincide with the process defined in the statistical analysis plan 
• Removed compound symmetry as a method to achieve convergence in the event of a 
convergence issue 
• Specified that the sandwich estimator for the variance covariance matrix will be 
derived when the covariance structure is not UN 
 
Other: 
• Removed score of ‘0 (not assessed)’ as a choice for the Clinical Global Impression 
Scale 
 
 
 
• Added ‘post-traumatic stress disorder’ and ‘bipolar disorder’ to the list of disorders 
for which full medical history will be documented 


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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 MAR 2019 
Date of Amendment 4 
Date of Amendment 5 
Version 5.0, 25 MAR 2019 
Version 6.0, 02 MAR 2020 
Date of Amendment 6 
Version 7.0, 14 SEP 2020 
Date of Amendment 7 
Version 8.0, 14 DEC 2020 
 
Confidentiality Statement 
The confidential information in this document is provided to you as an Investigator or consultant for review by you, 
your staff, and the applicable Institutional Review Board/Independent Ethics Committee. Your acceptance of this 
document constitutes agreement that you will not disclose the information contained herein to others without written 
authorization from Sage Therapeutics, Inc. 


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SPONSOR APPROVAL 
Protocol Number: 
217-MDD-301 
Study Drug: 
SAGE-217 
Study Phase: 
Phase 3 
Sponsor: 
Sage Therapeutics, Inc. 
Protocol Date: 
Version 8.0, 14 December 2020 
Sponsor Approval 
 
____________
____________________ ___________________________ 
 MD, MBA 
Date 
Sage Therapeutics 
 
___
_________________________ ___________________________ 
 MBBS (MD) 
Date 
Sage Therapeutics 
 
___
_
__________________________ ___________________________ 
Date 
Sage Therapeutics 
 
___
___________________________ ___________________________ 
Date 
Sage Therapeutics 
 
___
_
___________________________ ___________________________ 
Date 
Sage Therapeutics 
 
__
_________________________________ ___________________________ 
Date 
g 
Sage Therapeutics 
DocuSign Envelope ID: BCFA7DDD-10F2-4C08-BC37-5C2627C7A9B3
14-Dec-2020 | 15:53 EST
14-Dec-2020 | 16:03 EST
14-Dec-2020 | 15:45 EST
15-Dec-2020 | 13:52 EST
14-Dec-2020 | 15:56 EST
15-Dec-2020 | 12:33 EST


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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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PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Syneos Health Medical 
Monitor  
, MD   
  
Email: 
 
Office: 
 
Cell:  
 
Sage Study Physician 
, MD, MBA 
 
Email: 
 
Tel: 
 
24-Hour Serious
Adverse Event
Reporting
IQVIA Lifecycle Safety 
Email: Sage.Safety@iqvia.com 
Telephone 
Fax 
+1 855-564-2229
+1 855-638-1674
Product Complaint 
Reporting 
Sage Therapeutics, Inc. 
Email: productcomplaints@sagerx.com 
Tel: +1 833-554-7243 


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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: Part A: Approximately 55 sites in the United States 
Part B: Approximately 40 sites in the United States 
Phase of development: 3 
Planned Duration of Subject Participation: 
Part A: 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) 
Part B: up to 70 days (up to 28-day Screening Period, 14-day Double-blind Treatment Period, and 
a 28-day double-blind Follow-up Period) 
Objectives: 
Primary:  
• 
To evaluate the efficacy of SAGE-217 in the treatment of major depressive disorder 
(MDD) compared to placebo. 
Secondary: 
• 
Part A only: 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. 
Part A - 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  


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• 
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”  
• 
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) 
Part B - Key Secondary: 
• 
Change from baseline in CGI-S at Day 15 
• 
Change from baseline in HAM-D total score at Day 8, Day 3, and Day 42 
Part B – Other Secondary: 
• 
HAM-D response at Day 15 and Day 42 
• 
HAM-D remission at Day 15 and Day 42 
• 
CGI-I response, defined as “much improved” or “very much improved”, at Day 15 
• 
Change from baseline in MADRS total score at Day 15 
• 
Change from baseline in HAM-A total score at Day 15 
• 
Time to first HAM-D response 
• 
Change from baseline in PRO measures of health-related quality of life, as assessed by 
responses to SF-36v2, and of depressive symptoms, as assessed by the 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) 
 
 
  
 
  
 
 


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Study Description:  
This is a randomized, double-blind, parallel-group, placebo-controlled study in subjects with 
MDD. This study will be conducted in 2 parts – Part A and Part B. Part B will commence after 
all subjects in Part A have completed the Day 42 visit. Parts A and B will enroll unique subjects. 
For both study parts, 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. Each 
study part is described below. 
Part A 
Part A 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. 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. 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 2. 
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. 
Part B 
Part B will consist of a Screening Period of up to 28 days, a 14-day double-blind Treatment 
Period, and a 28-day follow-up period. Part B of the study may run concurrently with the 
extended follow-up period in Part A. 
The Screening Period begins with the signing of the ICF at the Screening Visit; the ICF must be 
signed prior to beginning any screening activities. Subjects will undergo preliminary screening 


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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 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 2 treatment groups 
(SAGE-217 50 mg or matching placebo) in a 1:1 ratio. Subjects will self-administer study drug 
once daily at approximately 8 PM with fat-containing food (eg, within 1 hour of an evening 
meal which contains fat, or with a fat-containing snack), on an outpatient basis, for 14 days. 
Subjects will return to the study center during the treatment and follow-up periods as outlined in 
Table 3.  
During the treatment period, subjects will be able to receive study drug as long as there are no 
dose limiting safety/tolerability concerns. Subjects who cannot tolerate 50 mg will receive 
40 mg for the remainder of the treatment period. At the discretion of the Investigator, subjects 
who cannot tolerate the 40-mg dose may be discontinued from study drug.  
Subjects who discontinue treatment early should return to the site for an 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 ET visit. If necessary, 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 EOT visit assessments should be 
conducted in addition to an abbreviated physical exam. 
Number of Subjects (planned):  
Part A: approximately 450 subjects will be randomized and dosed to obtain 399 evaluable 
subjects. 
Part B: up to 575 subjects will be randomized and dosed to obtain sufficient evaluable subjects 
for all analyses. 
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 64 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.  


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Sage Therapeutics, Inc. 
217-MDD-301 v8.0 
 
CONFIDENTIAL 
 
 
9 
 
6. For Part A, subject has a MADRS total score of ≥32 and a HAM-D total score ≥22 at 
screening and Day 1 (prior to dosing). For Part B, subject has a HAM-D total score 
≥24 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 who have stopped taking 
antidepressants within 60 days must have stopped for longer than 5 half-lives of the 
antidepressant 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 or 
without 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 is currently at significant risk of suicide, as judged by the Investigator, or 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. 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-MDD-301 v8.0 
 
CONFIDENTIAL 
 
 
10 
 
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. For 
Part A, 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. For Part B, a BMI 
≤18 or ≥45 kg/m2 is exclusionary; a BMI of 40 to 44.9 kg/m2, inclusive, at Screening is 
subject to a broader evaluation of medical comorbidities as described above.  
4. 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.  
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.  


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-MDD-301 v8.0 
 
CONFIDENTIAL 
 
 
11 
 
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. 
SAGE-217 Dosage and Mode of Administration:  
SAGE-217 is available as hard gelatin capsules for oral administration. Available dose strengths 
are: 
• 
Part A: a 30-mg or 20-mg dose 
• 
Part B: a 50-mg dose, with the option to reduce to 40 mg for intolerable AEs  
Reference Therapy, Dosage, and Mode of Administration: 
Placebo will be provided as hard gelatin capsules for oral administration.  
Duration of Treatment: 14 days 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-MDD-301 v8.0 
 
CONFIDENTIAL 
 
 
12 
 
Statistical methods: 
A detailed description of the statistical analyses to be performed in the study will be provided in 
the Statistical Analysis Plan (SAP). Separate SAPs will be generated for each part of the study. 
The SAP for each study part will be finalized and approved prior to treatment unblinding of each 
respective part.  
For Part A, 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. 
Part B will not include an extended follow-up period, and the database lock will occur at the end 
of the study after all subjects have completed the Day 42 visit. 
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.  
The Modified Full Analysis Set (mFAS) is defined as all participants in the FAS with a total 
HAM-D score ≥ 26 at baseline. 
 
Determination of Sample Size 
For Part A, 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%. 
For Part B, assuming a two-sided alpha level of 0.05, a sample size of 216 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 a standard deviation (SD) of 9 points. Assuming a 10% dropout rate and a 1:1 
randomization ratio within each stratum (antidepressant use at baseline, yes or no), 
approximately 240 total randomized subjects will be required to obtain 216 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. To provide more power for 
analyses of key secondary endpoints, up to 575 subjects will be randomized for Part B. 
 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-MDD-301 v8.0 
 
CONFIDENTIAL 
 
 
13 
 
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, 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 in Part A 
only (eg, sleep latency (SL), total sleep time (TST), wake after sleep onset (WASO)), ISI score 
in Part A only, 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 
will be assessed using the PWC-20. 
 
 
 
 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-MDD-301 v8.0 
 
CONFIDENTIAL 
 
 
14 
 
Table 2: 
Schedule of Events (Part A) 
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 
 
 
 
 
 
 
 
 
 
 
 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-MDD-301 v8.0 
 
CONFIDENTIAL 
 
 
15 
 
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) 
 
 
 
 
 
 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-MDD-301 v8.0 
 
CONFIDENTIAL 
 
 
16 
 
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. 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-MDD-301 v8.0 
 
CONFIDENTIAL 
 
 
17 
 
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. When ECGs 
 collection occur on the same day, the 12-lead ECGs will be performed 
 sample collection. 
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 during the extended follow-up period 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. 
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. 
 
 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-MDD-301 v8.0 
 
CONFIDENTIAL 
 
 
 
18 
 
Table 3: 
Schedule of Events (Part B) 
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 
EOT a 
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 Participant Check b 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
 
 
Serum FSH test c 
X 
 
 
 
 
 
 
 
 
 
 
SCID-5-CT 
X 
 
 
 
 
 
 
 
 
 
 
MGH ATRQ 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Family Historyd 
X 
 
 
 
 
 
 
 
 
 
 
Subject training e 
X 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Physical Examination f 
X 
X 
 
 
 
 
 
 
 
 
X 
Body Weight/Height 
X 
 
 
 
 
X 
(weight 
only) 
 
 
 
 
X 
(weight 
only) 
Clinical Laboratory 
Assessments g 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
Drug & Alcohol Screen h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-MDD-301 v8.0 
 
CONFIDENTIAL 
 
 
 
19 
 
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 
EOT a 
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 
 
Pregnancy Test i 
X 
X 
 
 
 
X 
 
 
X 
 
X 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs l 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
12-Lead ECG m 
X 
X 
 
 
 
X 
 
 
 
 
X 
C-SSRS n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAM-D o, p 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
MADRS 
 
X 
 
X 
 
X 
 
 
X 
 
X 
HAM-A p 
 
X 
 
X 
 
X 
 
 
X 
 
X 
CGI-S 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
SF-36v2 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
PHQ-9 
 
X 
 
X 
 
X 
 
 
X 
 
X 
PWC-20 
 
X 
 
 
 
X 
X 
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 
Visit Days 
D-28 to 
D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(+1d) 
and/or 
EOT a 
D18 
(±1d) 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
or 
ET  
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
Study Procedure 
 
Study Drug 
Accountability/Return 
 
 
 
X 
 
X 
 
 
 
 
X r 
Adverse Events/SAEsd, s 
X 
Prior/Concomitant 
Medications/Proceduresd, t 
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; 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. 
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. If 
necessary, 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 EOT 
visit assessments should be conducted in addition to an abbreviated physical exam.  
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 participants 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 Information regarding diagnosis, isolation, and/or hospitalization due to COVID-19 will be documented as part of Medical History, AE collection, and prior/concomitant 
medication/procedure collection at Screening and throughout the study. 
e Subjects will be trained on use of software applications and devices necessary for the conduct of the study by site personnel. 
f A full physical examination will be conducted at Screening and abbreviated physical examinations will be conducted thereafter. A full physical examination includes assessment 
of body systems (eg, head, eye, ear, nose, and throat; heart; lungs; abdomen; and extremities). An abbreviated physical exam includes a brief medical history followed by 
targeted physical exam. 
g Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. 
h Urine toxicology for selected drugs of abuse (as per the lab manual) and breath test for alcohol. 
i Serum pregnancy test at screening and urine pregnancy test thereafter for female subjects who are not surgically sterile and do not meet the protocol-defined criteria for being 
post-menopausal. 


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l Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing). Heart rate and blood pressure to be collected in supine position at 
all scheduled time points after the participant has been resting for 5 minutes and then after approximately 3 minutes in the standing position. Vital signs may be repeated at the 
discretion of the Investigator as clinically indicated. 
m Triplicate ECGs will be collected. When ECGs 
 sample collection occur on the same day, the 12-lead ECGs will be performed 
 collection. 
n 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. 
o The HAM-D is to be completed as early during the visit as possible. 
p The assessment timeframe for HAM-D scales will refer to the past 7 days (1 week) at Screening and “Since Last Visit” for all other visits. The assessment timeframe for HAM-A 
scales will refer to the past 7 days (1 week) at all visits. 
 
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 
SPONSOR APPROVAL .................................................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................4 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............22 
LIST OF TABLES .........................................................................................................................26 
LIST OF FIGURES .......................................................................................................................26 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................27 
5. 
INTRODUCTION ......................................................................................................29 
5.1. 
Background of Major Depressive Disorder and Unmet Medical Need ......................29 
5.2. 
SAGE-217 ...................................................................................................................29 
5.3. 
Potential Risks and Benefits .......................................................................................30 
5.4. 
Dose Justification ........................................................................................................30 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................36 
6.1. 
Study Objective ..........................................................................................................36 
6.1.1. 
Primary Objective .......................................................................................................36 
6.1.2. 
Secondary Objective(s) ...............................................................................................36 
6.1.3. 
Safety Objective ..........................................................................................................36 
 
36 
6.2. 
Endpoints ....................................................................................................................36 
6.2.1. 
Primary Endpoint ........................................................................................................36 
6.2.2. 
Part A - Secondary Endpoints .....................................................................................36 
6.2.3. 
Part B – Key Secondary Endpoints ............................................................................37 
6.2.4. 
Part B – Other Secondary Endpoints ..........................................................................37 
6.2.5. 
Safety Endpoints .........................................................................................................37 
 
37 
7. 
INVESTIGATIONAL PLAN .....................................................................................39 
7.1. 
Overall Study Design ..................................................................................................39 


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7.2. 
Number of Subjects ....................................................................................................40 
7.3. 
Treatment Assignment ................................................................................................40 
7.4. 
Dose Adjustment Criteria ...........................................................................................41 
7.5. 
Criteria for Study Termination ...................................................................................41 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................42 
8.1. 
Subject Inclusion Criteria ...........................................................................................42 
8.2. 
Subject Exclusion Criteria ..........................................................................................43 
8.3. 
Subject Withdrawal Criteria .......................................................................................45 
8.3.1. 
Replacement of Subjects .............................................................................................46 
9. 
TREATMENT OF SUBJECTS ..................................................................................47 
9.1. 
Study Drug ..................................................................................................................47 
9.2. 
Prior Medications, Concomitant Medications, and Restrictions ................................47 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................47 
9.2.2. 
Prohibited Medications ...............................................................................................47 
9.2.3. 
Other Restrictions .......................................................................................................48 
9.3. 
Treatment Adherence ..................................................................................................48 
9.4. 
Randomization and Blinding ......................................................................................49 
9.4.1. 
Emergency Identification of Study Drug ....................................................................49 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................51 
10.1. 
Description of Study Drug ..........................................................................................51 
10.2. 
Study Drug Packaging and Labeling ..........................................................................51 
10.3. 
Study Drug Storage .....................................................................................................51 
10.4. 
Study Drug Preparation ..............................................................................................51 
10.5. 
Study Drug Administration.........................................................................................51 
10.6. 
Study Drug Accountability .........................................................................................52 
10.7. 
Study Drug Handling and Disposal ............................................................................52 
10.8. 
Product Complaints ....................................................................................................53 
11. 
ASSESSMENT OF EFFICACY 
 .............................54 
11.1. 
Efficacy Assessments .................................................................................................54 
11.1.1. 
Hamilton Rating Scale for Depression (HAM-D) ......................................................54 
11.1.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) ........................................54 
11.1.3. 
Hamilton Anxiety Rating Scale (HAM-A) .................................................................54 


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11.1.4. 
Clinical Global Impression (CGI) ..............................................................................55 
11.1.5. 
Short Form-36 Version 2 (SF-36v2) ...........................................................................55 
11.1.6. 
Patient Health Questionnaire (PHQ-9) .......................................................................55 
11.1.7. 
Insomnia Severity Index (ISI; Part A Only) ...............................................................56 
11.1.8. 
Core Consensus Sleep Diary (Part A Only) ...............................................................56 
 
56 
 
.56 
 
57 
 
57 
 
57 
12. 
ASSESSMENT OF SAFETY .....................................................................................58 
12.1. 
Safety Parameters .......................................................................................................58 
12.1.1. 
Demographic/Medical History ...................................................................................58 
12.1.2. 
COVID-19 Questions .................................................................................................58 
12.1.3. 
Weight and Height ......................................................................................................58 
12.1.4. 
Physical Examination .................................................................................................59 
12.1.5. 
Vital Signs ..................................................................................................................59 
12.1.6. 
Electrocardiogram (ECG) ...........................................................................................59 
12.1.7. 
Laboratory Assessments .............................................................................................59 
12.1.7.1. 
Drugs of Abuse and Alcohol ......................................................................................61 
12.1.7.2. 
Pregnancy Screen ........................................................................................................61 
12.1.8. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................61 
12.1.9. 
Physician Withdrawal Checklist .................................................................................62 
12.2. 
Adverse and Serious Adverse Events .........................................................................62 
12.2.1. 
Definition of Adverse Events .....................................................................................62 
12.2.1.1. 
Adverse Event (AE) ....................................................................................................62 
12.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................63 
12.3. 
Relationship to Study Drug ........................................................................................63 
12.4. 
Recording Adverse Events .........................................................................................64 
12.5. 
Reporting Serious Adverse Events .............................................................................65 
12.6. 
Overdose .....................................................................................................................65 
13. 
STATISTICS ..............................................................................................................67 


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13.1. 
Data Analysis Sets ......................................................................................................67 
13.2. 
Handling of Missing Data ...........................................................................................67 
13.3. 
General Considerations ...............................................................................................67 
13.4. 
Demographics and Baseline Characteristics ...............................................................67 
13.5. 
Efficacy Analyses .......................................................................................................68 
13.6. 
Safety Analyses ..........................................................................................................69 
13.6.1. 
Adverse Events ...........................................................................................................69 
13.6.2. 
Clinical Laboratory Evaluations .................................................................................69 
13.6.3. 
Physical Examinations ................................................................................................70 
13.6.4. 
Vital Signs ..................................................................................................................70 
13.6.5. 
12-Lead Electrocardiogram ........................................................................................70 
13.6.6. 
Prior and Concomitant Medications ...........................................................................70 
13.6.7. 
Columbia Suicide Severity Rating Scale ....................................................................70 
13.6.8. 
Physician Withdrawal Checklist .................................................................................71 
 
71 
13.8. 
Determination of Sample Size ....................................................................................71 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................72 
14.1. 
Study Monitoring ........................................................................................................72 
14.2. 
Audits and Inspections ................................................................................................72 
14.3. 
Institutional Review Board (IRB) or Ethics Committee (EC) ....................................73 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................74 
16. 
ETHICS ......................................................................................................................75 
16.1. 
Ethics Review .............................................................................................................75 
16.2. 
Ethical Conduct of the Study ......................................................................................75 
16.3. 
Written Informed Consent ..........................................................................................75 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................76 
17.1. 
Inspection of Records .................................................................................................76 
17.2. 
Retention of Records ..................................................................................................76 
18. 
PUBLICATION POLICY ..........................................................................................77 
19. 
LIST OF REFERENCES ............................................................................................78 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Schedule of Events (Part A) .......................................................................................14 
Table 3: 
Schedule of Events (Part B) ........................................................................................18 
Table 4: 
Abbreviations and specialist terms .............................................................................27 
Table 5: 
Clinical Laboratory Tests ...........................................................................................59 
Table 6: 
Relationship to Study Drug ........................................................................................64 
 
LIST OF FIGURES 
Figure 1: 
Predicted SAGE-217 concentrations (Cavg and Cmax) following dosing of 30 
to 50 mg daily .............................................................................................................32 
Figure 2: 
Total score change on Day 15 (Studies 217-MDD-201B, 217-PPD-201, 
Part A of the current study) ........................................................................................33 
Figure 3: 
Predicted incidence of sedation or somnolence by dose ............................................34 
 
 


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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 4: 
Abbreviations and specialist terms 
Abbreviation or specialist term 
Explanation 
ADR 
adverse drug reaction 
AE 
adverse event 
AUC 
area under the curve 
Cavg 
average plasma concentration 
CGI-I 
Clinical Global Impression – Improvement 
CGI-S 
Clinical Global Impression – Severity 
Cmax  
maximum plasma concentration 
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  


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Abbreviation or specialist term 
Explanation 
IRB 
institutional review board 
IRT 
interactive response technology 
ISI 
Insomnia Severity Index 
MADRS 
Montgomery Åsberg Depression Rating Scale 
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 
MTD 
maximum tolerated dose 
NCS 
not clinically significant 
NOAEL 
no-observed-adverse-effect-level 
OS 
oral solution 
PCS 
Potentially clinically significant 
PHQ-9 
9-item Patient Health Questionnaire 
 
 
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 
This study is being conducted in 2 parts – Part A and Part B. Unless otherwise specified, text in 
the following sections applies to both study parts.  
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 suicide attempts in adults 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 mirtazapine 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). 
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 
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. 
Unlike other neurotropic medications that target GABAA receptors, SAGE-217 is an allosteric 
modulator of both synaptic as well as extrasynaptic GABAA receptors (Martinez Botella 2017). 


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As such, SAGE-217 may represent a therapeutic advantage in the treatment of depressive 
disorders by resetting the GABAergic imbalance in depression by affecting both phasic and tonic 
inhibition. 
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 (Gunduz-Bruce 2019). 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. The most common adverse 
events (AEs) associated with SAGE-217 are somnolence, dizziness, and sedation; most AEs 
were reported as mild or moderate in intensity. Refer to the Investigator’s Brochure for a detailed 
description of the chemistry, pharmacology, efficacy, and safety of SAGE-217.  
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 
Part A 
There will be 2 dose levels of SAGE-217 in Part A 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 
(MTD) for the oral solution formulation 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 
Part A. 
Part B 
To date, the current capsule utilized in clinical studies is not associated with an MTD. Initial 
MTD assessments were performed using SAGE-217 in an oral solution (OS) at steady-state in 
healthy subjects, which provided an MTD with a Cmax of 125 ng/mL at 30 mg OS. While re-
identification of the MTD using the capsule formulations was not conducted, steady-state 30 mg 


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capsules provide a model-derived Cmax approximately 50% lower (64 ng/mL) than the 
concentration associated with the MTD of 30 mg OS (125 ng/mL).  
Studies 217-MDD-201 and 217-PPD-201, employing 30 mg capsules administered each evening 
for 14 days, demonstrated significant reduction in symptoms of depression, anxiety and 
insomnia. The safety profile in these studies is consistent with the GABAA neurosteroid 
mechanism, including adverse drug reactions (ADRs) of somnolence, sedation, and dizziness at 
rates of 4 to 15%; the majority with mild intensity. Phase 3 studies in a broader patient 
population demonstrate activity of SAGE-217 associated with improvement in depressive 
symptoms, however, both the efficacy and safety findings support investigation of a higher dose, 
with predictable ADRs expected to be within an acceptable range. 
Preliminary data through Day 42 of the double-blind period in Part A of this study demonstrated 
significant anti-depressant effects compared to placebo at Day 3, 8, and 12 but not Day 15 
(primary endpoint) for the 30 mg dose. The 20 mg dose did not separate from placebo at any 
timepoint. The rates of expected ADRs of somnolence, sedation and dizziness in the 30 mg arm 
were each less than 10%; rates of discontinuation for AEs were lower with SAGE-217 30 mg 
(2.1%) than with placebo (3.2%). No clinically relevant changes in vital signs, laboratories, 
electrocardiogram measures, or suicidal thinking were observed in either Part A of the current 
study or across the full SAGE-217 program, now with over 2000 subjects exposed to treatment. 
In addition, approximately 112 additional subjects have received blinded study drug (SAGE-217 
or placebo) in ongoing blinded clinical studies. Relevant results from Part A of this study are 
available in the SAGE-217 Investigator’s Brochure.  
Direct and modeled data from completed studies to date (including efficacy studies 
217-MDD-201 and 217-PPD-201) in addition to Part A (through Day 42 of the double-blind 
period) of the current study, have been used to assess and predict the efficacy and safety 
outcomes at SAGE-217 concentrations expected with higher doses of SAGE-217 capsules (eg, 
40 and 50 mg).  
Direct safety data come from more than 140 subjects exposed to concentrations of SAGE-217 
which are higher than those achieved with a 30-mg capsule daily dose, primarily in the clinical 
pharmacology program. No serious adverse events were reported in association with any of these 
higher exposures. Consistent with the pharmacological action of SAGE-217 at the GABAA 
receptor, reports of somnolence, dizziness and sedation were increased at increased plasma 
concentrations. Results from a clinically-complete study which evaluated the effects of 
SAGE-217 on driving performance (Study 217-CLP-113), in which subjects (n=59) were 
exposed to 4 days of 30 mg capsules, followed by a single dose of 60 mg capsules administered 
the evening prior to a driving simulation test, are illustrative. During treatment with 30 mg 
capsules daily (Day 1 to 4), the rates of somnolence, and dizziness were 8.5%, and 13.6%, 
respectively. After a single dose of 60 mg on Day 5, the rates of somnolence and dizziness 
increased to 13.8% and 22.4%, respectively. For these ADRs, the events were mild or moderate 
in intensity, and no discontinuations due to the adverse events occurred. No events of sedation 
were reported but could be reflected as events of fatigue which were reported at a rate of 3.4% 
with 30 mg (Day 1 to 4) and 13.8% after a dose of 60 mg on Day 5. In addition, in this study, 
while there was an increase in incidence of somnolence, dizziness and fatigue at 60 mg, there 
was not an increase in the severity of events. Additional data from Study 217-CLP-113 are 
provided in the Investigator’s Brochure. 


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Direct evidence related to efficacy and safety outcomes following administration of SAGE-217 
capsules at doses above 30 mg is further provided by results from a Phase 1, placebo-controlled 
study in healthy subjects using a 5-hour phase advance model of insomnia (Study 
217-EXM-101). Administration of single doses of SAGE-217 up to 45 mg improved sleep 
efficiency, duration, maintenance and sleep quality compared with placebo. Evening 
administration of SAGE-217 was generally well tolerated, with an acceptable safety and 
tolerability profile. All reported TEAEs were mild and all resolved. Additional data from Study 
217-EXM-101 are provided in the Investigator’s Brochure. 
Using exposure-response models developed for both efficacy and safety outcomes, the 
benefit-risk profile of SAGE-217 at doses of 40 or 50 mg capsules is expected to be acceptable. 
In Figure 1, the predicted concentrations of SAGE-217 following doses of 30, 40 or 50 mg 
capsules once daily are shown relative to two important concentration markers: Cavg as a marker 
for efficacy, identified based on pharmacodynamic biomarker modeling and clinical 
effectiveness (40 ng/mL) and Cmax as a marker for safety, associated with the MTD of the oral 
solution (125 ng/mL).  
Figure 1: 
Predicted SAGE-217 concentrations (Cavg and Cmax) following dosing of 30 to 
50 mg daily 
 
Dashed vertical lines represent target concentrations for efficacy (Cavg >40 ng/mL) and safety (Cmax<125 ng/mL). 
Percentage next to dashed lines indicate the percentages with Cavg>40 ng/mL or with Cmax>124 ng.   
The selection of 50 mg dosed daily was based first on efficacy, enabling the largest number of 
subjects to achieve a steady-state Cavg over 40 ng/mL. Figure 1 shows a dose of 50 mg will allow 
>90% subjects to maintain the target Cavg yet remain within the range of acceptable tolerability. 
With respect to Cmax, less than 1 in 5 (19%) subjects at the 50 mg dose level are expected to 
exceed a Cmax over 125 ng/mL, a level observed in Phase 1 studies which utilized oral solution 
and which was associated with a greater rate of sedation events.  
Increased granularity of the exposure-efficacy relationship is provided in Figure 2. Across 
Studies 217-MDD-201B, 217-PPD-201, and Part A of the current study, increased 
concentrations of SAGE-217 were associated with a larger reduction in depressive symptoms 
(Figure 2). Based on linear regression modeling, effect sizes for HAM-D were dose dependent, 
with a 50 mg dose administered once daily for 14 days predicted to provide greater therapeutic 


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benefit compared to daily doses of 40 and 30 mg. Based on preliminary results from Part A of 
this study, a dose of 30 mg may be considered the minimally effective dose.  
Figure 2: 
Total score change on Day 15 (Studies 217-MDD-201B, 217-PPD-201, Part A 
of the current study) 
 
 
Solid blue line= linear regression line; shaded area=95% CI around the regression; horizontal dashed line=mean 
placebo response; Vertical dashed lines from left to right are average concentrations for 20 mg capsules 
217-MDD-301 Part A, 30 mg capsules 217-MDD-301 Part A, 30 mg capsules 217-MDD-201B; 30 mg capsules 
217-PPD-201  
Exposure-response modeling for safety quantified the relationship between maximum plasma 
concentration (Cmax) and safety from studies 217-MDD-201, 217-PPD-201, and Part A of the 
current study. The safety endpoint for modeling was selected as the incidence of sedation or 
somnolence during SAGE-217 treatment, as they represent on-target effects at the GABAA 
receptor and are the most commonly occurring adverse events with SAGE-217 when considering 
all doses and formulations. Logistic regression modeling indicated higher Cmax values were 
associated with an increased incidence of sedation or somnolence across mild, moderate and 
severe intensities. Based on this observed relationship, the predicted incidence rates of sedation 
or somnolence were simulated at SAGE-217 doses of 30, 40 or 50 mg administered once daily 
(Figure 3). 


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Figure 3: 
Predicted incidence of sedation or somnolence by dose 
 
Circle and solid line=point estimate and 95% prediction interval. Percentage on the right of bar=absolute percentage 
of patients with sedation or somnolence during treatment with SAGE-217; percentage in parenthesis=difference in 
percentage from placebo. 
While Figure 3 indicates an increasing incidence of sedation or somnolence with a higher dose 
the rates of such events across all levels of severity are expected to be approximately 20 to 25%, 
consistent with safety outcomes associated with some currently available anti-depressants. As 
with usual clinical practice, subjects will have the option to dose reduce to 40 mg at any time 
should a lack of tolerability develop. As a reflection of the model accuracy, the cohort in 
CLP-113 exposed to 30 mg daily for 4 days, followed by a single-dose of 60 mg achieved a 
mean plasma concentration of 97 ng/mL at 8.5 hours after dosing, suggesting the Cmax 
experienced by these subjects approached or exceeded 125 ng/mL and was higher than the 
predicted Cmax of 106 ng/mL for a 50 mg dose (data on file).  
Safety margins have been calculated using the NOAELs from the 6-month rat and 9-month dog 
general toxicology studies (most conservative approach) and predicted steady-state exposures in 
humans following daily administration of 30, 40, or 50 mg SAGE-217 capsules. At present, 
mean steady-state exposures in humans following daily administration of 30 mg SAGE-217 
capsules following a high fat meal (most conservative; Cmax = 64 ng/mL; AUC = 936 ng⸱hr/mL) 
maintain safety margins of approximately 5x to 8x in rat (Cmax or AUC) and 6x in dog (Cmax or 
AUC) relative to the NOAEL in the respective species. While these margins are expectedly 
reduced with higher SAGE-217 concentrations, they remain approximately 3x to 5x in rat and 4x 
in dog (Cmax or AUC) to predicted plasma exposures for a 50 mg capsule administered once 
daily). 
Sedation, an extension of the pharmacologic mechanism of SAGE-217, was the primary 
dose-limiting effect in toxicity studies in rats and dogs. In dogs, the toxicologic ‘effect dose’ 
levels of 2.5 mg/kg/day (9-month study, episodic dosing study) or 2 mg/kg/day (3-month study) 
associated with a low incidence of convulsion and/or early mortality during or following the 
dosing phase, were associated with exposures 7- to 11-fold above clinically relevant Cmax 
following administration of 30 mg capsules. Similar margin calculations for adverse effect levels 
in dogs to potential higher SAGE-217 dose levels (40 or 50 mg/day) remain at or above 4.5x for 
both Cmax and AUC. All non-clinical findings are provided in the SAGE-217 Investigator’s 
Brochure. The totality of the nonclinical safety data supports the use of SAGE-217 for the 


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treatment of patients at the higher clinical dose regimen, particularly in the context of the current 
safety database of greater than 2000 subjects exposed to SAGE-217 treatment.  
In summary, preliminary results through Day 42 of the double-blind period in Part A of this 
study support the need for higher steady-state concentrations of SAGE-217 to allow subjects to 
experience maximum anti-depressant, anti-anxiety, and anti-insomnia benefits. Doses of 
SAGE-217 40 and 50 mg will be utilized in this trial, as well as all other ongoing trials with 
SAGE-217, under the 14-day regimen of an initial evening dose of 50 mg with reduction to 
40 mg as needed based on tolerability. These higher doses of SAGE-217 are expected to exhibit 
a favorable benefit-risk profile in the context of 30 mg now being identified as a minimally 
effective dose. While higher rates of ADRs may be anticipated, SAGE-217 is expected to 
maintain an acceptable tolerability profile, based on a current safety database of greater than 
2000 subjects exposed to SAGE-217 treatment across different doses/concentrations. In addition, 
higher doses offer the potential for improved therapeutic benefit over the short 14-day treatment 
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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: 
• Part A only: 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. 
Part A - Secondary Endpoints 
• 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 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. 
Part B – Key Secondary Endpoints 
• Change from baseline in CGI-S at Day 15 
• Change from baseline in HAM-D total score at Day 8, Day 3, and Day 42 
6.2.4. 
Part B – Other Secondary Endpoints 
• HAM-D response at Day 15 and Day 42 
• HAM-D remission at Day 15 and Day 42 
• CGI-I response, defined as “much improved” or “very much improved”, at Day 15 
• Change from baseline in MADRS total score at Day 15 
• Change from baseline in HAM-A total score at Day 15 
• Time to first HAM-D response 
• Change from baseline in PRO measures of health-related quality of life, as assessed 
by responses to the SF-36v2, and of depressive symptoms as assessed by the PHQ-9 
6.2.5. 
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) 
 
 
 


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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. This study will be conducted in 2 parts – Part A and Part B. Bart B will commence after 
all subjects in Part A have completed the Day 42 visit. Part A and Part B will enroll unique 
subjects. For both study parts, 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. Each study part is described below. 
Part A 
Part A 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). 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 2. 
Part B 
Part B will consist of a Screening Period of up to 28 days, a 14-day Treatment Period, and a 
28-day double-blind follow-up period. Part B of the study may run concurrently with the 
extended follow-up period in Part A. 
The Screening Period begins with the signing of the 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 


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exclusion criteria due to participation in another clinical study (Section 8.2). 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 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 2 treatment groups 
(SAGE-217 50 mg or matching placebo) in a 1:1 ratio. Subjects will self-administer study drug 
once daily at approximately 8 PM with fat-containing food (eg, within 1 hour of an evening meal 
which contains fat or with a fat-containing snack), on an outpatient basis, for 14 days. See 
Section 10.5 for examples of fat-containing snacks. Subjects will return to the study center 
during the treatment and follow-up periods as outlined in Table 3.  
During the treatment period, subjects will be able to receive study drug as long as there are no 
dose limiting safety/tolerability concerns. Subjects who cannot tolerate 50 mg will receive 40 mg 
for the remainder of the treatment period. At the discretion of the Investigator, subjects who 
cannot tolerate the 40-mg dose may be discontinued from study drug.  
Subjects who discontinue treatment early should return to the site for an 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 ET visit. The EOT and ET visits 
can be on the same day if a subject discontinues study drug and decides to terminate the study on 
the same day during a clinic visit; in this case, all EOT visit assessments should be conducted in 
addition to an abbreviated physical exam.  
7.2. 
Number of Subjects 
In Part A, approximately 450 subjects will be randomized and dosed to obtain 399 evaluable 
subjects (see Section 13.8). In Part B, up to 575 subjects will be randomized and dosed to obtain 
sufficient evaluable subjects for all analyses. 
7.3. 
Treatment Assignment 
For both study parts, subjects will be randomly assigned to a treatment group on Day 1 and will 
be stratified based on use of antidepressant treatment (current/stable or not treated/withdrawn 
≥60 days) at baseline. In Part A, randomization will be performed within each stratum in a 1:1:1 
ratio to receive SAGE-217 20 mg, SAGE-217 30 mg, or matching placebo. In Part B, 
randomization will be performed within each stratum in a 1:1 ratio to receive SAGE-217 50 mg 
or matching placebo.  


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7.4. 
Dose Adjustment Criteria 
In Part A, dose adjustments are not permitted and subjects who cannot tolerate study drug will be 
discontinued from study drug and will receive treatment as clinically indicated (see Section 8.3). 
During the treatment period in Part B, subjects will be able to receive study drug as long as there 
are no dose limiting safety/tolerability concerns. Subjects who cannot tolerate 50 mg will receive 
40 mg for the remainder of the treatment period. At the discretion of the Investigator, subjects 
who cannot tolerate the 40-mg dose may be discontinued from study drug (refer to Section 8.3 
for procedures for early study drug discontinuation). If dose adjustment is deemed necessary by 
the Investigator at any time during the treatment period, the subject will return to the site to 
return any remaining study drug and for the adjusted dose to be dispensed. 
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 64 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. For Part A, subject has a MADRS total score of ≥32 and a HAM-D total score ≥22 at 
screening and Day 1 (prior to dosing). For Part B, subject has a HAM-D total score ≥24 
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 who have stopped taking antidepressants 
within 60 days must have stopped for longer than 5 half-lives of the antidepressant 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 


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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 or 
without 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 is currently at significant risk of suicide, as judged by the Investigator, or 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. For Part 
A, 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. For Part B, a BMI ≤18 
or ≥45 kg/m2 is exclusionary; a BMI of 40 to 44.9 kg/m2, inclusive, at Screening is 
subject to a broader evaluation of medical comorbidities as described above. 
4. 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 
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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 
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. 


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25. Subject is taking psychostimulants (eg, methylphenidate, amphetamine) or opioids, 
regularly or as-needed, at Day -28. 
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, including suicidality, at the discretion of the 
Investigator  
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 may withdraw the subject from the 
study at his/her discretion. 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.  
In Part A, 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.  
In Part B, subjects who discontinue study drug early should return to the site for an 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. If necessary, 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 EOT visit 
assessments should be conducted in addition to an abbreviated physical exam. 


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For both study parts, 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 
In Part A, subjects will self-administer SAGE-217 (20 or 30 mg) or matching placebo orally 
once daily in the evening with food for 14 days.  
In Part B, subjects will self-administer SAGE-217 (50 mg or 40 mg [for dose adjustments only 
as permitted as described in Section 7.4]) or matching placebo orally once daily at approximately 
8 PM with food for 14 days. The 50-mg and 40-mg doses will be administered as 2 capsules per 
dose (50 mg, administered as one 30 mg-capsule and one 20-mg capsule, and 40-mg, 
administered as two 20-mg capsules). Placebo will also be administered as 2 capsules to 
maintain the blind.  
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) 


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• Chronic or as-needed psychostimulants (eg, methylphenidate, amphetamine) or 
opioids from Day -28 through the Day 42 visit 
• First generation (typical) antipsychotics (eg, haloperidol, perphenazine) and second 
generation (atypical) antipsychotics (eg, aripiprazole, quetiapine) from Day -14 
through the Day 42 visit 
• Use of any non-GABA anti-insomnia medications (eg, 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 who are feeling sedated, somnolent, and/or dizzy are to refrain from driving or engaging 
in any activity requiring alertness. 
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 10.5,  Table 2, and Table 3).  
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 


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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 2 and Table 3, at which time the Investigator or designee will be responsible for ensuring 
the kit contains sufficient doses for the duration of the treatment period.  
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. For both study parts, 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.  
In Part A, 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. In Part B, randomization will be done within 
each stratum in a 1:1 ratio to receive SAGE-217 50 mg or matched placebo.  
In both study parts, subjects, clinicians, and the study team will be blinded to treatment 
allocation. Randomization will be performed centrally via an interactive response technology 
(IRT) system. Randomization schedules will be generated by an independent statistician. The 
allocation to treatment group will be based on the randomization schedule. The randomization 
schedules will be kept strictly confidential, accessible only to authorized personnel until the time 
of unblinding.  
In Part A, 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 Part B, the Sponsor, site personnel and subjects will remain blinded until the database lock 
when all subjects complete the Day 42 visit. 
9.4.1. 
Emergency Identification of Study Drug 
During the study, the blind is to be broken only when the safety of a subject is at risk and the 
treatment plan is dependent on the study treatment received. Unless a subject is at immediate 
risk, the Investigator should make diligent attempts to contact Sage prior to unblinding the study 
treatment administered to a subject. Requests from the Investigator about the treatment 
administered to study subjects should be discussed with the Sage Medical Monitor. If the 
unblinding occurs without Sage’s knowledge, the Investigator must notify Sage within 24 hours 
of breaking the blind. All circumstances surrounding a premature unblinding must be clearly 
documented in the source records.   
In all cases where the 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 


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eCRF. At the of withdrawal from the study/stopping participation, if possible, an EOT and/or ET 
visit should be conducted.  
If a subject(s) or study personnel become unblinded to subject’s treatment assignment before 
database lock, the subject(s) will be excluded from the Per Protocol Set, but included in Full 
Analysis Set, as detailed further in the statistical analysis plan. 


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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. 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. For Part A, each unit dose consists of 
1 capsule. For Part B, each unit dose consists of 2 capsules (see Section 9.1). 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 
In Part A, 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.  
In Part B, SAGE-217 is to be administered orally once daily at approximately 8 PM with 
fat-containing food (eg, within 1 hour of an evening meal which contains fat, or with a 
fat-containing snack). Examples of fat-containing snacks include nuts, peanut butter, avocado, 
eggs, and cheese.  
In both study parts, if a subject misses a dose, the subject should skip that dose (ie, they should 
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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 2 and Table 3.  
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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10.8. 
Product Complaints 
A product complaint is any written, electronic, or verbal expression of dissatisfaction regarding 
the identity, quality, reliability, safety, purity, potency, effectiveness or performance (applicable 
for approved marketed products) of a drug product after it is released for distribution. In the 
course of conduct of the study, study personnel may become aware of a product complaint 
associated with the use of a Sage product. Personnel shall notify Sage within 24 hours by 
forwarding the product complaint information via the contact information listed in Table 1. 
Where possible, personnel should segregate any product, materials, or packaging associated with 
the product complaint. 


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11. 
ASSESSMENT OF EFFICACY 
 
All assessments will be conducted according to the schedule of assessments (Table 2 and 
Table 3). 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 past 7 days 
(1 week) will be used at Screening and during the extended Follow-up Period (Part A only), 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: 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; Part A Only) 
The ISI will be assessed in Part A only. 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 (Part A Only) 
The Core Consensus Sleep Diary will be assessed in Part A only. This instrument 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 2 and 
Table 3). 
12.1.1. 
Demographic/Medical History 
Demographic characteristics (age, race, gender, ethnicity, employment status, highest education 
level, marital/civil status) and a full medical history, including: family psychiatric history, 
generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic 
stress disorder, bipolar disorder, persistent depressive disorder, postpartum depression, substance 
use disorder, alcohol use disorder, major depressive disorder with seasonal pattern, major 
depressive disorder with psychotic features, premenstrual dysphoric disorder, major depressive 
disorder with atypical features, schizophrenia; or schizoaffective disorder will be documented. 
The diagnosis of MDD will be determined using the SCID-5-CT. If available, the disease code 
associated with the diagnosis of MDD based on the 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. 
COVID-19 Questions 
Information regarding diagnosis, isolation, and/or hospitalization due to COVID-19 will be 
documented as part of Medical History, AE collection, and prior/concomitant 
medication/procedure collection at Screening and throughout the study. 
Questions to be asked are as follows: 
•
Were you diagnosed with COVID-19 by a healthcare professional?
−
If the answer is “no”, no further questions.
−
If the answer is “yes”, the following questions are asked:
o
Did you have a test?  If yes, was the result positive, negative or inconclusive?
o
Were you isolated?  If yes, what were the dates of isolation?
o
Were you hospitalized?  If yes, what were the dates of hospitalization?
12.1.3. 
Weight and Height 
Height (Screening only) and weight will be measured and documented. 


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12.1.4. 
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. An abbreviated physical exam includes a 
brief medical history followed by a targeted physical exam. 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. 
12.1.5. 
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.  
12.1.6. 
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. When ECG 
 sample collection occur during the same visit, the ECGs will be 
conducted first. 
12.1.7. 
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 5. 
Table 5: 
Clinical Laboratory Tests 
Hematology  
Serum Chemistry 
Urinalysis 
Coagulation 
Red blood cell count 
Hemoglobin  
Hematocrit 
White blood cell count with 
differential  
Platelet count 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Total bilirubin 
Direct bilirubin 
pH 
Specific gravity 
Protein 
Glucose 
Red blood cell 
Nitrite 
Activated partial 
thromboplastin 
time 
Prothrombin time 
International 
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Red Blood Cell Indices 
(MCV, MCH, MCHC) 
Reflex to Red blood cell 
morphology if indices are 
abnormal 
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  
Leukocyte 
esterase 
Ketones 
Bilirubin 
Urobilinogen 
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 


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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). 
 
 
 
 
 
 
 
 
 
 
 
 
12.1.7.1. Drugs of Abuse and Alcohol 
Urine toxicology tests will be performed for selected drugs of abuse (see Table 5). A breath test 
for alcohol will be performed. 
12.1.7.2. 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. 
12.1.8. 
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 
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The “Baseline/Screening” C-SSRS form will be completed at screening (lifetime history and past 
24 months). The “Since Last Visit” C-SSRS form will be completed at all subsequent time 
points, as outlined in Table 2 and Table 3). 
12.1.9. 
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. 
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. 


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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 
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.”  


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Table 6: 
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. 
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 


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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. Any complication during 
pregnancy  (eg, anemia, infections, pre-eclampsia) should be reported as an AE/SAE. If the 
outcome of the pregnancy meets the criteria for immediate classification as an SAE (ie, 
spontaneous abortion, stillbirth, neonatal death, 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 
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. 
Overdose 
An overdose is defined as more than 2 capsules of study drug taken by a subject in an 18-hour 
period or more than 4 capsules taken by a subject in a 36-hour period.  
 
Overdoses, regardless of presence of associated clinical manifestation(s) (eg, headache, 
abnormal laboratory value) will be considered an AE and recorded as such on the eCRF. Any 
clinical manifestation(s) of overdose must also be recorded as an AE on the eCRF. In addition, 


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all overdoses must be recorded on an Overdose form and sent to Sage or designee within 
24 hours of the site becoming aware of the overdose.  
 


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13. 
STATISTICS 
A separate statistical analysis plan (SAP) will provide a detailed description of the analyses to be 
performed in the study. Separate SAPs will be generated for each part of the study. The SAP for 
each study part will be finalized and approved prior to treatment unblinding of each respective 
part. 
In Part A, 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. Data from Part A may be 
analyzed and reported following final database lock and before Part B is complete. For Part B, 
the final database lock will occur when all subjects complete the study; treatment unblinding and 
analyses will follow the database lock. 
Separate clinical study reports will be produced for each part of the study. 
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.  
The Modified Full Analysis Set (mFAS) is defined as all participants in the FAS with a total 
HAM-D score ≥ 26 at baseline.  
  
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.  


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Hepatitis, HIV, drug and alcohol, and pregnancy screening results will be listed, but not 
summarized as they are considered part of the inclusion/exclusion criteria.  
Medical/family history will be listed by subject.  
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 defined as follows: 
1) The treatment regimen for participants is placebo or SAGE-217 for 14 days. 
2) The target population is adult participants with a current diagnosis of MDD marked by 
baseline HAM-D total score ≥26. 
3) The variable of interest is the change from baseline in HAM-D total score at Day 15. 
4) The intercurrent events could be: 
a. The premature discontinuation of treatment for any reason, thus not having a 
Day 15 HAM-D total score available. This will be dealt with by a sensitivity 
analysis using multiple imputation technique (details will be provided in the SAP).  
b. Certain medications including, but not limited to, new antidepressants and 
benzodiazepines are prohibited until Day 42; however, the treatment policy 
strategy dictates that the results following prohibited medication use will not be 
manipulated but will be used ‘as is’ in analyses. (Note that no rescue medication is 
defined in this protocol; hence, there is no rescue medication to be considered). 
5) 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. 
Data 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, 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 diary endpoints in Part A 
only (eg, sleep latency (SL), total sleep time (TST), wake after sleep onset (WASO)), ISI score 
in Part A only, and selected individual items and/or subscale scores in HAM-D for change from 
baseline.  


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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 
clinically significant (PCS) values are provided in the SAP. 
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. 


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13.6.3. 
Physical Examinations 
The occurrence of a physical examination (Y/N) and the date performed will be listed by subject. 
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 
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.  


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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 
For Part A, 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%. 
For Part B, assuming a two-sided alpha level of 0.05, a sample size of 216 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 a standard deviation (SD) of 9 points. Assuming a 10% dropout rate and a 
1:1 randomization ratio within each stratum (antidepressant use at baseline, yes or no), 
approximately 240 total randomized subjects will be required to obtain 216 evaluable subjects. 
Evaluable subjects are defined as those randomized subjects who receive study drug and have a 
valid baseline and at least 1 postbaseline HAM-D assessment. To provide more power for 
analyses of key secondary endpoints, up to 575 subjects will be randomized for Part B. 


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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. 
DSM-5.  Diagnostic and statistical manual of mental disorders (5th ed.).  American Psychiatric 
Association 2013.  Arlington, VA: American Psychiatric Publishing. 
Greenberg PE, Fournier AA, Sisitsky T, Pike CT, Kessler RC. The economic burden of adults 
with major depressive disorder in the United States (2005 and 2010). J Clin Psychiatry. 2015 
Feb;76(2):155-62. 
Gunduz-Bruce H, Silber C, Kaul I, et al. Trial of SAGE-217 in Patients with Major Depressive 
Disorder. N Engl J Med. 2019; 381:903-911. 
Martinez Botella G, Salituro FG, Harrison BL, et al. Neuroactive steroids. 2. 3α-hydroxy-3β-
methyl-21-(4-cyano-1H-pyrazol-1’-yl)-19-nor-5β-pregnan-20-one (SAGE-217): A clinical next 
generation neuroactive steroid positive allosteric modulator of the (γ-aminobutyric acid) A 
receptor. J Med Chem 2017;28;60(18):7810-19. 
   
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. 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-MDD-301 v8.0 
 
CONFIDENTIAL 
 
 
79 
 
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. 
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. 
 


217-MDD-301 Summary of Changes 
Sage Therapeutics 
Version 8, Amendment 7  
 
 
1 
Protocol 217-MDD-301, Amendment 7 
Date of Amendment: 14 December 2020 
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 increase the sample size of Part B (from 
approximately 370 to up to 575 participants) to provide more power for key secondary 
endpoints. In addition, a Modified Full Analysis Set has been added to the data analysis sets and 
details of the estimand for the primary efficacy analysis have been added. 
The administrative changes outlined in Administrative Letter #4 from 14 October 2020 are also 
incorporated in this amendment, which are to correct footnotes in Table 3 ‘Schedule of Events 
(Part B)’. 
 


o (617) 949.4256    f (617) 299.8379 
215 First Street, Cambridge, MA 02142 
www.sagerx.com 
 
 
 
October 14, 2020 
 
217-MDD-301 Protocol Administrative Letter #4 
 
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 
 
 
To Whom It May Concern: 
 
This memo is to inform you of a clarification to 217-MDD-301 Protocol Version 7.0 (Amendment 6), 
dated 14Sep2020.  
 
In Table 3: Schedule of Events (Part B), footnotes o, p, q, r, s, and t were inadvertently shifted from the 
procedure(s) that they were intended to be associated with. The corrections are listed below, and a 
copy of the corrected Table 3: Schedule of Events (Part B) is included with this letter for reference.  
 
Study Procedure 
Incorrect Footnote(s) 
Correct Footnote(s) 
HAM-A 
o 
p 
Study Drug 
Accountability/Return  
(Day 42/ET Visit Column) 
q 
r 
Adverse Events/SAEs 
r 
d, s 
Prior/Concomitant 
Medications/Procedures 
s 
d, t 
 
The clarification will be incorporated into the next protocol amendment, if one is needed. Any 
questions may be directed to the study team or to Syneos CST. 
 
Sincerely, 
 
 
 
 
 
 
 MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DocuSign Envelope ID: 55E143BA-DD55-474A-89BA-F00667469B87


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-MDD-301 v7.0 
 
CONFIDENTIAL 
 
Table 3: 
Schedule of Events (Part B) 
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 
EOT a 
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 Participant Check b 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
 
 
Serum FSH test c 
X 
 
 
 
 
 
 
 
 
 
 
SCID-5-CT 
X 
 
 
 
 
 
 
 
 
 
 
MGH ATRQ 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Family Historyd 
X 
 
 
 
 
 
 
 
 
 
 
Subject training e 
X 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Physical Examination f 
X 
X 
 
 
 
 
 
 
 
 
X 
Body Weight/Height 
X 
 
 
 
 
X 
(weight 
only) 
 
 
 
 
X 
(weight 
only) 
Clinical Laboratory 
Assessments g 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
Drug & Alcohol Screen h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test i 
X 
X 
 
 
 
X 
 
 
X 
 
X 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-MDD-301 v7.0 
 
CONFIDENTIAL 
 
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 
EOT a 
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 
 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs l 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
12-Lead ECG m 
X 
X 
 
 
 
X 
 
 
 
 
X 
C-SSRS n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAM-D o, p 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
MADRS 
 
X 
 
X 
 
X 
 
 
X 
 
X 
HAM-A p 
 
X 
 
X 
 
X 
 
 
X 
 
X 
CGI-S 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
SF-36v2 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
PHQ-9 
 
X 
 
X 
 
X 
 
 
X 
 
X 
PWC-20 
 
X 
 
 
 
X 
X 
X 
 
 
 
Study Drug Dispensation 
 
X 
 
X 
 
 
 
 
 
 
 
Study Drug Administration 
 
X (Day 1 through Day 14) 
 
 
 
 
 
Study Drug 
Accountability/Return 
 
 
 
X 
 
X 
 
 
 
 
X r 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-MDD-301 v7.0 
 
CONFIDENTIAL 
 
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 
EOT a 
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 
 
Adverse Events/SAEsd, s 
X 
Prior/Concomitant 
Medications/Proceduresd, t 
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; 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. 
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. If 
necessary, 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 EOT 
visit assessments should be conducted in addition to an abbreviated physical exam.  
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 participants 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 Information regarding diagnosis, isolation, and/or hospitalization due to COVID-19 will be documented as part of Medical History, AE collection, and prior/concomitant 
medication/procedure collection at Screening and throughout the study. 
e Subjects will be trained on use of software applications and devices necessary for the conduct of the study by site personnel. 
f A full physical examination will be conducted at Screening and abbreviated physical examinations will be conducted thereafter. A full physical examination includes assessment 
of body systems (eg, head, eye, ear, nose, and throat; heart; lungs; abdomen; and extremities). An abbreviated physical exam includes a brief medical history followed by 
targeted physical exam. 
g Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. 
h Urine toxicology for selected drugs of abuse (as per the lab manual) and breath test for alcohol. 
i Serum pregnancy test at screening and urine pregnancy test thereafter for female subjects who are not surgically sterile and do not meet the protocol-defined criteria for being 
post-menopausal. 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-MDD-301 v7.0 
 
CONFIDENTIAL 
 
l Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing). Heart rate and blood pressure to be collected in supine position at 
all scheduled time points after the participant has been resting for 5 minutes and then after approximately 3 minutes in the standing position. Vital signs may be repeated at the 
discretion of the Investigator as clinically indicated. 
m Triplicate ECGs will be collected. When ECGs 
 sample collection occur on the same day, the 12-lead ECGs will be performed 
 sample collection. 
n 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. 
o The HAM-D is to be completed as early during the visit as possible. 
p The assessment timeframe for HAM-D scales will refer to the past 7 days (1 week) at Screening and “Since Last Visit” for all other visits. The assessment timeframe for HAM-A 
scales will refer to the past 7 days (1 week) at all visits. 
 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. 
 

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
NCT04442490
Document Date: 
SAP Version 1.0: 25 May 2021


Clinical Study Report 
217-MDD-301 Part B
16.1 Study Information 
1 
9.
DOCUMENTATION OF STATISTICAL METHODS
The statistical analysis plan (version 1.0) is provided. 


Statistical Analysis Plan Methods Version 1.0 25May2021 
               Page 1 
Protocol Number: 217-MDD-301 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
METHODS 
Protocol Number 217-MDD-301 
 
A PHASE 3, MULTICENTER, DOUBLE-BLIND, RANDOMIZED, 
PLACEBO-CONTROLLED STUDY EVALUATING THE EFFICACY OF 
SAGE-217 IN THE TREATMENT OF ADULT SUBJECT WITH MAJOR 
DEPRESSIVE DISORDER (PART B) 
 
Author of SAP: 
 
Version: 1.0  
Version Date of SAP: 25 May 2021 
 
Sponsor: 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, Massachusetts 02142 
 
 
 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure 
without the prior written consent of Sage Therapeutics, Inc. is strictly prohibited except to the 
extent required under applicable laws or regulations.  Persons to whom the information is 
disclosed must be informed that the information is confidential and may not be further 
disclosed by them. 
 
 


Statistical Analysis Plan Methods Version 1.0 25May2021 
Page 2 
Protocol Number: 217-MDD-301 
 
 
Authorization Signature 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  
 
Author: 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
Approved by: 
 
 
 
 
 
 
____________
___________________ 
Sage Therapeutics, Inc. 
 
 
 
_________________ 
Date 
 
 
 
 
____________
________________________ 
Sage Therapeutics, Inc. 
 
 
 
 
____________
___________________________ 
Sage Therapeutics, Inc. 
 
 
 
 
 
_______________ 
Date 
 
 
 
 
 
_________________ 
Date 
 
DocuSign Envelope ID: 93C120A4-F6C4-4D54-B80A-5E67D8DB5FBD
25-May-2021 | 16:39 EDT
25-May-2021 | 17:40 EDT
25-May-2021 | 16:31 EDT
26-May-2021 | 15:30 EDT


Statistical Analysis Plan Methods Version 1.0 25May2021 
Page 3 
Protocol Number: 217-MDD-301 
 
TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS................................................................... 6 
2. 
INTRODUCTION .................................................................................... 8 
3. 
STUDY OBJECTIVES ............................................................................ 8 
3.1. 
Primary Objective ..................................................................................... 8 
3.2. 
Secondary Objective ................................................................................. 8 
3.3. 
Safety Objective ........................................................................................ 8 
 
 8 
4. 
STUDY ENDPOINTS .............................................................................. 9 
4.1. 
Efficacy Endpoints .................................................................................... 9 
4.1.1. 
Primary Efficacy Endpoint and Estimand ................................................ 9 
4.1.2. 
Secondary Efficacy Endpoints .................................................................. 9 
4.1.2.1. 
Key Secondary Efficacy Endpoints .......................................................... 9 
4.1.2.2. 
Other Secondary Efficacy Endpoints ........................................................ 9 
4.2. 
Safety Endpoints ....................................................................................... 9 
 
 9 
5. 
STUDY DESIGN ................................................................................... 10 
5.1. 
Overall Design ........................................................................................ 10 
5.2. 
Sample Size and Power .......................................................................... 11 
5.3. 
Randomization ........................................................................................ 11 
5.4. 
Blinding and Unblinding ........................................................................ 12 
6. 
MODIFICATIONS ................................................................................. 12 
6.1. 
Modifications to the Approved Clinical Study Protocol ........................ 12 
6.2. 
Modifications to the Approved Statistical Analysis Plan ....................... 13 
6.3. 
Modifications to the Approved DMC Charter ........................................ 13 
7. 
ANALYSIS SETS .................................................................................. 13 
7.1. 
Full Analysis Set ..................................................................................... 13 
7.2. 
Modified Full Analysis Set ..................................................................... 13 
7.3. 
Safety Set ................................................................................................ 13 
7.4. 
Randomized Set ...................................................................................... 13 
7.5. 
Per Protocol Set ...................................................................................... 13 
 
 14 


Statistical Analysis Plan Methods Version 1.0 25May2021 
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Protocol Number: 217-MDD-301 
 
8. 
STATISTICAL ANALYSIS .................................................................. 14 
8.1. 
General Considerations ........................................................................... 14 
8.1.1. 
Study Day Definition .............................................................................. 15 
8.1.2. 
Missing Data ........................................................................................... 15 
8.2. 
Background Characteristics .................................................................... 15 
8.2.1. 
Participant Disposition ............................................................................ 15 
8.2.2. 
Protocol Deviations ................................................................................ 16 
8.2.3. 
Demographics and Baseline Characteristics ........................................... 16 
8.2.4. 
Medical/Surgical History ........................................................................ 18 
8.2.5. 
Prior and Concomitant Medications ....................................................... 18 
8.2.6. 
Concomitant Procedures ......................................................................... 19 
8.2.7. 
Investigational Product Exposure ........................................................... 19 
8.2.8. 
Investigational Product Adherence ......................................................... 20 
8.3. 
Efficacy Analysis .................................................................................... 21 
8.3.1. 
Definition of Efficacy Variables ............................................................. 21 
8.3.1.1. 
Hamilton Rating Scale for Depression (HAM-D) .................................. 21 
8.3.1.2. 
Clinical Global Impression – Improvement (CGI-I) .............................. 22 
8.3.1.3. 
Clinical Global Impression – Severity (CGI-S) ...................................... 23 
8.3.1.4. 
Hamilton Anxiety Rating Scale (HAM-A) ............................................. 23 
8.3.1.5. 
Montgomery-Åsberg Depression Rating Scale (MADRS) .................... 23 
8.3.1.6. 
Short Form-36 Version 2 (SF-36v2) ....................................................... 23 
8.3.1.7. 
Patient Health Questionnaire (PHQ-9) ................................................... 24 
8.3.2. 
Visit Windows ........................................................................................ 24 
8.3.3. 
Analysis of Efficacy Variable(s) ............................................................ 25 
8.3.3.1. 
Mixed Effects Model for Repeated Measures ........................................ 27 
8.3.3.2. 
Generalized Estimating Equation (GEE) Models ................................... 28 
8.3.3.3. 
Sensitivity Analysis ................................................................................ 29 
8.3.3.4. 
Analysis of Time to First HAM-D Response/Remission ....................... 30 
8.3.3.5. 
Multiplicity Adjustment for Key Secondary Endpoints ......................... 31 
8.3.4. 
Characterization of Durability of SAGE-217 Treatment Effect ............. 31 
8.3.4.1. 
Durability of Clinically Meaningful Treatment Effect for SAGE-217 .. 31 


Statistical Analysis Plan Methods Version 1.0 25May2021 
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Protocol Number: 217-MDD-301 
 
8.3.4.2. 
Durability of Treatment Effect at Day 42 via Statistical Comparison of 
SAGE-217 Versus Placebo ..................................................................... 33 
8.4. 
Safety Analysis ....................................................................................... 33 
8.4.1. 
Adverse Events ....................................................................................... 34 
8.4.2. 
Clinical Laboratory ................................................................................. 36 
8.4.3. 
Vital Signs .............................................................................................. 39 
8.4.4. 
Electrocardiogram ................................................................................... 40 
8.4.5. 
Physical Examination ............................................................................. 41 
8.4.6. 
Columbia Suicide Severity Rating Scale (C-SSRS) ............................... 41 
8.4.7. 
Physician Withdrawal Checklist (PWC) ................................................ 42 
 
 42 
 
 42 
9. 
SUMMARY OF INTERIM AND DMC ANALYSES .......................... 42 
10. 
REFERENCES ....................................................................................... 43 
11. 
LIST OF APPENDICES......................................................................... 44 
11.1. 
Appendix A: Schedule of Assessments .................................................. 44 
11.2. 
Appendix B: Details of Statistical Methodology .................................... 48 
11.3. 
Appendix C: Handling of Missing Dates ................................................ 49 
11.4. 
Appendix E: List of Displays ................................................................. 51 
 
LIST OF TABLES 
Table 1: 
Diagnostic Screening Tests..................................................................... 17 
Table 2: 
HAM-D Subscale Calculation ................................................................ 22 
Table 3: 
Visit Windows for Efficacy Analysis ..................................................... 25 
Table 4: 
Safety Endpoints and Variables in the Summary Tables ........................ 34 
Table 5: 
Clinical Laboratory Tests ....................................................................... 36 
Table 6: 
Potentially Clinically Significant Values for Specific Laboratory 
Parameters ............................................................................................... 38 
Table 7: 
Potentially Clinically Significant Values and Change for Vital Sign 
Parameters ............................................................................................... 39 
Table 8: 
Potentially Clinically Significant Values and Change for ECG 
Parameters ............................................................................................... 40 
 


Statistical Analysis Plan Methods Version 1.0 25May2021 
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Protocol Number: 217-MDD-301 
 
1. 
LIST OF ABBREVIATIONS 
Abbreviation or specialist term 
Explanation 
AE 
adverse event 
AR 
autoregressive 
ATC 
anatomical therapeutic chemical 
BMI 
body mass index 
CGI-I 
Clinical Global Impression scale for improvement 
CGI-S 
Clinical Global Impression scale for severity 
C-SSRS 
Columbia Suicide Severity Rating Scale 
ECG 
electrocardiogram 
eCRF  
electronic case report form  
EOT 
end of treatment 
ET 
early termination 
FAS 
Full Analysis Set 
GEE  
generalized estimating equation  
HAM-A  
Hamilton Rating Scale for Anxiety  
HAM-D 
Hamilton Depression Rating Scale 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
ICF 
informed consent form 
IP 
Investigational product 
IRT 
interactive response technology  
LFT 
Liver Function Tests 
LLOQ 
Lower limit of quantification 
mFAS 
Modified Full Analysis Set 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MDD 
major depressive disorder 
MMRM  
mixed effects model for repeated measures  
MedDRA 
Medical Dictionary for Regulatory Activities 
PCS 
potentially clinically significant  
PCSC 
potentially clinically significant change 
PHQ-9 
Patient Health Questionnaire 


Statistical Analysis Plan Methods Version 1.0 25May2021 
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Protocol Number: 217-MDD-301 
 
Abbreviation or specialist term 
Explanation 
 
 
PRO 
patient-reported outcome 
PT 
preferred term 
PWC-20 
20-item Physician Withdrawal Checklist  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SF-36 
36-item Short Form survey 
SI 
International System of Units 
SOC 
System Organ Class 
TEAE 
treatment-emergent adverse event 
UN 
unstructured 
 


Statistical Analysis Plan Methods Version 1.0 25May2021 
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Protocol Number: 217-MDD-301 
 
2. 
INTRODUCTION 
This statistical analysis plan (SAP) is for the final analysis of Part B data from 217-MDD-
301 study, and is based on clinical study protocol, version 8.0, dated 14 December 2020.  
Protocol 217-MDD-301 is a single protocol which is being conducted in 2 separate non-
overlapping parts – Part A and Part B. The study protocol version 6.0 is amended after the 
participants enrollment was completed in Part A. Part B will enroll unique participants. 
The analysis methods for data from Part A of the study are described separately, in the SAP 
that was approved on 12 November 2019, prior to unblinding the Part A database.  
The purpose of this SAP is to describe in detail the statistical methodology and analyses to be 
conducted for Part B of 217-MDD-301 protocol. The SAP will be finalized and approved 
before database lock for Part B.  
Any changes made to this SAP after the clinical database lock has occurred will be 
documented and discussed in the clinical study report for this study. 
3. 
STUDY OBJECTIVES  
3.1. 
Primary Objective 
The primary objective of Study 217-MDD-301 Part B is to evaluate the efficacy of SAGE-
217 in the treatment of major depressive disorder (MDD) compared to placebo. 
3.2. 
Secondary Objective 
The secondary objective of Study 217-MDD-301 Part B is to assess patient-reported outcome 
(PRO) measures as they relate to health-related quality of life and depressive symptoms.  
3.3. 
Safety Objective 
The safety objective of Study 217-MDD-301 Part B is to evaluate the safety and tolerability 
of SAGE-217. 
 
 
 
 


Statistical Analysis Plan Methods Version 1.0 25May2021 
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Protocol Number: 217-MDD-301 
 
4. 
STUDY ENDPOINTS 
4.1. 
Efficacy Endpoints 
4.1.1. 
Primary Efficacy Endpoint and Estimand 
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. The estimand is the treatment 
difference in mean change from baseline(see Section 8.3.3.1 for more details). 
4.1.2. 
Secondary Efficacy Endpoints  
4.1.2.1. 
Key Secondary Efficacy Endpoints  
   Change from baseline in CGI-S at Day 15 
   Change from baseline in HAM-D total score at Day 8, Day 3, and Day 42 
4.1.2.2. 
Other Secondary Efficacy Endpoints  
   HAM-D response at Day 15 and Day 42 
   HAM-D remission at Day 15 and Day 42 
   CGI-I response, defined as “much improved” or “very much improved”, at Day 15 
   Change from baseline in MADRS total score at Day 15 
   Change from baseline HAM-A total score at Day 15 
   Time to first HAM-D response 
   Change from baseline in PRO measures of health-related quality of life, as assessed 
        by responses to SF-36v2, and of depressive symptoms, as assessed by the PHQ-9 
4.2. 
Safety Endpoints 
  Incidence and severity of adverse events/serious adverse events;  
  Changes from baseline in clinical laboratory measures, vital signs, and 
electrocardiogram (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)  
 
 
 
 


Statistical Analysis Plan Methods Version 1.0 25May2021 
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Protocol Number: 217-MDD-301 
 
5. 
STUDY DESIGN  
5.1. 
Overall Design  
Study 217-MDD-301 is a randomized, double-blind, parallel-group, placebo-controlled study 
in participants with major depressive disorder (MDD). This study will be conducted in 2 
parts – Part A and Part B. Part B will commence after all participants in Part A have 
completed the Day 42 visit. Part A and Part B will enroll unique participants. For both study 
parts, the diagnosis of MDD must be made according to Structured Clinical Interview for 
Diagnostic and Diagnostic and Statistical Manual of Mental Disorder, fifth Edition for 
Clinical Trial (SCID-5-CT) performed by a qualified healthcare professional.  
Part B 
Part B will consist of a Screening Period of up to 28 days, a 14-day Treatment Period, and a 
28-day double-blind 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, participants will also be asked to authorize 
that their unique participant identifiers be entered into a registry (www.subjectregistry.com) 
with the intent of identifying participants who may meet exclusion criteria due to 
participation in another clinical study. Participants 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 participants are on a stable dose for at least 60 days 
prior to Day 1 and agree 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 will not be allowed between screening and completion 
of the Day 42 assessments.  
Eligible participants 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 2 treatment 
groups (SAGE-217 50 mg or matching placebo) in a 1:1 ratio. Participants will 
self-administer investigational product (IP) once daily at approximately 8 PM with fat-
containing food (e.g., within 1 hour of an evening meal which contains fat or with a fat-
containing snack), on an outpatient basis, for 14 days. Participants will return to the study 
center during the treatment and follow-up periods as outlined in Section 11.1 Appendix A.  
During the treatment period, participants will be able to receive IP as long as there are no 
dose limiting safety/tolerability concerns. Participants who cannot tolerate 50 mg will receive 
40 mg for the remainder of the treatment period. At the discretion of the Investigator, 
participants who cannot tolerate the 40-mg dose may be discontinued from IP.  
Participants who discontinue treatment early should return to the site for an 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 (e.g., if a participant’s last dose 
is on Day 13, their first follow-up visit, Visit 7, should occur 4 days later). If at any time after 


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the EOT visit, a participant decides to terminate the study, the participant should return for an 
ET visit. The EOT and ET visits can be on the same day if a participant discontinues IP and 
decides to terminate the study on the same day during a clinic visit; in this case, all EOT visit 
assessments should be conducted in addition to an abbreviated physical exam.  
5.2. 
Sample Size and Power 
Using a two-sided alpha level of 0.05, a sample size of 216 evaluable participants 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 a standard deviation (SD) of 9 points. Assuming a 10% dropout rate and a 
1:1 randomization ratio within each stratum (antidepressant use at baseline, yes or no), 
approximately 240 total randomized participants will be required to obtain 216 evaluable 
participants. Evaluable participants are defined as those randomized participants who receive 
IP and have a valid baseline and at least 1 postbaseline HAM-D assessment. 
Sample size for Part B of this study was adjusted (i.e., increase) in the following 
amendments:  
1. In amendment #6 dated 02Mar2020, the sample size was increased to 370 to ensure 
enough power for subgroup analyses, and for primary efficacy endpoint analysis based 
on a modified Full Analysis Set (mFAS, baseline HAM-D total score >=26) that was 
under consideration and was included in the draft SAP version dated 14 Sep 2020. 
 
2. In amendment #7 dated 14Dec2020, the sample size was further increased to 
approximately 575 randomized participants to provide more power for the analyses of 
key secondary endpoints. The increase in sample size also ensured enough power (at 
least 90%) for the change in primary analysis set from Full Analysis Set (FAS) to 
modified Full Analysis Set (mFAS) consisting all participants in the FAS with baseline 
HAM-D total score >=26 (mFAS is estimated to be around 60% of FAS)  and to enhance 
comparative statistical analyses for some key subgroups. Naturally, this would also 
result in a higher number of subjects exposed to the SAGE-217 dose level. 
 
It is to note that the protocol was amended to increase the sample size to up to 575 before 
study enrollment close out activities were initiated 18 February 2021. 
5.3. 
Randomization  
This is a randomized, double-blind, placebo-controlled study. Participants 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; In Part B, 
randomization will be done within each stratum in a 1:1 ratio to receive SAGE-217 50 mg or 
matched placebo. 
Randomization schedules will be generated by an independent statistician. The allocation to 
treatment group (SAGE-217 50 mg, or placebo) will be based on the randomization schedule. 
Randomization will be performed centrally via an interactive response technology (IRT) 
system.   


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5.4. 
Blinding and Unblinding 
This is a randomized, double-blind, placebo-controlled study. The Sponsor, site personnel 
and participants will remain blinded to treatment assignment until database lock which is 
scheduled to occur when all participants have completed the Day 42 visit. 
During the study, the blind is to be broken only when the safety of a participant is at risk and 
the treatment plan is dependent on the IP received. Unless a participant is at immediate risk, 
the Investigator should make diligent attempts to contact Sage prior to unblinding the IP 
administered to a participant. Requests from the Investigator about the treatment 
administered to study participants should be discussed with the Sage Medical Monitor. If the 
unblinding occurs without Sage’s knowledge, the Investigator must notify Sage within 24 
hours of breaking the blind.  
All circumstances surrounding a premature unblinding must be clearly documented in the 
source records.   
In all cases where the investigational product allocation for a participant is unblinded, 
pertinent information (including the reason for unblinding) must be documented in the 
participant’s records and on the eCRF.  
If a participant(s) or site personnel become unblinded to participant’s treatment assignment 
before database lock, participant(s) will be excluded from the Per Protocol Set (See 
Section 7.5) but included in the Full Analysis Set (See Section 7.1).  
6. 
MODIFICATIONS  
6.1. 
Modifications to the Approved Clinical Study Protocol 
 
Protocol 217-MDD-301, Amendment #5, 02 March 2020 introduced the Part B of 217-
MDD-301 study for which this SAP is designed.  The following key modifications from this 
initial protocol have been made: 
  
Protocol 217-MDD-301, Amendment #6, 14 September 2020 
1. Increased sample size from 240 to approximately 370 randomized participants to 
ensure enough power for subgroup analyses.  
2. Revised timepoints for the key secondary endpoint, change from baseline in HAM-D 
total score, to coincide with those defined in the statistical analysis plan  
3. Added COVID-19 questions  
4. Removed compound symmetry as a method to achieve convergence in the event of a 
convergence issue and specified that the sandwich estimator for the variance 
covariance matrix will be derived when the covariance structure is not UN  
5. Removed score of ‘0 (not assessed)’ as a choice for the Clinical Global Impression 
Scale  


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Protocol 217-MDD-301, Amendment #7, 14 December 2020  
1. Increase sample size from approximately 370 to up to 575 randomized participants to 
ensure more power for the analyses of secondary endpoints.  
2. Added a Modified Full Analysis Set (mFAS) to the data analysis sets and details of 
the estimand for the primary efficacy analysis.  
Subsequent SAP reviews by FDA led to change in protocol specified target population – it 
has been changed from baseline HAM-D total score >=26 to baseline HAM-D total score  
≥ 24.  The primary analysis will use Full Analysis Set instead of Modified FAS mentioned in 
the protocol. 
 
This decision was made well in advance of database lock and unblinding of the database. 
6.2. 
Modifications to the Approved Statistical Analysis Plan 
Not applicable 
6.3. 
Modifications to the Approved DMC Charter 
Not applicable 
7. 
ANALYSIS SETS 
7.1. 
Full Analysis Set 
The Full Analysis Set (FAS) is defined as all randomized participants administered IP with 
valid baseline HAM-D total score and at least 1 valid post-baseline HAM-D total score.  
7.2. 
Modified Full Analysis Set 
The Modified Full Analysis Set (mFAS) is defined as all participants in the FAS with a total 
HAM-D score ≥ 26 at baseline. 
7.3. 
Safety Set 
The Safety Set is defined as all participants who are administered IP. 
7.4. 
Randomized Set 
The Randomized Set is defined as all participants who are randomized. 
7.5. 
Per Protocol Set 
The Per Protocol Set is defined as all participants in the FAS without any major protocol 
deviations related to efficacy. For further details, see Section 8.2.2.  
In addition, Per Protocol Set will also exclude FAS participant with any of the following 
conditions: 


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1. Participants who consumed <22 capsules (i.e. <80% of assigned number of capsules) 
2. Participants who consumed incorrect IP (i.e. IP other than which a participant was 
randomized to receive) at any time during the study 
3. Participants or study personnel who were unblinded to participant’s treatment 
assignment before database lock 
 
 
 
   
8. 
STATISTICAL ANALYSIS 
8.1. 
General Considerations 
Unless otherwise specified, continuous endpoints will be summarized with n, mean standard 
deviation (SD), median, minimum (min) and maximum (max). If the measurements in the 
source (raw) data are integers, then the corresponding mean and median will be presented to 
1 decimal place and the SD to 2 decimal places; if the measurements are obtained to 1 
decimal place, then the mean and median will be presented to 2 decimal places and the SD to 
3 decimal places; and so forth. Minimum and maximum will be displayed as reported in the 
source (raw) data. In addition, change from baseline values (visit value – baseline value) will 
be calculated at each time point and summarized descriptively. All parameters will be 
converted to the International System of Units (SI) before analysis. 
For categorical endpoints, descriptive summaries will include counts and percentages. 
Percentages will be presented to 1 decimal place unless otherwise specified; the denominator 
of percentages will be the number of participants in the analysis set used unless specified 
otherwise.  
All analyses and summary outputs will be generated using SAS® 9.4 or higher. 
All summaries and figures will be provided by treatment group: placebo or SAGE-217. The 
SAGE-217 treatment group includes participants that received the 50 mg starting dose as 
well as those that received any 40 mg dose as a result of dose reduction. Efficacy data are 
analyzed by the treatment group that the participant is randomized to. Safety data are 
analyzed by the actual treatment received, and this is determined as follows: if a participant 
received any dose of SAGE-217 at any point of time, the participant is assigned to actual 
treatment of SAGE-217.   
All participant data, including those derived, to support tables and figures will be presented 
in the participant data listings. In general, the participant data listings will be sorted by 
participant number and assessment visit and date (and time, if applicable). The treatment will 
be identified for each participant – either planned or actual – according to the analysis set 
used. 
For the purpose of all safety and efficacy analyses, baseline is defined as the last non-missing 
measurement including unscheduled visits prior to the first dose of investigational product, 


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unless stated otherwise. If the time of an assessment is collected, baseline will be the latest 
assessment prior to first dose of IP  administration time; if the time of an assessment is not 
collected, the assessment on Day 1 is assumed to be prior to dosing if the protocol mentions 
that this assessment needs to be before dosing or it is collected as “predose”.  
8.1.1. 
Study Day Definition 
It is to be noted that the IP is administered in the evening with food. The assessments at the 
clinic on Day 1 are hence before the first dose of IP. 
Study day will be defined as follows:  
 The day of participant receiving the first dose of IP is designated as Day 1. 
 For visit/assessment days after Day 1, study day = visit/assessment date – Day 1 date 
+ 1. 
 For visit/assessment days prior to Day 1, study day = visit/assessment date – Day 1 
date.  
 Thus, study days for screening visit are negative numbers.  There is no “Day 0”. 
8.1.2. 
Missing Data 
All participants will be used in the analyses, as per the analysis populations, using all non-
missing data available.  Sensitivity analyses will be conducted to assess the impact of 
missing data on efficacy analysis findings.   Handling of missing or incomplete dates is 
discussed in Section 11.3 Appendix C. Unless otherwise specified,  no imputation of missing 
data is planned for safety analyses. 
8.2. 
Background Characteristics  
All summary tables in this section will be presented for placebo, SAGE-217, and Overall. 
8.2.1. 
Participant Disposition 
Participant disposition will be based on all participants who provided written inform consent 
to the study. 
The summaries of participant disposition will include the number of participants who were  
 screened,  
 randomized,  
 received IP.  
 number and percentage of participants who completed the study,  
 number and percentage of participants who prematurely withdrew from the study and 
primary reasons for not completing the study, who completed treatment,  
 number and percentage of participants who discontinued treatment prematurely, and 
primary reasons for discontinuing treatment.                          


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All percentages will be calculated based on the participants randomized and administered IP; 
treatment group assignment will be as planned treatment. If a participant is rescreened 
because the participant was a screen failure the first time, the status of the participant will be 
determined from the second screening. In the count of screened participants, this participant 
will be counted only once.   
A completer for the study is defined as one who completed the last follow up visit (Day 42) 
based on the study completion CRF page with the completion question answered Yes.  
A participant is marked as completing the treatment if the complete treatment question on the 
study treatment completion CRF page is answered Yes. 
The number of participants in each analysis set will be provided.  Using Randomized Set, the 
reason for not being included in other analysis sets will be summarized. 
The summary of participant disposition will also be provided using FAS as well as mFAS. 
A separate data listing will be provided for all participants who prematurely discontinued 
treatment or prematurely withdrew from the study with reasons, number of days on IP, date 
of withdrawal from the study, using Safety Set. 
8.2.2. 
Protocol Deviations 
Protocol deviations identified during the study will be captured and categorized by the study 
team review as major or minor deviations in blinded fashion on an ongoing basis until 
database lock.   
Study team will identify the major protocol deviations could affect efficacy to determine the 
participants in FAS to be excluded from the Per Protocol Set prior to database lock in a 
blinded fashion (Some major protocol deviations may not lead to participants’ data to be 
excluded from the Per Protocol Set).  
In addition, COVID-19 related protocol deviations such as remoted telephone/video 
visit/assessment, home healthcare visit, missed visit/assessment, out of window 
visit/assessment, safety reporting, IP administration, and others will be documented and 
provided in a separate listing if there are 10 or more participants with COVID-19 related 
protocol deviations. The major protocol deviations will be summarized by randomized 
treatment received using FAS.  
All protocol deviations – major and minor - will be included in a data listing using 
randomized set and randomized treatment.  
Any violation of inclusion/exclusion criteria will be presented with the randomized treatment 
in a separate data listing using Randomized Set. 
8.2.3. 
Demographics and Baseline Characteristics 
The following analyses will be provided separately for the Safety Set (using actual treatment 
received), the FAS (using randomized treatment), and mFAS (using randomized treatment). 


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Demographic data (age at informed consent date, race, sex, ethnicity, employment status, 
highest education level, marital/civil status) and baseline characteristics, such as height, 
weight, and body mass index (BMI), will be summarized by treatment group  and overall. 
Baseline subgroups will be summarized for the following categories (for definition of 
antidepressants, see Section 8.2.5): 

Antidepressant use at baseline: Yes, No

 Age: 18-24, 25-50, 51-64 years

Sex: Female, Male

Race: Black or African American, White, Other

 BMI at baseline: ≤18.4, 18.5-24.9, 25-29.9, ≥30 kg/m2

 HAM-D total score at baseline: < 26, ≥ 26; this category will not be used for mFAS.

COVID-19 History:  COVID-19 virus test positive , Suspected COVID-19, Home
isolation COVID-19, COVID-19 related hospitalization, Not impacted; participant’s
COVID-19 history status will be collected via medical history eCRF page, and if
none is present, the level is designated as ‘Not impacted’.
A separate listing for participant who were randomized under incorrect stratification of 
antidepressant use at baseline will be provided.   
The antidepressants are identified from concomitant medication records with Anatomic 
Therapeutic Classification (ATC) level 3 = N06A. The stratum for antidepressant use at 
baseline is determined from the coding of antidepressant, comparing the start/end dates of the 
medication versus the date of first dose of IP. Any deviation from the antidepressant stratum 
recorded at IRT system are part of protocol deviations and will be included in the protocol 
deviation listing.  
Diagnostic labs are part of screening. The results of the diagnostic screening tests in Table 1 
will be provided in a data listing using the Safety Set. 
Child-bearing potential data will be collected at screening and will be listed in a data listing 
using the Safety Set. 
Table 1: 
Diagnostic Screening Tests 
Diagnostic 
Serum 
Urine 
Breathalyzer 
Hepatitis B 
Drug screen: including amphetamines, 
barbiturates, benzodiazepines, 
cannabinoids, cocaine, opiates, 
phencyclidine 
Alcohol 


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Diagnostic 
Hepatitis C 
Female participants 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 participants that are not 
surgically sterile and do not meet the 
protocol-defined criteria for being 
post-menopausal: serum hCG 
 
 
Female Participants, if menopause is 
suspected and not surgically sterile: 
FSH 
 
 
 Abbreviations: FSH=follicle stimulating hormone; hCG=human chorionic gonadotropin; HCV = hepatitis 
 virus; HIV = human immunodeficiency virus 
8.2.4. 
Medical/Surgical History 
The following analyses will use the Safety Set.  
Years since initial diagnosis of MDD, lifetime antidepressant 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 IP – date of interest. For imputation of incomplete dates in medical history, 
please see Section 11.3. Medical/surgical history collected at screening will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA), Version 23.0 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.   
Participant history of psychiatric disorders and family psychiatric history will be 
summarized.   
8.2.5. 
Prior and Concomitant Medications  
The following analyses will use the Safety Set. 
All medications taken during the study will be recorded; in addition, psychotropic 
medications taken within 6 months prior to screening, and non-psychotropic medications 
taken within 30 days prior to screening will also be collected.  All medications will be coded 
using World Health Organization-Drug (WHO) Global B3 March 2020 or later. 
Medications will be presented according to whether they are being taken prior to and/or 
during the study (concomitant).  Prior medications are defined as those taken prior to the 
initiation of the start of IP.  Concomitant medications are defined as those with a start date on 
or after the first dose of IP or those with a start date before the first dose of IP that are 


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ongoing or with a stop date on or after the first dose of IP. If medication dates are incomplete 
and it is not clear whether the medication was concomitant, it will be assumed concomitant.  
For imputation of missing concomitant medication dates, please refer to Appendix C, Section 
11.3. Note that medication taken before the initial dosing of investigational product and 
continued after the initial dosing will be categorized as a prior medication and separately as a 
concomitant medication.  
Concomitant medications will be further divided by usage period as follows:  
 On-treatment concomitant medications are those that have been used any time from 
start of first dose to the last dose of IP. 
 Post-treatment concomitant medications are those that have been started after the last 
dose of IP. 
Prior and concomitant non-psychotropic medication use will be summarized by anatomical 
therapeutic chemical (ATC) level 1 and Standard Medication Name. Similar summary tables 
will be provided for psychotropic medications. Separate but similar summaries will be 
provided for concomitant medication use for on-treatment and post-treatment periods as 
defined above. 
In addition, for prior and concomitant psychotropic medication separate summaries will be 
provided by ATC level 1 and ATC level 4. 
Antidepressants that have been taken at the same dose for at least 60 days prior to the first 
dose of IP are permitted if the participant 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. Antidepressant 
medications are identified by ATC3 level code of N06A.  A summary of antidepressant use 
at baseline and any change in these medications post-baseline (including the follow up 
period) will be provided. Follow-up period antidepressants are defined as those starting after 
the last dose of IP, but on or before the last IP dose date + 28 days.  
Prohibited medications are reviewed by the medical monitor in the study team on an ongoing 
basis in blinded fashion; any medication identified as prohibited medication intake is 
captured in the protocol deviations list.   
8.2.6. 
Concomitant Procedures 
Concomitant procedures undergone during the study will be recorded on a separate eCRF 
page; this will be presented in a listing by participant. The study day for the end date of the 
procedure will be provided when a complete end date is available.  
8.2.7. 
Investigational Product Exposure 
The following analyses will use the Safety Set. 
Total drug exposure (in mg) is defined as the total mg for SAGE-217 that was taken during 
the study.  Total drug exposure for participants randomized to placebo is zero, unless the 
participant has taken SAGE-217 by mistake due to being provided wrong IP kits, in which 


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case the total exposure comes from SAGE-217 exposure.  If the participant skips the dose on 
any of the days, the dose taken is 0 mg.   
The kit for 50 mg dose contains two capsules – one for 30 mg, the other for 20 mg.  For 
participants who took only 1 capsule inadvertently for a dosing day of 50 mg, it is assumed 
that the participant took the higher dose (i.e. 30 mg) for the day and will be calculated as 
such for the total drug exposure and percent of the planned exposure received. For 
participants who took more than 2 capsules for a dosing day of 50 mg, it assumed that the 
participant took all capsules as the higher dose for the day and will be calculated as such for 
the total drug exposure and percent of the planned exposure received. 
The kit for 40 mg dose contains two capsules, 20 mg each; therefore, taking one capsule will 
unambiguously be assigned to 20 mg. 
Total exposure duration to IP (in days) is defined as: date of last dose – date of first dose + 1. 
Note that this may include days when a dose is missed. 
Percent of the planned exposure received is defined as the total drug exposure, divided by 
planned exposure, times 100.  For participants randomized to SAGE-217 who complete the 
treatment period without dose reduction, planned exposure is 14 days of treatment planned, 
times 50 mg. For participants randomized to SAGE-217 who reduce dose to 40 mg, the 
planned exposure is the number of days (last date of 50 mg – first dose date + 1), times 50 
mg, plus the number of days (date of study day 14 – first date of 40 mg + 1), times 40 mg. 
For participants randomized to SAGE-217 who discontinue the treatment early and reduce 
dose, the planned exposure is the number of days (last date of 50 mg – first dose date + 1) 
times 50 mg, plus the number of days (last date of dose - first date of 40 mg + 1) times 40 
mg. For participants randomized to SAGE-217 who discontinued the treatment early without 
dose reduction, the planned exposure is the number of days (last date of 50 mg – first dose 
date + 1) times 50 mg. For participants 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 participants with less than 22 
capsules consumed will be provided.  
The number and percent of participants who had dose adjustment (reduced, interrupted, 
withdrawn) and dose modification (missed dose, took an extra day of dosing, took more than 
the planned dose for dosing day, partial dose, other) will also be summarized descriptively.  
IP will be self-administered by participant once daily at approximately 8 PM with fat-
containing food.  Whether the participant has eaten fat-containing food within the last 1 hour 
of the IP administration will be included in the IP exposure data listing. 
8.2.8. 
Investigational Product Adherence 
The following analyses will use the FAS and mFAS. IP adherence (%) is defined as the 
number of capsules taken, divided by the number of capsules planned to be taken, times 100.   
The schedule of IP is two capsules per day. The number of capsules planned to be taken is 
defined as follows: 


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1.    If the participant discontinues treatment within Day 2 and Day 14 (both inclusive), 
the number of capsules planned to be taken is the last dose day of IP, times 2.  
2.    If the participant does not discontinue treatment, the number of capsules planned to 
be taken is 28.  
IP adherence will be summarized descriptively.  Number and percentage of participants with 
IP adherence in categories - <80%, 80-100%, >100% - will be provided.   
8.3. 
Efficacy Analysis  
8.3.1. 
Definition of Efficacy Variables 
The efficacy variables are defined as follows: 
8.3.1.1. 
 Hamilton Rating Scale for Depression (HAM-D) 
The 17-item HAM-D will be used to rate the severity of depression in participants already 
diagnosed as depressed.  HAM-D is collected during the clinic visit on Screening, Days 1, 3, 
8, 12, 15, 21, 28, 35, and 42. The 17-item HAM-D comprises of individual ratings related to 
the following symptoms: depressed mood (sadness, hopeless, helpless, worthless), feelings of 
guilt, suicide, insomnia (early, middle, late), work and activities, retardation (slowness of 
thought and speech; impaired ability to concentrate; decreased motor activity), agitation, 
anxiety (psychic and somatic), somatic symptoms (gastrointestinal and general), genital 
symptoms, hypochondriasis, loss of weight, and insight.  Each item is scored in a range of 0 
to 2 or 0 to 4, with higher scores indicating a greater degree of depression.  The score for 
each item will be summed to compute a total score, which ranges from 0 to 52.   If more than 
3 individual items are missing a response, the HAM-D total score will not be calculated and 
will be left as missing.  If less than or equal to 3 individual item scores are missing, the 
missing item scores will be imputed by the mean of all other available item scores, or the 
maximum possible values for the missing responses, whichever is smaller, to calculate the 
HAM-D total score. 
Four HAM-D subscale scores will be calculated as the sum of the individual rating scores 
related to each subscale, divided by the total possible score within the subscale, multiplied by 
100, and rounded to a whole number. If more than one item is missing or HAM-D total score 
is missing, the subscale score is left as missing; if one item on a particular subscale is 
missing, but has been imputed for the calculation of total score, the imputed value from total 
score calculation will be used in subscale score calculation for that item. Table 2 describes 
the subscale score calculation. 
HAM-D response will be defined as having a 50% or greater reduction from baseline in 
HAM-D total score; only participants who have a non-missing total score of HAM-D at 
baseline as well as the visit will be considered in HAM-D response evaluations.  
HAM-D remission will be defined as having a HAM-D total score of ≤7; if HAM-D total 
score is missing, remission will not be defined. For a sensitivity analysis the worst-case 
scenario imputation will be used, i.e. missing values for HAM-D response (remission) will be 
considered as “No response” (“No remission”). 


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Table 2: 
HAM-D Subscale Calculation 
HAM-D Subscales 
Items 
Calculation 
Core 
Depressed mood 
Feeling of guilt 
Suicide 
Work and activities 
Retardation 
Sum of the 5-item responses/20 x 100.   
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale. 
Anxiety 
Anxiety psychic 
Anxiety somatic 
Somatic symptoms gastrointestinal 
Somatic symptoms general 
Hypochondriasis 
Insight 
Sum of the 6-item responses/18 x 100.   
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale. 
Bech-6 
Depressed mood 
Feeling of guilt 
Work and activities 
Retardation 
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. 
8.3.1.2. 
Clinical Global Impression – Improvement (CGI-I) 
The Clinical Global Impression - Improvement (CGI-I) employs a 7-point Likert scale to 
measure the overall improvement in the participant’s condition post-treatment. The 
Investigator will rate the participant’s total improvement. Response choices include: 1=very 
much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally 
worse, 6=much worse, and 7=very much worse. The CGI-I is only rated at post-treatment 
assessments on Days 3, 8, 12, 15, 21, 28, 35, and 42. By definition, all CGI-I assessments are 
evaluated against baseline conditions. 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. 


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8.3.1.3. 
 Clinical Global Impression – Severity (CGI-S) 
The Clinical Global Impression - Severity (CGI-S) uses a 7-point Likert scale to rate the 
severity of the participant’s illness at the time of assessment, relative to the clinician’s past 
experience with participants who have the same diagnosis. Considering total clinical 
experience, a participant is assessed on severity of mental illness at the time of rating as 
1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly 
ill; 6=severely ill; and 7=extremely ill.  CGI-S is collected at Screening, Days 1, 3, 8, 12, 15, 
21, 28, 35, and 42. 
8.3.1.4. 
Hamilton Anxiety Rating Scale (HAM-A) 
The 14-item HAM-A will be used to rate the severity of symptoms of anxiety. HAM-A is 
collected during the clinic visit at Days 1, 8, 15, 28, and 42.  Each of the 14 items is defined 
by a series of symptoms, and measures both psychic anxiety (mental agitation and 
psychological distress) and somatic anxiety (physical complaints related to anxiety). Scoring 
for HAM-A is calculated by assigning scores of 0 (not present) to 4 (very severe), with a total 
score range of 0 to 56, where <17 indicates mild severity, 18 to 24, mild to moderate 
severity, and 25 to 30, moderate to severe severity. The HAM-A total score will be calculated 
as the sum of the 14 individual item scores. If more than 3 individual items are missing a 
response, the HAM-A total score will not be calculated and will be left as missing.  If less 
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 for the HAM-A total score.       
8.3.1.5. 
 Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive 
episodes in participants with mood disorders.  MADRS is collected at Screening, during the 
clinic visit on Days 1, 8, 15, 28, and 42. 
Each MADRS item ranges from 0 to 6; higher MADRS scores indicate more severe 
depression.  The MADRS total score will be calculated as the sum of the 10 individual item 
scores, which ranges from 0 to 60. If more than 2 individual items are missing, the MADRS 
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 for the MADRS total score.    
MADRS response will be defined as having a 50% or greater reduction from baseline in 
MADRS total score; only participants who have a non-missing total score of MADRS at 
baseline as well as the visit will be considered in MADRS response evaluations.  MADRS 
remission will be defined as having a MADRS total score of ≤10; if MADRS total score is 
missing, remission will not be defined. 
8.3.1.6. 
 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, and 42. 


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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 a 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 participant at each 
assessment, which will be used for analyses. 
8.3.1.7. 
Patient Health Questionnaire (PHQ-9)  
The PHQ-9 is a 9-item participant-rated depressive symptom severity scale. It is collected 
during the clinic visit on Days 1, 8, 15, 28, and 42. Scoring is based on responses to specific 
questions, as follows: 0=not at all; 1=several days; 2=more than half the days; and 3=nearly 
every day.  
The PHQ-9 total score will be calculated as the sum of the 9 individual item scores. If more 
than 1 individual item is missing, the PHQ-9 total score will not be calculated and will be left 
as missing. 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. 
8.3.2. 
Visit Windows 
The scheduled visits will not be windowed and will be used at nominal visit value for 
treatment period visits (Day 3, Day 8, Day 12, and Day 15). For post-treatment period visits 
(Day 21, Day 28, Day 35, and Day 42) including unscheduled, end-of-treatment (EOT) and 
early termination (ET) visit will be mapped to a scheduled visit for analysis.   
The windows outlined in the Table 3 for each scheduled visit have been widened compared 
to protocol-specified operational window, to have no gap between them; these windows are 
used for analysis purposes only.  Once analysis visit windows are assigned, all visits, 
including scheduled visits, and windowed visits will be eligible for being flagged as the 
“analyzed record” within the analysis window; a participant’s individual analysis visit 
window could potentially contain more than 1 visit.  In the event of multiple visits falling 
within an analysis window or in case of a tie, the following rules will be used in sequence to 
determine the “analyzed record” for the analysis visit window: 
  If the data from the scheduled visit is available within treatment period, then the 
scheduled visit data will be used.  
 If no data from the scheduled visit within treatment period is available, then the 
windowed visit data will be used.  


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
If more than one visit is in the same window, the data closest to target day will be
used.
o
If there is a tie with distance from target days, the data after the target day will
be used.
o
If there is a tie within a target day, the data measured at the later time will be
used.
The summary by visit will use the “analyzed records” only – at most one per participant.  The 
data not flagged as the “analyzed record” will be included in listings. A windowed visit does 
not fall under any analysis window will remain in the database and will be included in the 
listings.   
Table 3 displays windows for efficacy analysis. 
Table 3: 
Visit Windows for Efficacy Analysis 
Scheduled Visit  
(+/1 window days) in protocol 
Target Study Day 
Study Day Window for Visit 
in Analysis 
Day 1 
Day 1 (pre-dose) 
Day 1 (pre-dose) or last non-
missing assessment before 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 (±1 day) 
Day 21 
Day 18 - Day 23 
Day 28 (±3 day) 
Day 28 
Day 24 - Day 31 
Day 35 (±3 days) 
Day 35 
Day 32 – Day 38 
Day (±3 days) 
Day 42 
>=Day 39 
8.3.3. 
 Analysis of Efficacy Variable(s) 
The FAS will be used for primary efficacy analyses. Participants will be analyzed according 
to randomized treatment. The mFAS will be considered as a subgroup and used for efficacy 
analyses for further understanding of data. 
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


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 HAM-D individual item score – observed, change from baseline  
 HAM-D response  
 HAM-D response – missing response counted as No response 
 HAM-D remission  
 HAM-D remission – missing remission counted as No remission 
 CGI-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  
 MADRS remission  
 SF-36v2 domain/component score– observed, change from baseline, percent 
change from baseline  
 PHQ-9 score – observed (including categories), change from baseline  
The HAM-D change from baseline in total score along with model-based estimates will also 
be presented by the following subgroups: 
 Antidepressant use at baseline: yes, no 
 Age group: 18-24, 25-50, 51-64 years 
 Sex: Male, Female  
 Race: White, Black, or African American, Other 
 BMI at baseline: ≤18.4, 18.5-24.9, 25-29.9, ≥30 kg/m2 
 HAM-D total score at baseline: < 26, ≥ 26; this category will not be used for 
mFAS.  
 COVID-19 History: COVID-19 virus test positive, Suspected COVID-19, Home 
isolation COVID-19, COVID-19 related hospitalization, Not impacted.  
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-


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D total score will also be presented in histogram over scheduled visits: ≤7, >7 to ≤15, >15 to 
≤ 23, > 23 to <26, >=26.  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.  In addition, line plots for LS means for HAM-D total 
score, and bar charts for HAM-D response and remission will be provided by antidepressant 
use at baseline. 
HAM-D total scores will be also summarized for Per Protocol Set.  
8.3.3.1. 
Mixed Effects Model for Repeated Measures 
The estimand for the primary efficacy analysis is defined as follows: 
1) The treatment regimen for participants are: placebo or SAGE-217 for 14 days. 
2) The target population is adult participants with a current diagnosis of MDD.  marked 
by baseline HAM-D total score >=24. 
3) The variable of interest is the change from baseline in HAM-D total score at Day 15. 
4) The intercurrent events could be: 
a. The premature discontinuation of treatment for any reason, thus not having a 
Day 15 HAM-D total score available.  This will be dealt with by a sensitivity 
analysis using multiple imputation technique in Section 8.3.3.3.   
b. Certain medications including, but not limited to, new antidepressants and 
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.  Note that no rescue process is specified in the protocol, hence 
there is no rescue medication to be considered. 
5) 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. 
Data from SAGE-217 group versus placebo group will be analyzed using a mixed effects 
model for repeated measures (MMRM); the model will include treatment (SAGE-217 or 
placebo), baseline HAM-D total score, antidepressant use at baseline (Yes or No), 
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. Model-based point estimates i.e., treatment difference in least squares [LS] mean, is 
the estimate of the effect 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-participant errors. If there is a convergence issue with the unstructured covariance 
model, Toeplitz, or Autoregressive (1) [AR (1)] covariance structure will be used, following 
this sequence until convergence is achieved. If the model still does not converge with AR (1) 
structure, no results will be reported. When the covariance structure is not UN, the sandwich 
estimator for the variance covariance matrix will be derived, using the EMPIRICAL option 
in the PROC MIXED statement in SAS. The p-value will be interpreted at 0.05 level of 
significance. 


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If the comparison of SAGE-217 versus placebo is significant at a two-sided 0.05 level, the 
hypotheses testing for the key secondary endpoints in FAS will proceed with multiplicity 
adjustment, as described in Section 8.3.3.5. 
Similar to those methods described above for the primary endpoint, MMRM will be used for 
the analysis of the change from baseline in other time points in HAM-D total score, all time 
points in HAM-D subscale scores (Core Subscale score, Anxiety Subscale score, Bech-6 
Subscale score and Maier Subscale score), HAM-D individual item scores, CGI-S score, 
HAM-A total score, HAM-A individual item score, MADRS total score, MADRS individual 
item scores, SF-36v2 Domain/Component Score, and PHQ-9 total score.  
For each model, the primary comparison of interest will be between SAGE-217 and placebo 
at the 15-day time point. In addition, model-based point estimates (i.e., LS means), 95% 
confidence intervals, and p-values will be reported for the primary time point (Day 15) and 
all other time points. 
The MMRM analysis will also be provided for change from baseline in HAM-D total score 
within each baseline subgroup level in Section 8.2.3  separately. If any treatment group for 
any level of subgroup has <=5 participants, the subgroup level will not be used in the 
analysis.  
Line plot of model-based LS Mean and standard error (SE) over time will be presented for 
change from baseline in HAM-D total score, CGI-S score, HAM-A total score, and MADRS 
total score. Forest plot for subgroup analysis for change from baseline in HAM-D total score 
at Day 15 – LS mean, 95% confidence interval, and P-value – will be provided. In addition, a 
Forest plot for individual items in HAM-D and for subscales of HAM-D will also be 
provided.   
SF-36v2 domain/component score– observed, change from baseline, percent change from 
baseline – will be summarized.  Bar graphs of SF-36 domain/component score for day 15 
will be provided by treatment. 
PHQ-9 total score -observed, change from baseline, and total score category – will be 
summarized. 
All efficacy analyses will be performed on FAS and also repeated on mFAS. 
Summary of HAM-D model-based estimates will be provided for Per Protocol Set.  
8.3.3.2. 
Generalized Estimating Equation (GEE) Models 
Generalized estimating equation (GEE) methods will be used for the analysis of HAM-D 
response and HAM-D remission. GEE models will include terms for treatment (SAGE-217, 
or Placebo), baseline HAM-D score, antidepressant use at baseline (Yes or No), assessment 
time point, and time point-by-treatment as explanatory variables.  
An unstructured (UN) covariance structure will be used to model the within-participant 
errors. If there is a convergence issue with the unstructured covariance model, then 
exchangeable covariance structure will be used, following this sequence until convergence is 
achieved. If the model still does not converge with exchangeable structure, no results will be 
reported. 


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Model-based point estimates (i.e., odds ratios), 95% confidence intervals, and p-values will 
be reported. These analyses will use both FAS and mFAS. 
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. 
Similarly, 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.   
8.3.3.3. 
Sensitivity Analysis 
A sensitivity analysis will be performed to investigate the impact of missing data if ≥ 5% of 
participants 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 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 
FAS will be used for sensitivity analyses. Sample SAS codes for MI imputation is provided 
in Section 11.2, Appendix B. 
Imputation distribution: 
All randomized participants will be classified as non-missing category, missing category 1, 
or missing category 2, based on the following rules: 
 Non-missing category: Participant with non-missing change from baseline in HAM-D 
total score at Day X 
 Missing category 1: Participant discontinued due to adverse events, physician 
decision, protocol deviation, non-compliance with IP, or other, and is missing change 
from baseline in HAM-D total score at Day X 
 Missing category 2: Participant discontinued due to pregnancy, lost to follow-up, 
participant decision, withdrawal by participant, sponsor decision, or with missing 
assessment due to COVID-19, and is missing change from baseline in HAM-D total 
score at Day X, or participant completed study but is missing change from baseline in 
HAM-D total score at Day X. 
Imputation algorithm: 
Missing values of HAM-D total score at all visits will be imputed using the fully conditional 
specification models. Two different imputation models will be used based on reasons of 
missing:  
 Missing category 1: simulate missing values of HAM-D total score using an 
imputation model based on the non-missing HAM-D total scores for placebo group.  
This represents a conservative approach as it tends to reduce the difference between 
treatment and placebo group since higher values of change from baseline represents 
worse outcome, and placebo is supposed to provide a higher value. 


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 Missing category 2: simulate missing values of HAM-D total score using an 
imputation model based on the non-missing HAM-D total scores within the same 
treatment group.  
Analysis model: 
The complete multiple imputation method is described below: 
 Repeat the process K (K=100) times, using the procedure described above to form K 
imputed complete datasets with the same variance structure. 
 Fit the MMRM model including treatment, baseline antidepressant use, baseline 
HAM-D total score, assessment time point, and time point-by-treatment to each 
imputed dataset, to estimate the treatment effect and its variance. 
 Combine the results from the K imputed datasets using the SAS procedure 
MIANALYZE, to derive the MI estimator. 
We fit the analysis model (MMRM model specified before) to the kth completed dataset, 
denoting the estimate of the treatment difference θ by θk from the kth completed dataset and 
denoting the corresponding estimate of the variance Vk. The MI estimator of θ, θ̃MI, is the 
average of the K individual estimators: 
𝜃̃𝑀𝐼= 1
𝐾∑𝜃𝑘
𝐾
𝑘=1
 
The estimated variance of θ̃MI is a combination of the between- and within-imputation 
variability as follows: 
𝑉𝑀𝐼= 𝑊+ (1 + 1
𝐾) 𝐵 
where W =
1
K ∑
VK
K
k=1
is the within-imputation variability and B =
1
K-1 ∑
(θk-θ̃MI)
2
K
k=1
is the 
between-imputation variance. 
It has been shown that the statistic 
T = 𝜃̃𝑀𝐼−𝜃
√𝑉𝑀𝐼
 
has an approximate t distribution where V = (K-1) (1 +
W
B)
2
. 
8.3.3.4. 
Analysis of Time to First HAM-D Response/Remission 
Using the 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 participant 
will be censored at the participant’s last day of HAM-D evaluation in the database if the 
participant did not have a response.  Similar analysis will be done for first HAM-D 
remission.  


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These analyses will be also provided on mFAS. 
8.3.3.5. 
Multiplicity Adjustment for Key Secondary Endpoints 
Multiplicity adjustment to statistical testing of hypotheses of the key secondary endpoint 
analyses in FAS is conducted by using pre-specified fixed sequence strategy (Dmitrienko et 
al, 2013). Only if the primary endpoint in FAS is statistically significant at α level, the key 
secondary endpoints in FAS will be tested sequentially, testing each endpoint at α level of 
significance only if the previous endpoint in the below sequence has been significant at α 
level. If an endpoint is not significant at α level, formal testing of hypothesis stops and the 
next endpoint in the sequence will be interpreted only with nominal p-value.  
The sequence of testing key secondary endpoints in FAS is as follows: 

Change from Baseline in CGI-S at Day 15

Change from Baseline in HAM-D total score at Day 8

Change from Baseline in HAM-D total score at Day 3

Change from Baseline in HAM-D total score at Day 42
Other secondary endpoints not included above are not adjusted for multiplicity, and hence 
will be interpreted with nominal p-value.     
8.3.4. 
Characterization of Durability of SAGE-217 Treatment Effect
After completion of 14 days of treatment, the study participant is followed for 28 days, 
without any further treatment with study drug.  During this 28-day follow-up period, clinic 
visits are scheduled for Day 21, 28, 35 and 42.  Day 42 change from baseline in HAM-D 
total score is pre-specified as a key secondary endpoint in this study. 
Demonstration of SAGE-217 durable effect will be characterized via 2 complementary 
approaches:  
1) clinically meaningful durable SAGE-217 treatment effect at Day 42 (see Section 8.3.4.1 
below), and
2) statistically significant change from baseline at Day 42 in SAGE-217 versus placebo (for 
statistical demonstration of durable SAGE-217 treatment effect, see Section 8.3.3.1 and 
Section 8.3.3.2 above, and Section 8.3.4.2  below).
8.3.4.1. 
Durability of Clinically Meaningful Treatment Effect for SAGE-217 
Durability of treatment effect is assessed over the post-treatment period in the SAGE-217 
group, based on the efficacy observed at Day 15.  The primary endpoint for clinically durable 
effect will be examined by the percent retention of the Day 15 reduction from baseline in 
HAM-D total score among SAGE-217 participants who had improvement in HAM-D total 
score at Day 15 compared to baseline; i.e. HAM-D total score at Day 15< HAM-D total score 
at baseline (referred to as “percent retention of Day 15 change from baseline (CFB)” going 
forward).   


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Percent retention of D15 CFB is defined as follows: Let Xb be baseline HAM-D total score, 
X15 be Day 15 HAM-D total score, Xy be Day Y (Y>15) HAM-D total score. Then percent 
retention (%) for Day Y is 
𝑋𝑦−𝑋𝑏
𝑋15−𝑋𝑏× 100.  It will be calculated for the scheduled visits in 
Table 3 after Day 15, only for the participants randomized to SAGE-217. For example, for a 
participant with a baseline HAM-D of 27 (Xb) and a HAM-D score of 13 (X15) at Day 15, 
percent retention at Day 42 with HAM-D of 16 (Xy) would be 79%. If Day 42 HAM-D score 
is 18, percent retention would be 64%.  
A summary of percent retention of D15 CFB will be presented for SAGE-217 participants at 
Day 15 for post-Day 15 visits, based on FAS. This will serve as the primary approach for 
assessing clinically durable effect; mean percent retention (%) of D15 CFB at Day 42 is 
considered clinically meaningful durability if it is >=65%. The mean (±SE) percent retention 
over time will be presented in a line plot.  The above analysis will also be provided for 
mFAS.  In addition, the number and percent of participants with at least 65% retention of 
D15 CFB at each of post-Day 15 visit will also be provided.  
Following analysis will be presented for supportive purposes to assist with further 
understanding of clinical durability of effect of SAGE-217.  These analyses will be 
conducted using both FAS and mFAS. 
A. A summary of percent retention of D15 CFB will be presented for SAGE-217 HAM-
D responders at Day 15 for post-Day 15 visits. The mean (±SE) percent retention 
over time will be presented in a line plot.  In addition, the number and percent of 
participants with at least 65% retention of D15 CFB at each of post-Day 15 visit will 
also be provided. 
B. The number and percent of HAM-D responders at post-Day 15 visits among the 
SAGE-217 HAM-D responders at Day 15 will be provided. A bar chart will be 
provided. 
C. The number and percent of HAM-D remitters (HAM-D total score <=7) at post-Day 
15 visits among the SAGE-217 HAM-D remitters at Day 15 will be provided. A bar 
chart will be provided. 
D. Relapse: A relapse is defined only for SAGE-217 HAM-D responders at Day 15.  A 
relapse is defined as having at least 2 consecutive HAM-D total score >=20 after Day 
15, including the last value.  The number and percent of participants with relapse will 
be provided.    
E. Rebound: A rebound is defined for only SAGE-217 HAM-D responders at Day 15.  
A rebound is any HAM-D total score (after Day 15) >= Baseline HAM-D total score.  
The number and percent of participants with rebound will be provided.  
F. The number and percent of CGI-I responders (CGI-IR) at post-Day 15 visits among 
the SAGE-217 CGI-I responders at Day 15 will be provided. A bar chart will be 
provided. 
Post Day 15 HAM-D results supporting the above analyses will be listed separately for the 
SAGE-217 participants based on FAS. 


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8.3.4.2. 
Durability of Treatment Effect at Day 42 via Statistical Comparison of 
SAGE-217 Versus Placebo 
These analyses have been discussed in Section 8.3.3.1 and Section 8.3.3.2  as part of the 
efficacy analyses with Day 42 as one of key secondary efficacy endpoints – using FAS as 
primary, mFAS as subgroup: 
A. MMRM analysis of change from baseline at Day 42 (key secondary efficacy 
endpoint), comparing SAGE-217 versus placebo (LS mean, p-value and 95% CI) will 
be provided. 
B. GEE analysis of response/remission rates comparing SAGE-217 versus placebo at 
Day 42 (Odds Ratio, p-value and 95% CI) will be provided.  
8.4. 
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 participant has been randomized; for definition of actual treatment assignment, see 
Section 8.1. 
The safety endpoints will be summarized by scheduled visits for treatment period visits, 
without any windowing.  For post-treatment period visits,  the choice of the visit record will 
be following the same rule as described in Section 8.3.2. Vital signs, C-SSRS and PWC-20 
are collected as Day 18 visit for which no window exists; the evaluations will be summarized 
as nominal visit of Day 18. 
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 IP (exclusive) and up to last dose of IP + 1 days 
(inclusive).  Last value on study is defined as the last post-baseline value after the first dose 
of IP.  
Any value during treatment is defined as a value on or after first IP intake but on or before 
last dose of randomized IP + 1 day (both inclusive). Fourteen days after last dose is defined 
as any value after last dose of randomized IP but on or before last dose of randomized IP + 
14 days. 
The safety endpoints and variables considered in the summary tables for this study are 
summarized in Table 4. 


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Table 4: 
Safety Endpoints and Variables in the Summary Tables 
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 8.4.2-8.4.4  
X = to be summarized in tables  
Z = to be presented in listings only 
8.4.1. 
Adverse Events 
Adverse events (AEs) are collected starting at the time of informed consent and throughout 
the duration of participation in the study.  A treatment-emergent adverse event (TEAE) is 
defined as an adverse event with onset on or after the start of IP. The TEAEs will be further 
categorized by the phase of occurrence as follows: 
Adverse events are assigned an AE period based on the onset date/time.  AE periods are 
defined as follows: 
 Pre-treatment AE: AE onset date before first IP dosing date/time 
 TEAE: AE onset date/time on or after first IP dose date/time (If an AE start date same as 
IP first dose date, but no time either in AE start or treatment start, then consider this AE 
to be a TEAE.)   
 On-Treatment TEAE: AE onset date/time on or after first IP dose date/time and on or 
before IP last dose date + 1 day (Note that time does not matter for the end of this 
period.) 
 Post-Treatment TEAE: AE onset date after IP last dose date +1 day (Typically, Day 16 
through Day 42 – time does not matter) 
If the date of an adverse event is incomplete and an unambiguous determination could not be 
made with respect to its onset time versus the first dose of IP and/or last dose of IP, the 
adverse event will be assumed to be a TEAE and a treatment period TEAE.  For imputation 
of missing AE dates, please refer to Appendix C, Section 11.3.  
All adverse events will be coded using MedDRA version 23.0 or higher.  
An overview summary table of TEAEs will present the number and percentage of 
participants as well as the number of events for the following: 


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 TEAE  
  On-Treatment TEAE 
  Post-Treatment TEAE 
 TEAEs by maximum severity (severe>moderate>mild) 
 TEAE leading to discontinuation of IP 
 TEAE leading to withdrawal from the study 
 Treatment-emergent Serious Adverse Event (TESAE) 
 Death 
Incidence of TEAEs in following categories will be provided by SOC and PT. A participant 
is counted only once under each SOC and PT in case of multiple occurrences of the same 
AE. In these tables, the display will be sorted by descending frequency of SOC in the SAGE-
217 group, then of SOC in the placebo group; if 2 or more SOCs have the same frequency, 
the order will be alphabetical. Within each SOC, preferred terms will be sorted by the same 
algorithm as in SOC.  
 TEAE 
 On-Treatment TEAE 
 Post-Treatment TEAE 
 TEAEs by maximum Severity 
 TEAEs by relationship  
 Serious TEAEs 
 TEAEs leading to discontinuation of IP 
 TEAEs leading to withdrawal from the study  
Listing of AEs with onset prior to first dose of IP will be provided.  All listings on TEAEs 
will provide 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.  
For maximum severity, participants will be counted only once within each SOC and PT at the 
maximum severity in the following order: severe> moderate> mild; an AE with missing 
severity will be omitted from severity presentation.  A participant will be counted only once 
within each SOC and PT at the strongest relationship to IP in the following order: related > 
not related. Adverse events with onset before the first dose of IP will be provided in a 
separate listing.  Separate data listing for deaths, SAEs, and participants who had AEs 
leading lose reduction will be provided. 
In addition, TEAE summary by SOC/PT will also be presented by the following subgroups: 
 Antidepressant use at baseline: yes, no 


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
Age group: 18-24, 25-50, 51-64 years

Sex: Male, Female

Race: White, Black, or African American, Other

BMI at baseline: ≤18.4, 18.5-24.9, 25-29.9, ≥30 kg/m2

Baseline HAM-D total score: < 26, ≥ 26

COVID-19 History: COVID-19 virus test positive, Suspected COVID-19, Home
isolation COVID-19, COVID-19 related hospitalization, Not impacted
8.4.2. 
Clinical Laboratory
The clinical laboratory tests to be performed for monitoring of safety are listed in Table 5.  
They are collected on screening day, days 1, 8, 15, 21, 28, and 42. 
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 below limit of quantification (BLQ) and a lower limit of 
quantification (LLOQ) value is provided – LLOQ value will be used for calculation in the 
summary tables. The actual results as collected will be displayed in the listings. 
Table 5: 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Coagulation 
Red blood cell count 
Hemoglobin  
Hematocrit  
White blood cell count 
   with differential 
Platelet count 
Red Blood Cell Indices 
(MCV, MCH, MCHC)  
Reflex to Red blood cell 
morphology if indices are 
abnormal 
Alanine aminotransferase  
Albumin  
Alkaline phosphatase  
Aspartate aminotransferase  
Total bilirubin  
Direct bilirubin  
Indirect bilirubin  
Total protein  
Creatinine  
Blood urea nitrogen  
Creatine kinase  
Gamma-glutamyl transferase 
Potassium  
Sodium  
Lactate dehydrogenase  
Glucose  
Chloride  
Bicarbonate  
Calcium  
Phosphorus  
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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Hematology 
Serum Chemistry 
Urinalysis 
Coagulation 
Triglycerides  
Thyroid stimulating hormone 
(TSH) 
Reflex to free T3/T4 if TSH is 
abnormal 
Summary tables on lab parameters will include descriptive statistics for the observed values 
and changes from baseline by scheduled assessment timepoint 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 participant data listings.  A shift table for these parameters 
from normal at baseline to high or low at any time during treatment, last value on treatment, 
and 14 days after the treatment. Qualitative urinalysis parameters will be summarized 
descriptively.  
The number and percentage of participants with PCS values will be provided in separate 
displays in hematology, serum chemistry, liver function tests and urinalysis tests provided for 
any time during treatment, last value on treatment, and anytime within 14 days after last 
dose. Potentially clinically significant values will be identified for specific laboratory 
parameters as outlined in Table 6.  
Liver function tests will be summarized for occurrence for the following parameters for these 
PCS threshold (for condition involving more than one parameter, the results need to be from 
the same timepoint): 
Alanine Aminotransferase: >3xULN, >5xULN, >10xULN 
Aspartate Aminotransferase: >3xULN, >5xULN, >10xULN 
Alanine Aminotransferase or Aspartate Aminotransferase: >3xULN, >5xULN, >10xULN 
Alkaline Phosphatase: >1.5xULN, >2xULN 
Total Bilirubin: >1.5xULN, >2xULN 
Total Bilirubin > 2xULN AND (Alanine Aminotransferase or Aspartate Aminotransferase 
>3xULN) 
Total Bilirubin >2xULN AND Alkaline Phosphatase >2xULN AND (Alanine 
Aminotransferase or Aspartate Aminotransferase >3xULN) 
Any lab results considered clinically significant by the investigator will be captured as 
adverse events and included in AE displays. 
Pregnancy test results will be listed but not summarized.  


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


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Laboratory 
Parameter 
Units 
Criteria for PCS Values (Observed 
values) 
Liver Function Tests (LFT) 
Bilirubin 
μmol/L 
>2xULN
NA 
Aspartate Aminotransferase 
U/L 
>3xULN
NA 
Alanine Aminotransferase 
U/L 
>3xULN
NA 
Alkaline Phosphatase 
U/L 
>1.5xULN
NA 
8.4.3. 
Vital Signs 
Vitals for the following parameters - respiratory rate (breaths/minute), oral temperature 
(degrees C), supine heart rate (beats/minute), supine systolic blood pressure (mmHg), supine 
diastolic blood pressure (mmHg), standing heart rate (beats/minute), standing systolic blood 
pressure (mmHg), standing diastolic blood pressure (mmHg), – are collected at screening, 
days 1, 3, 8, 12, 15, 18, 28,  and 42. Descriptive summaries of observed values 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 participants with PCS and potentially clinically 
significant change (PCSC) values will be summarized for any time during treatment, last 
value on treatment, and anytime within 14 days after last dose. Potentially clinically 
significant values will be identified for vital sign parameters as outlined in Table 7.  
Table 7: 
Potentially Clinically Significant Values and Change for Vital Sign 
Parameters 
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 


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Vital Sign 
Units 
Criteria for PCS Values 
(Observed values) 
Criteria for PCSC values 
(Change from Baseline 
values) 
Possible orthostatic 
hypotension: supine – 
standing SBP and DBP 
mmHg 
SBP >= 20 
and DBP 
>= 10 
Possible orthostatic 
hypotension: supine – 
standing SBP and DBP 
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 and included in AE displays. 
8.4.4. 
Electrocardiogram 
Supine 12-lead ECGs will be performed in triplicate, and are collected on screening, days 1, 
15, and 42. The following ECG parameters will be listed for each participant: heart rate 
(beats per minute), PR (msec), RR (bmp), QRS (msec), QT (msec), and QTcF (msec).     
The average of the triplicate values will be used in the summary, including baseline ECG 
values.  The observed value at each time point 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.  Each ECG is evaluated as ‘normal’, ‘abnormal, not 
clinically significant’ and ‘abnormal, clinically significant’; the number and percentage of 
participants 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. 
The number and percentage of participants with PCS and PCSC values will be summarized for 
any time during treatment, last value on treatment, and anytime within 14 days after last dose. 
Potentially clinically significant values will be identified for ECG parameters as outlined in 
Table 8. This analysis includes triplicate values individually and is not based on average 
value. In addition, the maximum value of QTcF if within any of the PCS criteria will be summarized. 
Table 8: 
Potentially Clinically Significant Values and Change for ECG Parameters 
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 


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8.4.5. 
Physical Examination  
Physical examination is scheduled on screening, day 1 and 42/ET. 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.  
8.4.6. 
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, 18, 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 participant’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 are 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 are 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 IP, excluding the lifetime version.  This will typically include the ‘past 24-month 
‘version from screening and ‘since last visit version’ from Day 1, as well as any unscheduled 
visits done before the first dose of IP; any Yes will make the baseline value as Yes. 
The number and percentage of participants with at least one response of ‘Yes’ to any C-
SSRS suicidal ideation or suicidal behavior item, as well as for Participant’s non-suicidal 


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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 all available answers for the 
1st and 2nd assessment in suicidal ideation and all available 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 available 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.    
8.4.7. 
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 (e.g., 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. A 
higher total score indicates a greater degree withdrawal symptom.  
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 for the 
PWC total score.     
 Instead of baseline, the first assessment on or after the last dose within 1 day of last dose of 
IP will be used as anchor for Day 18 and Day 21 results. The observed and change from the 
first assessment on or after last dose within 1 day of last dose will be summarized for PWC 
total score. 
 
 
 
 
 
 
 
 
   
9. 
SUMMARY OF INTERIM AND DMC ANALYSES 
Not applicable 


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10. 
REFERENCES 
1. Dmitrienko A., D’Agostino, Sr. R.B., and Huque, M.F. Key multiplicity issues in 
clinical drug development. Statistics in Medicine. 2013 Mar; 32(7); 1079-1111 
 


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11. 
LIST OF APPENDICES 
11.1. 
Appendix A: Schedule of Assessments 
 
Visits 
Screening 
Period 
Double-Blind, Placebo-Controlled 
Treatment Period 
Follow-up Period 
Visit Days 
D-28 to 
D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(+1d) 
and/or 
EOT a 
D18 
(±1d) 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
or 
ET  
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
Study Procedure 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Duplicate Participant Check b 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
 
 
Serum FSH test c 
X 
 
 
 
 
 
 
 
 
 
 
SCID-5-CT 
X 
 
 
 
 
 
 
 
 
 
 
MGH ATRQ 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Family Historyd 
X 
 
 
 
 
 
 
 
 
 
 
Participant training e 
X 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Physical Examination f 
X 
X 
 
 
 
 
 
 
 
 
X 
Body Weight/Height 
X 
 
 
 
 
X 
(weight 
only) 
 
 
 
 
X 
(weight 
only) 


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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 
EOT a 
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 
 
Clinical Laboratory 
Assessments g 
X 
X 
 
X 
 
X 
 
X 
X 
 
X 
Drug & Alcohol Screen h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test i 
X 
X 
 
 
 
X 
 
 
X 
 
X 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs l 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
12-Lead ECG m 
X 
X 
 
 
 
X 
 
 
 
 
X 
C-SSRS n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAM-Do,p 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
MADRS 
 
X 
 
X 
 
X 
 
 
X 
 
X 
HAM-Ap  
 
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 
SF-36v2 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
PHQ-9 
 
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 
Visit Days 
D-28 to 
D-1 
D1 
D3 
(±1d) 
D8 
(+1d) 
D12 
(±1d) 
D15 
(+1d) 
and/or 
EOT a 
D18 
(±1d) 
D21 
(±1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)  
or 
ET  
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
Study Procedure 
 
Investigational product 
Dispensation 
 
X 
 
X 
 
 
 
 
 
 
 
Investigational product 
Administration 
 
X (Day 1 through Day 14) 
 
 
 
 
 
Investigational product 
Accountability/Return 
 
 
 
X 
 
X 
 
 
 
 
X r 
Adverse Events/SAEsd, s 
X 
Prior/Concomitant 
Medications/Proceduresd, t 
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; 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. 
 a Participants who discontinue treatment early should return to the site for an end of treatment (EOT) visit as soon as possible, preferably the day after treatment is 
discontinued. If necessary, the EOT and ET visits can be on the same day if a participant discontinues investigational product and terminates the study on the same day 
during a clinic visit; in this case, all EOT visit assessments should be conducted in addition to an abbreviated physical exam.  
b Participants will be asked to authorize that their unique participant identifiers be entered into a registry (www.subjectregistrysubject.com) with the intent of identifying 
participants 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 participants that are not surgically sterile to confirm whether a female participant with 
≥12 months of spontaneous amenorrhea meets the protocol-defined criteria for being post-menopausal. 
d Information regarding diagnosis, isolation, and/or hospitalization due to COVID-19 will be documented as part of Medical History, AE collection, and prior/concomitant 
medication/procedure collection at Screening and throughout the study. 
e.Participants will be trained on use of software applications and devices necessary for the conduct of the study by site personnel. 


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f A full physical examination will be conducted at Screening and abbreviated physical examinations will be conducted thereafter. A full physical examination includes 
assessment of body systems (e.g., head, eye, ear, nose, and throat; heart; lungs; abdomen; and extremities). An abbreviated physical exam includes a brief medical history 
followed by targeted physical exam. 
g Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. 
h Urine toxicology for selected drugs of abuse (as per the lab manual) and breath test for alcohol. 
i Serum pregnancy test at screening and urine pregnancy test thereafter for female participants who are not surgically sterile and do not meet the protocol-defined criteria for 
being post-menopausal. 
 
l Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing). Heart rate and blood pressure to be collected in supine 
position at all scheduled time points after the participant has been resting for 5 minutes and then after approximately 3 minutes in the standing position. Vital signs may be 
repeated at the discretion of the Investigator as clinically indicated. 
m Triplicate ECGs will be collected. When ECGs 
 sample collection occur on the same day, the 12-lead ECGs will be performed 
 sample collection. 
n 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. 
o The HAM-D is to be completed as early during the visit as possible. 
p The assessment timeframe for HAM-D scales will refer to the past 7 days (1 week) at Screening and “Since Last Visit” for all other visits. The assessment timeframe for 
HAM-A scales will refer to the past 7 days (1 week) at all visits. 
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 participant’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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11.2. 
Appendix B: Details of Statistical Methodology 
Sample SAS code for Mixed Effects Model for Repeated Measures (MMRM): 
 If type=un: 
ods output lsmeans=estimates diffs=diffs; 
proc mixed data=&data; 
class trtpn avisitn usubjid antidep; 
model chg=base trtpn avisitn trtpn*avisitn antidep / ddfm=kr s; 
repeated avisitn / subject=usubjid type=un;  
lsmeans trtpn*avisitn /diff=all cl alpha=0.05; 
** assuming trtpn=1 for the placebo, trtpn=2 for SAGE-217 
run;  
 
 If type=un does not converge, use type=TOPE or AR(1); 
ods output lsmeans=estimates diff=diffs; 
proc mixed data=&data empirical; 
class trtpn avisitn usubjid antidep; 
model chg=base trtpn avisitn trtpn*avisitn antidep / s; 
repeated avisitn / subject=usubjid type=TOEP;  
**If type=TOEP does not converge, use type=AR(1); 
lsmeans trtpn*avisitn /diff=all cl alpha=0.05; 
** assuming trtpn=1 for the placebo, trtpn=2 for SAGE-217 
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 / within=avisitn 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=&data seed=xxxx nimpute=100 round=. . 1 1 1 1 1 1 1 1 1  
out= fcs_reg1; 
class trtp antidep; 


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FCS reg; 
mnar model (base day3 day8 day 12 day15 day21 day28 day42/ modelobs= (trtp='A')); 
var strata base day3 day8 day12 day15 day21 day28 day35 day42; 
run; 
** Missing category 2 
 
proc mi data=&data seed=xxxx nimpute=100 round=. . 1 1 1 1 1 1 1 1 1 out=fcs_reg2; 
class trtp strata; 
fcs nbiter=20 reg (base day3 day8 day12 day15 day21 day28 day35 day42/details); 
var trtp strata base day3 day8 day12 day15 day21 day28 day35 day42; 
run;  
11.3. 
Appendix C: Handling of Missing Dates 
Dates missing the day, or both the day and month of the year will adhere to the following 
conventions in order to classify TEAEs and to classify prior and concomitant medications.  
In general, listings will present the actual partial or missing values rather than the imputed 
values that may be used in derivation. In instances where imputed values will be presented, 
imputed values will be flagged.  
Adverse Events 
If the AE start date is completely missing, do not impute a date but consider it as TEAE, 
unless the AE end date is before the initiation of treatment, in which case the AE will be 
considered prior. 
For partial AE start dates: 
 When the year is known, but the month and day is unknown, then: 
o If the year matches the year of first dose date and the end date (if present) is 
after first dose date, or AE is ongoing, then impute as the month and day of 
min (first dose date + 1 day, last dose date). 
o If the year of AE onset < year of initiation of the treatment, then the month 
and day will be set to December 31st.  
o If the year of AE onset > the year of initiation of treatment, then the month 
and day will be set to January 1st. 
 If the year and month are known, but the day is unknown, then: 
o If the year of AE onset = the year of initiation of the treatment and: 
 the month of AE onset = the month of initiation of the treatment, 
then the day will be set to the day of initiation of the treatment. 
 the month of AE onset < the month of initiation of the treatment, 
then the day will be set to the last day of month of the particular 
year. 
 if the month of AE onset > the month of initiation of the treatment, 
then the day will be set to the 1st 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 last day of month of the particular year. 
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. 
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 
 
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 end date (imputed date if 
applicable) of medication, then the start date will be set to the end date of 
medication. 
For the partial end date of medication: 
o If the year is present and the month and day are missing, then the month and day 
will be set to min (December 31, date of death). 
o If the year and day are present and the month is missing, then the month will be 
set to min (December, month of death). If the year and month are present and the 
day is missing, then the day will be set to min (last day of the month, month of 
death). 
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 min (December 31, date of death).   
 
 


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11.4. 
Appendix E: List of Displays  
Tables 
Table Number 
Title 
Analysis Set 
Table 14.1.1.1 
Summary of Participant Disposition 
All Participants 
Table 14.1.1.2 
Summary of Analysis Sets 
All Participants 
Table 14.1.1.3 
Summary of Participant Disposition 
Full Analysis Set 
Table 14.1.1.4 
Summary of Participant Disposition 
Modified Full Analysis Set 
Table 14.1.2.1 
Summary of Major Protocol Deviations 
Full Analysis Set 
Table 14.1.2.2 
Reasons for Exclusion from Analysis Sets 
Randomized Set 
Table 14.1.3.1.1 
Summary of Demographics and Baseline Characteristics 
Safety Set 
Table 14.1.3.1.2 
Summary of Demographics and Baseline Characteristics 
Full Analysis Set 
Table 14.1.3.1.2.1 
Summary of Demographics and Baseline Characteristics 
Modified Full Analysis Set 
Table 14.1.3.1.3 
Summary of Baseline Subgroups 
Safety Set 
Table 14.1.3.1.4 
Summary of Baseline Subgroups 
Full Analysis Set 
Table 14.1.3.1.5 
Summary of 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 Participant 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 


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Table Number 
Title 
Analysis 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 Investigational Product Exposure  
Safety Set 
Table 14.1.4.11 
Summary of Investigational Product Adherence 
Full Analysis Set 
Table 14.1.4.12 
Summary of Investigational Product 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 Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-D) Total Score by Study Visit 
Full Analysis Set 
Table 14.2.1.1.3 
Model-based Sensitivity Analysis on Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score at Day 15 
Full Analysis Set 
Table 14.2.1.1.4 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Study Visit 
Per Protocol Set 
Table 14.2.1.1.5 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-D) Total Score by Study Visit 
Per Protocol Set 
Table 14.2.1.1.6 
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 Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-D) Total Score by Study Visit 
Modified Full Analysis Set 


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Table Number 
Title 
Analysis Set 
Table 14.2.1.1.8 
Model-based Sensitivity Analysis on Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score at Day 15 
Modified Full Analysis Set 
Table 14.2.1.2.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Subscale Scores by Study 
Visit 
Full Analysis Set 
Table 14.2.1.2.2 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-D) Subscale Score by Study Visit 
Full Analysis Set 
Table 14.2.1.2.3 
Summary of Hamilton Rating Scale for Depression (HAM-D) Subscale Scores by Study 
Visit 
Modified Full Analysis Set 
Table 14.2.1.2.4 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-D) Subscale Score by Study Visit 
Modified Full Analysis Set 
Table 14.2.1.3.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Individual Item Score by 
Study Visit 
Full Analysis Set 
Table 14.2.1.3.2 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Individual 
Item Score, Change from Baseline by Study Visit 
Full Analysis Set 
Table 14.2.1.3.3 
Summary of Hamilton Rating Scale for Depression (HAM-D) Individual Item Score by 
Study Visit 
Modified Full Analysis Set 
Table 14.2.1.3.4 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-D) Individual Item Score by Study Visit 
Modified Full Analysis Set 
Table 14.2.1.4.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Response by Study Visit 
Full Analysis Set 
Table 14.2.1.4.2 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Response by 
Study Visit 
Full Analysis Set 
Table 14.2.1.4.3 
Sensitivity Analysis: Summary of Hamilton Rating Scale for Depression (HAM-D) 
Response by Study Visit  
Full Analysis Set 
Table 14.2.1.4.4 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score – Percent 
Improvement – by Study Visit 
Full Analysis Set 


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Table Number 
Title 
Analysis Set 
Table 14.2.1.4.5 
Summary of Time to First Hamilton Rating Scale for Depression (HAM-D) Response – 
Kaplan-Meier Analysis 
Full Analysis Set 
Table 14.2.1.4.6 
Summary of Hamilton Rating Scale for Depression (HAM-D) Response by Study Visit 
Modified Full Analysis Set 
Table 14.2.1.4.7 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Response by 
Study Visit 
Modified Full Analysis Set 
Table 14.2.1.4.8 
Sensitivity Analysis: Summary of Hamilton Rating Scale for Depression (HAM-D) 
Response by Study Visit  
Modified Full Analysis Set 
Table 14.2.1.4.9 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score – Percent 
Improvement – by Study Visit 
Modified Full Analysis Set 
Table 14.2.1.4.10 
Summary of Time to First Hamilton Rating Scale for Depression (HAM-D) Response – 
Kaplan-Meier Analysis 
Modified Full Analysis Set 
Table 14.2.1.5.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Remission by Study Visit 
Full Analysis Set 
Table 14.2.1.5.2 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Remission by 
Study Visit 
Full Analysis Set 
Table 14.2.1.5.3 
Sensitivity Analysis: Summary of Hamilton Rating Scale for Depression (HAM-D) 
Remission by Study Visit 
Full Analysis Set 
Table 14.2.1.5.4 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score in Categories, 
by Study Visit 
Full Analysis Set 
Table 14.2.1.5.5 
Summary of Time to First Hamilton Rating Scale for Depression (HAM-D) Remission – 
Kaplan-Meier Analysis 
Full Analysis Set 
Table 14.2.1.5.6 
Summary of Hamilton Rating Scale for Depression (HAM-D) Remission by Study Visit 
Modified Full Analysis Set 
Table 14.2.1.5.7 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Remission by 
Study Visit 
Modified Full Analysis Set 
Table 14.2.1.5.9 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score in Categories, 
by Study Visit 
Modified Full Analysis Set 


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Table Number 
Title 
Analysis Set 
Table 14.21.5.10 
Summary of Time to First Hamilton Rating Scale for Depression (HAM-D) Remission – 
Kaplan-Meier Analysis 
Modified Full Analysis Set 
Table 14.2.1.6.1 
Summary of HAM-D Total Score by Study Visit and Antidepressant Use at Baseline 
Full Analysis Set 
Table 14.2.1.6.2 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-D) Total Score by Study Visit and Antidepressant Use at Baseline 
Full Analysis Set 
Table 14.2.1.6.3 
Summary of HAM-D Total Score by Study Visit and Age Group 
Full Analysis Set 
Table 14.2.1.6.4 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-D) Total Score by Study Visit and Age Group  
Full Analysis Set 
Table 14.2.1.6.5 
Summary of HAM-D Total Score by Study Visit and Sex 
Full Analysis Set 
Table 14.2.1.6.6 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-D) Total Score by Study Visit and Sex 
Full Analysis Set 
Table 14.2.1.6.7 
Summary of HAM-D Total Score by Study Visit and Race Group 
Full Analysis Set 
Table 14.2.1.6.8 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-D) Total Score by Study Visit and Race Group 
Full Analysis Set 
Table 14.2.1.6.9 
Summary of HAM-D Total Score by Study Visit and BMI at Baseline 
Full Analysis Set 
Table 14.2.1.6.10 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-D) Total Score by Study Visit and BMI at Baseline 
Full Analysis Set 
Table 14.2.1.6.11 
Summary of HAM-D Total Score by Study Visit and Baseline HAM-D Total Score 
Category 
Full Analysis Set 
Table 14.2.1.6.12 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-D) Total Score by Study Visit and Baseline HAM-D Total Score Category 
Full Analysis Set 
Table 14.2.1.6.13 
Summary of HAM-D Total Score by Study Visit and COVID-19 History 
Full Analysis Set 
Table 14.2.1.6.14 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-D) Total Score by Study Visit and COVID-19 History 
Full Analysis Set 
Table 14.2.1.6.15 
Summary of HAM-D Total Score by Study Visit and Antidepressant Use at Baseline 
Modified Full Analysis Set 


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Table Number 
Title 
Analysis Set 
Table 14.2.1.6.16 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-D) Total Score by Study Visit and Antidepressant Use at Baseline 
Modified Full Analysis Set 
Table 14.2.1.6.17 
Summary of HAM-D Total Score by Study Visit and Age Group 
Modified Full Analysis Set 
Table 14.2.1.6.18 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-D) Total Score by Study Visit and Age Group  
Modified Full Analysis Set 
Table 14.2.1.6.19 
Summary of HAM-D Total Score by Study Visit and Sex 
Modified Full Analysis Set 
Table 14.2.1.6.20 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-D) Total Score by Study Visit and Sex 
Modified Full Analysis Set 
Table 14.2.1.6.21 
Summary of HAM-D Total Score by Study Visit and Race Group 
Modified Full Analysis Set 
Table 14.2.1.6.22 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-D) Total Score by Study Visit and Race Group 
Modified Full Analysis Set 
Table 14.2.1.6.23 
Summary of HAM-D Total Score by Study Visit and BMI at Baseline 
Modified Full Analysis Set 
Table 14.2.1.6.24 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-D) Total Score by Study Visit and BMI at Baseline 
Modified Full Analysis Set 
Table 14.2.1.6.27 
Summary of HAM-D Total Score by Study Visit and COVID-19 History 
Modified Full Analysis Set 
Table 14.2.1.6.28 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-D) Total Score by Study Visit and COVID-19 History 
Modified Full Analysis Set 
Table 14.2.1.6.29 
Summary of HAM-D Response by Study Visit and Antidepressant Use at Baseline 
Full Analysis Set 
Table 14.2.1.6.30 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Response by 
Study Visit and Antidepressant Use at Baseline 
Full Analysis Set 
Table 14.2.1.6.31 
Summary of HAM-D Response by Study Visit and Antidepressant Use at Baseline 
Modified Full Analysis Set 
Table 14.2.1.6.32 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Response by 
Study Visit and Antidepressant Use at Baseline 
Modified Full Analysis Set 
Table 14.2.1.6.33 
Summary of HAM-D Remission by Study Visit and Antidepressant Use at Baseline 
Full Analysis Set 


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Table Number 
Title 
Analysis Set 
Table 14.2.1.6.34 
Model-based Results Hamilton Rating Scale for Depression (HAM-D) Remission by 
Study Visit and Antidepressant Use at Baseline 
Full Analysis Set 
Table 14.2.1.6.35 
Summary of HAM-D Remission by Study Visit and Antidepressant Use at Baseline 
Modified Full Analysis Set 
Table 14.2.1.6.36 
Model-based Results on Hamilton Rating Scale for Depression (HAM-D) Remission by 
Study Visit and Antidepressant Use at Baseline 
Modified Full Analysis Set 
Table 14.2.2.1.1 
Summary of Clinical Global Impression – Improvement (CGI-I) by Study Visit 
Full Analysis Set 
Table 14.2.2.2.1 
Summary of Clinical Global Impression – Improvement (CGI-I) Response by Study 
Visit 
Full Analysis Set 
Table 14.2.2.2.2 
Model-based Results on Clinical Global Impression – Improvement (CGI-I) Response by 
Study Visit 
Full Analysis Set 
Table 14.2.2.3.1 
Summary of Clinical Global Impression – Improvement (CGI-I) by Study Visit 
Modified Full Analysis Set 
Table 14.2.2.3.2 
Summary of Clinical Global Impression – Improvement (CGI-I) Response by Study 
Visit 
Modified Full Analysis Set 
Table 14.2.2.3.3 
Model-based Results on Clinical Global Impression – Improvement (CGI-I) Response by 
Study Visit 
Modified Full Analysis Set 
Table 14.2.3.1.1 
Summary of Clinical Global Impression – Severity (CGI-S) by Study Visit 
Full Analysis Set 
Table 14.2.3.1.2 
Model-based Results on Change from Baseline in Clinical Global Impression – Severity 
(CGI-S) by Study Visit 
Full Analysis Set 
Table 14.2.3.1.3 
Summary of Clinical Global Impression – Severity (CGI-S) by Study Visit 
Modified Full Analysis Set 
Table 14.2.3.1.4 
Model-based Results on Change from Baseline in Clinical Global Impression – Severity 
(CGI-S) by Study Visit 
Modified Full Analysis Set 
Table 14.2.4.1.1 
Summary of Hamilton Rating Scale for Anxiety (HAM-A) Total Score by Visit 
Full Analysis Set 
Table 14.2.4.1.2 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-A) Total Score by Study Visit 
Full Analysis Set 


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Table Number 
Title 
Analysis Set 
Table 14.2.4.2.1 
Summary of Hamilton Rating Scale for Anxiety (HAM-A) Individual Item Score by 
Study Visit 
Full Analysis Set 
Table 14.2.4.2.2 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-A) Individual Item Score by Study Visit 
Full Analysis Set 
Table 14.2.4.3.1 
Summary of Hamilton Rating Scale for Anxiety (HAM-A) Total Score by Visit 
Modified Full Analysis Set 
Table 14.2.4.3.2 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-A) Total Score by Study Visit 
Modified Full Analysis Set 
Table 14.2.4.4.1 
Summary of Hamilton Rating Scale for Anxiety (HAM-A) Individual Item Score by 
Study Visit 
Modified Full Analysis Set 
Table 14.2.4.4.2 
Model-based Results on Change from Baseline in Hamilton Rating Scale for Depression 
(HAM-A) Individual Item Score by Study Visit 
Modified Full Analysis Set 
Table 14.2.5.1.1 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Total Score by 
Study Visit 
Full Analysis Set 
Table 14.2.5.1.2 
Model-based Results on Change from Baseline in Montgomery-Asberg Depression 
Rating Scale (MADRS) Total Score by Study Visit 
Full Analysis Set 
Table 14.2.5.2.1 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Individual Item 
Score by Study Visit 
Full Analysis Set 
Table 14.2.5.2.2 
Model-based Results on Change from Baseline in Montgomery-Asberg Depression 
Rating Scale (MADRS) Individual Item Score 
Full Analysis Set 
Table 14.2.5.3.1 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Response by 
Study Visit 
Full Analysis Set 
Table 14.2.5.3.2 
Model-based Results on Montgomery-Asberg Depression Rating Scale (MADRS) 
Response by Study Visit 
Full Analysis Set 
Table 14.2.5.4.1 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Remission by 
Study Visit 
Full Analysis Set 


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Table Number 
Title 
Analysis Set 
Table 14.2.5.4.2 
Model-based Results on Montgomery-Asberg Depression Rating Scale (MADRS) 
Remission by Study Visit 
Full Analysis Set 
Table 14.2.5.5.1 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Total Score by 
Study Visit 
Modified Full Analysis Set 
Table 14.2.5.5.2 
Model-based Results on Change from Baseline in Montgomery-Asberg Depression 
Rating Scale (MADRS) Total Score by Study Visit 
Modified Full Analysis Set 
Table 14.2.5.6.1 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Individual Item 
Score by Study Visit 
Modified Full Analysis Set 
Table 14.2.5.6.2 
Model-based Results on Change from Baseline in Montgomery-Asberg Depression 
Rating Scale (MADRS) Individual Item Score 
Modified Full Analysis Set 
Table 14.2.5.7.1 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Response by 
Study Visit 
Modified Full Analysis Set 
Table 14.2.5.7.2 
Model-based Results on Montgomery-Asberg Depression Rating Scale (MADRS) 
Response by Study Visit 
Modified Full Analysis Set 
Table 14.2.5.8.1 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Remission by 
Study Visit 
Modified Full Analysis Set 
Table 14.2.5.8.2 
Model-based Results on Montgomery-Asberg Depression Rating Scale (MADRS) 
Remission by Study Visit 
Modified Full Analysis Set 
Table 14.2.6.1.1 
Summary of Short Form-36 Version 2 (SF-36v2) Domain/Component Score by Study 
Visit 
Full Analysis Set 
Table 14.2.6.1.2 
Model-based Results on Change from Baseline in Short Form-36 Version 2 (SF-36v2) 
Individual Domain/Component by Study Visit 
Full Analysis Set 
Table 14.2.6.2.1 
Summary of Short Form-36 Version 2 (SF-36v2) Domain/Component Score by Study 
Visit 
Modified Full Analysis Set 
Table 14.2.6.2.2 
Model-based Results on Change from Baseline in Short Form-36 Version 2 (SF-36v2) 
Individual Domain/Component by Study Visit 
Modified Full Analysis Set 


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Table Number 
Title 
Analysis Set 
Table 14.2.7.1.1 
Summary of Patient Health Questionnaire (PHQ-9) Total Score by Study Visit 
Full Analysis Set 
Table 14.2.7.1.2 
Summary of Patient Health Questionnaire (PHQ-9) Total Score Category by Study Visit 
Full Analysis Set 
Table 14.2.7.1.3 
Model-based Results on Change from Baseline in Patient Health Questionnaire (PHQ-9) 
Total Score by Study Visit 
Full Analysis Set 
Table 14.2.7.2.1 
Summary of Patient Health Questionnaire (PHQ-9) Total Score by Study Visit 
Modified Full Analysis Set 
Table 14.2.7.2.2 
Summary of Patient Health Questionnaire (PHQ-9) Total Score Category by Study Visit 
Modified Full Analysis Set 
Table 14.2.7.2.3 
Model-based Results on Change from Baseline in Patient Health Questionnaire (PHQ-9) 
Total Score by Study Visit 
Modified Full Analysis Set 
Table 14.2.8.1 
Summary of Percent Retention (%) of Day 15 Change from Baseline in Hamilton Rating 
Scale for Depression (HAM-D) at Post-Day15 Visits 
Full Analysis Set- 
Participants who had 
improvement at Day 15  
Table 14.2.8.2 
Summary of Percent Retention (%) of Day 15 Change from Baseline in Hamilton Rating 
Scale for Depression (HAM-D)  at Post-Day 15 Visits 
Modified Full Analysis Set- 
Participants who had 
improvement at Day 15  
Table 14.2.8.3 
Summary of Percent Retention (%) of Day 15 Change from Baseline in Hamilton Rating 
Scale for Depression (HAM-D) at Post-D15 Visits, for HAM-D Responders at Day 15 
Full Analysis Set -Day 15 
HAM-D Responders Only 
Table 14.2.8.4 
Summary of Percent Retention (%) of Day 15 Change from Baseline in Hamilton Rating 
Scale for Depression (HAM-D) at Post-D15 Visits, for HAM-D Responders at Day 15 
Modified Full Analysis Set 
-Day 15 HAM-D 
Responders Only 
Table 14.2.8.5 
Summary of Hamilton Rating Scale for Depression (HAM-D) Response at Post-Day 15 
Visits, for HAM-D Responders at Day 15 
Full Analysis Set -Day 15 
HAM-D Responders Only 
Table 14.2.8.6 
Summary of Hamilton Rating Scale for Depression (HAM-D) Response at Post-Day 15 
Visits, for HAM-D Responders at Day 15 
Modified Full Analysis Set 
-Day 15 HAM-D 
Responders Only 
Table 14.2.8.7 
Summary of Hamilton Rating Scale for Depression (HAM-D) Remission at Post-Day 15 
Visits, for HAM-D Remitters at Day 15 
Full Analysis Set -Day 15 
HAM-D Responders Only 


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Table Number 
Title 
Analysis Set 
Table 14.2.8.8 
Summary of Hamilton Rating Scale for Depression (HAM-D) Remission at Post-Day 15 
Visits, for HAM-D Remitters at Day 15 
Modified Full Analysis Set- 
Day 15 HAM-D 
Responders Only 
Table 14.2.8.9 
Summary of Hamilton Rating Scale for Depression (HAM-D) Relapse and Rebound 
Post-Day 15, for HAM-D Responders at Day 15 
Full Analysis Set-Day 15 
HAM-D Responders Only 
Table 14.2.8.10 
Summary of Hamilton Rating Scale for Depression (HAM-D) Relapse and Rebound 
Post-Day 15, for HAM-D Responders at Day 15 
Modified Full Analysis Set- 
Day 15 HAM-D 
Responders Only 
Table 14.2.8.11 
Summary of Clinical Global Impression – Improvement (CGI-I) Response at Post-Day 
15 Visits, for CGI-I Responders at Day 15 
Full Analysis Set-Day 15 
HAM-D Responders Only 
Table 14.2.8.12 
Summary of Clinical Global Impression – Improvement (CGI-I) Response at Post-Day 
15 Visits, for CGI-I Responders at Day 15 
Modified Full Analysis Set-
Day 15 HAM-D 
Responders Only 
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 14.3.1.3.1 
Summary of On-Treatment Emergent Adverse Events by System Organ Class and 
Preferred Term 
Safety Set 
Table 14.3.1.3.2 
Summary of Post- Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
Safety Set 
Table 14.3.1.4.1 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term, and Use of Antidepressant at Baseline 
Safety Set 
Table 14.3.1.4.2 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term, and Age Group 
Safety Set 
Table 14.3.1.4.3 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term, and Sex 
Safety Set 
Table 14.3.1.4.4 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term, and Race Group 
Safety Set 


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Table Number 
Title 
Analysis Set 
Table 14.3.1.4.5 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term, and BMI at Baseline 
Safety Set 
Table 14.3.1.4.6 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term, and Baseline HAM-D Total Score 
Safety Set 
Table 14.3.1.4.7 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term, and COVID-19 History 
Safety Set 
Table 14.3.1.5 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term, and Maximum Severity 
Safety Set 
Table 14.3.1.6 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term, and Relationship to Investigational Product  
Safety Set 
Table 14.3.1.7 
Summary of Treatment Period Treatment-Emergent Adverse Events Leading to 
Discontinuation of Investigational Product by System Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.8 
Summary of Treatment-Emergent Adverse Events Leading to Withdrawal from the 
Study by System Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.9 
Summary of Treatment-Emergent Serious Adverse Events by System Organ Class and 
Preferred Term 
Safety Set 
Table 14.3.1.10 
Summary of Most Common (>2%) Treatment-Emergent Adverse Events by Preferred 
Term 
Safety Set 
Table 14.3.1.11 
Summary of Treatment-Emergent Adverse Events Leading to Dose Reduction by System 
Organ Class, Preferred Term 
Safety Set 
Table 14.3.4.1.1 
Summary of Serum Chemistry Results by Study Visit 
Safety Set 
Table 14.3.4.1.2 
Summary of Shift in Serum Chemistry Results  
Safety Set 
Table 14.3.4.1.3 
Summary of Potentially Clinically Significant Liver Function Tests  
Safety Set 
Table 14.3.4.1.4 
Summary of Potentially Clinically Significant Serum Chemistry (excluding LFT)  
Safety Set 
Table 14.3.4. 2.1 
Summary of Hematology Results by Study Visit 
Safety Set 


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Table Number 
Title 
Analysis Set 
Table 14.3.4.2.2 
Summary of Shift in Hematology Results  
Safety Set 
Table 14.3.4.2.3 
Summary of Potentially Clinically Significant Hematology Results  
Safety Set 
Table 14.3.4. 3.1 
Summary of Urinalysis Results by Study Visit – Quantitative Results 
Safety Set 
Table 14.3.4. 3.2 
Summary of Urinalysis by Study Visit – Qualitative Results 
Safety Set 
Table 14.3.4.4.1 
Summary of Coagulation Results by Study Visit  
Safety Set 
Table 14.3.4.5.1 
Summary of Vital Signs by Study Visit 
Safety Set 
Table 14.3.4.5.2 
Summary of Potentially Clinically Significant Vital Signs Any Time Post-Baseline 
Safety Set 
Table 14.3.4.5.3 
Summary of Orthostatic Changes (Supine minus Standing in Vital Signs by Study Visit 
Safety Set 
Table 14.3.4.6.1 
Summary of ECG data by Study Visit 
Safety Set 
Table 14.3.4.6.2 
Summary of Abnormal ECG by Study Visit 
Safety Set 
Table 14.3.4.6.3 
Summary of Potentially Clinically Significant QTcF in ECG Data Any Time Post-
Baseline 
Safety Set 
Table 14.3.4.7.1 
Summary of Columbia Suicide Rating Scale (C-SSRS) Suicidal Ideation and Suicidal 
Behavior by Study Visit and Treatment Group 
Safety Set 
Table 14.3.4.7.2 
Summary of Columbia-Suicide Severity Rating Scale (C-SSRS) on Suicidal Ideation and 
Suicidal Behavior Data 
Safety Set 
Table 14.3.4.7.3.1 
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. 7.3.2 
Summary of Shift from Baseline in C-SSRS Maximum Severity Score in Suicidal 
Ideation at Any Time Post-Baseline 
Safety Set 
Table 14.3.4.8 
Summary of Physical Withdrawal Checklist (PWC)-20 Total Scores by Study Visit 
Safety Set 
 
 


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Figures 
Figure Number 
Title 
Analysis Set 
Figure 14.2.1.1 
 
Line Plot of LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score Over Time by Treatment Group 
Full Analysis Set 
Figure 14.2.1.1.1 
 
Line Plot of LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score Over Time by Treatment Group and Antidepressant 
Use at Baseline 
Full Analysis Set 
Figure 14.2.1.2 
 
Forest Plot of Change from Baseline in Hamilton Rating Scale for Depression (HAM-
D) Total Score at Day 15 by Treatment Group and Subgroups  
Full Analysis Set 
Figure 14.2.1.3 
 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Response over Time 
Full Analysis Set 
Figure 14.2.1.3.1 
 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Response over Time, 
by Antidepressant Use at Baseline 
Full Analysis Set 
Figure 14.2.1.4 
 
Histogram of Hamilton Rating Scale for Depression (HAM-D) Percentage 
Improvement over Time 
Full Analysis Set 
Figure 14.2.1.5 
 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Remission over Time 
Full Analysis Set 
Figure 14.2.1.5.1 
 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Remission over Time, 
by Antidepressant Use at Baseline 
Full Analysis Set 
Figure 14.2.1.6 
 
Histogram of Hamilton Rating Scale for Depression (HAM-D) Total Score in 
Categories over Time 
Per Protocol Set 
Figure 14.2.1.7 
 
Forest Plot of Change from Baseline in Hamilton Rating Scale for Depression (HAM-
D) Subscales on Day 15 by Treatment Group  
Full Analysis Set 
Figure 14.2.1.8 
 
Forest Plot of Change from Baseline in Hamilton Rating Scale for Depression (HAM-
D) for Individual Items on Day 15 by Treatment Group  
Full Analysis Set 
Figure 14.2.2 
 
Bar Chart of CGI-I Response over Time by Treatment Group 
Full Analysis Set 
Figure 14.2.3 
 
Line Plot of LS Mean (±SE) Change from Baseline in CGI-S over Time by Treatment 
Group 
 Full Analysis Set 


Statistical Analysis Plan Methods Version 1.0 25May2021 
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Figure Number 
Title 
Analysis Set 
Figure 14.2.4 
 
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 14.2.5 
 
Line Plot of LS Mean (±SE) Change from Baseline in Montgomery-Åsberg 
Depression Rating Scale (MADRS) Total Score over Time by Treatment Group 
Full Analysis Set 
Figure 14.2.6 
Bar Chart of LS mean (± SE) Change from Baseline in Short Form-36 Version 
2 at Day 15 by Domain/Component and Treatment Group 
Full Analysis Set 
Figure 14.2.7 
 
Distribution of Participants with Suicide-Related Events Based on the C-SSRS Scores 
over Time by Treatment Group 
Safety Set 
Figure 14.2.8.1 
 
Line Plot of LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score Over Time by Treatment Group 
Modified Full Analysis Set 
Figure 14.2.8.1.1 
 
Line Plot of LS Mean (±SE) Change from Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score Over Time by Treatment Group and Antidepressant 
Use at Baseline 
Modified Full Analysis Set 
Figure 14.2.8.2 
 
Forest Plot of Change from Baseline in Hamilton Rating Scale for Depression (HAM-
D) Total Score at Day 15 by Treatment Group and Subgroups 
Modified Full Analysis Set 
Figure 14.2.8.3 
 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Response over Time 
Modified Full Analysis Set 
Figure 14.2.8.3.1 
 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Response over Time, 
by Antidepressant Use at Baseline 
Modified Full Analysis Set 
Figure 14.2.8.4 
 
Histogram of Hamilton Rating Scale for Depression (HAM-D) Percentage 
Improvement over Time 
Modified Full Analysis Set 
Figure 14.2.8.5 
 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Remission over Time 
Modified Full Analysis Set 
Figure 14.2.8.5.1 
 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Remission over Time, 
by Antidepressant Use at Baseline 
Modified Full Analysis Set 
Figure 14.2.8.6 
 
Histogram of Hamilton Rating Scale for Depression (HAM-D) Total Score in 
Categories over Time 
Modified Full Analysis Set 
Figure 14.2.8.7 
 
Forest Plot of Change from Baseline in Hamilton Rating Scale for Depression (HAM-
D) Subscales on Day 15 by Treatment Group  
Modified Full Analysis Set 
Figure 14.2.8.8 
 
Forest Plot of Change from Baseline in Hamilton Rating Scale for Depression (HAM-
D) for Individual Items on Day 15 by Treatment Group  
Modified Full Analysis Set 


Statistical Analysis Plan Methods Version 1.0 25May2021 
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Figure Number 
Title 
Analysis Set 
Figure 14.2.9 
 
Bar Chart of CGI-I Response over Time by Treatment Group 
Modified Full Analysis Set 
Figure 14.2.10 
 
Line Plot of LS Mean (±SE) Change from Baseline in CGI-S over Time by Treatment 
Group 
Modified Full Analysis Set 
Figure 14.2.11 
 
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 14.2.12 
 
Line Plot of LS Mean (±SE) Change from Baseline in Montgomery-Åsberg 
Depression Rating Scale (MADRS) Total Score over Time by Treatment Group 
Modified Full Analysis Set 
Figure 14.2.13 
Bar Chart of LS mean (± SE) Change from Baseline in Short Form-36 Version 2 at 
Day 15 by Domain/Component and Treatment Group 
Modified Full Analysis Set 
Figure 14.2.14 
Line Plot of Percent Retention (%) of Day 15 Change from Baseline in Hamilton 
Rating Scale for Depression (HAM-D) over Time 
Full Analysis Set- 
Participants who had 
improvement at Day 15  
Figure 14.2.15 
Line Plot of Percent Retention (%) of Day 15 Change from Baseline in Hamilton 
Rating Scale for Depression (HAM-D) over Time 
Modified Full Analysis Set- 
Participants who had 
improvement at Day 15  
Figure 14.2.16 
Line Plot of Percent Retention (%) of Day 15 Change from Baseline in Hamilton 
Rating Scale for Depression (HAM-D) over Time, for HAM-D Responders at Day 15  
Full Analysis Set -Day 15 
HAM-D Responders Only 
Figure 14.2.17 
Line Plot of Percent Retention (%) of Day 15 Change from Baseline in Hamilton 
Rating Scale for Depression (HAM-D) over Time, for HAM-D Responders at Day 15 
Modified Full Analysis Set- 
-Day 15 HAM-D 
Responders Only 
Figure 14.2.18 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Response at Post-Day 
15 Visits, for HAM-D Responders at Day 15, for HAM-D Responders at Day 15 
Full Analysis Set -Day 15 
HAM-D Responders Only 
Figure 14.2.19 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Response at Post-Day 
15 Visits, for HAM-D Responders at Day 15, for HAM-D Responders at Day 15 
Modified Full Analysis Set- 
-Day 15 HAM-D 
Responders Only 
Figure 14.2.20 
Bar Chat of Hamilton Rating Scale for Depression (HAM-D) Remission at Post-Day 
15 Visits, for HAM-D Remitters at Day 15, for HAM-D Remitters at Day 15 
Full Analysis Set -Day 15 
HAM-D Remitters Only 


Statistical Analysis Plan Methods Version 1.0 25May2021 
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Figure Number 
Title 
Analysis Set 
Figure 14.2.21 
Bar Chat of Hamilton Rating Scale for Depression (HAM-D) Remission at Post-Day 
15 Visits, for HAM-D Remitters at Day 15, for HAM-D Remitters at Day 15 
Modified Full Analysis Set- 
Day 15 HAM-D Remitters 
Only 
Figure 14.2.22 
Bar Chart of Clinical Global Impression – Improvement (CGI-I) Response at Post-
Day 15 Visits, for CGI-I Responders at Day 15, for CGI-I Responders at Day 15 
Full Analysis Set-Day 15 
CGI-I Responders Only 
Figure 14.2.23 
Bar Chart of Clinical Global Impression – Improvement (CGI-I) Response at Post-
Day 15 Visits, for CGI-I Responders at Day 15, for CGI-I Responders at Day 15 
Modified Full Analysis Set- 
Day 15 CGI-I Responders 
Only 
Figure 14.2.24 
Box Plot of Physician Withdrawal Checklist (PWC)-20 Total Score from First 
Assessment after Last Dose within 1 Day Past Last Dose by Study Visit 
Safety Set 
 
 
 


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Listings 
Listing Number 
Title 
Analysis Set 
Listing 16.1.7 
Participant Randomization 
Randomized Set 
Listing 16.2.1.1 
Participant Disposition 
Randomized Set 
Listing 16.2.1.2 
Premature Discontinuation from Investigational Product and/or Withdrawal 
from the Study 
Safety Set 
Listing 16.2.2.1 
Protocol Deviations 
Safety Set 
Listing 16.2.2.1.1 
Assessments Affected by COVID-19 
Safety Set 
Listing 16.2.2.2 
Inappropriate Investigational Product 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 16.2.4.2.3 
Child-Bearing Potential at Screening 
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 
Participant 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 
Concomitant Procedures 
Safety Set 


Statistical Analysis Plan Methods Version 1.0 25May2021 
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Listing Number 
Title 
Analysis Set 
Listing 16.2.5.1 
Investigational Product Administration 
Safety Set 
Listing 16.2.5.2 
Investigational Product Exposure 
Safety Set 
Listing 16.2.5.3 
Investigational Product Adherence 
Safety Set 
Listing 16.2.6.1 
Hamilton Rating Scale for Depression (HAM-D) 
Full Analysis Set 
Listing 16.2.6.2 
Clinical Global Impression (CGI) – Improvement 
Full Analysis Set 
Listing 16.2.6.3 
Clinical Global Impression (CGI) – Severity 
Full Analysis Set 
Listing 16.2.6.4 
Hamilton Anxiety Rating Scale (HAM-A) 
Full Analysis Set 
Listing 16.2.6.5 
Montgomery-Asberg Depression Rating Scale (MADRS) 
Full Analysis Set 
Listing 16.2.6.6 
Short-Form 36 (SF-36) Individual Item Scores 
Full Analysis Set 
Listing 16.2.6.7 
Short-Form 36 (SF-36) Domain/Component Scores 
Full Analysis Set 
Listing 16.2.6.8 
Patient Health Questionnaire (PHQ-9) 
Full Analysis Set 
Listing 16.2.6.9 
Hamilton Rating Scale for Depression (HAM-D) with Percent Retention (%), 
Response, Remission, Relapse and Rebound 
Full Analysis Set  
Listing 16.2.7.1 
Treatment-Emergent Adverse Events 
Safety Set 
Listing 16.2.7.2 
Non-fatal Serious Adverse Events 
Safety Set 
Listing 16.2.7.3 
Adverse Events Leading to Death 
Safety Set 
Listing 16.2.7.4 
Adverse Events with Onset Prior to First Dose of Investigational Product  
Safety Set 
Listing 16.2.7.5 
Adverse Events leading to Premature Discontinuation of Investigational 
Product  
Safety Set 
Listing 16.2.7.6 
Adverse Events leading to Premature Withdrawal from the Study 
Safety Set 
Listing 16.2.7.7 
Adverse Events leading to Dose Reduction 
Safety Set 
Listing 16.2.8.1.1 
Serum Chemistry Data (excluding Liver Function Tests) 
Safety Set 


Statistical Analysis Plan Methods Version 1.0 25May2021 
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Listing Number 
Title 
Analysis 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 
Liver Function Tests  
Safety Set 
Listing 16.2.8.1.2.1 
Potentially Clinically Significant Values of 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 16.2.8.2.1 
Potentially Clinically Significant Vital Signs Values 
Safety Set 
Listing 16.2.8.3 
Electrocardiogram (ECG) Data 
Safety Set 
Listing 16.2.8.3.1 
Potentially Clinically Significant QTcF Values 
Safety Set 
Listing 16.2.8.4 
Physical Examination 
Safety Set 
Listing 16.2.8.5.1 
Columbia-Suicide Severity Rating Scale (C-SSRS) – Suicidal Ideation 
Safety Set 
Listing 16.2.8.5.2 
Columbia-Suicide Severity Rating Scale (C-SSRS) – Suicidal Behavior 
Safety Set 
Listing 16.2.8.6 
Physician Withdrawal Checklist (PWC)-20 
Safety Set