A Phase 3, Open-Label, 1-Year Study of the Safety, Tolerability, and Need for Re-Treatment With SAGE-217 in Adult Subjects With Major Depressive Disorder
Phase: PHASE3
Conditions: Major Depressive Disorder
Sponsor: Biogen

COVER PAGE 
Official Title: 
A Phase 3, Open-Label, 1-Year Study of the Safety, Tolerability, and Need 
for Re-Treatment with SAGE-217 in Adult Subjects with Major Depressive 
Disorder 
NCT Number: 
 NCT03864614 
Document Date: Protocol Version 7.0: 10 May 2021 
 
 

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A PHASE 3, OPEN-LABEL, 1-YEAR STUDY OF THE SAFETY, 
TOLERABILITY, AND NEED FOR RE-TREATMENT WITH 
SAGE-217 IN ADULT SUBJECTS WITH MAJOR DEPRESSIVE  
DISORDER 
 
PROTOCOL NUMBER: 217-MDD-303 
 
Study Drug 
SAGE-217 
Clinical Phase 
Phase 3 
Sponsor 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 
Sponsor Contact 
Tel:
E-mail: 
Sponsor Medical Monitor 
MD  
Tel:
E-mail:
Date of Original Protocol 
Date of Amendment 1 
Date of Amendment 2 
Date of Amendment 3 
Version 1.0, 18 October 2018 
Version 2.0, 09 January 2019 
Version 3.0, 25 April 2019 
Version 4.0, 06 February 2020 
Date of Amendment 4 
Date of Amendment 5 
Date of Amendment 6 
Version 5.0, 19 March 2020 
Version 6.0, 24 November 2020 
Version 7.0, 10 May 2021 
 
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. Your acceptance of 
this document constitutes agreement that you will not disclose the information contained herein 
to others without written authorization from Sage Therapeutics, Inc. 
 

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INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for SAGE-217. I have read the 
217-MDD-303 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 MMM YYYY) 

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

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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Sage Therapeutics, Inc. (hereafter referred to as Sage Therapeutics, or Sage) 
Name of Study Drug: SAGE-217 Capsules 
Name of Active Ingredient: SAGE-217 
Title of Study:  
A Phase 3, Open-label, 1-year Study of the Safety, Tolerability, and Need for Re-treatment with 
SAGE-217 in Adult Subjects with Major Depressive Disorder 
Number of Sites and Study Location: This study will take place at approximately 75 sites in the 
United States; non-US sites may be included as needed. 
Phase of Development: 3 
Planned Duration of Subject Participation: 
For Part A de novo subjects, the planned duration of participation is approximately 56 weeks: 
Screening Period (28 days), Initial Treatment Period (14 days), Follow-up Period (14 days), and 
Observational Period (48 weeks). In Part B, rollover subjects will enter the study during the 
Observational Period, therefore the planned duration of participation is approximately 46 weeks. 
Additional 14-day treatment periods with SAGE-217 may occur during the Observational Period. 
The following objectives and endpoints will be evaluated in 2 separate study parts: Part A (de novo 
subjects who have their initial treatment cycle in the current study) and Part B (rollover subjects who 
have their initial treatment cycle in the parent study). 
Objectives: 
Primary: 
• 
To determine the safety and tolerability of initial treatment and/or re-treatment(s) with 
SAGE-217 in adults with Major Depressive Disorder (MDD) experiencing a major 
depressive episode (MDE) at study entry for de novo subjects or at entry in the parent 
study for rollover subjects over a 1-year period 
Secondary: 
• 
To assess the need for re-treatment with SAGE-217 following initial treatment in adults 
with MDD experiencing an MDE at study entry for de novo subjects or at entry in the 
parent study for rollover subjects over a 1-year period 
• 
To assess the response of initial treatment and/or re-treatment(s) with SAGE-217 
following an initial 2-week treatment period in adults with MDD experiencing an MDE at 
study entry for de novo subjects or at entry in the parent study for rollover subjects over a 
1-year period 
 
• 
 
 
• 
 

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• 
 
 
Endpoints: 
Primary: 
• 
The safety and tolerability of the initial treatment with SAGE-217 and/or re-treatment with 
SAGE-217, as assessed by the incidence and severity of adverse events/serious adverse 
events; changes from baseline in clinical laboratory measures, vital signs, and 
electrocardiograms (ECGs); and suicidal ideation and behavior using the Columbia 
Suicide Severity Rating Scale (C-SSRS). 
Secondary: 
• 
The need for re-treatment with SAGE-217 as assessed by: 
− 
Time to first re-treatment (Kaplan-Meier curves) 
− 
Number of subjects achieving the requirements for re-treatment 
− 
Number of re-treatment cycles for each subject 
• 
The response of initial treatment and/or re-treatment as assessed by: 
− 
Change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D) 
total score at the end of each 14-day treatment (initial and/or re-treatment) period  
− 
HAM-D response at the end of each 14-day treatment (initial and/or re-treatment) 
period, defined as a ≥50% reduction in HAM-D score from baseline; 
− 
HAM-D remission at the end of each 14-day treatment (initial and/or re-treatment) 
period, defined as HAM-D total score ≤7 
− 
Clinical Global Impression - Improvement (CGI-I) response, defined as “much 
improved” or “very much improved”, at the end of each 14-day treatment (initial 
and/or re-treatment) period  
− 
Change from baseline in Clinical Global Impression - Severity (CGI-S) score at the 
end of each 14-day treatment (initial and/or re-treatment) period  
 
• 
 
 
• 
 
 
• 
 
• 
 

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• 
 
• 
 
Study Description:  
This is an open-label, long-term, longitudinal study in adult subjects with MDD. With protocol 
amendment 5, this study will be conducted in 2 parts - Part A and Part B. Each part will enroll unique 
subjects and may be enrolled concurrently. Each study part is described below.  
Part A – de novo subjects 
In Part A, de novo subjects currently experiencing an MDE will complete a Screening Period of up to 
28 days, an Initial Treatment Period (14 days) and Follow-Up Period (14 days). Subjects achieving 
response or remission with SAGE-217 will be followed for 48 weeks (Observational Period).  
The Screening Period for de novo subjects begins with the signature of the informed consent form 
(ICF); the ICF must be signed prior to beginning any screening activities. At the time of providing 
informed consent for the study, subjects will also be asked to authorize that their unique subject 
identifiers be entered into a registry (www.subjectregistry.com) with the intent of identifying subjects 
who may meet exclusion criteria due to participation in another clinical study (Section 8.2). 
The diagnosis of MDD must be made according to Structured Clinical Interview for Diagnostic and 
Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Clinical Trial Version (SCID-5-CT) 
performed by a qualified healthcare professional. Subjects will undergo preliminary screening 
procedures at the Screening Visit to determine eligibility, including completion of the MADRS, 
HAM-D, and Clinical Global Impression - Severity (CGI-S).  
Beginning on Day 1, qualified 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.  
During the initial treatment, antidepressants are permitted provided a subject is on a stable dose for at 
least 60 days prior to Day 1 and agrees to continue on the stable dose through at least the initial 
treatment and follow-up period. After the initial treatment period, subjects who respond (defined as a 
≥50% reduction in HAM-D score from baseline) by Day 15 will be followed naturalistically for 
48 weeks (see Part A study schematic below). 
If a subject does not exhibit a response to SAGE-217 by Day 15 of the initial treatment, the subject 
will be terminated from the study upon completion of the 14-day follow-up period.  
Qualified subjects (ie, HAM-D Responders at Day 15) will return to the site every 8 weeks during the 
48-week observational period for clinical assessments. A follow-up visit to collect any AEs and any 
concomitant medications and/or procedures, and to remind subjects to complete remote assessment(s) 
during the observational period will be conducted 14 days (±1 day) after the completion of the 
treatment period. 
A Part A study schematic is shown in the figure below.  

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exhibit maximal efficacy. Rollover subjects, therefore, will not be eligible to begin their first 
SAGE-217 treatment period until 56 days has elapsed from the date of last dose of blinded study drug 
(SAGE-217 or placebo) administered in the parent study. 
As this is the first study in which longitudinal re-treatment with SAGE-217 will be examined, and 
based on known withdrawal symptoms with other GABAergic drugs and non-clinical findings in a 
9-month study of SAGE-217 in dogs (Investigator’s Brochure), the potential for withdrawal-related 
events, including seizure, will be monitored following the guidelines outlined in Section 8.5.1, which 
include study drug discontinuation or dose reduction. 
If a subject exhibits suicidality at any time, they will return to the site as soon as possible for 
assessment by the Investigator. The assessments for the Screening Period and Treatment and Follow-
up Periods in Part A – de novo subjects are summarized in Table 1; the assessments for the 
Observational Period in Part A - de novo subjects are summarized in Table 2. The assessments for 
Screening and Observational Period in Part B - rollover subjects are summarized in Table 3; the 
assessments for the Treatment and Follow-Up Periods in Part B – rollover subjects are summarized in 
Table 4.  
Number of Subjects (Planned): In Part A, approximately 1200 de novo subjects will be dosed, with 
the expectation to achieve follow-up of 675 subjects for 6 months and 235 subjects for 1 year. In 
Part B, approximately 350 rollover subjects may be enrolled. 
Eligibility Criteria: 
Part A – de novo subjects 
Inclusion Criteria: 
Qualified de novo 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 75 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 during any 14-day treatment period.  
5. Subject has a diagnosis of MDD as diagnosed by SCID-5-CT, with symptoms that have been 
present for at least a 4-week period.  
6. Subject has a MADRS total score of ≥28 and a HAM-D total score of ≥20 at Screening and 
Day 1 (prior to dosing).  
7. Subjects taking antidepressants indicated for the treatment of major depressive disorder 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 must have done so for at least 60 days prior 
to Day 1. Subjects receiving psychotherapy must have been receiving therapy on a regular 
schedule for at least 60 days prior to Day 1. 
8. Female subject agrees to use at least one method of highly effective contraception as listed in 
Section 9.2.4 during participation in the study and for 30 days following the last dose of study 
drug, unless she is postmenopausal (at least 12 months of spontaneous amenorrhea without an 
alternative medical cause, with confirmatory follicular stimulation hormone [FSH] >40 

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mIU/mL), and/or surgically sterile (hysterectomy or bilateral oophorectomy, and/or bilateral 
salpingectomy), or does not engage in sexual relations which carry a risk of pregnancy. 
9. Male subject agrees to use an acceptable method of effective contraception for the duration of 
study and for 5 days after receiving the last dose of the study drug, unless the subject does not 
engage in sexual relations which carry a risk of pregnancy. Acceptable methods of effective 
contraception are listed in Section 9.2.4. 
10. Male subject is willing to abstain from sperm donation for the duration of the study and for 
5 days after receiving the last dose of the study drug. 
11. Subject agrees to refrain from drugs of abuse and alcohol for the duration of the study. 
Exclusion Criteria: 
De novo 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 has a recent history or active clinically significant manifestations of metabolic, hepatic, 
renal, hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, 
dermatological, urogenital, neurological, or eyes, ears, nose, and throat disorders, or any other 
acute or chronic condition that, in the Investigator's opinion, would limit the subject's ability to 
complete or participate in this clinical study. A body mass index (BMI) ≤18 or ≥45 kg/m2 at 
Screening is exclusionary; a BMI of 40 to 44.9 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. 
3. 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 will be 
used for this purpose. 
4. Subject has had vagus nerve stimulation, electroconvulsive therapy, or has taken ketamine 
(including esketamine) within the current major depressive episode. 
5. Subject is taking any of the following: 
a. benzodiazepines, barbiturates, or GABAA modulators (eg, eszopiclone, zopiclone, 
zaleplon, zolpidem, brexanolone) at Day -28, 
b. benzodiazepines, barbiturates, or GABAA modulators (eg, eszopiclone, zopiclone, 
zaleplon, zolpidem, brexanolone) daily or near-daily (≥4 days per week) for 1 year, in 
the year prior to first dose of study drug, 
c. benzodiazepine or GABAA modulator with a half-life of ≥48 hours (eg, diazepam) 
from 60 days prior to Day 1 
6. Subject is taking non-GABA anti-insomnia medications (eg, prescribed therapeutics 
specifically for insomnia, over-the-counter sleep aids, melatonin) first generation (typical) 
antipsychotics (eg, haloperidol, perphenazine), and/or second generation (atypical) 

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antipsychotics (eg, aripiprazole, quetiapine) at Day -14. Note that antihistamines used during 
the day solely for indication(s) other than insomnia are permitted. 
7. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds.  
8. Subject has a positive pregnancy test at Screening or on Day 1 prior to the start of study drug 
administration for any treatment cycle.  
9. Subject that is breastfeeding at Screening or on Day 1 (prior to administration of study drug) 
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 in each treatment 
cycle.  
10. Subject has detectable hepatitis B surface antigen, anti-hepatitis C virus (HCV) and positive 
HCV viral load, or human immunodeficiency virus (HIV) antibody at Screening. 
11. 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.  
12. Subject has active psychosis per Investigator assessment.  
13. Subject has a medical history of seizures.  
14. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder.  
15. 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. 
16. Subject has been taking chronic or as-needed psychostimulants (eg, methylphenidate, 
amphetamine) or opioids at Day -28. 
17. Subject has had exposure to another investigational medication or device within 30 days prior 
to Screening.  
18. Subject has previously participated in a SAGE-217 or a SAGE-547 (brexanolone) clinical trial.  
19. Use of any known strong inhibitors of cytochrome P450 (CYP)3A4 within 28 days or 5 half-
lives (whichever is longer) or consumed grapefruit juice, grapefruit, or Seville oranges, or 
products containing these within 14 days prior to the first dose of study drug for any 
SAGE-217 treatment cycle.  
20. Use of strong CYP3A inducers within 28 days prior to the first dose of study drug for any 
SAGE-217 treatment cycle or planned use during any treatment cycle. Examples include: 
rifampin, carbamazepine, enzalutamide, mitotane, phenytoin, and St John’s Wort. 
21. Subject has a positive drug and/or alcohol screen at Screening or on Day 1 prior to dosing of 
the initial treatment cycle. 
22. Subject plans to undergo elective surgery during the initial treatment and follow-up period.  
23. Subject has been diagnosed with and/or treated for any type of cancer (excluding basal cell 
carcinoma and in situ melanoma) within the past year prior to Screening. 

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24. Subject has a history of sleep apnea. 
25. Subject has had gastric bypass surgery, has a gastric sleeve or lap band, or has had any related 
procedures that interfere with gastrointestinal transit. 
26. Subject ≥65 years of age has a history of cognitive impairment, increased risk for falls 
(including but not limited to impaired balance and/or gait) or is already taking ≥2 CNS active 
drugs as per the American Geriatrics Society 2015 Updated Beers Criteria for Potentially 
Inappropriate Medication Use in Older Adults. 
Part B – rollover subjects 
Inclusion Criteria: 
Qualified rollover 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 in good physical health and has no clinically significant findings, as determined by 
the investigator. 
3. Subject has completed treatment with double-blind study drug and has completed the final 
(end-of-study) visit in the parent study. 
4. Subject agrees to adhere to the study requirements, including not participating in night shift 
work during any 14-day treatment period. 
5. Female subject agrees to use at least one method of highly effective contraception as listed in 
Section 9.2.4 during participation in the study and for 30 days following the last dose of study 
drug, unless she is postmenopausal (at least 12 months of spontaneous amenorrhea without an 
alternative medical cause, with confirmatory follicular stimulation hormone [FSH] >40 
mIU/mL), and/or surgically sterile (hysterectomy or bilateral oophorectomy, and/or bilateral 
salpingectomy), or does not engage in sexual relations which carry a risk of pregnancy. 
6. Male subject agrees to use an acceptable method of effective contraception for the duration of 
study and for 5 days after receiving the last dose of the study drug, unless the subject does not 
engage in sexual relations which carry a risk of pregnancy. Acceptable methods of effective 
contraception are listed in Section 9.2.4 
7. Male subject is willing to abstain from sperm donation for the duration of the study and for 
5 days after receiving the last dose of the study drug. 
8.  Subject agrees to refrain from drugs of abuse and alcohol for the duration of the study. 
Exclusion Criteria: 
Rollover subjects who meet any of the following criteria are disqualified from participation in this 
study:    
1. Experienced major protocol deviations or adverse events in the parent study which could 
potentially compromise subject safety, in the investigator’s opinion. 
2. Subject is currently at significant risk of suicide, as judged by the Investigator, or has 
attempted suicide since enrolling in the parent study 

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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. 
4. Subject has had vagus nerve stimulation, electroconvulsive therapy, or has taken ketamine 
(including esketamine) since enrolling in the parent study 
5. Subject is taking first generation (typical) antipsychotics (eg, haloperidol, perphenazine), 
and/or second generation (atypical) antipsychotics (eg, aripiprazole, quetiapine) at Screening 
or within the time period between completion of the parent study and Screening. 
6. Subject has taken an antidepressant other than sertraline, escitalopram, citalopram, duloxetine 
or desvenlafaxine within 60 days prior to screening, including within the time period between 
completion of the parent study and Screening. 
7. Subject has a known allergy to SAGE-217, brexanolone, allopregnanolone, or related 
compounds. 
8. Subject has a positive pregnancy test at Screening. 
9. Subject that is breastfeeding at Screening 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 in each treatment cycle, if applicable. 
10. Subject has active psychosis per Investigator assessment. 
11. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder. 
12. Subject has a new history of mild, moderate, or severe substance use disorder (including 
benzodiazepines) diagnosed using DSM-5 criteria from the time of enrollment in the parent 
study or within the time period between completion of the parent study and Screening. 
13. Subject has taken psychostimulants (eg, methylphenidate, amphetamine) or opioids during the 
parent study or within the time period between completion of the parent study and Screening. 
14. Subject has had exposure to another investigational medication (other than SAGE-217) or 
device during the parent study or within the time period between completion of the parent 
study and Screening. 
15. Subject has a positive drug and/or alcohol screen at Screening. 
16. Subject has been diagnosed with and/or treated for any type of cancer (excluding basal cell 
carcinoma and in situ melanoma) during the parent study or within the time period between 
completion of the parent study and Screening. 
17. History of poor compliance with the study drug and/or procedures in the parent study as 
determined by the Investigator 

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SAGE-217 Dosage and Mode of administration:  
SAGE-217 is available as hard gelatin capsules for oral administration. Available dose strengths are as 
30-mg or 20-mg capsules, with single or multiple capsules administered as appropriate to achieve the 
total daily dose of 50 mg or 40 mg specified per all treatment cycles (initial or re-treatment).  
Reference Therapy, Dosage and Mode of Administration:  
Not applicable 
Duration of Treatment:  
In Part A, all de novo subjects will receive a daily oral dose of SAGE-217 from Day 1 through Day 14 
of the first treatment cycle.  
In Part B, rollover subjects will enter the current study after completing a 14-day double-blind 
treatment period and 4-week follow-up in the parent study.  
According to the re-emergence of depressive symptoms, SAGE-217 may be administered to both de 
novo and rollover subjects in subsequent 14-day treatment periods. 
Statistical Methods: 
Separate statistical analysis plans (SAP) will be generated for each part of the study and will provide a 
detailed description of the analyses to be performed in the study. For Part B- rollover subjects, the 
parent study database will be used in analysis. 
The SAP for each study part will be finalized and approved prior to database lock for respective parts. 
The data for Part A – de novo subjects may be analyzed and reported prior to database lock for Part B 
– rollover subjects. Any deviations from or changes to the SAPs following database lock will be 
described in detail in the clinical study report.   
General Considerations 
For the purpose of all analyses where applicable, baseline will be defined as the latest value before the 
first dose of SAGE-217 Cycle 1 for de novo subjects. A period-specific baseline will be defined as the 
latest value before the first dose of SAGE-217 in each 14-day treatment cycle.  
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. 
Analysis Sets 
The Safety Set for both Part A and Part B is defined as all subjects administered study drug. 
The Full Analysis Set for de novo subjects is defined as all subjects in the Safety Set who completed 
Treatment Cycle 1 and moved on to Observational Period 1 (ie, these subjects had HAM-D response 
by Day 15 and did not discontinue the study for any reason within Treatment Cycle 1). 
The Full Analysis Set for rollover subjects is defined as all subjects in the Safety Set who have at least 
one HAM-D total score available after the first dose of study drug within this protocol. 
In addition, the cohorts of subjects who started with the 30-mg dose versus the 50-mg dose may be 
analyzed separately for de novo subjects. 
Determination of Sample Size 
The sample size is not based on a formal sample size calculation. The sample size of 1200 de novo 
subjects in Part A was chosen in order to have at least 675 subjects complete 24 weeks of the study and 
at least 235 subjects complete through 56 weeks, consistent with the objective of assessing SAGE-217 

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long-term safety. Approximately 350 subjects are expected to roll over from the parent study and 
enroll in Part B. 
Analysis of Primary Endpoint 
Safety and tolerability of SAGE-217 will be evaluated by incidence and severity of adverse 
events/serious adverse events, concomitant medication usage, vital signs, clinical laboratory 
evaluations, and 12-lead ECG. Suicidality will be monitored by the C-SSRS. In addition to overall 
study results, the results from each treatment cycle will be provided separately whenever applicable. 
Safety analyses will use the Safety Set for overall safety.  
A study period is defined as a treatment cycle and its subsequent observation period; the Safety Set for 
a given study period includes subjects in the Safety Set who are dosed in the respective study period. 
Safety analyses will be provided based on the Safety Set for each study period when appropriate. 
Analysis of Secondary Endpoints 
Using the Full Analysis Set, Kaplan-Meier (KM) survival curve will be provided for time to first re-
treatment; the estimand is the median time to first re-treatment, and it will be estimated from KM 
analysis.  
Number and percentage of subjects needing at least one re-treatment (ie, meeting the criteria for re-
treatment, but not necessarily retreated) will be provided. Number of re-treatment cycles per subject 
will be summarized. 
Change from baseline and/or from period-specific baseline, when appropriate, in HAM-D total score 
and subscale scores will be summarized by each treatment cycle. 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) will be summarized for each treatment cycle. Change from baseline and/or from period-specific 
baseline, when appropriate, in CGI-S will be summarized for each treatment period. CGI-I will be 
summarized for each treatment cycle. 
 
  
 

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Table 1: 
Schedule of Events (Screening, Treatment, and Follow-up Periods) – Part A 
(de novo subjects) 
 
Screening 
Perioda, b 
Cyclec 
Open-label Treatment Period 
(Initial and Re-treatments) 
Follow-up 
Days 
D-28 to D-1 
D1 
D8 
(+1d) 
D15 
(±1d)/ 
EOTd 
D28 
(±1d)  
and/or 
ET 
Study Procedure 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
Duplicate Subject Checke 
X 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
Demographics 
X 
 
 
 
 
Medical/Family History 
X 
 
 
 
 
SCID-5 
X 
 
 
 
 
ICD-10 
X 
 
 
 
 
MGH ATRQ 
X 
 
 
 
 
Serum FSH testf 
X 
 
 
 
 
Physical Examinationg 
X 
X 
 
 
 
Body Weight/Height 
X 
 
 
X (wt only) 
 
Clinical Laboratory Assessmentsh 
X 
X 
X 
X 
 
Drug & Alcohol Screeni 
X 
X 
X 
X 
 
Pregnancy Testj 
X 
X 
 
X 
 
Hepatitis & HIV Screen 
X 
 
 
 
 
Vital Signsm 
X 
X 
X 
X 
X 
12-Lead ECGn 
X 
X 
 
X 
 
C-SSRSo 
X 
X 
X 
X 
X 
MADRS 
X 
X 
 
 
 
HAM-Dp, q 
X 
X 
X 
X 
Xr 
CGI-S 
X 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
PHQ-9 
 
X 
X 
X 
X 

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Study Drug Dispensation 
 
X 
X 
 
 
Study Drug Administration 
 
X (Day 1 through Day 14) 
 
Study Drug Accountability/Return 
 
 
X 
X 
 
Adverse Events/SAEst 
X 
Prior/Concomitant Medicationsu 
X 
CGI-I = Clinical Global Impression - Improvement; CGI-S – Clinical Global Impression - Severity; C-SSRS = 
Columbia Suicide Severity Rating Scale; D = day; ET = early termination; ECG = electrocardiogram; EOT = end of 
treatment; FSH = follicle stimulating hormone; HAM-D = Hamilton Rating Scale for Depression, 17-item; HIV = 
human immunodeficiency virus; ICD-10 = International Statistical Classification of Diseases and Related Health 
Problems version 10; 
 MADRS = Montgomery-Åsberg Depression Rating Scale; 
MGH ATRQ = Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; O = Optional; 
SCID-5 = Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; 
PHQ-9 = 9-item Patient Health Questionnaire; 
SAE = serious adverse event; 
wt = weight 
a Screening procedures are to be conducted before initial (Cycle 1) treatment period only. 
c Each cycle is 28 days (±1 day) and is comprised of a 14-day treatment period and a 14-day follow-up period. The 
initial treatment is considered Cycle 1 and re-treatments will be numbered sequentially. Each re-treatment cycle 
will begin with Day 1 (eg, the first day of the first re-treatment will be Day 1 of Cycle 2). 
d Subjects who discontinue treatment early should return to the site for an end of treatment (EOT) visit as soon as 
possible, preferably the day after treatment is discontinued. The follow-up visit should occur 14 days after the last 
dose of treatment. Subjects who discontinue treatment due to tolerability should be followed without any further 
administration of study drug in any subsequent cycle. 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 EOT visit will be conducted. 
e 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. 
f A serum FSH test will be conducted at Screening for female subjects who 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. 
g 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). 
h Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. 
i Urine toxicology for selected drugs of abuse (as per the laboratory manual) and breath test for alcohol. 
j Serum pregnancy test at Screening and urine pregnancy test thereafter.  
m 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 

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repeated at the discretion of the Investigator as clinically indicated. When vital signs are scheduled at the same 
time as blood draws, vital signs should be obtained first.  
n Triplicate ECGs will be collected. When ECG and blood draws are scheduled at the same time, ECG should be 
performed before blood draws.  
o 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. 
p The HAM-D is to be completed as early during the visit as possible. 
q The assessment timeframe for the HAM-D scale will refer to the past 7 days (1 week). 
r Subjects that do not exhibit a response to SAGE-217 by Day 15 of the initial treatment, defined as a ≥50% 
reduction in HAM-D score from baseline, will be terminated from the study upon completion of the follow-up 
visit.  
t Adverse events will be collected starting at the time of informed consent and throughout the duration of the 
subject’s participation in the study. 
u Prior medications will be collected at Screening and concomitant medications will be collected at each subsequent 
visit. 
 

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Table 2: 
Schedule of Events (Observational Period) – Part A (de novo subjects) 
 
Observational Perioda 
(Day 29 through Week 52) 
EOS/Week 52 
(±7 d) 
 
Remote 
Assessment 
Q2W (±1 d) 
Visit Q8W/ET (± 3 d) 
Unscheduled 
Visit 
(as needed)b 
Study Procedure 
 
 
 
 
PHQ-9c 
Xd 
X 
X 
X 
Abbreviated Physical 
Examination 
 
X 
 
X 
Body Weight 
 
X 
 
X 
Clinical Laboratory 
Assessments 
 
X 
  
X 
Drug & Alcohol Screen 
 
X 
 
X 
Pregnancy Test 
 
X  
 
X  
Vital Signs 
 
X 
 
X 
12-Lead ECG 
 
X 
 
X 
C-SSRS 
 
X 
 
X 
HAM-De 
 
X 
X 
X 
CGI-S 
 
X 
 
X 
CGI-I 
 
X 
 
X 
Concomitant Medicationsf 
 
X 
X 
X 
Adverse Events/SAEsh 
X 
ECG = electrocardiogram; ET = early termination; d = days; EOS = end of study; 
HAM-D = Hamilton Rating Scale for Depression, 17-item; 
 
O = optional; PHQ-9 = 9-item Patient Health Questionnaire; Q2W = once every 2 weeks; Q8W = 
once every 8 weeks;
SAE = serious adverse event 
 
a Within an Observational Period, the Q2W remote assessments will begin on Day 42 (±1 day) and occur every 2 
weeks (14 days) thereafter. The Q8W visits will begin on Day 70 (±3 days) and occur every 8 weeks (56 days) 
thereafter. 
b A subject will return to the site outside of the Q8W visit schedule if the PHQ-9 score is ≥10 and/or upon any 
suicidal thoughts or behaviors.  
c All PHQ-9 assessments will be performed via a 
. 
d The subject will take the PHQ-9 every 14 days; if the PHQ-9 score is ≥10, then the subject will return to the site to 
be assessed by the clinician-administered HAM-D in approximately one week. If the HAM-D score is <20, the 
subject will take the PHQ-9 on a weekly basis: the subject will return to the site to be assessed by the HAM-D 

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each week that the PHQ-9 score remains ≥10; if the PHQ-9 score is <10, the subject will take the PHQ-9 every 2 
weeks thereafter. 
e If the HAM-D score is ≥20 (assessed approximately one week from having a PHQ-9 score ≥10) and it has been at 
least 8 weeks since the last treatment day of the previous SAGE-217 treatment cycle (ie, Day 70 or later), the 
subject will begin a 14-day re-treatment period with a 14-day follow-up visit (see Table 1). If the HAM-D score is 
≥20 but it has been less than 8 weeks since the last treatment day of the previous SAGE-217 treatment cycle (ie, 
Day 69 or earlier), see Section 9.2.1 for guidance on allowable interventions; the subject will take the PHQ-9 on a 
weekly basis until the 8-week period has lapsed, at which time the subject may begin a re-treatment period with 
SAGE-217 (see Table 1), or until the PHQ-9 score is <10. 
f Concomitant medications will be collected at each in-clinic visit. 
h Adverse events will be collected starting at the time of informed consent and throughout the duration of the 
subject’s participation in the study. 
 
 

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Table 3: 
Schedule of Events (Screening and Observational Period) – Part B (rollover 
subjects) 
 
Screeninga (within 5 days of 
completing the final, end-
of-study visit in the parent 
study) 
Observational Periodb 
(Day 56 through Week 52) 
EOS/Week 
52 (±7 d) 
 
 
Remote 
Assessment 
Q2W (±1 d) 
Visit 
Q8W/ ET 
(±3 d) 
Unscheduled 
Visit 
(as needed)c 
Study Procedure 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
Interim Medical History d 
X 
 
 
 
 
PHQ-9 e 
 
Xf 
X 
X 
X 
Inclusion/Exclusion 
X 
 
 
 
 
Abbreviated Physical 
Examination 
 
 
X 
 
X 
Body Weight 
 
 
X  
 
X  
Clinical Laboratory 
Assessments 
 
 
X 
  
X 
Drug & Alcohol Screen 
X g 
 
X 
 
X 
Pregnancy Test (urine) 
X g 
 
X 
 
X 
Vital Signs 
 
 
X 
 
X 
12-Lead ECG 
 
 
X 
 
X 
C-SSRS 
 
 
X 
 
X 
HAM-D h 
 
 
X 
X 
X 
CGI-S 
 
 
X 
 
X 
CGI-I 
 
 
X 
 
X 
Prior/Concomitant 
Medications i 
X 
 
X 
X 
X 
Adverse Events/SAEs j 
X 
ECG = electrocardiogram; ET = early termination; d = days; EOS = end of study; HAM-D = Hamilton Rating Scale 
for Depression, 17-item;
O = optional; PHQ-9 = 9-item Patient Health 
Questionnaire; Q2W = once every 2 weeks; Q8W = once every 8 weeks; 
SAE = serious adverse event 
a Rollover subjects will enter the study for screening at the Day 42 visit during the Observational Period. This visit 
may occur on the same day as the final, end-of-study visit in the parent study. If conducted on the same day, the 
assessments listed at this visit do not need to be repeated; in this case, the informed consent and 

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inclusion/exclusion criteria only will be documented. If the Screening Visit is not conducted on the same day as 
the final, end-of-study visit in the parent study, the pregnancy test and drug and alcohol screen are to be 
conducted. Additional assessments may be conducted if necessary. 
b  Within an Observational Period, the Q2W remote assessments will begin on Day 56 (±1 day) and occur every 
2 weeks (14 days) thereafter. The Q8W visits will begin on Day 70 (±3 days) and occur every 8 weeks (56 days) 
thereafter. 
c A subject will return to the site outside of the Q8W visit schedule if the PHQ-9 score is ≥10 and/or upon any 
suicidal thoughts or behaviors.  
d Any new medical conditions or procedures with onset/start date after completion of the parent study and prior to 
signing informed consent in the current study will be recorded as interim medical history. 
e  All PHQ-9 assessments will be performed via a 
. 
f The subject will take the PHQ-9 every 14 days; if the PHQ-9 score is ≥10, then the subject will return to the site to 
be assessed by the clinician-administered HAM-D in approximately one week. If the HAM-D score is <20, the 
subject will take the PHQ-9 on a weekly basis: the subject will return to the site to be assessed by the HAM-D 
each week that the PHQ-9 score remains ≥10; if the PHQ-9 score is <10, the subject will take the PHQ-9 every 2 
weeks thereafter.  
g  To be assessed if the visit is not conducted on the same calendar day as the final (end-of-study) visit in the parent 
study. 
h  If the HAM-D score is ≥20 (assessed approximately one week from having a PHQ-9 score ≥10) and it has been at 
least 8 weeks since the last dose of double-blind treatment in the parent study (ie, Day 70 or later), the subject will 
begin a 14-day SAGE-217 treatment period with a 14-day follow-up visit (see Table 4). If the HAM-D score is 
≥20 but it has been less than 8 weeks since the last dose of double-blind treatment in the parent study (ie, Day 69 
or earlier), see Section 9.2.1 for guidance on allowable interventions; the subject will take the PHQ-9 on a weekly 
basis until the 8-week period has lapsed, at which time the subject may begin a treatment period with SAGE-217 
(see Table 4), or until the PHQ-9 score is <10. 
i  See Section 9.2.1. 
j Adverse events will be collected starting at the time of informed consent and throughout the duration of the 
subject’s participation in the study. Ongoing adverse events from the parent study will be recorded at the 
Screening Visit. 
 
 
 

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Table 4: 
Schedule of Events (Treatment and Follow-Up Periods) – Part B (rollover 
subjects) 
Cyclea 
Open-label Treatment Period 
(Re-treatments) 
Follow-up 
Days 
D1 
D8 
(+1d) 
D15 
(±1d)/ 
EOTb 
D28 
(±1d) 
Study Procedure 
Abbreviated Physical Examination 
X 
Body Weight 
X 
Clinical Laboratory Assessmentsc 
X 
X 
X 
Drug & Alcohol Screend 
X 
X 
X 
Pregnancy Teste 
X 
X 
Vital Signsg 
X 
X 
X 
X 
12-Lead ECGh
X 
X 
C-SSRSi
X 
X 
X 
X 
MADRS 
X 
HAM-D j,k 
X 
X 
X 
X 
CGI-S 
X 
X 
X 
X 
CGI-I 
X 
X 
X 
PHQ-9 
X 
X 
X 
X 
Study Drug Dispensation 
X 
X 
Study Drug Administration 
X (Day 1 through Day 14) 
Study Drug Accountability/Return 
X 
X 
Adverse Events/SAEsl 
X 
Prior/Concomitant Medicationsm
X 
CGI-I = Clinical Global Impression - Improvement; CGI-S – Clinical Global Impression - Severity; C-SSRS = 
Columbia Suicide Severity Rating Scale; D = day; ET = early termination; ECG = electrocardiogram; EOT = end of 
treatment; FSH = follicle stimulating hormone; HAM-D = Hamilton Rating Scale for Depression, 17-item; HIV = 
human immunodeficiency virus; MADRS = Montgomery-Åsberg Depression Rating Scale; O = Optional; PHQ-9 = 
9-item Patient Health Questionnaire; 
 SAE = serious adverse event;
wt = weight
a Each cycle is 28 days (±1 day) and is comprised of a 14-day treatment period and a 14-day follow-up period.
Rollover subjects may be eligible for re-treatment beginning on Day 1 of Cycle 2; any subsequent re-treatments 
will be numbered sequentially. 

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b Subjects who discontinue treatment early should return to the site for an end of treatment (EOT) visit as soon as 
possible, preferably the day after treatment is discontinued. The follow-up visit should occur 14 days after the last 
dose of treatment. Subjects who discontinue treatment due to tolerability should be followed without any further 
administration of study drug in any subsequent cycle. 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 EOT visit will be conducted. 
c Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. 
d Urine toxicology for selected drugs of abuse (as per the laboratory manual) and breath test for alcohol. 
e Urine pregnancy test.  
g 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. When vital signs are scheduled at the same 
time as blood draws, vital signs should be obtained first.  
h Triplicate ECGs will be collected. When ECG and blood draws are scheduled at the same time, ECG should be 
performed before blood draws.  
i The “Since Last Visit” C-SSRS form will be completed at any time of day. 
j The HAM-D is to be completed as early during the visit as possible. 
k The assessment timeframe for the HAM-D scale will refer to the past 7 days (1 week). 
l Adverse events will be collected starting at the time of informed consent and throughout the duration of the 
subject’s participation in the study. 
m See Section 9.2.1.  
 
 
 
 
 

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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
1. 
TITLE PAGE ................................................................................................................1 
INVESTIGATOR’S AGREEMENT ...............................................................................................4 
CONTACT INFORMATION ..........................................................................................................5 
2. 
SYNOPSIS ...................................................................................................................6 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............27 
LIST OF TABLES .........................................................................................................................30 
LIST OF FIGURES .......................................................................................................................31 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................32 
5. 
INTRODUCTION ......................................................................................................34 
5.1. 
Background of Major Depressive Disorder and Unmet Medical Need ......................34 
5.2. 
SAGE-217 ...................................................................................................................34 
5.3. 
Potential Risks and Benefits .......................................................................................35 
5.4. 
Dose Justification ........................................................................................................35 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................41 
6.1. 
Study Objective ..........................................................................................................41 
6.1.1. 
Primary Objective .......................................................................................................41 
6.1.2. 
Secondary Objectives .................................................................................................41 
41 
6.2. 
Endpoints ....................................................................................................................41 
6.2.1. 
Primary Endpoint ........................................................................................................41 
6.2.2. 
Secondary Endpoints ..................................................................................................42 
2 
7. 
INVESTIGATIONAL PLAN .....................................................................................43 
7.1. 
Overall Study Design ..................................................................................................43 
Part A – de novo subjects...............................................................................................................43 
Part B – rollover subjects ...............................................................................................................44 
7.2. 
Number of Subjects ....................................................................................................46 
7.3. 
Treatment Assignment ................................................................................................46 
7.4. 
Dose Adjustment Criteria ...........................................................................................46 
7.5. 
Criteria for Study Termination ...................................................................................47 

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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................48 
8.1. 
Subject Inclusion Criteria – Part A de novo subjects .................................................48 
8.2. 
Subject Exclusion Criteria – Part A de novo subjects ................................................48 
8.3. 
Subject Inclusion Criteria – Part B rollover subjects ..................................................51 
8.4. 
Subject Exclusion Criteria – Part B rollover subjects ................................................51 
8.5. 
Subject Withdrawal Criteria .......................................................................................52 
8.5.1. 
Individual Subject Stopping Criteria ..........................................................................53 
8.5.2. 
Replacement of Subjects .............................................................................................54 
9. 
TREATMENT OF SUBJECTS ..................................................................................55 
9.1. 
Study Drug ..................................................................................................................55 
9.2. 
Prior Medications, Concomitant Medications, and Restrictions ................................55 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................55 
9.2.1.1. 
Medication use for depressive symptom worsening following a SAGE-217 
treatment cycle ............................................................................................................55 
9.2.2. 
Prohibited Medications ...............................................................................................58 
9.2.3. 
Other Restrictions .......................................................................................................59 
9.2.4. 
Acceptable Forms of Contraception ...........................................................................59 
9.3. 
Treatment Adherence ..................................................................................................60 
9.4. 
Randomization and Blinding ......................................................................................60 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................61 
10.1. 
Description of Study Drug ..........................................................................................61 
10.2. 
Study Drug Packaging and Labeling ..........................................................................61 
10.3. 
Study Drug Storage .....................................................................................................61 
10.4. 
Study Drug Preparation ..............................................................................................61 
10.5. 
Study Drug Administration.........................................................................................61 
10.6. 
Study Drug Accountability .........................................................................................61 
10.7. 
Study Drug Handling and Disposal ............................................................................62 
10.8. 
Product Complaints ....................................................................................................62 
11. 
ASSESSMENT OF EFFICACY ................................................................................63 
11.1. 
Response Parameters ..................................................................................................63 
11.1.1. 
Hamilton Rating Scale for Depression .......................................................................63 
11.1.2. 
Clinical Global Impression .........................................................................................63 
64 

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11.1.4. 
PHQ-9 .........................................................................................................................64 
64 
64 
.64 
12. 
ASSESSMENT OF SAFETY .....................................................................................65 
12.1. 
Safety Parameters .......................................................................................................65 
12.1.1. 
Demographic/Medical History ...................................................................................65 
12.1.2. 
Weight and Height ......................................................................................................65 
12.1.3. 
Physical Examination .................................................................................................65 
12.1.4. 
COVID-19 Questions .................................................................................................66 
12.1.5. 
Vital Signs ..................................................................................................................66 
12.1.6. 
Electrocardiogram .......................................................................................................66 
12.1.7. 
Laboratory Assessments .............................................................................................66 
12.1.7.1. 
Drugs of Abuse and Alcohol ......................................................................................68 
12.1.7.2. 
Pregnancy Screen ........................................................................................................68 
12.1.8. 
Columbia-Suicide Severity Rating Scale ....................................................................69 
12.2. 
Adverse and Serious Adverse Events .........................................................................69 
12.2.1. 
Definition of Adverse Events .....................................................................................69 
12.2.1.1. 
Adverse Event .............................................................................................................69 
12.2.1.2. 
Serious Adverse Event ................................................................................................70 
12.3. 
Relationship to Study Drug ........................................................................................70 
12.4. 
Recording Adverse Events .........................................................................................71 
12.5. 
Reporting Serious Adverse Events .............................................................................72 
12.6. 
Overdose .....................................................................................................................72 
13. 
STATISTICS ..............................................................................................................73 
13.1. 
Data Analysis Sets ......................................................................................................73 
13.2. 
Handling of Missing Data ...........................................................................................73 
13.3. 
General Considerations ...............................................................................................73 
13.4. 
Demographics and Baseline Characteristics ...............................................................74 
13.5. 
Response Analyses .....................................................................................................74 
13.6. 
Safety Analyses ..........................................................................................................74 
13.6.1. 
Adverse Events ...........................................................................................................75 

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13.6.2. 
Clinical Laboratory Evaluations .................................................................................75 
13.6.3. 
Physical Examinations ................................................................................................75 
13.6.4. 
Vital Signs ..................................................................................................................75 
13.6.5. 
12-Lead Electrocardiogram ........................................................................................75 
13.6.6. 
Prior and Concomitant Medications ...........................................................................76 
13.6.7. 
Columbia Suicide Severity Rating Scale ....................................................................76 
13.7. 
Determination of Sample Size ....................................................................................76 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................77 
14.1. 
Study Monitoring ........................................................................................................77 
14.2. 
Audits and Inspections ................................................................................................77 
14.3. 
Institutional Review Board .........................................................................................78 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................79 
16. 
ETHICS ......................................................................................................................80 
16.1. 
Ethics Review .............................................................................................................80 
16.2. 
Ethical Conduct of the Study ......................................................................................80 
16.3. 
Written Informed Consent ..........................................................................................80 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................81 
17.1. 
Inspection of Records .................................................................................................81 
17.2. 
Retention of Records ..................................................................................................81 
18. 
PUBLICATION POLICY ..........................................................................................82 
19. 
LIST OF REFERENCES ............................................................................................83 
 
LIST OF TABLES 
Table 1: 
Schedule of Events (Screening, Treatment, and Follow-up Periods) – Part A 
(de novo subjects) .......................................................................................................18 
Table 2: 
Schedule of Events (Observational Period) – Part A (de novo subjects) ...................21 
Table 3: 
Schedule of Events (Screening and Observational Period) – Part B (rollover 
subjects) ......................................................................................................................23 
Table 4: 
Schedule of Events (Treatment and Follow-Up Periods) – Part B (rollover 
subjects) ......................................................................................................................25 
Table 5: 
Allowed Concomitant Psychotropic Medications During the Study (Part A 
and Part B) ..................................................................................................................57 
Table 6: 
Clinical Laboratory Tests ...........................................................................................67 

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Table 7: 
Relationship to Study Drug ........................................................................................71 
 
LIST OF FIGURES 
Figure 1: 
Predicted SAGE-217 concentrations (Cavg and Cmax) following dosing of 30 
to 50 mg daily .............................................................................................................37 
Figure 2: 
Total score change on Day 15 (Studies 217-MDD-201B, 217-MDD-301A, 
217-PPD-201) .............................................................................................................38 
Figure 3: 
Predicted incidence of sedation or somnolence by dose ............................................39 
Figure 4: 
Part A Study Design Schematic ..................................................................................44 
Figure 5: 
Part B Study Design Schematic ..................................................................................45 
 
  

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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or specialist term 
Explanation 
ADT 
Antidepressant therapy 
AE 
adverse event 
CGI-I 
Clinical Global Impression – Improvement 
CGI-S 
Clinical Global Impression – Severity 
CS 
clinically significant 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CYP 
cytochrome P450 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
end of treatment 
ET 
early termination 
FSH 
follicle stimulating hormone 
GABA 
γ-aminobutyric acid 
HAM-D 
Hamilton Rating Scale for Depression 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
IRB 
institutional review board 
IRT 
interactive response technology 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MDD 
major depressive disorder 
MDE 
major depressive episode 
NCS 
not clinically significant 
PHQ-9 
9-item Patient Health Questionnaire 
PK 
pharmacokinetic(s) 
QTcF 
QT corrected according to Fridericia’s formula 
SAE 
serious adverse event 

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Abbreviation or specialist term 
Explanation 
SAP 
statistical analysis plan 
SCID-5-CT 
Structured Clinical Interview for Diagnostic and DSM-5 
Clinical Trial Version 
SD 
standard deviation 
SUSAR 
suspected, unexpected, serious adverse reactions 
TEAE 
treatment-emergent adverse event 
WHO 
World Health Organization 
 

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5. 
INTRODUCTION 
5.1. 
Background of Major Depressive Disorder and Unmet Medical Need 
The World Health Organization (WHO) has identified depression as the leading cause of 
disability worldwide, and as a major contributor to the overall global burden of disease 
(http://www.who.int/mediacentre/factsheets/fs369/en/). Globally, depression has been estimated 
to affect over 300 million people. 
In the United States, the economic burden of depression, including workplace costs, direct costs, 
and suicide-related costs, was estimated to be $210.5 billion in 2010 (Greenberg 2015). As per 
WHO statistics, over 800,000 people die due to suicide every year, and suicide is the second 
leading cause of death in 15- to 29-year-olds. The rate of US adults making a suicide attempt has 
increased (0.62% from 2004 to 2005 to 0.79% from 2012 to 2013), with a shift to more attempts 
among younger adults (42% to 50%, respectively) and among those with a depressive disorder 
(26% to 54%, respectively; Olfson 2017). 
In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5, American 
Psychiatric Association 2013), depression refers to an overarching set of diagnoses, including 
major depressive disorder (MDD). Diagnostic criteria for MDD includes a set of at least 5 
depressive symptoms out of 9, including depressed mood and/or loss of interest or pleasure, and 
other changes affecting appetite or weight, sleep, psychomotor activity, energy level, feelings of 
guilt, concentration ability, and suicidality during the same 2-week period, that represents a 
change from previous functioning (DSM-5). 
Antidepressants are a mainstay of pharmacological treatment for depressive disorders. Selective 
serotonin uptake inhibitors, serotonin norepinephrine reuptake inhibitors, tricyclic 
antidepressants, monoamine oxidase inhibitors, and other compounds that affect monoaminergic 
neurotransmission, such as mirtrazapine and bupropion, represent the major classes of 
antidepressants. While antidepressants are widely used, large scale studies have demonstrated 
their limited efficacy, including low remission rates and untreated symptoms (Trivedi 2006; 
Conradi 2011; Romera 2013). 
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. 
SAGE-217 has been generally well tolerated in clinical studies to date. The most common 
treatment-emergent adverse events (TEAEs) associated with SAGE-217 (overall) were sedation, 
somnolence, and dizziness; most adverse events 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.  

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5.3. 
Potential Risks and Benefits 
The apparent risks of SAGE-217 are based on clinical data reports of adverse events in 
completed and ongoing studies and the known pharmacology of the drug. Sedation, somnolence, 
and dizziness were identified as adverse drug reactions. Most AEs were reported as mild or 
moderate in intensity and reversible. 
SAGE-217 may present a treatment option for MDD that has more rapid onset of action (days 
instead of weeks), when compared to available therapies. 
Based on nonclinical findings, embryo-fetal toxicity and withdrawal effects are considered 
important potential risk for SAGE-217. Risk mitigation measures in this study include 
monitoring for adverse effects, monitoring for potential withdrawal effects, requiring highly 
effective contraceptive measures for study participants, and inclusion of dose adjustment criteria 
and individual subject stopping criteria (Section 8.5.1). Finally, due to the sedation/somnolence 
observed, SAGE-217 is administered in the evening in this study. 
Given the outcome of the completed studies of SAGE-217 in subjects with MDD and PDD, the 
current significant unmet need in the treatment of depression, and a favorable benefit-risk 
profile, further investigation of SAGE-217 in adults with MDD is justified. 
5.4. 
Dose Justification 
To date, the current capsule utilized in clinical studies is not associated with a maximum 
tolerated dose (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).  
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. 
Study 217-MDD-301A, a randomized, multi-center, 3-arm study examining SAGE-217 20 and 
30 mg capsules compared to placebo, found significant anti-depressant effects compared to 
placebo at Days 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 
adverse events were lower with SAGE-217 30 mg (2.1%) than with placebo (3.2%). No 
clinically relevant changes in vital signs, laboratory results, electrocardiogram measures, or 
suicidal thinking were observed in either 217-MDD-301A or across the full SAGE-217 program, 
now with over 2000 subjects exposed to treatment. Relevant results from 217-MDD-301A are 
available in the SAGE-217 Investigator’s Brochure.  

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Direct and modeled data from completed studies to date (including efficacy studies 
217-MDD-201 and 217-PPD-201) in addition to 217-MDD-301A (through Day 42 of the 
double-blind period), 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 
that 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 that evaluated the effects of SAGE-217 
on driving performance (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 (Days 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. 
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 maximally tolerated dose of the 
oral solution (125 ng/mL).  

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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-MDD-301A, and 217-PPD-201, 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 the 217-MDD-301A results, a dose of 30 mg may be 
considered the minimally effective dose.  

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Figure 2: 
Total score change on Day 15 (Studies 217-MDD-201B, 217-MDD-301A, 
217-PPD-201) 
 
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-301A, 30 mg capsules MDD-301A, 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-301A, 217-MDD-201, and 
217-PPD-201. 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 antidepressants. 
As with usual clinical practice, all 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 
Study 217-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 

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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 over 2000 subjects exposed to SAGE-217 treatment. 
In summary, recent results from a large, multicenter trial of SAGE-217 in MDD 
(217-MDD-301A) 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 over 2000 
subjects exposed across different doses/concentrations. In addition, higher doses offer the 
potential for improved therapeutic benefit over the short 14-day treatment course.  
According to the DSM-5, a period of 8 weeks is required to establish ‘full remission’ of a 
depressive episode (American Psychiatric Association 2013). Further, available antidepressant 
therapies (ADT) often take up to 8 weeks to exhibit maximal efficacy. Thus, a minimum period 
of 8 weeks (56 days) is required between the end of a 14-day treatment period and the beginning 
of a new SAGE-217 treatment cycle.  

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6. 
STUDY OBJECTIVES AND PURPOSE 
The following objectives and endpoints will be evaluated in 2 separate study parts: Part A (de 
novo subjects who have their initial treatment cycle in the current study) and Part B (rollover 
subjects who have their initial treatment cycle in the parent study). 
6.1. 
Study Objective 
6.1.1. 
Primary Objective 
The primary objective of this study is to determine the safety and tolerability of initial treatment 
and/or re-treatment(s) with SAGE-217 in adults with MDD experiencing a major depressive 
episode (MDE) at study entry for de novo subjects or at entry in the parent study for rollover 
subjects over a 1-year period. 
6.1.2. 
Secondary Objectives 
Secondary objectives of this study are: 
• To assess the need for re-treatment with SAGE-217 following initial treatment in 
adults with MDD experiencing an MDE at study entry for de novo subjects or at entry 
in the parent study for rollover subjects over a 1-year period 
• To assess the response of initial treatment and/or re-treatment(s) with SAGE-217 
following an initial 2-week treatment period in adults with MDD experiencing an 
MDE at study entry for de novo subjects or at entry in the parent study for rollover 
subjects over a 1-year period 
 
 
 
• 
• 
 
• 
6.2. 
Endpoints 
6.2.1. 
Primary Endpoint 
The primary endpoint of this study is the safety and tolerability of the initial treatment with 
SAGE-217 and re-treatment with SAGE-217, as assessed by measures including the incidence 
and severity of AEs/SAEs; changes from baseline in clinical laboratory measures, vital signs, 
and electrocardiograms (ECGs); and suicidal ideation and behavior using the Columbia Suicide 
Severity Rating Scale (C-SSRS). 

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6.2.2. 
Secondary Endpoints 
Secondary endpoints of this study are: 
• The need for re-treatment with SAGE-217 as assessed by: 
− Time to first re-treatment (Kaplan-Meier curves) 
− Number of subjects achieving the requirements for re-treatment 
− Number of re-treatment cycles for each subject 
• The response of initial treatment and/or re-treatment as assessed by: 
− Change from baseline in the 17-item HAM-D total score at the end of each 14-day 
treatment (initial and/or re-treatment) period  
− HAM-D response at the end of each 14-day treatment (initial and/or re-treatment) 
period, defined as a ≥50% reduction in HAM-D score from baseline 
− HAM-D remission at the end of each 14-day treatment (initial and/or re-
treatment) period, defined as HAM-D total score ≤7 
− CGI-I response, defined as “much improved” or “very much improved”, at the 
end of each 14-day treatment (initial and/or re-treatment) period  
− Change from baseline in Clinical Global Impression - Severity (CGI-S) score at 
the end of each 14-day treatment (initial and/or re-treatment) period. 
 
 
 
• 
• 
• 
 
• 
• 
 
• 

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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is an open-label, long-term, longitudinal study in adult subjects with MDD. With protocol 
amendment 5, this study will be conducted in 2 parts – Part A and Part B. Each part will enroll 
unique subjects and may be enrolled concurrently. Each study part is described below and 
schematics of the study designs are shown in Figure 4 and Figure 5.  
Part A – de novo subjects 
In Part A, de novo subjects currently experiencing an MDE will complete a Screening Period of 
up to 28 days, an Initial Treatment Period (14 days) and Follow-Up Period (14 days). Subjects 
achieving response or remission with SAGE-217 will be followed for 48 weeks (Observational 
Period).  
The Screening Period for de novo subjects begins with the signature of the informed consent 
form (ICF); 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 (see Section 8.2).  
The diagnosis of MDD must be made according to Structured Clinical Interview for DSM-5 
Clinical Trial Version (SCID-5-CT) performed by a qualified healthcare professional. Subjects 
will undergo preliminary screening procedures at the Screening Visit to determine eligibility, 
including completion of the MADRS, HAM-D, and CGI-S.  
Beginning on Day 1, qualified 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.  
During the initial treatment, antidepressants are permitted provided a subject is on a stable dose 
for at least 60 days prior to Day 1 and agrees to continue on the stable dose through at least the 
initial treatment and follow-up period. After the initial treatment period, subjects who respond 
(defined as a ≥50% reduction in HAM-D score from baseline) by Day 15 will be followed 
naturalistically for 48 weeks (see Figure 4 below). 
If a subject does not exhibit a response to SAGE-217 by Day 15 of the initial treatment, the 
subject will be terminated from the study upon completion of the 14-day follow-up period.  
Qualified subjects (ie, HAM-D Responders at Day 15) will return to the site every 8 weeks 
during the 48-week observational period for clinical assessments. A follow-up visit to collect any 
AEs and any concomitant medications and/or procedures, and to remind subjects to complete 
remote assessment(s) during the observational period will be conducted 14 days (±1 day) after 
the completion of the treatment period. 
 
 

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approximately 1 week from the PHQ-9 score ≥10. In all subjects, the End of Study/Week 52 
Visit is mandatory if another scheduled on site visit does not fall in the Week 52 window. 
A minimum period of 8 weeks (56 days) is required between SAGE-217 treatment periods. This 
is based on the period of 8 weeks establishing ‘full remission’ of a depressive episode 
(American Psychiatric Association 2013) and is aligned with the treatment period which would 
be required for any available antidepressant (ADT) to exhibit maximal efficacy. Rollover 
subjects, therefore, will not be eligible to begin their first SAGE-217 treatment period until 
56 days has elapsed from the date of last dose of blinded study drug (SAGE-217 or placebo) 
administered in the parent study. 
Details guiding the use of as-needed benzodiazepines and GABA-modulators for insomnia (eg, 
eszopiclone, zopiclone, zaleplon, and zolpidem), new ADT use, or increases in concomitant 
medication ADT dose are provided in Section 9.2.1. 
As this is the first study in which longitudinal re-treatment with SAGE-217 will be examined, 
and based on known withdrawal symptoms with other GABAergic drugs and non-clinical 
findings in a 9-month study of SAGE-217 in dogs (Investigator’s Brochure), the potential for 
withdrawal-related events, including seizure, will be monitored following the guidelines outlined 
in Section 8.5.1, which include study drug discontinuation or dose reduction. 
If a subject exhibits suicidality at any time, they will return to the site as soon as possible for 
assessment by the Investigator. 
The assessments for the Screening Period and Treatment and Follow-up Periods in Part A – de 
novo subjects are summarized in Table 1; the assessments for the Observational Period in Part A 
- de novo subjects are summarized in Table 2. The assessments for Screening and Observational 
Period in Part B - rollover subjects are summarized in Table 3; the assessments for the Treatment 
and Follow-Up Periods in Part B – rollover subjects are summarized in Table 4. 
7.2. 
Number of Subjects 
In Part A, approximately 1200 de novo subjects will be dosed (Section 13.7). An estimated 25% 
will not exhibit response/remission during the first treatment exposure, leaving 900 to be 
followed for 1 year, expected to result in at least 675 subjects followed for 6 months and 
235 subjects followed for 1 year. In Part B, approximately 350 rollover subjects may be enrolled. 
7.3. 
Treatment Assignment 
This is an open-label study in which all subjects will receive SAGE-217. 
7.4. 
Dose Adjustment Criteria 
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. If a subject has been shown to not tolerate the 50 mg 
dose, and has previously been dose reduced to 40 mg, they may be started at the 40 mg dose for 
any needed subsequent re-treatments, as determined by the investigator. 
At the discretion of the investigator, subjects who cannot tolerate the 40-mg dose at any time 
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possible. These subjects should be followed without any further administration of study drug in 
any subsequent cycle, and complete assessments per the schedules of events (Table 1, Table 2 
Table 3, and Table 4). 
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 
IRB and initiate withdrawal procedures for participating subjects.  

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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria – Part A de novo subjects 
Qualified de novo 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 75 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 during any 14-day treatment period.  
5. Subject has a diagnosis of MDD as diagnosed by SCID-5-CT, with symptoms that have 
been present for at least a 4-week period.  
6. Subject has a MADRS total score of ≥28 and a HAM-D total score of ≥20 at Screening 
and Day 1 (prior to dosing).  
7. Subjects taking antidepressants used to treat major depressive disorder 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 must have done so for at least 60 days prior to 
Day 1. Subjects receiving psychotherapy must have been receiving therapy on a regular 
schedule for at least 60 days prior to Day 1. 
8. Female subject agrees to use at least one method of highly effective contraception as 
listed in Section 9.2.4 during participation in the study and for 30 days following the last 
dose of study drug, unless she is postmenopausal (at least 12 months of spontaneous 
amenorrhea without an alternative medical cause, with confirmatory follicular stimulation 
hormone [FSH] >40 mIU/mL), and/or surgically sterile (hysterectomy or bilateral 
oophorectomy, and/or bilateral salpingectomy), or does not engage in sexual relations 
which carry a risk of pregnancy. 
9. Male subject agrees to use an acceptable method of effective contraception for the 
duration of study and for 5 days after receiving the last dose of the study drug, unless the 
subject does not engage in sexual relations which carry a risk of pregnancy. Acceptable 
methods of effective contraception are listed in Section 9.2.4.  
10. Male subject is willing to abstain from sperm donation for the duration of the study and 
for 5 days after receiving the last dose of the study drug. 
11. Subject agrees to refrain from drugs of abuse and alcohol for the duration of the study. 
8.2. 
Subject Exclusion Criteria – Part A de novo subjects 
De novo subjects who meet any of the following criteria are disqualified from participation in 
this study: 

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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 has a recent history or active clinically significant manifestations of metabolic, 
hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, 
musculoskeletal, dermatological], urogenital, neurological, or eyes, ears, nose, and throat 
disorders, or any other acute or chronic condition that, in the Investigator's opinion, 
would limit the subject's ability to complete or participate in this clinical study. A body 
mass index (BMI) ≤18 or ≥45 kg/m2 at Screening is exclusionary; a BMI of 40 to 
44.9 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. 
3. 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 will be used for this purpose. 
4. Subject has had vagus nerve stimulation, electroconvulsive therapy, or has taken 
ketamine (including esketamine) within the current major depressive episode. 
5. Subject is taking any of the following: 
a. benzodiazepines, barbiturates, or GABAA modulators (eg, eszopiclone, zopiclone, 
zaleplon, zolpidem, brexanolone) at Day -28,  
b. benzodiazepines, barbiturates, or GABAA modulators daily or near-daily (≥4 days per 
week) for 1 year, in the year prior to first dose of study drug,  
c. benzodiazepine or GABAA modulator with a half-life of ≥48 hours (eg, diazepam) 
from 60 days prior to Day 1 
6. Subject is taking non-GABA anti-insomnia medications (eg, prescribed therapeutics 
specifically for insomnia, over-the-counter sleep aids, melatonin), first generation 
(typical) antipsychotics (eg, haloperidol, perphenazine) and/or second generation 
(atypical) antipsychotics (eg, aripiprazole, quetiapine) at Day -14. Note that 
antihistamines used during the day solely for indication(s) other than insomnia are 
permitted. 
7. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds.  
8. Subject has a positive pregnancy test at Screening or on Day 1 prior to the start of study 
drug administration for any treatment cycle.  
9. Subject that is breastfeeding at Screening or on Day 1 (prior to administration of study 
drug) 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 in 
each treatment cycle.  
10. Subject has detectable hepatitis B surface antigen, anti-hepatitis C virus (HCV) and 
positive HCV viral load, or human immunodeficiency virus (HIV) antibody at Screening. 

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11. 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.  
12. Subject has active psychosis per Investigator assessment.  
13. Subject has a medical history of seizures.  
14. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder.  
15. 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. 
16. Subject has been taking chronic or as-needed psychostimulants (eg, methylphenidate, 
amphetamine) or opioids at Day -28. 
17. Subject has had exposure to another investigational medication or device within 30 days 
prior to Screening.  
18. Subject has previously participated in a SAGE-217 or a SAGE-547 (brexanolone) clinical 
trial.  
19. Use of any known strong inhibitors of cytochrome P450 (CYP)3A4 within 28 days or 
5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, or Seville 
oranges, or products containing these within 14 days prior to the first dose of study drug 
for any SAGE-217 treatment cycle.  
20. Use of strong CYP3A4 inducers within 28 days prior to the first dose of study drug for 
any SAGE-217 treatment cycle or planned use during any treatment cycle. Examples 
include: rifampin, carbamazepine, enzalutamide, mitotane, phenytoin, and St John’s 
Wort. 
21. Subject has a positive drug and/or alcohol screen at Screening or on Day 1 prior to dosing 
of the initial treatment cycle. 
22. Subject plans to undergo elective surgery during the initial treatment and follow-up 
period. 
23. Subject has been diagnosed with and/or treated for any type of cancer (excluding basal 
cell carcinoma and in situ melanoma) within the past year prior to Screening. 
24. Subject has a history of sleep apnea. 
25. Subject has had gastric bypass surgery, has a gastric sleeve or lap band, or has had any 
related procedures that interfere with gastrointestinal transit. 
26. Subject ≥65 years of age has a history of cognitive impairment, increased risk for falls 
(including but not limited to impaired balance and/or gait), or is already taking ≥2 CNS 
active drugs as per the American Geriatrics Society 2015 Updated Beers Criteria for 
Potentially Inappropriate Medication Use in Older Adults. 

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8.3. 
Subject Inclusion Criteria – Part B rollover subjects 
Qualified rollover 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 in good physical health and has no clinically significant findings, as 
determined by the investigator. 
3. Subject has completed treatment with double-blind study drug and has completed the 
final (end-of-study) visit in the parent study. 
4. Subject agrees to adhere to the study requirements, including not participating in night 
shift work during any 14-day treatment period. 
5. Female subject agrees to use at least one method of highly effective contraception as 
listed in Section 9.2.4 during participation in the study and for 30 days following the last 
dose of study drug, unless she is postmenopausal (at least 12 months of spontaneous 
amenorrhea without an alternative medical cause, with confirmatory follicular stimulation 
hormone [FSH] >40 mIU/mL), and/or surgically sterile (hysterectomy or bilateral 
oophorectomy, and/or bilateral salpingectomy), or does not engage in sexual relations 
which carry a risk of pregnancy. 
6. Male subject agrees to use an acceptable method of effective contraception for the 
duration of study and for 5 days after receiving the last dose of the study drug, unless the 
subject does not engage in sexual relations which carry a risk of pregnancy.  Acceptable 
methods of effective contraception are listed in Section 9.2.4.  
7. Male subject is willing to abstain from sperm donation for the duration of the study and 
for 5 days after receiving the last dose of the study drug. 
8.  Subject agrees to refrain from drugs of abuse and alcohol for the duration of the study. 
8.4. 
Subject Exclusion Criteria – Part B rollover subjects 
Rollover subjects who meet any of the following criteria are disqualified from participation in 
this study:    
1. Experienced major protocol deviations or adverse events in the parent study which could 
potentially compromise subject safety, in the investigator’s opinion. 
2. Subject is currently at significant risk of suicide, as judged by the Investigator, or has 
attempted suicide since enrolling in the parent study 
3. Subject has a recent history or active clinically significant manifestations of metabolic, 
hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, 
musculoskeletal, dermatological, urogenital, neurological, or eyes, ears, nose, and throat 
disorders, or any other acute or chronic condition that, in the investigator’s opinion, 
would limit the subject’s ability to complete or participate in this clinical study. 
4. Subject has had vagus nerve stimulation, electroconvulsive therapy, or has taken 
ketamine (including esketamine) since enrolling in the parent study 

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5. Subject is taking first generation (typical) antipsychotics (eg, haloperidol, perphenazine), 
and/or second generation (atypical) antipsychotics (eg, aripiprazole, quetiapine) at 
Screening or within the time period between completion of the parent study and 
Screening. 
6. Subject has taken an antidepressant other than sertraline, escitalopram, citalopram, 
duloxetine or desvenlafaxine within 60 days prior to Screening, including within the time 
period between completion of the parent study and Screening. 
7. Subject has a known allergy to SAGE-217, brexanolone, allopregnanolone, or related 
compounds. 
8. Subject has a positive pregnancy test at Screening. 
9. Subject that is breastfeeding at Screening 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 in each treatment cycle, if applicable. 
10. Subject has active psychosis per Investigator assessment. 
11. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder. 
12. Subject has a new history of severe substance use disorder (including benzodiazepines) 
diagnosed using DSM-5 criteria within the 12 months prior to Screening or within the 
time period between completion of the parent study and Screening; or subject has a 
history of mild or moderate substance use disorder not in sustained remission for at least 
6 months prior to Screening. 
13. Subject has taken psychostimulants (eg, methylphenidate, amphetamine) or opioids 
during the parent study or within the time period between completion of the parent study 
and Screening. 
14. Subject has had exposure to another investigational medication (other than SAGE-217) or 
device during the parent study or within the time period between completion of the parent 
study and Screening. 
15. Subject has a positive drug and/or alcohol screen at Screening. 
16. Subject has been diagnosed with and/or treated for any type of cancer (excluding basal 
cell carcinoma and in situ melanoma) during the parent study or within the time period 
between completion of the parent study and Screening. 
17. History of poor compliance with the study drug and/or procedures in the parent study as 
determined by the Investigator 
8.5. 
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 

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• 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.  
Subjects who discontinue study drug early during a treatment period should return to the site for 
an end of treatment (EOT) visit as soon as possible, preferably the day after treatment is 
discontinued. The follow-up visit should take place 14 days after the last dose of treatment. 
Thereafter the subject should continue the observational period as scheduled (Table 2 or 
Table 3). 
If at any time during a follow-up period or the observational period, a subject decides to 
terminate the study, the subject should contact the site and complete their remote assessments at 
an early termination (ET) visit. An ET visit may be on the same day as an EOT visit if a subject 
discontinues study drug and terminates the study on the same day during a treatment period; in 
this case, all events scheduled for the EOT visit will be conducted.  
A subject will be deemed lost to follow-up after attempts at contacting the subject have been 
unsuccessful. 
8.5.1. 
Individual Subject Stopping Criteria 
This is the first study in which longitudinal re-treatment with SAGE-217 will be examined. 
Based on known withdrawal symptoms with other GABAergic drugs and non-clinical findings in 
a 9-month study of SAGE-217 in dogs (Investigator’s Brochure), there is a potential for 
withdrawal-related events, including seizure. The following guidelines for study drug 
discontinuation or dose reduction are presented to support subject safety: 
1. Any subject reporting a confirmed or suspected seizure at any time will be discontinued 
from treatment and will not be eligible for another treatment cycle but will continue to be 
followed in the study. 
2. Following the first treatment period, the Investigator should monitor the course of 
CNS-based signs and symptoms suggestive of a seizure which are not accounted for by 
comorbid psychiatric or medical conditions. Examples of reported serious or severe 

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events which may reflect an oncoming and/or increased risk for seizure may include 
temporary confusion, tremors, involuntary muscle fasciculations or jerking movements of 
arms or legs, or paresthesia. Should such symptoms occur, the investigator should 
consider decreasing the dose of study drug to 40 mg, stopping treatment to assess the 
effect on the symptom(s) (eg, resolution, improvement, etc), or discontinuing the subject 
from treatment. A subject who discontinues treatment should remain in the study and 
continue protocol-required assessments until the end of the study. 
As this is an open-label study, any severe or serious events, will be evaluated in an ongoing 
manner, including an evaluation of the benefit/risk profile of SAGE-217 in the context of the 
current study. As a result, the Sponsor may modify or discontinue the study. 
8.5.2. 
Replacement of Subjects 
Subjects will not be replaced.

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9.
TREATMENT OF SUBJECTS
9.1. 
Study Drug
In treatment cycles initiated prior to 217-MDD-303 Protocol Amendment 3, subjects were to 
self-administer SAGE-217 (30 mg or reduced dose of 20 mg, per criteria in Section 7.4) orally 
once daily in the evening with food for 14 days. 
After 217-MDD-303 Protocol Amendment 4, in all treatment cycles all subjects will self-
administer SAGE-217 50 mg (or reduced dose of 40 mg, per criteria in Section 7.4) orally once 
daily at approximately 8 PM with fat-containing food for 14 days. The 50-mg dose will be 
administered as 2 capsules per dose (one 30-mg capsule and one 20-mg capsule). If the dose is 
reduced to 40 mg, it will be administered as two 20-mg capsules. 
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 (for subjects in Part A only) and throughout 
the duration of the study (for all subjects) will be recorded. In addition, antidepressant therapies 
taken in the 3 years prior to Screening will be recorded for subjects in Part A only. 
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.  
For Part A de novo subjects, 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 the 
initial treatment and follow-up period (through Day 28 of Cycle 1). De novo subjects who have 
stopped taking antidepressants must have done so for at least 60 days prior to Day 1. 
For Part B rollover subjects, antidepressant use within 60 days prior to Screening other than 
sertraline, escitalopram, citalopram, duloxetine or desvenlafaxine is not permitted. Use of these 
antidepressants throughout the study is permitted. 
See Table 5 for allowed concomitant psychotropic medications during each period of the study 
for both study parts. 
9.2.1.1. 
Medication use for depressive symptom worsening following a SAGE-217 
treatment cycle 
Study 217-MDD-201, Part B, found that for subjects achieving remission or response at Day 15 
(78.6%), 6.1% had a HAM-D ≥22 at Day 42; another 18.2% had a HAM-D score of 16 to 21 at 
Day 42 (Data on File, Sage Therapeutics). This indicates that most subjects who may experience 
a new MDE will have this experience after they reach the minimal required period (8 weeks or 
56 days) before a new SAGE-217 treatment cycle. Because of this, most subjects will be eligible 
(ie, PHQ-9 ≥10 and HAM-D ≥20 confirmed over 2 weeks) for a SAGE-217 treatment cycle 
when needed; a 2-week period is required to establish a new MDE (DSM-5).  
For de novo subjects who experience worsening depressive symptoms after Day 28 or for 
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eligible for a new SAGE-217 treatment cycle, there are 2 intervention options: as-needed 
medications (limited to a maximum of 4 days per week) and/or introduction of a new ADT or an 
increase in the dose of a current ADT (Table 5). To maintain equivalence in clinical status across 
all ADT use (ie, new SAGE-217, new ADT, or increase dose of current ADT), a requirement for 
PHQ-9 ≥10 and HAM-D ≥20 confirmed over 2 weeks will be required in all ADT use 
conditions. If a subject on a stable ADT is experiencing worsening depressive symptoms 
(PHQ-9 ≥10), it is recommended that only as-needed medications be used if the HAM-D score is 
<20; if the HAM-D score is ≥20, the current dose may be increased or a new ADT may be 
introduced. Furthermore, clinicians should consider an individual subject’s initial experience 
with SAGE-217 when starting any new ADT, as it may substantially reduce the likelihood that 
the subject will be eligible for a new SAGE-217 treatment cycle once time allows (ie, HAM-D 
may be <20). There is no PHQ-9 or HAM-D score requirement for as-needed medication use. 
Permitted as-needed medications for symptom management include benzodiazepines, 
GABA-modulators for insomnia (eg, eszopiclone, zopiclone, zaleplon, and zolpidem), and 
non-GABA treatments for insomnia; use of such treatments should be limited to a maximum of 
4 days per week.  
If as-needed medications and/or a new ADT was introduced or the dose of a current ADT was 
increased and the subject continues to exhibit a HAM-D ≥20, a new SAGE-217 treatment cycle 
can be initiated at Day 70 or later. After completion of a new SAGE-217 cycle, continued use of 
any intervention(s) used during the previous Observational Period will be at the investigator’s 
discretion. 
Any benzodiazepines and/or GABA-modulating medication use during the Observational Period 
must be stopped 7 days prior to any new SAGE-217 treatment cycle. As-needed non-GABA 
modulating medication use must be discontinued 1 day prior to any new SAGE-217 treatment 
cycle.  
Medications intended for contraception are permitted for female subjects (see Section 8.1). 
 

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Table 5: 
Allowed Concomitant Psychotropic Medications During the Study (Part A 
and Part B) 
Period 
Timing 
(Part A)* 
Timing (Part B) 
Psychotropic 
medications 
allowed 
Rationale 
SAGE-217 
Treatment 
Day 1 to 14 
Day 1 to 14 
• SAGE-217 
• Stable ADT  
• No as-needed 
medicationsa 
• No new ADT  
Assess SAGE-217 
response 
SAGE-217 
Follow-up 
Day 15 to 28 
Day 15 to 28 
• Stable ADT  
• No as-needed 
medicationsa 
• No new ADT 
Assess SAGE-217 
safety in follow-up  
Observation 
Day 29 to 7 
days prior to 
next 
SAGE-217 
treatment 
cycle, if 
applicable 
• At study entry (first 
observational period): 
Screening to 7 days prior to 
SAGE-217 treatment cycle, if 
applicable 
• For any subsequent 
observational period: Day 29 
to 7 days prior to next 
SAGE-217 treatment cycle, if 
applicable 
• Benzodiazepines 
(t1/2 <48 hours; 
regular or as-
needed) 
• As-needed 
GABA-
modulators for 
insomnia (t1/2 
<48 hours) 
• Establish ‘full 
remission’ 
• Assess symptom 
course over time 
Day 29 to 1 
day prior to 
next 
SAGE-217 
treatment 
cycle, if 
applicable 
• At study entry (first 
observation period): 
Screening to 1 day prior to 
SAGE-217 treatment cycle, if 
applicable 
• For any subsequent 
observational period: Day 29 
to 1 day prior to SAGE-217 
treatment cycle, if applicable 
• As-needed non-
GABA-
modulating 
treatments for 
insomnia 
Day 29 
through next 
SAGE-217 
treatment 
cycle, if 
applicable 
• At study entry (first 
observational period): 
Screening through 
SAGE-217 treatment cycle, if 
applicable 
• For any subsequent 
observation period: Day 29 
through next SAGE-217 
treatment cycle, if applicable 
• Stable ADT 
• New ADT (except 
benzodiazepines)b 

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a As-needed medications (benzodiazepines, GABA-modulators for insomnia [eg, eszopiclone, zopiclone, zaleplon, 
and zolpidem], and non-GABA treatments for insomnia [eg melatonin, over-the-counter sleep aids, trazodone, 
mirtazapine, etc]) should be limited to a maximum of 4 days per week. 
b If a subject on a stable ADT is experiencing worsening depressive symptoms (PHQ-9 ≥10), it is recommended that 
only as-needed medications be used if the HAM-D score is <20; if the HAM D score is ≥20, the current ADT dose 
may be increased or a new ADT may be introduced. 
*Timing relative to the initial/previous cycle of SAGE-217 
ADT = antidepressant; Stable ADT = ADT started prior to study and continued at baseline or any new ADT started 
during an observation period and continued thereafter through a new SAGE-217 cycle; t1/2 = half-life 
9.2.2. 
Prohibited Medications 
The following medications are prohibited at the specified times: 
• See Table 5 for timing of psychotropic medications 
• For Part A de novo subjects: benzodiazepines, barbiturates, GABAA modulators (eg, 
eszopiclone, zopiclone, zaleplon, zolpidem, brexanolone), or GABA-containing ‘over 
the counter’ supplements in relationship to the first SAGE-217 treatment cycle: from 
28 days prior to the first dose of SAGE-217 through the 14-day follow-up period; 
thereafter, these medications are prohibited in the 7 days prior to any new SAGE-217 
treatment cycle and through the follow-up period of the cycle. For Part B rollover 
subjects, these agents are prohibited in the 7 days prior to any SAGE-217 treatment 
cycle and through the follow-up period of the cycle. For de novo subjects, any 
benzodiazepine or GABA modulator with a half-life of ≥48 hours is prohibited from 
60 days prior to the first dose of SAGE-217 and throughout the duration of the study. 
For rollover subjects, these agents are prohibited at Screening and throughout the 
duration of the study.  
• For Part A de novo subjects, first generation (typical) (eg, haloperidol, perphenazine) 
or second generation (atypical) antipsychotics (eg, aripiprazole, quetiapine)are 
prohibited from 14 days prior to the first treatment cycle  and throughout the duration 
of the study; for Part B rollover subjects, these agents are prohibited at Screening and 
throughout the duration of the study. 
• For Part A de novo subjects, non-GABA anti-insomnia medications (eg, prescribed 
therapeutics specifically for insomnia, over-the-counter sleep aids, melatonin) from 
14 days prior to the first dose of SAGE-217 through the first 14-day treatment period; 
thereafter, these medications are prohibited 1 day prior to any new SAGE-217 
treatment cycle and through the follow-up period of the cycle. For Part B rollover 
subjects, these agents are prohibited 1 day prior to any SAGE-217 treatment cycle 
and through the follow-up period of the cycle. Note that antihistamines used during 
the day solely for indication(s) other than insomnia are permitted for both de novo 
and rollover subjects. 
• For Part A de novo subjects, the use of chronic or as-needed psychostimulants 
(eg, methylphenidate, amphetamine) or opioids from 28 days prior to the first 
treatment cycle and throughout the duration of the study; for Part B rollover subjects, 
these agents are prohibited during the parent study, within the time period between 

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completion of the parent study and Screening, and throughout the duration of the 
study. 
• For Part A de novo subjects, exposure to another investigational medication or device 
from 30 days prior to Screening and throughout the duration of the study; for Part B 
rollover subjects, exposure to another investigational medication (other than 
SAGE-217) or device is prohibited during the parent study, within the time period 
between completion of the parent study and Screening, and throughout the duration of 
the study. 
• Any known strong inhibitors of CYP3A4 within 28 days or 5 half-lives (whichever is 
longer) prior to a cycle of SAGE-217 and any time during a SAGE-217 treatment 
cycle. 
• Use of strong CYP3A inducers such as rifampin, carbamazepine, enzalutamide, 
mitotane, phenytoin, and St John’s Wort within 28 days prior to a cycle of SAGE-217 
and any time during a SAGE-217 treatment cycle. 
9.2.3. 
Other Restrictions 
The consumption of grapefruit juice, grapefruit, or Seville oranges, or products containing these 
is prohibited within 14 days prior to a cycle of SAGE-217 and at any time during a treatment 
cycle. 
Consumption of alcohol or use of drugs of abuse is discouraged throughout the duration of the 
study. 
Female subjects that are lactating or actively breastfeeding must stop giving breast milk to the 
baby(ies) from just prior to receiving study drug until 7 days after the last dose of study drug 
following each treatment period, if applicable. 
Elective surgeries are prohibited during the initial treatment and follow-up period (through 
Day 28 of Cycle 1; Part A de novo subjects only). 
Subjects must not participate in night shift work during any 14-day treatment period. 
Subjects who are feeling sedated, somnolent, or dizzy, are to refrain from driving or engaging in 
any activity requiring alertness. 
De novo 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 therapy through at least the first 14-day 
follow-up period. Rollover subjects receiving psychotherapy on a regular schedule at Screening 
are permitted. 
9.2.4. 
Acceptable Forms of Contraception 
Acceptable forms of highly effective contraception for participants of childbearing potential or 
for partners of male participants who are of childbearing potential include: 
• Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation 

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• Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation  
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Laparoscopic or abdominal occlusion procedure (including bilateral tubal ligation) 
• Hysteroscopic bilateral tubal occlusion procedure performed at least 3 months prior to 
Screening 
• Vasectomized partner (performed at least 3 months prior to Screening) 
Acceptable forms of contraception for male participants include: 
• Sexual abstinence (no sexual intercourse) 
• History of vasectomy (performed at least 3 months prior to Screening) 
• Condom with spermicide used together with highly effective female contraceptive 
methods if the female partner(s) is of childbearing potential (see above for list of 
acceptable female contraceptive methods) 
9.3. 
Treatment Adherence 
SAGE-217 will be self-administered by subjects once daily at approximately 8 PM with 
fat-containing food during the 14-day treatment periods (see Section 10.5). Sites will dispense 
study drug to the subjects to take at home with instructions for use (see Section 10.6, Table 1, 
and Table 4).  
Subjects will be instructed to bring their dosing kit to the site as outlined in Table 1 and Table 4, 
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 dosing instructions at clinic visits during any 
SAGE-217 treatment period. 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 an open-label study in which all subjects will receive SAGE-217. 

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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, colloidal silicon 
dioxide, and sodium stearyl fumarate as excipients. Capsules will be available in 20-mg and 
30-mg dose strengths.  
10.2. 
Study Drug Packaging and Labeling 
SAGE-217 will be provided to the clinic pharmacist and/or designated site staff responsible for 
dispensing the study drug in appropriately labeled, subject-specific kits containing sealed unit 
doses. Each unit dose for 30-mg treatment cycles consists of 1 capsule, and each unit dose for 
40-mg and 50-mg treatment cycles consists of 2 capsules. 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 is to be stored at room temperature (59 to 86°F; 15 to 30°C), safely and separately 
from other drugs. 
10.4. 
Study Drug Preparation 
Not applicable. 
10.5. 
Study Drug Administration 
SAGE-217 is to be administered orally once daily at 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.  
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 the next evening. 
10.6. 
Study Drug Accountability 
Upon receipt of study drug, the Investigator(s), or the responsible pharmacist or designee, will 
inspect the study drug and complete and follow the instructions regarding receipt in the 
Pharmacy Manual. A copy of the shipping documentation will be kept in the study files. 
The designated site staff will dispense the supplied subject-specific kits to subjects at the planned 
dispensation visit intervals outlined in Table 1 and Table 4.   
Site staff will access the interactive response technology (IRT) at the Screening Visit to obtain a 
subject ID number for each subject. On Day 1, site staff will access the IRT and provide the 

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necessary subject-identifying information, including the subject ID number assigned at 
Screening, to enroll the eligible subject into the initial treatment cycle 1 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 visits for any other treatment cycles, 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. 
10.8. 
Product Complaints 
A product complain 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 the table on 
page 5. 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 schedules of events (Table 1, Table 2 
Table 3, and Table 4). 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. 
Every effort should be made for the same rater to perform the assessments at all visits for a 
particular subject. For rollover subjects, assessments in the current study should, if possible, be 
conducted by a different rater than the one who performed the assessments in the parent study.  
11.1. 
Response Parameters 
11.1.1. 
Hamilton Rating Scale for Depression 
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. An assessment 
timeframe of 7 days will be used for all visits. 
The HAM-D total score will be calculated as the sum of the 17 individual item scores.  
The HAM-D subscale scores will be calculated as the sum of the items comprising each 
subscale. A response will be defined as having a 50% or greater reduction from baseline in 
HAM-D total score. Remission will be defined as having a HAM-D total score of ≤7.  
11.1.2. 
Clinical Global Impression  
The CGI is a validated measure often utilized in clinical trials to allow clinicians to integrate 
several sources of information into a single rating of the subject’s condition. The CGI scale 
consists of 3 items. Only the first 2 items are being used in this study.  
The CGI-S uses a 7-point Likert scale to rate the severity of the subject’s illness at the time of 
assessment, relative to the clinician’s past experience with subjects who have the same diagnosis. 
Considering total clinical experience, a subject is assessed on severity of mental illness at the 
time of rating as 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately 
ill; 5=markedly ill; 6=severely ill; and 7=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.”  

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11.1.4. 
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 total based on 
responses to specific questions, as follows: 0=not at all; 1=several days; 2=more than half the 
days; and 3=nearly every day.  
The PHQ-9 total score will be calculated as the sum of the 9 individual item scores. The PHQ-9 
total score will be categorized as follows: 1 to 4=minimal depression, 5 to 9=mild depression, 
10 to 14=moderate depression, 15 to 19=moderately severe depression; and 20 to 27=severe 
depression. 

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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
All assessments will be conducted according to the schedules of events Table 1, Table 2, 
Table 3, and Table 4). 
12.1.1. 
Demographic/Medical History 
Demographic characteristics (age, race, gender, ethnicity, employment status, highest education 
level, marital/civil status) and a full medical history, including family psychiatric history, will be 
documented. For Part B rollover subjects, demographic characteristics and medical history will 
be obtained from the parent study. Interim medical history (ie, any new medical conditions or 
procedures with onset/start date after completion of the parent study and prior to signing 
informed consent in the current study) will also be documented for rollover subjects. For Part A 
de novo subjects only, the diagnosis of MDD will be determined using the SCID-5-CT. If 
available, the disease code associated with the diagnosis of MDD based on the 10th revision of 
the International Statistical Classification of Diseases and Related Health Problems should be 
recorded. 
For Part A de novo subjects only, the Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire 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. 
For Part A de novo subjects only, the severity of the depressive episode upon entry into the study 
will be evaluated using the MADRS, a 10-item diagnostic questionnaire. The MADRS total 
score will be calculated as the sum of the 10 individual item scores. 
12.1.2. 
Weight and Height 
Height (Screening only) and weight will be measured and documented. For Part B rollover 
subjects, height will be obtained from the parent study. 
12.1.3. 
Physical Examination 
Physical examinations assessing body systems (eg, head, eyes, ears, nose, and throat; heart; 
lungs; abdomen; and extremities), as well as cognitive and neurological examinations and mental 
status examinations will be conducted and documented. Whenever possible, the same individual 
is to perform all physical examinations for a given subject. Unscheduled brief, symptom-driven 
physical examinations may also be conducted per the Investigator’s discretion. 
Any abnormality in physical examinations will be interpreted by the Investigator as abnormal, 
not clinically significant (NCS); or abnormal, clinically significant (CS) in source documents. 
New or worsening abnormalities that are judged to be clinically significant will be recorded as 
AEs, assessed according to Section 12.2.1.1. 

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12.1.4. 
COVID-19 Questions  
Information regarding diagnosis, isolation, and/or hospitalization due to COVID-19 will be 
documented as part of medical history, AE collection, and prior/concomitant 
medication/procedure collection 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:  
 Did you have a test? If yes, was the result positive, negative or 
inconclusive?  
 Were you isolated? If yes, what were the dates of isolation?  
 Were you hospitalized? If yes, what were the dates of hospitalization? 
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  
Supine 12-lead ECGs will be performed in triplicate at all scheduled time points. The standard 
parameters (heart rate, PR, QRS, QT, and QTcF) as well as any rhythm abnormalities will be 
recorded.  
Any abnormality in ECG intervals will be interpreted by the Investigator as abnormal, NCS; or 
abnormal, CS in source documents. New or worsening abnormalities that are judged to be CS 
will be recorded as AEs, assessed according to Section 12.2.1.1. 
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 6. 

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Table 6: 
Clinical Laboratory Tests 
Hematology  
Serum Chemistry 
Urinalysis 
Coagulation 
Red blood cell count 
Hemoglobin  
Hematocrit  
White blood cell count with 
differential  
Platelet count 
Red Blood Cell Indices (MCV, 
MCH, MCHC)  
Reflex to Red blood cell 
morphology if indices are 
abnormal 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
Total protein 
Creatinine 
Blood urea nitrogen 
Creatine kinase 
Gamma-glutamyl transferase 
Potassium 
Sodium 
Lactate dehydrogenase 
Glucose 
Chloride 
Bicarbonate 
Calcium 
Phosphorus 
Triglycerides 
Thyroid stimulating hormone 
(TSH) 
Reflex to free T3/T4 if TSH is 
abnormal 
pH 
Specific gravity 
Color 
Protein 
Glucose 
Red blood cell 
Nitrite 
Leukocyte esterase 
Ketones 
Bilirubin 
Urobilinogen 
Activated partial 
thromboplastin 
time 
Prothrombin time 
International 
normalized ratio 
Diagnostic  
 
 
 
Serum 
Urine 
Breathalyzer 
 
Hepatitis B 
Hepatitis C 
Reflex HCV RNA 
HIV-1 and -2 
Female subjects who 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 who are not 
surgically sterile and do not 
meet the protocol-defined 
criteria for being post-
menopausal: urine hCG  
Alcohol 
 

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thereafter, as outlined in Table 1 and Table 2, including the ET visit for subjects who 
prematurely discontinue.  
In Part B, for rollover female subjects who complete the Screening Visit on the same day as the 
final, end-of-study visit in the parent study, a pregnancy test does not need to be repeated. If the 
Screening Visit is not conducted on the same day as the final, End of Study Visit in the parent 
study, a urine pregnancy test should be conducted. Urine pregnancy tests will be performed in 
females who are not surgically sterile and do not meet the protocol-defined criteria for being 
post-menopausal at all other scheduled timepoints, as outlined in Table 3 and Table 4 including 
the ET Visit for subjects who prematurely discontinue. 
12.1.8. 
Columbia-Suicide Severity Rating Scale  
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).  
In Part A, 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 in Part A and in Part B, as outlined in Table 1, Table 2, Table 3, and 
Table 4. 
12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Definition of Adverse Events 
12.2.1.1. Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the use of a 
medicinal (investigational) product whether or not related to the medicinal (investigational) 
product. In clinical studies, an AE can include an undesirable medical condition occurring at any 
time, including baseline or washout periods, even if no study 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 CS. 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 

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attributable to another AE do not require discrete reporting (eg, electrolyte disturbances in the 
context of dehydration, chemistry and hematologic disturbances in the context of sepsis). 
All AEs that occur after any subject has signed the ICF and throughout the duration of the study, 
whether or not they are related to the study, must be reported to Sage Therapeutics. 
12.2.1.2. Serious Adverse Event  
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). Serious adverse 
events occurring after a subject’s final visit (including the last follow-up visit) should be reported 
to Sage or designee only if the Investigator considers the SAE to be related to study treatment.  
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the subject is hospitalized. The site must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was scheduled 
(or on a waiting list to be scheduled) prior to obtaining the subject’s consent to participate 
in the study 
• The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress, in the opinion of the 
Investigator, between the subject’s consent to participate in the study and at the time of 
the procedure or treatment.  
12.3. 
Relationship to Study Drug 
The Investigator must make the determination of relationship to the study drug for each adverse 
event (not related, possibly related or probably related). The Investigator should decide whether, 
in his or her medical judgment, there is a reasonable possibility that the event may have been 
caused by the investigational product. If no valid reason exists for suggesting a relationship, then 
the adverse event should be classified as “not related.” If there is any valid reason, even if 
undetermined, for suspecting a possible cause-and-effect relationship between the investigational 

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product and the occurrence of the adverse event, then the adverse event should be considered at 
least “possibly related.”  
Table 7: 
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. For subjects in Part B, ongoing adverse events with onset during the parent 
study will also be recorded at the Screening Visit. 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. 

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The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) must be followed up and documented on the Sage Therapeutics 
pregnancy outcome form, even if the subject was discontinued from the study. If the pregnancy 
ends for any reason before the anticipated date, the investigator should notify Sage.  
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. If the outcome of the 
pregnancy meets the criteria for immediate classification as an SAE (ie, postpartum 
complication, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly/birth 
defects), the investigator should follow the procedures for reporting an SAE.  
12.5. 
Reporting Serious Adverse Events 
All SAEs must be reported to Sage, or designee, immediately. A written account of the SAE 
must be sent to Sage, or designee, within 24 hours of the first awareness of the event by the 
investigator and/or his staff. The Investigator must complete, sign and date the SAE report form, 
verify the accuracy of the information recorded on the SAE report form with the corresponding 
source documents, and send a copy to Sage, or designee.  
Additional follow-up information, if required or available, should all be sent to Sage 
Therapeutics, or designee, within 24 hours of receipt on a follow-up SAE report form and placed 
with the original SAE information and kept with the appropriate section of the case report form 
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 IRB of all SAEs that occur at 
his or her site. Investigators will also be notified of all suspected, unexpected, serious, adverse 
reactions (SUSARs) that occur during the clinical study. Institutional Review Boards will be 
notified of SAEs and/or SUSARs as required by local law.  
12.6. 
Overdose 
Overdoses, regardless of presence of associated clinical manifestation(s) (eg, headache, 
abnormal laboratory value), will be considered an AE and recorded as such on the eCRF. Any 
clinical manifestation(s) of overdose must also be recorded as an AE on the eCRF. In addition, 
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 
Separate statistical analysis plans (SAP) will be generated for each part of the study and will 
provide a detailed description of the analyses to be performed in the study. For Part B rollover 
subjects, the parent study database will be used in analysis. The SAP for each study part will be 
finalized and approved prior to database lock for respective parts. The data for Part A de novo 
subjects may be analyzed and reported prior to database lock for Part B rollover subjects. Any 
deviations from or changes to the SAPs following database lock will be described in detail in the 
clinical study report. 
13.1. 
Data Analysis Sets 
Part A (de novo subjects) 
The Safety Set is defined as all subjects administered study drug.  
The Full Analysis Set (FAS) s is defined as all subjects in the Safety Set who completed 
Treatment Cycle 1 and moved on to Observational Period 1 (ie, these subjects had HAM-D 
response at Day 15 and did not discontinue the study for any reason within Treatment Cycle 1). 
In addition, the cohorts of subjects who started with the 30-mg dose versus the 50-mg dose may 
be analyzed separately for de novo subjects. 
Part B (rollover subjects) 
The Safety Set is defined as all subjects administered study drug. 
The FAS is defined as all subjects in the Safety Set who have at least one HAM-D total score 
available after the first dose of study drug within this protocol.  
13.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data. All subjects will be used in the analyses, as 
per the analysis populations, using all non-missing data available.  
13.3. 
General Considerations 
For the purpose of all analyses where applicable, baseline will be defined as the latest value 
before the first dose of study drug in Cycle 1 for de novo subjects. A period-specific baseline 
will be defined as the latest value before the first dose of study drug in each treatment cycle.  
For rollover subjects, the first cycle of treatment in this study will be marked in the database as 
Cycle 2. For purposes of analysis, the treatment cycles and study periods within this protocol 
will be renumbered as 1-4 for subjects who received placebo in the parent study.  
Continuous endpoints will be summarized with number (n), mean, standard deviation (SD), 
median, minimum, and maximum. In addition, change from baseline and/or period-specific 
baseline values will be calculated at each time point and summarized descriptively. For 
categorical endpoints, descriptive summaries will include counts and percentages.  

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13.4. 
Demographics and Baseline Characteristics 
Demographic data (Section 12.1.1) and baseline characteristics, such as height, weight, and body 
mass index, will be summarized using the Safety Set.  
Hepatitis, HIV, drug and alcohol, and pregnancy screening results will be listed, but not 
summarized as they are considered part of the inclusion/exclusion criteria.  
Medical/family history, including interim medical history for Part B rollover subjects (see 
Section 12.1.1), will be listed by subject. 
13.5. 
Response Analyses 
For de novo subjects, response analyses for the first treatment cycle will be provided based on 
the Safety Set. Subjects who do not achieve HAM-D response at Day 15 (at least 50% reduction 
from baseline HAM-D total score or missing Day 15 HAM-D) will be discontinued from the 
study after the 14-day follow-up period with treatment cycle 1. 
Using the Full Analysis Set, Kaplan-Meier (KM) survival curve will be provided for time to first 
re-treatment; the estimand is the median time to first re-treatment -time from the last dose of 
study drug in Cycle 1 to first dose of study drug in Cycle 2- for de novo subjects and will be 
estimated from KM analysis. Number and percentage of subjects needing at least one 
re-treatment (ie, meeting the criteria for re-treatment, but not necessarily retreated) will be 
provided. Number of treatment cycles per subject will be summarized. 
For rollover subjects, using the Full Analysis Set, KM survival curve will be provided for time to 
first re-treatment; the estimand is the median time to first re-treatment -time from the last dose of 
study drug in Cycle 1 to first dose of study drug in Cycle 2 - and will be estimated from KM 
analysis. Number and percentage of subjects needing at least one re-treatment (ie, meeting the 
criteria for re-treatment, but not necessarily retreated) will be provided. Number of treatment 
cycles per subject will be summarized. 
Change from baseline, and/or from period-specific baseline when appropriate, in HAM-D total 
score and subscale scores will be summarized by each treatment cycle. 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) will be summarized for each treatment cycle. Change from 
baseline, and/or from period-specific baseline when applicable, in CGI-S will be summarized for 
each treatment cycle. CGI-I will be summarized for each treatment cycle.  
 
13.6. 
Safety Analyses 
The primary endpoint, the safety and tolerability of SAGE-217, will be evaluated by incidence 
and severity of AEs/SAEs, concomitant medication usage, vital signs, clinical laboratory 
evaluations, and 12-lead ECG. Suicidality will be monitored by the C-SSRS. In addition to 
overall study results, the results from each treatment cycle will be provided separately whenever 
applicable. Safety analyses will use the Safety Set for overall safety.  
A study period is defined as a treatment cycle and its subsequent observation period; the Safety 
Set for a given study period includes subjects in the Safety Set who are dosed in the respective 

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study period. Safety analyses will be provided based on the Safety Set for each study period 
within this protocol when appropriate.  
13.6.1. 
Adverse Events 
The analysis of adverse events will be based on the concept of TEAEs. The incidence of TEAEs 
will be summarized overall and by Medical Dictionary for Regulatory Activities Version 21.0 or 
higher, System Organ Class, and preferred term. Incidences will be presented in order of 
decreasing frequency. In addition, summaries will be provided by intensity (mild, moderate, 
severe) and by causality (related, not related) to study drug (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 
and/or modified baseline will be summarized in standard units for each treatment cycle. Normal 
range of each parameter is provided by the laboratory; shift from baseline (and/or period-specific 
baseline) to post-baseline values in abnormality of results will be provided. Potentially CS values 
will be summarized. 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 
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 and/or period-specific baseline in vital 
signs will be summarized for each treatment cycle. Any abnormality deemed CS by the 
Investigator will be reported as an AE (see Section 12.2). Potentially CS values will be 
summarized. 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 
CS abnormalities or changes in mean ECGs should be reported as an AE (see Section 12.2). 
Mean ECG data will be summarized by visit for each treatment cycle. Potentially CS values of 
QTcF will be summarized. Electrocardiogram findings will be listed by subject and visit for each 
treatment cycle.  

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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 September 2015, or later.  
The medications taken prior to the initiation of the start of study drug within each part of the 
study 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.  
Anxiolytics, anti-insomnia, and/or antidepressant drug use between treatment cycles will be 
summarized, and such use may be explored with respect to the need for re-treatment with 
SAGE-217, response to SAGE-217, and safety of SAGE-217. In particular, for de novo subjects 
only, the time to first anxiolytic or anti-insomnia use, and time to first antidepressant use will be 
provided with KM plots. . 
13.6.7. 
Columbia Suicide Severity Rating Scale 
Suicidality data collected on the C-SSRS at baseline (or period-specific baseline) and by visit 
during the treatment cycle will be summarized by treatment cycle. Listings will include all data, 
including behavior type and/or category for Suicidal Ideation and Suicidal Behavior of the 
C-SSRS.  
13.7. 
Determination of Sample Size 
The sample size is not based on a formal sample size calculation. The sample size of 1200 de 
novo subjects in Part A was chosen in order to have at least 675 subjects complete 24 weeks of 
the study and at least 235 subjects complete through 56 weeks, consistent with the objective of 
assessing SAGE-217 long-term safety. Approximately 350 subjects are expected to rollover from 
the parent study and enroll in 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 Institutional Review 
Board (IRB) 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  
The Principal Investigator must obtain IRB approval for the investigation. Initial IRB approval, 
and all materials approved by the IRB 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. 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 of any amendment to the protocol 
in accordance with local requirements. In addition, the IRB must approve all advertising used to 
recruit subjects for the study. The protocol must be re-approved by the IRB 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 
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.