Conditions: Bipolar Disorder I Bipolar Disorder II Major Depressive Episode
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 35
Healthy volunteers: no

Brief summary:
This is an open-label study evaluating the safety, tolerability, pharmacokinetics, and efficacy of SAGE-217 in the treatment of participants with bipolar I/II disorder with a current major depressive episode.

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

Arms:
arm 1: Participants self-administered SAGE-217, 30 milligrams (mg), oral capsule, once daily (QD), in the evening, from Day 1 to Day 14. arm 2: Participants were to receive SAGE-217, 30 mg, oral capsule, QD, in the evening, from Day 1 to Day 14 in Part B of the study. However, as per the Sponsor's decision, the Part B of the study was not conducted. arm 3: Participants were to receive SAGE-217 matching placebo capsule, orally, QD, in the evening, from Day 1 to Day 14 in Part B of the study. However, as per the Sponsor's decision, the Part B of the study was not conducted.

Interventions: intervention 1: SAGE-217 intervention 2: Placebo
Intervention descriptions: intervention 1: SAGE-217 capsule intervention 2: SAGE-217 matching placebo capsule

Protocol document:
Prot_000.pdf: 
Official Title: 
A 2-Part Study (Open-label Followed by Double-blind, Randomized, Placebo - 
Controlled, Parallel Group) of the Safety, Tolerability, Pharmacokinetics, and
Efficacy of SAGE-217 in the Treatment of Subjects With Bipolar I/II Disorder With
a Current Major Depressive Episode
NCT Number: 
NCT03692910
Document Dates: 
Protocol Version 4.0: 16 January 2019
Protocol Version 3.0: 18 October 2018
Protocol Version 2.0: 13 September 2018
Protocol Version 1.0: 03 July 2018


Clinical Study Report 
217-BPD-201
16.1 Study Information 
1 
1.
PROTOCOL AND AMENDMENTS
Protocol Version 1.0, 03 July 2018 
Protocol Amendment 1, Version 2.0, 13 September 2018 
•
Amendment 1 Summary of Changes
Protocol Amendment 2, Version 3.0, 18 October 2018 
•
Amendment 2 Summary of Changes
Protocol Memo to Sites, 18 November 2018 
Protocol Amendment 3, Version 4.0, 16 January 2019 
•
Amendment 3 Summary of Changes


Clinical Protocol
Sage Therapeutics, Inc.
217-BPD-201 v1.0
CONFIDENTIAL
1
1.
TITLE PAGE
STUDY TITLE: A 2-PART STUDY (OPEN-LABEL
FOLLOWED BY DOUBLE-BLIND, RANDOMIZED, 
PLACEBO-CONTROLLED, PARALLEL GROUP) OF 
THE SAFETY, TOLERABILITY, 
PHARMACOKINETICS, AND EFFICACY OF SAGE-217
IN THE TREATMENT OF SUBJECTS WITH 
BIPOLAR I/II DISORDER WITH A CURRENT MAJOR 
DEPRESSIVE EPISODE
PROTOCOL NUMBER: 217-BPD-201
Study Drug
SAGE-217
Clinical Phase
Phase 2
Sponsor
Sage Therapeutics, Inc.
215 First Street
Cambridge, MA 02142
Sponsor Contact
Tel: 
email:
Sponsor Medical Monitor
, MD, MBA
Tel: 
email:
Date of Original Protocol
Version 1.0, 03 JUL 2018
Confidentiality Statement
The confidential information in this document is provided to you as an Investigator or consultant for 
review by you, your staff, and the applicable Institutional Review Board/Independent Ethics Committee.
Your acceptance of this document constitutes agreement that you will not disclose the information 
contained herein to others without written authorization from Sage Therapeutics, Inc.




Clinical Protocol 
Sage Therapeutics, Inc. 
217-BPD-201 v1.0
CONFIDENTIAL 
3 
INVESTIGATOR’S AGREEMENT 
I have received and read the Investigator’s Brochure for SAGE-217. I have read the 217-BPD-
201 clinical protocol and agree to conduct the study as outlined. I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol.  
Printed name of Investigator 
Signature of Investigator 
Date (DD Month YYYY) 


Clinical Protocol 
Sage Therapeutics, Inc. 
217-BPD-201 v1.0
CONFIDENTIAL 
4 
2.
SYNOPSIS
Name of Sponsor/Company: 
Sage Therapeutics 
Name of Investigational Product: 
SAGE-217 Capsule 
Name of Active Ingredient: 
SAGE-217 
Title of Study:  
A 2-Part Study (Open-label followed by Double-blind, Randomized, Placebo-controlled, Parallel 
Group) of the Safety, Tolerability, Pharmacokinetics, and Efficacy of SAGE-217 in the Treatment of 
Subjects with Bipolar I/II Disorder with a Current Major Depressive Episode 
Number of Sites and Study Location:  
Part A: Approximately 10 sites in the United States 
Part B: Approximately 40 sites in the United States 
Phase of Development: 2 
Planned Duration of participation: Up to 87 days (28-day Screening Period; 28-day Treatment 
Period, and 28-day [±3 days] Follow-up Period) 
Objectives: 
Part A Primary: 
•
To evaluate the safety and tolerability of SAGE-217 in subjects with bipolar I or II disorder
with a current major depressive episode (MDE).
Part A Secondary: 
•
To assess the efficacy of SAGE-217 in reducing depressive symptoms in subjects with bipolar
I/II disorder with a current MDE.
•
To assess the effect of SAGE-217 on sleep.
Part B Primary: 
•
To assess the efficacy of SAGE-217 in reducing depressive symptoms in subjects with bipolar
I/II disorder with a current MDE.
Part B Secondary: 
•
To evaluate the safety and tolerability of SAGE-217 in subjects with bipolar I/II disorder with
a current MDE.
•
To assess the effect of SAGE-217 on sleep.
 


Clinical Protocol 
Sage Therapeutics, Inc. 
217-BPD-201 v1.0
CONFIDENTIAL 
5 
Endpoints:  
Part A Primary: 
•
The safety and tolerability of SAGE-217 as assessed by the frequency and severity of adverse
events; changes from baseline in clinical laboratory measures, vital signs, and
electrocardiogram (ECGs); and suicidal ideation and behavior using the Columbia Suicide
Severity Rating Scale (C-SSRS); and mania using the Young Mania Rating Scale (YMRS).
Part A Secondary: 
•
The reduction in depressive symptoms, as assessed by:
o
Change from baseline in the 17-item Hamilton Depression Rating Scale (HAM-D)
total score at Day 25 and all other time points as outlined in Table 1;
o
HAM-D response at Day 25 and all other time points as outlined in Table 1;
o
HAM-D remission at Day 25 and all other time points as outlined in Table 1;
o
Change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS)
total score at Day 25 and all other time points as outlined in Table 1;
o
Change from baseline in MADRS individual item scores at Day 25 and all other time
points as outlined in Table 1;
o
The response to the Clinical Global Impression scale for severity and improvement
(CGI-S and CGI-I, respectively) at Day 25 and all other time points as outlined in
Table 1.
•
The reduction in insomnia severity, as assessed by Insomnia Severity Index (ISI).
Part B Primary: 
•
The primary endpoint in Part B is the reduction in depressive symptoms with SAGE-217
treatment, as assessed by the change from baseline in the HAM-D total score at Day 25.
Part B Secondary: 
•
The reduction in depressive symptoms, as assessed by:
o
Change from baseline in HAM-D total score at all other time points as outlined in
Table 1;
o
HAM-D response at Day 25 and all other time points as outlined in Table 1;
o
HAM-D remission at Day 25 and all other time points as outlined in Table 1;
o
Change from baseline in the MADRS total score at Day 25 and all other time points as
outlined in Table 1;
o
Change from baseline in MADRS individual item scores at Day 25 and all other time
points as outlined in Table 1;
o
CGI-S and CGI-I response at Day 25 and all other time points as outlined in Table 1.
•
The safety and tolerability of SAGE-217 as assessed by the frequency and severity of adverse
events; changes from baseline in clinical laboratory measures, vital signs, and ECGs; and
suicidal ideation and behavior using the C-SSRS; and mania using the YMRS.
•
The reduction in insomnia severity, as assessed by ISI.
 


Clinical Protocol 
Sage Therapeutics, Inc. 
217-BPD-201 v1.0
CONFIDENTIAL 
6 
Study Description:   
This study will be conducted in 2 sequential parts: Part A (open-label) and Part B (randomized, double-
blind, placebo-controlled, parallel group). Part B will be initiated pending the review of Part A data. 
The methods of the 2 parts will be identical unless otherwise noted. Subjects who participate in Part A 
will not be allowed to participate in Part B. The study is designed to assess the safety, tolerability, 
 
and efficacy of SAGE-217 in adult subjects with bipolar I/II disorder, who are currently experiencing 
an MDE.  
The assessments are summarized in the Schedule of Events (Table 1). 
Screening begins with the signing of the informed consent form at the Screening Visit The diagnosis of 
bipolar I or II disorder will be made using the Structured Clinical Interview for Diagnostic and 
Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) for clinical trials (SCID-5-CT) 
performed by a qualified healthcare professional.  
Beginning on Day 1, qualified subjects will self-administer the study drug once daily in the evening 
with food for 28 days. In Part A, all subjects will receive SAGE-217. For Part B, subjects will be 
randomized in a 1:1 ratio to receive SAGE-217 or placebo; randomization will be stratified based on 
use of mood stabilizers (Y/N). Subjects on antidepressants or mood stabilizers (lamotrigine, lithium, 
and valproic acid only) that have been taken at the same dose for at least 60 days prior to Day 1 are to 
continue the stable dose throughout the treatment period. The planned dosing regimen is as follows: 
Treatment 
Days 1-3 
Days 4-24 
Days 25-28 
SAGE-217 
SAGE-217, 20 mg 
SAGE-217, 30 mg 
SAGE-217, 20 mg 
Placebo (Part B only) 
Placebo 
Placebo 
Placebo 
If at any time, 30 mg is not tolerated, as assessed by the occurrence of a severe AE judged by the 
investigator to be related to study drug, the dose on the next day will be reduced to 20 mg and 
continued for the remainder of the treatment period. Dose adjustments related to moderate AEs will be 
judged by the Investigator. If a dose adjustment from 30 mg to 20 mg is deemed necessary by the 
Investigator, the subject will return to the site for the adjusted dose to be dispensed. Subjects who 
cannot tolerate the 20-mg dose at any time will be discontinued from study drug.  
If at any time during the study, a subject has a YMRS score of ≥13, the Investigator will clinically 
assess the subject for a manic or hypomanic switch. If the clinical assessment is consistent with 
hypomania or mania, the subject will be discontinued from study drug and treated as clinically 
appropriate. These incidents will be documented as AEs. 
Subjects will return to the study center during the treatment and follow-up periods as outlined in 
Table 1. 
Number of Subjects (planned):   
Part A: Approximately 30 subjects will be dosed. 
Part B: Approximately 132 subjects will be randomized and dosed to obtain a total of 112 evaluable 
subjects. 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-BPD-201 v1.0 
 
CONFIDENTIAL 
 
7 
 
Eligibility criteria:  
Inclusion Criteria: 
1. Subject has signed an informed consent form (ICF) prior to the conduct of any study-specific 
procedures. 
2. Subject agrees to adhere to the study requirements, including use of prior, concomitant, and 
prohibited medications. 
3. Subject is an ambulatory man or woman, aged 18 to 65 years, inclusive, at Screening. 
4. 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. 
5. Subject has a documented history of hypomanic or manic episode (verified by medical records 
and/or treating healthcare professional) and a diagnosis of bipolar I or bipolar II disorder with 
a current MDE as per DSM-5 SCID-5-CT. 
6. Subject has a HAM-D score of ≥22 at Screening.  
7. Female subject agrees to use one of the following methods of contraception during 
participation in the study and for 30 days following the last dose of study drug, unless they are 
postmenopausal (defined as no menses for 12 months without an alternative medical cause and 
confirmed by follicle stimulating hormone [FSH] level ≥40 mIU/mL) and/or surgically sterile 
(hysterectomy or bilateral oophorectomy): 
• 
Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation. 
• 
Oral, injectable, or implantable progestogen-only hormonal contraception associated with 
inhibition of ovulation.  
• 
Intrauterine device. 
• 
Intrauterine hormone-releasing system. 
• 
Bilateral tubal ligation/occlusion. 
• 
Vasectomized partner. 
• 
Sexual abstinence (no sexual intercourse).  
8. Male subject agrees to use an acceptable method of effective contraception for the duration of 
study and for 5 days after receiving the last dose of the study drug. Acceptable methods of 
effective contraception for males includes sexual abstinence, vasectomy, or a condom with 
spermicide used together with highly effective female contraception methods (if the female 
partner is of child-bearing potential, see Inclusion Criteria #7 for acceptable method of 
contraception for females). 
9. 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. 
Exclusion Criteria: 
1. Subject has a history of suicide attempt within the last 2 years. 
2. Subject has current suicidal ideation with plans based on Investigator clinical assessment 
and/or the C-SSRS response at Screening or Day 1. 
3. Subject has a history of rapid cycling bipolar disorder as per DSM-5 SCID-5-CT. 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-BPD-201 v1.0 
 
CONFIDENTIAL 
 
8 
 
4. Subject’s current depressive episode meets the DSM-5 specifier criteria for mixed features. 
5. Subject has ≥25% reduction in HAM-D score from Screening to Day 1. 
6. 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. 
7. Subject has abnormal liver function as shown by an abnormal liver function profile at 
screening (eg, repeated values of aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), or total bilirubin ≥2x the upper limit of normal). 
8. Subject has a clinically significant abnormal 12-lead ECG at the Screening or Day 1 visits. 
NOTE: mean QT interval calculated using the Fridericia method (QTcF) of >450 msec in male 
or >470 msec in female subjects will be the basis for exclusion from the study.  
9. Subject has a YMRS score ≥13 at Screening or Day 1. 
10. Subject presents for the study receiving a mood stabilizer other than lamotrigine, lithium, or 
valproic acid. 
11. Subject presents for the study receiving psychotropic medications, which have not been taken 
at the same dose for at least 60 days prior to Day 1. 
12. Subject that presents for the study receiving psychotropic medications and does not intend to 
continue the current treatment regimen during the treatment period.  
13. Subject is taking typical or atypical antipsychotics, monoamine oxidase inhibitors (MAOIs), 
and/or benzodiazepines at the Screening Visit. 
14. Subject has a history of severe rashes or Stevens-Johnson Syndrome associated with 
lamotrigine and is currently taking lamotrigine. 
15. Subject’s current depressive episode is treatment resistant; defined as persistent depressive 
symptoms despite treatment with adequate doses of antidepressants from two different classes 
for an adequate amount of time (ie, at least 4 weeks of treatment). This will be assessed using 
the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire. 
16. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds. 
17. Subject has a positive pregnancy test at the Screening Visit or on Day 1 (prior to 
administration of study drug). 
18. Subject has detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) and 
HCV viral load, or human immunodeficiency virus (HIV) antibody at screening. 
19. Subject has active psychosis per Investigator assessment. 
20. Subject has a medical history of seizures. 
21. Subject has a medical history schizophrenia, and/or schizoaffective disorder. 
22. Subject has a history of mild, moderate, or severe substance use disorder diagnosed using 
DSM-5 criteria in the 12 months prior to screening. 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-BPD-201 v1.0 
 
CONFIDENTIAL 
 
9 
 
23. Subject has a positive drug and/or alcohol screen at screening or on Day 1 prior to dosing. 
24. Subject has had exposure to another investigational medication or device within 30 days prior 
to the Screening visit. 
25. Subject has been previously treated or randomized in any study using SAGE-217. Subjects 
who participate in Part A are not eligible to participate in Part B. 
26. Subject has used any known strong inhibitors of cytochrome P450 (CYP)3A4 within 28 days 
or five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, or Seville 
oranges, or products containing these within 14 days prior to receiving the first dose of study 
drug. 
27. Subject has used any CYP inducer, such as such as rifampin, carbamazepine, ritonavir, 
enzalutamide, efavirenz, nevirapine, phenytoin, phenobarbital and St John’s Wort, within 
28 days prior to the first dose of study drug. 
28. Subject plans to undergo elective surgery during participation in the study. 
SAGE-217 dosage and mode of administration:  
SAGE-217 Capsules are available as hard gelatin capsules containing a white to off-white powder. In 
addition to SAGE-217 Drug Substance, the SAGE-217 Capsules contain croscarmellose sodium, 
mannitol, silicified microcrystalline cellulose, and sodium stearyl fumarate as excipients. Subjects will 
take the assigned dose orally once daily in the evening with food. 
Reference therapy, dosage and mode of administration (Part B only):  
In Part B, placebo capsules are visually matched to the active capsules and are available as hard gelatin 
capsules containing only the excipients listed above for the active capsule treatment. Study drug will 
be administered orally once daily in the evening, with food. 
Duration of Treatment: 28 days 
Statistical methods:   
A separate statistical analysis plan (SAP) for each part (Part A and Part B) will provide a detailed 
description of the analyses to be performed in the respective part of the study. The SAPs will be 
finalized and approved prior to database lock. Any deviations from or changes to the SAP following 
database lock will be described in detail in the clinical study report. 
General: 
The data from Part A and Part B will be analyzed separately. For the purpose of all safety and efficacy 
analyses where applicable, baseline is defined as the last available measurement prior to the start of 
study drug administration.  
Continuous endpoints will be summarized with n, mean, standard deviation, median, minimum, and 
maximum. In addition, change from baseline values will be calculated at each time point and 
summarized descriptively. For categorical endpoints, descriptive summaries will include counts and 
percentages. 
Analysis Sets:  
Randomized set (Part B only) will be defined as all subjects who are randomized. This analysis set will 
be used of all data listings in Part B. Data listings for Part A will be based on Safety or Efficacy Set, as 
appropriate. 
The Safety Set, defined as all subjects received at least 1 dose of study drug, will be used to provide 
descriptive summaries of safety data.  


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-BPD-201 v1.0 
 
CONFIDENTIAL 
 
10 
 
The Efficacy Set, defined as all subjects who are in Safety Set and have at least one post-baseline 
HAM-D evaluation, will be used to analyze efficacy data unless otherwise specified. 
 
Safety Analysis:  
The overall incidence of adverse events will be summarized by Medical Dictionary for Regulatory 
Activities (MedDRA) system organ class and preferred term. Data for vital signs, clinical laboratory 
measurements, ECG, and concomitant medication usage will also be summarized.  
Safety data will be summarized and examined for possible relationships between subject characteristics 
and plasma SAGE-217 concentrations, as appropriate. Suicidality data collected using the C-SSRS and 
evaluation of mania collected using the YMRS at baseline and at each visit during the active Treatment 
Period will be listed for all subjects. Out-of-range safety endpoints may be categorized as low or high, 
where applicable. Subjects will be summarized according to treatment received for the purpose of 
safety.  
Efficacy Analysis:  
The primary endpoint in Part B, the change from baseline in HAM-D total score, will be analyzed 
using a mixed effects model for repeated measures (MMRM); the model will include treatment, 
baseline HAM-D total score, stratification factor, assessment time point, and time point-by-treatment 
as explanatory variables. All explanatory variables will be considered as fixed effects and the subject 
effect will be considered random in the model. All post-baseline time points will be included in the 
model. The primary comparison will be between SAGE-217 and matching placebo at Day 25. Model-
based point estimates (ie, least squares [LS] means, 95% confidence intervals, and p-values) will be 
reported. An unstructured covariance structure will be used to model the within-subject errors. Other 
continuous endpoints will be analyzed using similar methods.  
Other efficacy analyses, including those in Part A, will be specified in the SAP. In general, data will be 
analyzed using appropriate descriptive statistics or pre-specified statistical methods as applicable; 
subject listings will be provided for all efficacy data. Subjects will be analyzed according to 
randomized treatment for the purpose of efficacy unless otherwise specified. 
 
 
 
 
 
 
Sample Size Calculation 
Part A: The sample size of approximately 30 subjects was selected based on clinical and not statistical 
considerations. 
Part B: Assuming a two-sided alpha level of 0.05, a sample size of 112 total evaluable subjects (56 per 
treatment group) would provide 80% power to detect a placebo-adjusted treatment difference of 
approximately 4 points in the primary endpoint, change from baseline in HAM-D total score at Day 25, 
assuming standard deviation (SD) of 7.5 points.  
Assuming a 15% dropout rate, approximately 132 total randomized subjects will be required to obtain 
a total of 112 evaluable subjects. Evaluable subjects are defined as those randomized subjects who 
receive study drug and have a valid baseline and at least 1 post-baseline HAM-D assessment. 
Additional subjects may be randomized if the drop-out rate is higher than 15%.  
 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-BPD-201 v1.0 
 
CONFIDENTIAL 
 
11 
 
Table 1: 
Schedule of Events 
Study Period 
Screening 
Period 
Treatment Period 
Follow-up Perioda 
Visit Day 
D-28 to  
D-1 
D1 
D4 
(+1d) 
D8 
(±1d) 
D11 
(±1d) 
D18 
(±1d) 
D25 
(±1d) 
D29 
(±1d)/ 
EOTa 
D35 
(±3d) 
D42 
(±3d) 
D49 
(±3d) 
D56 
(±3d)/ 
ET 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/Family History 
X 
 
 
 
 
 
 
 
 
 
 
 
SCID-5-CT 
X 
 
 
 
 
 
 
 
 
 
 
 
MGH-ATRQ 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH test 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization (Part B 
only) 
 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
Body Weight/Heightc 
X 
 
 
 
 
 
 
X 
 
 
 
X 
Clinical Laboratory 
Assessmentsd 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
Drug & Alcohol Screene 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Testf 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
Hepatitis & HIV 
Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGj 
X 
X 
X 
 
 
X 
 
X 
 
 
 
X 
C-SSRSk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAM-Dl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MADRSl 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-S 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
YMRSl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ISI 
 
X 
 
 
 
 
X 
 
 
 
 
X 


Clinical Protocol 
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217-BPD-201 v1.0
CONFIDENTIAL 
12 
Study Period 
Screening 
Period 
Treatment Period 
Follow-up Perioda 
Visit Day 
D-28 to
D-1
D1 
D4 
(+1d) 
D8 
(±1d) 
D11 
(±1d) 
D18 
(±1d) 
D25 
(±1d) 
D29 
(±1d)/ 
EOTa 
D35 
(±3d) 
D42 
(±3d) 
D49 
(±3d) 
D56 
(±3d)/ 
ET 
Study Drug Dispensationo 
X 
X 
X 
X 
X 
Study Drug 
Administration 
X (Day 1 – Day 28) 
Study Drug 
Accountability/Return 
X 
X 
X 
X 
X 
X 
Adverse Events/Serious 
Adverse Eventsp 
X 
Prior/Concomitant 
Medications/ Proceduresq 
X 
CGI-I = Clinical Global Impression - Improvement; CGI-S – Clinical Global Impression - Severity; C-SSRS = Columbia Suicide 
Severity Rating Scale; D = day; EOT = end of treatment; ECG = electrocardiogram; ET = early termination; 
 
 FSH = follicle stimulating hormone; HAM-D = Hamilton Rating Scale for Depression, 17-item; HIV = 
human immunodeficiency virus; ISI = Insomnia Severity Index; MADRS = Montgomery-Åsberg Depression Rating Scale; 
MGH-ATRQ = Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; O = optional; 
 
 SCID-5-CT = Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition for clinical trials; 
 YMRS = Young Mania 
Rating Scale 
a For subjects that discontinue study drug prior to Day 29, all efforts should be made for these subjects to complete 
the 28-day follow-up period starting 7 days after the last dose of study drug. 
b A serum follicle stimulating hormone test will be conducted for female subjects at Screening to confirm whether a 
female subject with ≥12 months of spontaneous amenorrhea meets the protocol-defined criteria for being post-
menopausal. 
c Height measured at screening only 
d Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. Laboratory 
assessments are to be completed in the morning. 
e Urine toxicology for selected drugs of abuse, and breath test for alcohol (as per the standard procedures at each 
site).  
f For women of child-bearing potential, serum pregnancy test at screening and urine pregnancy test at all other 
scheduled timepoints. 
 
 
 
 
i Vital signs include oral temperature (°C), respiratory rate, heart rate, pulse oximetry 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 in the standing position. Vital signs may be repeated at the 
discretion of the Investigator as clinically indicated.
j Triplicate 12-lead ECGs will be performed with the subject in the supine position. When ECG 
 sample 
collection occur during the same visit, ECGs will be collected first. 
k 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. 
l For MADRS, HAM-D, and YMRS, the “Since Last Evaluation” forms will be completed at all subsequent time
points following the initial assessment.
 
 
 
o Additional unscheduled dispensation visits may be needed for dose reductions or titration.


Clinical Protocol 
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217-BPD-201 v1.0
CONFIDENTIAL 
13 
p AEs/SAEs will be collected starting at the time of informed consent and throughout the duration of the subject’s 
participation in the study.  
q Prior medications will be collected at Screening and concomitant medications will be collected at each subsequent 
visit. All medications taken within 30 days prior to Screening through the duration of the study will be recorded. In 
addition, all psychotropic medications taken within 6 months prior to Screening will be recorded. 


Clinical Protocol 
 
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CONFIDENTIAL 
 
14 
 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............14 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................19 
5. 
INTRODUCTION ......................................................................................................21 
5.1. 
Background of Bipolar Disorders and Unmet Medical Need .....................................21 
5.2. 
SAGE-217 ...................................................................................................................22 
5.3. 
Potential Risks and Benefits .......................................................................................23 
5.4. 
Dose Justification ........................................................................................................23 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................24 
6.1. 
Study Objective ..........................................................................................................24 
6.1.1. 
Primary Objective .......................................................................................................24 
6.1.2. 
Secondary Objectives .................................................................................................24 
 
24 
6.2. 
Endpoints ....................................................................................................................25 
6.2.1. 
Primary Endpoint ........................................................................................................25 
6.2.2. 
Secondary Endpoints ..................................................................................................25 
 
26 
7. 
INVESTIGATIONAL PLAN .....................................................................................27 
7.1. 
Overall Study Design ..................................................................................................27 
7.2. 
Number of Subjects ....................................................................................................28 
7.3. 
Treatment Assignment ................................................................................................28 
7.4. 
Dose Adjustment Criteria ...........................................................................................28 
7.5. 
Study Termination ......................................................................................................29 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................30 
8.1. 
Subject Inclusion Criteria ...........................................................................................30 
8.2. 
Subject Exclusion Criteria ..........................................................................................31 
8.3. 
Subject Withdrawal Criteria .......................................................................................32 
8.3.1. 
Withdrawal from the Study or Discontinuation of Study Drug ..................................32 
8.3.2. 
Replacement of Subjects .............................................................................................33 
9. 
TREATMENT OF SUBJECTS ..................................................................................34 


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9.1. 
Study Drug ..................................................................................................................34 
9.2. 
Prior Medications, Concomitant Medications, and Restrictions ................................34 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................34 
9.2.2. 
Prohibited Medications ...............................................................................................34 
9.2.3. 
Other Restrictions .......................................................................................................34 
9.3. 
Treatment Adherence ..................................................................................................34 
9.4. 
Randomization and Blinding ......................................................................................35 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................36 
10.1. 
Description of Study Drug ..........................................................................................36 
10.2. 
Study Drug Packaging and Labeling ..........................................................................36 
10.3. 
Study Drug Storage .....................................................................................................36 
10.4. 
Study Drug Preparation ..............................................................................................36 
10.5. 
Study Drug Administration.........................................................................................36 
10.6. 
Study Drug Accountability .........................................................................................36 
10.7. 
Study Drug Handling and Disposal ............................................................................37 
11. 
ASSESSMENT OF EFFICACY 
 .............................38 
11.1. 
Efficacy Assessments .................................................................................................38 
11.1.1. 
Hamilton Rating Scale for Depression (HAM-D) ......................................................38 
11.1.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) ........................................38 
11.1.3. 
Clinical Global Impression (CGI) ..............................................................................38 
11.1.4. 
Insomnia Severity Index (ISI) ....................................................................................39 
 
39 
 
39 
 
40 
 
40 
 
40 
 
40 
 
40 
12. 
ASSESSMENT OF SAFETY .....................................................................................41 
12.1. 
Safety Parameters .......................................................................................................41 
12.1.1. 
Demographic/Medical History ...................................................................................41 
12.1.2. 
Weight and Height ......................................................................................................41 
12.1.3. 
Physical Examination .................................................................................................41 


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12.1.4. 
Vital Signs ..................................................................................................................41 
12.1.5. 
Electrocardiogram (ECG) ...........................................................................................41 
12.1.6. 
Laboratory Assessments .............................................................................................42 
12.1.6.1. 
Drugs of Abuse and Alcohol ......................................................................................43 
12.1.6.2. 
Pregnancy Screen ........................................................................................................44 
12.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................44 
12.1.8. 
Young Mania Rating Scale (YMRS) ..........................................................................44 
12.2. 
Adverse and Serious Adverse Events .........................................................................44 
12.2.1. 
Definition of Adverse Events .....................................................................................44 
12.2.1.1. 
Adverse Event (AE) ....................................................................................................44 
12.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................45 
12.3. 
Relationship to Study Drug ........................................................................................45 
12.4. 
Recording Adverse Events .........................................................................................46 
12.5. 
Reporting Serious Adverse Events .............................................................................46 
12.6. 
Emergency Identification of Study Drug ....................................................................47 
13. 
STATISTICS ..............................................................................................................48 
13.1. 
Data Analysis Sets ......................................................................................................48 
13.2. 
Handling of Missing Data ...........................................................................................48 
13.3. 
General Considerations ...............................................................................................48 
13.4. 
Demographics and Baseline Characteristics ...............................................................48 
13.5. 
Efficacy Analysis ........................................................................................................48 
13.6. 
Safety Analyses ..........................................................................................................49 
13.6.1. 
Adverse Events ...........................................................................................................49 
13.6.2. 
Clinical Laboratory Evaluations .................................................................................49 
13.6.3. 
Physical Examinations ................................................................................................49 
13.6.4. 
Vital Signs ..................................................................................................................49 
13.6.5. 
12-Lead Electrocardiogram ........................................................................................50 
13.6.6. 
Prior and Concomitant Medications ...........................................................................50 
13.6.7. 
Columbia Suicide Severity Rating Scale ....................................................................50 
13.6.8. 
Young Mania Rating Scale .........................................................................................50 
 
50 
13.8. 
Determination of Sample Size ....................................................................................50 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................52 


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14.1. 
Study Monitoring ........................................................................................................52 
14.2. 
Audits and Inspections ................................................................................................52 
14.3. 
Protocol Deviations ....................................................................................................52 
14.4. 
Institutional Review Board (IRB) or Ethics Committee (EC) ....................................52 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................53 
16. 
ETHICS ......................................................................................................................54 
16.1. 
Ethics Review .............................................................................................................54 
16.2. 
Ethical Conduct of the Study ......................................................................................54 
16.3. 
Written Informed Consent ..........................................................................................54 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................55 
17.1. 
Inspection of Records .................................................................................................55 
17.2. 
Retention of Records ..................................................................................................55 
18. 
PUBLICATION POLICY ..........................................................................................56 
19. 
LIST OF REFERENCES ............................................................................................57 
 


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LIST OF TABLES 
Table 1:
Schedule of Events .....................................................................................................11
Table 2:
Abbreviations and specialist terms .............................................................................19
Table 3:
Clinical Laboratory Tests ...........................................................................................42
Table 4:
Relationship to Study Drug ........................................................................................45
LIST OF FIGURES 
Figure 1:
Study Design (Part A) .................................................................................................27
Figure 2:
Study Design (Part B) .................................................................................................28


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and specialist terms  
Abbreviation or specialist term 
Explanation 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CGI-I 
Clinical Global Impression scale for improvement 
CGI-S 
Clinical Global Impression scale for severity 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CYP 
cytochrome P450 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition 
EC 
ethics committee 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EOT 
end of treatment 
ET 
early termination 
 
 
FSH 
follicle-stimulating hormone 
GABA 
γ-aminobutyric acid 
HAM-D 
Hamilton Depression Rating Scale 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ID 
identification 
IRT 
interactive response technology 
ISI 
Insomnia Severity Index 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MDD 
major depressive disorder 
MDE 
major depressive episode 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGH-ATRQ 
Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire 


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Abbreviation or specialist term 
Explanation 
MMRM 
mixed effects model for repeated measures 
PI 
Principal Investigator; the investigator who leads the study 
conduct at an individual study center. Every study center has a 
principal investigator. 
 
 
QTcF 
QT corrected according to Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCID-5-CT 
Structured Clinical Interview for Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition for clinical trials 
SD 
standard deviation 
 
 
 
 
TEAE 
treatment-emergent adverse event 
YMRS 
Young Mania Rating Scale 
 


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5. 
INTRODUCTION 
5.1. 
Background of Bipolar Disorders and Unmet Medical Need 
Bipolar disorder is a chronic and episodic illness that is associated with significant disability 
worldwide (Sachs 2007). The Global Burden of Disease Study revealed that in 2013, there were 
48.8 million cases of bipolar disorder globally (Ferrari 2016). Bipolar disorder accounted for 
9.9 million disability-adjusted life years (DALYs) globally, explaining 0.4% of total DALYs and 
1.3% of total years lived with disability.  
There are subtypes of bipolar disorder; this study includes the bipolar I and II subtypes. Bipolar I 
is characterized by a manic episode, whereas bipolar II is characterized by a hypomanic episode. 
The difference in the severity of the manic features relies on functional impairment that is caused 
by these episodes (DSM-5). The National Comorbidity Survey estimate of the lifetime 
prevalence of bipolar disorder is 2.1% in the US population when bipolar I disorder and 
bipolar II Disorder are combined (Merikangas 2007). 
While the manic or hypomanic episodes represent distinct departure from the baseline mood 
state and easily attract attention, evidence suggests that depressive episodes of both bipolar I and 
II are associated with more disability than any other aspect of the illness. A seminal long-term 
study of patients with bipolar I disorder demonstrated that over the 13-year follow-up period, 
patients were symptomatic about 47% of the time, and depressive symptoms were present in 
32% of the follow-up weeks vs manic features, which were present in 9% (Judd 2002). A similar 
analysis in patients with bipolar II disorder with a longer follow up of up to 20 years found that 
patients were symptomatic more than half of the time (54%) where depressive symptoms 
dominated the course at 50% of the follow-up weeks vs 1.3% for the hypomanic symptoms 
(Judd 2003). A study in patients with unipolar depression found a prevalence of depressive 
symptoms 47% of the time (Judd 1998), suggesting a comparable time spent with depressive 
symptoms in the bipolar spectrum. These naturalistic studies have also found that about half the 
time patients reported taking psychotropic medications. In another large-scale study with a 
follow-up period of up to 2 years, 58% of nearly 1500 patients with bipolar disorder who were 
symptomatic at study entry achieved recovery (Perlis 2006). Similarly, during the follow-up 
period, 49% of these individuals experienced recurrent episodes, where depressive episodes 
(38%) outweighed manic, hypomanic, or mixed episodes combined (13.8%). In the Stanley 
Foundation Bipolar Network Study, in which year-long, daily clinician ratings were included, 
despite treatment with an average of 4.1 psychotropic medications, patients with bipolar disorder 
spent 3 times as much time with depressive symptoms as manic symptoms (Post 2003). 
There are only 3 medications approved in the US for the treatment of bipolar depression, 
(lurasidone, olanzapine-fluoxetine combination, and quetiapine), all of which include atypical 
antipsychotics that are associated with significant adverse metabolic effects. None of the 
currently available antidepressants are indicated for bipolar depression due to their limited 
efficacy, and the possibility that their use may be associated with a manic switch and rapid 
cycling. While some studies reported varying levels of efficacy with antidepressants 
(Gijsman 2004), a large-scale, double-blind, placebo-controlled clinical trial sponsored by the 
National Institutes of Mental Health, The Systematic Treatment Enhancement Program for 
Bipolar Disorder (STEP-BD), found that only 23.5% of patients with bipolar depression 
receiving a mood stabilizer and adjunctive antidepressants vs 27.3% of those receiving a mood 


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stabilizer and placebo experienced a durable recovery, confirming the lack of effectiveness of 
antidepressants in bipolar depression (Sachs 2007). The tolerability profile of the approved 
atypical antipsychotics and limited efficacy of available antidepressants highlight the critical 
unmet need in the treatment of bipolar depression. 
In 1998, the lifetime cost of bipolar disorder in the US was estimated at $24 billion. The cost of a 
single manic episode was estimated at $11,720 to $624,785 for persons with 
nonresponsive/chronic episodes (Begley 1998); the cost of bipolar depression specifically, is less 
well studied, however, available estimates indicate a higher cost associated with bipolar 
depression than for mania (Bowden 2004). 
Kessler has studied the impact of mood disorders on work performance in a representative 
sample of over 3,000 US workers (Kessler 2006). Bipolar disorder and major depressive disorder 
were associated with 65.5 and 27.2 lost workdays per worker per year, respectively. Moreover, it 
was found that the increase in bipolar disorder was attributable to depressive symptoms rather 
than manic episodes in bipolar disorder. 
Taken together, these findings point to substantial predominance of depressive symptoms across 
the spectrum of bipolar disorder. In particular, they also highlight the importance of successful 
depressive symptom control, and an unmet need in the treatment of depressive episodes for both 
bipolar I and bipolar II disorder. 
5.2. 
SAGE-217 
SAGE-217 is a positive allosteric modulator of γ-aminobutyric acid (GABA)A 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. 
Data from an open-label portion of the Phase 2a study of SAGE-217 administered to subjects 
with moderate to severe major depressive disorder (MDD) showed clinically significant 
improvements from baseline in depression scale scores (HAM-D, Montgomery-Åsberg 
Depression Rating Scale [MADRS], and Clinical Global Impression – Improvement [CGI-I]) as 
early as Day 2 of the 14-day treatment period, with durable responses following the end of 
treatment. This result was further supported by the randomized, double-blind portion of this 
study (N=89) in which a rapid and substantial decrease in HAM-D scores was observed at 
Day 15 (primary endpoint), starting at Day 2. This response pattern was also observed with other 
efficacy scales, including MADRS and CGI-I. Statistically significant differences from the 
placebo group favoring the SAGE-217 arm were observed for 2 weeks in the follow-up period. 
SAGE-217 has been generally well tolerated in clinical studies to date. The most common 
treatment-emergent adverse events (TEAEs) were sedation, somnolence, and dizziness. Most 
AEs were reported as mild or moderate in intensity. Among the over 260 subjects exposed to 
SAGE-217 in clinical trials, there have been no deaths and only one subject with essential tremor 


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experienced a serious adverse event (SAE) of transient confusion leading to discontinuation of 
study drug. No other SAEs have been reported in any study of SAGE-217.  
Additional information on nonclinical and clinical data is provided in the Investigator’s 
Brochure.  
5.3. 
Potential Risks and Benefits 
Non-serious events of sedation, somnolence, and dizziness were the most commonly reported 
AEs with SAGE-217. Given the outcome of the Phase 2 study of SAGE-217 in subjects with 
MDD and the current significant unmet need in the treatment of depressive episodes associated 
with bipolar I/II disorders, a favorable risk-benefit balance and investigation of SAGE-217 in 
patients with bipolar I/II disorders are justified. 
5.4. 
Dose Justification 
The highest dose level of SAGE-217 to be administered in this study (30 mg) was determined 
based on the maximum tolerated dose in the multiple ascending dose study of SAGE-217 in 
healthy subjects and is the same dose level that has been used and generally well tolerated in 
clinical studies in various patient populations, including patients with MDD. Due to the observed 
improved tolerability of sedation/somnolence effects when taken in the evening in previous 
clinical studies, SAGE-217 will be administered in the evening in this study as well.  
Further consideration was given to the duration of dosing in this trial. Bipolar depression is 
known to be more difficult to treat compared to unipolar depression. This is evident by the fact 
that none of the available 25 antidepressants have been approved for the treatment of bipolar 
depression (Sachs 2007). Given this foreseen challenge, the duration in this trial has been set at a 
total of 28 days, including a titration of 20 mg for 3 days, then a dose at 30 mg for 21 days, and a 
titration down to 20 mg for 4 days. The first 3 days at 20 mg of SAGE-217 are thought to 
provide immediate tolerability data at this relatively lower dose when combined with other 
concomitant medications including mood stabilizers and increase the probability of tolerance on 
the 30 mg dose level. The 30 mg dose level is based on previous clinical trial data with SAGE-
217 demonstrating highly effective improvement in depressive symptoms in patients with MDD. 
Based on the absence of clinical data for a treatment duration longer than 2 weeks at this time, 
and the GABAergic mechanism of action of SAGE-217, a titration down to 20 mg is included in 
the study design. 


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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Study Objective 
6.1.1. 
Primary Objective 
Part A 
The primary objective of Part A of this study is to evaluate the safety and tolerability of 
SAGE-217 in subjects with bipolar I/II disorder with a current major depressive episode (MDE). 
Part B 
The primary objective of Part B of this study is to assess the efficacy of SAGE-217 in reducing 
depressive symptoms in subjects with bipolar I/II disorder with a current MDE. 
6.1.2. 
Secondary Objectives 
Part A 
Secondary objectives of Part A of this study are: 
• To assess the efficacy of SAGE-217 in reducing depressive symptoms in subjects 
with bipolar I/II disorder with a current MDE. 
• To assess the effect of SAGE-217 on sleep. 
Part B 
Secondary objectives of Part B of this study are: 
• To evaluate the safety and tolerability of SAGE-217 in subjects with bipolar I/II 
disorder with a current MDE. 
• To assess the effect of SAGE-217 on sleep. 
 
 
 
 
 
 
 
 
 
 
 
 


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6.2. 
Endpoints 
6.2.1. 
Primary Endpoint 
Part A 
The primary endpoint for Part A of this study is the safety and tolerability of SAGE-217, as 
assessed by the frequency and severity of adverse events (AEs); changes from baseline in clinical 
laboratory measures, vital signs, and electrocardiograms (ECGs); suicidal ideation and behavior 
using the Columbia Suicide Severity Rating Scale (C-SSRS); and mania using the Young Mania 
Rating Scale (YMRS). 
Part B 
The primary endpoint of Part B of this study is the reduction in depressive symptoms with 
SAGE-217 treatment, as assessed by the change from baseline in the 17-item HAM-D total score 
at Day 25. 
6.2.2. 
Secondary Endpoints 
Part A 
Secondary endpoints of Part A of this study are: 
• The reduction in depressive symptoms, as assessed by: 
 Change from baseline in the 17-item HAM-D total score at Day 25 and all other 
time points as outlined in Table 1; 
 HAM-D response at Day 25 and all other time points as outlined in Table 1;  
 HAM-D remission at Day 25 and all other time points as outlined in Table 1;  
 Change from baseline in the MADRS total score at Day 25 and all other time 
points as outlined in Table 1;  
 Change from baseline in MADRS individual item scores at Day 25 and all other 
time points as outlined in Table 1;  
 The response to the CGI-S and CGI-I at Day 25 and all other time points as 
outlined in Table 1. 
• The reduction in insomnia severity as assessed by the Insomnia Severity Index (ISI). 
Part B 
Secondary endpoints of Part B of this study are: 
• The reduction in depressive symptoms, as assessed by: 
 Change from baseline in total HAM-D score at all other time points as outlined in 
Table 1; 
 HAM-D response at Day 25 and all other time points as outlined in Table 1;  


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 HAM-D remission at Day 25 and all other time points as outlined in Table 1;  
 Change from baseline in the MADRS total score at Day 25 and all other time 
points as outlined in Table 1;  
 Change from baseline in MADRS individual item scores at Day 25 and all other 
time points as outlined in Table 1;  
 CGI-S and CGI-I response at Day 25 and all other time points as outlined in 
Table 1. 
• The safety and tolerability of SAGE-217 as assessed by the frequency and severity of 
AEs; changes from baseline in clinical laboratory measures, vital signs, and ECGs; 
and suicidal ideation and behavior using the C-SSRS, and the YMRS. 
• The reduction in insomnia severity, as assessed by the ISI. 
 
 
 
 
 
 
 
 
 
 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This study will be conducted in 2 sequential parts: Part A (open-label) and Part B (randomized, 
double-blind, placebo-controlled, parallel group). Part B will be initiated pending the review of 
Part A data.The methods of the 2 parts will be identical unless otherwise noted. The study is 
designed to assess the safety, tolerability, 
and efficacy of SAGE-217 in adult subjects with 
bipolar I/II disorder, who are currently experiencing an MDE. 
Screening begins with the signing of the informed consent form (ICF) at the Screening Visit. The 
diagnosis of bipolar I or II disorder will be made using the Structured Clinical Interview for 
DSM-5 for clinical trials (SCID-5-CT) performed by a qualified healthcare professional. 
Subjects on antidepressants or mood stabilizers (lamotrigine, lithium, and valproic acid only) that 
have been taken at the same dose for at least 60 days prior to Day 1 are to continue the stable 
dose throughout the treatment period. 
Subjects will return to the study center during the treatment and follow-up periods as outlined in 
the Schedule of Events (Table 1). All assessments to be performed are summarized in Table 1. 
If at any time during the study, a subject has a YMRS score of ≥13, the Investigator will 
clinically assess the subject for a manic or hypomanic switch. If the clinical assessment is 
consistent with hypomania or mania, the subject will be discontinued from study drug and 
treated as clinically appropriate (see Section 8.3). 
Part A 
The study design for Part A is presented in Figure 1. In Part A, all subjects will receive SAGE-
217. Beginning on Day 1, qualified subjects will self-administer the study drug once daily in the 
evening with food for 28 days: 20 mg SAGE-217 for 3 days, 30 mg SAGE-217 for 21 days, and 
then 20 mg-SAGE-217 for 4 days. Dose adjustments based on study drug tolerability are 
permitted following the guidelines outlined in Section 7.4. 
 
Figure 1: 
Study Design (Part A) 
 
QD = once daily 
*A dose adjustment to 20-mg SAGE-217 is permitted if the 30-mg dose is not tolerated at any time during Days 4 to 
24. 
 
Part B 
The study design for Part B is presented in Figure 2. In Part B, subjects will be randomized in a 
1:1 ratio to receive SAGE-217 or placebo; randomization will be stratified based on use of mood 
stabilizers (Y/N). Beginning on Day 1, qualified subjects will self-administer the study drug once 
daily in the evening with food for 28 days: 20 mg SAGE-217 for 3 days, 30 mg SAGE-217 for 
Day -28 to -1
Screening
Days 1 to 3
SAGE-217
20 mg QD
Days 4 to 24
SAGE-217
30 mg QD*
Days 25 to 28
SAGE-217
20 mg QD
Days 35, 42, 49, 56
Follow-up Visits


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21 days, and then 20 mg-SAGE-217 for 4 days. Dose adjustments based on study drug 
tolerability are permitted following the guidelines outlined in Section 7.4. 
 
Figure 2: 
Study Design (Part B) 
 
QD = once daily 
*A dose adjustment to 20-mg SAGE-217 is permitted if the 30-mg dose is not tolerated at any time during Days 4 to 
24. 
7.2. 
Number of Subjects 
Part A 
Approximately 30 subjects will be dosed in Part A.  
Part B 
After review of Part A data, approximately 132 subjects will be randomized and dosed in Part B 
to obtain a total of 112 evaluable subjects (see Section 13.8). 
7.3. 
Treatment Assignment 
Part A 
In Part A, all subjects will receive SAGE-217 in an open-label manner.  
Part B 
In Part B, subjects will be randomized to a treatment group (SAGE-217 or placebo) in a 
1:1 ratio; randomization will be stratified based on use of mood stabilizers (Y/N).  
7.4. 
Dose Adjustment Criteria 
If at any time, 30 mg is not tolerated, as assessed by the occurrence of a severe AE judged by the 
investigator to be related to study drug, the dose on the next day will be reduced to 20 mg and 
continued for the remainder of the treatment period. Dose adjustments related to moderate AEs 
will be judged by the Investigator. If a dose adjustment from 30 mg to 20 mg is deemed 
necessary by the Investigator, the subject will return to the site for the adjusted dose to be 
Day -28 to -1
Screening
Day 1
Randomization
Days 1 to 28
Placebo QD
Days 1 to 3
SAGE-217
20 mg QD
Days 4 to 24
SAGE-217
30 mg QD*
Days 25 to 28
SAGE-217
20 mg QD
Days 35, 42, 49, 56
Follow-up Visits


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dispensed. Subjects who cannot tolerate the 20-mg dose at any time will be discontinued from 
study drug (see Section 8.3).  
7.5. 
Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons including the occurrence of AEs or other findings suggesting unacceptable risk to 
subjects, or for administrative reasons. In the event of study termination, Sage Therapeutics will 
provide written notification to the Investigator. Investigational sites must promptly notify their 
ethics committee and initiate withdrawal procedures for participating subjects.  


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
Qualified subjects will meet all of the following criteria: 
1. Subject has signed an ICF prior to the conduct of any study-specific procedures. 
2. Subject agrees to adhere to the study requirements, including use of prior, concomitant, 
and prohibited medications. 
3. Subject is an ambulatory man or woman, aged 18 to 65 years, inclusive, at Screening. 
4. 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. 
5. Subject has a documented history of hypomanic or manic episode (verified by medical 
records and/or treating healthcare professional) and a diagnosis of bipolar I or bipolar II 
disorder with a current MDE as per DSM-5 SCID-5-CT. 
6. Subject has a HAM-D score of ≥22 at Screening.  
7. Female subject agrees to use one of the following methods of contraception during 
participation in the study and for 30 days following the last dose of study drug, unless 
they are postmenopausal (defined as no menses for 12 months without an alternative 
medical cause and confirmed by follicle stimulating hormone [FSH] level ≥40 mIU/mL) 
and/or surgically sterile (hysterectomy or bilateral oophorectomy): 
• Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation. 
• Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation.  
• Intrauterine device. 
• Intrauterine hormone-releasing system. 
• Bilateral tubal ligation/occlusion. 
• Vasectomized partner. 
• Sexual abstinence (no sexual intercourse).  
8. Male subject agrees to use an acceptable method of effective contraception for the 
duration of study and for 5 days after receiving the last dose of the study drug. 
Acceptable methods of effective contraception for males includes sexual abstinence, 
vasectomy, or a condom with spermicide used together with highly effective female 
contraception methods (if the female partner is of child-bearing potential, see Inclusion 
Criteria #7 for acceptable method of contraception for females). 
9. 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. 


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8.2. 
Subject Exclusion Criteria 
Subjects who meet any of the following criteria are disqualified from participation in this study: 
1. Subject has a history of suicide attempt within the last 2 years. 
2. Subject has current suicidal ideation with plans based on Investigator clinical assessment 
and/or the C-SSRS response at Screening or Day 1. 
3. Subject has a history of rapid cycling bipolar disorder as per DSM-5 SCID-5-CT. 
4. Subject’s current depressive episode meets the DSM-5 specifier criteria for mixed 
features. 
5. Subject has ≥25% reduction in HAM-D score from Screening to Day 1. 
6. 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. 
7. Subject has abnormal liver function as shown by an abnormal liver function profile at 
screening (eg, repeated values of aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), or total bilirubin ≥2x the upper limit of normal). 
8. Subject has a clinically significant abnormal 12-lead ECG at the Screening or Day 1 
visits. NOTE: mean QT interval calculated using the Fridericia method (QTcF) of 
>450 msec in male or >470 msec in female subjects will be the basis for exclusion from 
the study.  
9. Subject has a YMRS score ≥13 at Screening or Day 1. 
10. Subject presents for the study receiving a mood stabilizer other than lamotrigine, lithium, 
or valproic acid. 
11. Subject presents for the study receiving psychotropic medications, which have not been 
taken at the same dose for at least 60 days prior to Day 1. 
12. Subject that presents for the study receiving psychotropic medications and does not 
intend to continue the current treatment regimen during the treatment period.  
13. Subject is taking typical or atypical antipsychotics, MAOIs, and/or benzodiazepines at 
the Screening Visit. 
14. Subject has a history of severe rashes or Stevens-Johnson Syndrome associated with 
lamotrigine and is currently taking lamotrigine. 
15. Subject’s current depressive episode is treatment resistant; defined as persistent 
depressive symptoms despite treatment with adequate doses of antidepressants from two 
different classes for an adequate amount of time (ie, at least 4 weeks of treatment). This 
will be assessed using the Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire. 
16. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds. 


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17. Subject has a positive pregnancy test at the Screening Visit or on Day 1 (prior to 
administration of study drug). 
18. Subject has detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) 
and HCV viral load, or human immunodeficiency virus (HIV) antibody at screening. 
19. Subject has active psychosis per Investigator assessment. 
20. Subject has a medical history of seizures. 
21. Subject has a medical history schizophrenia, and/or schizoaffective disorder. 
22. Subject has a history of mild, moderate, or severe substance use disorder diagnosed using 
DSM-5 criteria in the 12 months prior to screening. 
23. Subject has a positive drug and/or alcohol screen at screening or on Day 1 prior to 
dosing. 
24. Subject has had exposure to another investigational medication or device within 30 days 
prior to the Screening visit. 
25. Subject has been previously treated or randomized in any study using SAGE-217. 
Subjects who participate in Part A are not eligible to participate in Part B. 
26. Subject has used any known strong inhibitors of cytochrome P450 (CYP)3A4 within 28 
days or five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, or 
Seville oranges, or products containing these within 14 days prior to receiving the first 
dose of study drug. 
27. Subject has used any CYP inducer, such as such as rifampin, carbamazepine, ritonavir, 
enzalutamide, efavirenz, nevirapine, phenytoin, phenobarbital and St John’s Wort, within 
28 days prior to the first dose of study drug. 
28. Subject plans to undergo elective surgery during participation in the study. 
8.3. 
Subject Withdrawal Criteria 
8.3.1. 
Withdrawal from the Study or Discontinuation of Study Drug 
Subjects may discontinue study drug or withdraw from the study at any time for any reason. The 
Investigator may discontinue the subject from the study drug for any of the following reasons: 
• The subject is unwilling or unable to adhere to the protocol 
• The subject experiences an intolerable AE  
• Other medical or safety reason, at the discretion of the Investigator and/or the 
Medical Monitor 
In addition, if at any time during the study, a subject has a YMRS score of ≥13, the Investigator 
will clinically assess the subject for a manic or hypomanic switch. If the clinical assessment is 
consistent with hypomania or mania, the subject will be discontinued from study drug and 
treated as clinically appropriate. These incidents will be documented as AEs. 
The reasons for study drug discontinuation and/or subject withdrawal from the study must be 
recorded in the subject’s electronic case report form (eCRF). The Investigator must notify the 


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Sponsor and/or the Medical Monitor immediately when a subject has discontinued or been 
withdrawn for any reason. 
Subjects who discontinue study drug early/withdraw during the treatment period should, if 
possible, have an end of treatment (EOT) visit, including the EOT assessments as summarized in 
the Schedule of Events (see Table 1). The EOT visit should be scheduled as soon as possible, 
preferably the day after the subject’s last dose. All details of the EOT visit should be recorded in 
the subject’s medical source documents. For subjects that discontinue study drug early, follow-
up visits should take place every 7 days after the last dose of treatment for 28 days. If at any time 
after the EOT visit, a subject decides to terminate the study early, the subject should return for an 
early termination (ET) visit. The EOT and ET visits can be on the same day if a subject 
discontinues study drug and terminates the study on the same day during a clinic visit; in this 
case, all events scheduled for both visits will be conducted only once.  
If the subject fails or refuses to return to the study center, an attempt must be made to contact the 
subject by telephone in order to assess as many safety and efficacy parameters as possible. All 
data collected over the telephone must be documented and kept in the subject’s record. A subject 
will be deemed lost to follow-up after 3 attempts at contact have been made and it has been at 
least 1 month since the last subject contact. The third attempt at contact must be a certified letter 
accompanied by a survey inquiring the reason for study discontinuation. All attempts at contact 
will be documented. 
Subjects who discontinue the study drug 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.  
If a subject failed to attend scheduled assessments during the course of the study, the 
Investigators must determine the reasons and the circumstances as completely and accurately as 
possible, and document this in the subject's source documents. 
8.3.2. 
Replacement of Subjects 
Part A 
In Part A, subjects will not be replaced. 
Part B 
In Part B, subjects will not be replaced. Additional subjects may be randomized if the drop-out 
rate is higher than anticipated (see Section 13.8). 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Study Drug 
Subjects will self-administer study drug orally once daily in the evening with food for 28 days as 
outlined in Section 7.1.  
9.2. 
Prior Medications, Concomitant Medications, and Restrictions 
9.2.1. 
Prior and Concomitant Medications and/or Supplements 
The start and end dates, route of administration, dose/units, frequency, and indication for all 
medications and/or supplements taken within 60 days prior to Day 1 and throughout the duration 
of the study will be recorded. In addition, psychotropic drugs taken within 6 months prior to 
Screening will be recorded. 
Any concomitant medication determined necessary for the welfare of the subject may be given at 
the discretion of the Investigator at any time during the study under the guidance outlined in 
these sections.  
Antidepressants and mood stabilizers (lamotrigine, lithium, and valproic acid only) 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 throughout the treatment period. 
Medications intended for contraception are permitted for female subjects (see Section 8.1): 
9.2.2. 
Prohibited Medications 
The following medications are prohibited throughout the treatment period: 
• Benzodiazepines 
• Typical or atypical antipsychotics 
• MAOIs 
• Any known strong inhibitors of CYP3A4 
• Use of any CYP inducer, such as such as rifampin, carbamazepine, ritonavir, 
enzalutamide, efavirenz, nevirapine, phenytoin, phenobarbital and St John’s Wort. 
9.2.3. 
Other Restrictions 
The consumption of grapefruit juice, grapefruit, or Seville oranges, or products containing these 
is prohibited throughout the treatment period. 
Consumption of drugs of abuse and alcohol is discouraged throughout the duration of the study. 
9.3. 
Treatment Adherence 
SAGE-217 or placebo (Part B only) will be self-administered by subjects once every evening 
with food. Sites will dispense study drug to the subjects to take at home with instructions for use 
(see Section 10.4).  


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Administration of study drug will be monitored by a medication adherence monitoring platform 
used on smartphones to visually confirm medication ingestion. Subjects will receive a reminder 
within a predefined time window to take study drug while using the application. Subjects will 
follow a series of prescribed steps in front of the front-facing webcam to visually confirm their 
ingestion of the medication. The application will record the date and time of study drug 
administration by dose level, as well as missed doses. 
In addition, the subject will be instructed to bring their dosing kit to each visit during the 
treatment period, at which time the Investigator or designee will be responsible for ensuring the 
kit contains sufficient doses until the next scheduled dispensation. 
If the subject is persistently noncompliant with the study drug, the Investigator should discuss 
with Sage Therapeutics the potential discontinuation of the subject (see Section 8.3). Dosing 
requirements will be reviewed with each subject during all study contacts. The authorized study 
personnel conducting the re-education must document the process in the subject source records. 
9.4. 
Randomization and Blinding 
Part A 
Part A is an open-label design in which all subjects will receive SAGE-217. 
Part B 
Part B is a randomized, double-blind, placebo-controlled, parallel group design. Subjects who 
meet the entrance criteria will be stratified based on use of mood stabilizers (Y/N) and randomly 
assigned within each stratum in a 1:1 ratio to receive SAGE-217 or matched placebo. Subjects, 
clinicians, and the study team will be blinded to treatment allocation. Randomization will be 
performed centrally via an interactive response technology (IRT) system. 
Randomization schedules will be generated by an independent statistician. The allocation to 
treatment group (SAGE-217 or placebo) will be based on the randomization schedule. The 
randomization schedules will be kept strictly confidential, accessible only to authorized 
personnel until the time of unblinding.  
During the study, the blind is to be broken only if the safety of a subject is at risk and the 
treatment plan is dependent on the study treatment received. See Section 12.6 for details of 
unblinding in the event of a medical emergency or pregnancy.  
In all cases where the study drug allocation for a subject is unblinded, pertinent information 
(including the reason for unblinding) must be documented in the subject’s records and on the 
eCRF. If the subject or study center personnel have been unblinded, the subject will be 
permanently discontinued from the study. 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Description of Study 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, and sodium 
stearyl fumarate as excipients. Capsules will be available in 10-mg, 20-mg, and 30-mg strengths 
to achieve the target dose of 20 mg or 30 mg. Subjects will be administered 2 capsules per dose.  
Matching placebo capsules are hard gelatin capsules containing only the excipients listed for the 
active capsule treatment.  
10.2. 
Study Drug Packaging and Labeling 
SAGE-217 capsules and matched placebo capsules will be provided to the clinic pharmacist 
and/or designated site staff responsible for dispensing the study drug in appropriately labeled, 
subject-specific kits each containing sealed unit doses. Each unit dose 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 Code of Federal 
Regulations and Good Manufacturing Practices/Good Clinical Practices guidelines will be 
prepared by the clinical research organization.Study Drug Storage 
SAGE-217 and matched placebo are to be stored at room temperature, 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 in the evening with food. 
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.  
Site staff will access the IRT at the Screening Visit to obtain a subject identification (ID) number 
for each subject. On Day 1, site staff will access the IRT and provide the necessary subject-
identifying information, including the subject ID number assigned at Screening, to randomize the 
eligible subject into the study and obtain the medication ID number for the study drug to be 
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At the subsequent study drug-dispensing visit, the investigator or designee will access the IRT, 
providing the same subject ID number assigned at Screening, to obtain the medication ID 
number for the study drug to be dispensed at that visit. In the event of an unscheduled dose 
reduction (Section 7.4), a new subject-specific kit will be dispensed. 
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 medication 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 within usual 
business hours and with appropriate notice during or after completion of the study to perform 
drug accountability reconciliation. 
10.7. 
Study Drug Handling and Disposal 
At the end of the study, all used and unused study drug will be reconciled and returned to Sage 
Therapeutics for destruction or destroyed locally; disposition of study drug will be documented. 
A copy of the inventory record and a record of any clinical supplies that have been received, 
dispensed or destroyed must be documented by the site as directed. This documentation must 
include at least the information below:  
• the number of dispensed units; 
• the number of unused units; 
• the number of units destroyed at the end of the study; 
• the date, method and location of destruction. 
 


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11. 
ASSESSMENT OF EFFICACY 
 
All assessments will be conducted according to the schedule of assessments (Table 1). 
11.1. 
Efficacy Assessments 
11.1.1. 
Hamilton Rating Scale for Depression (HAM-D) 
The primary outcome measure is the change from baseline in the 17-item HAM-D total score at 
Day 25.  
The 17-item HAM-D will be used to rate the severity of depression in subjects who are identified 
as experiencing an MDE (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. Every effort should be 
made for the same rater to perform all HAM-D assessments for an individual subject.  
The HAM-D total score will be calculated as the sum of the 17 individual item scores.  
In addition to the primary efficacy endpoint of change from baseline in HAM-D total score, 
several secondary efficacy endpoints will be derived for the HAM-D. Hamilton Rating Scale for 
Depression subscale scores will be calculated as the sum of the items comprising each subscale. 
Hamilton Rating Scale for Depression response will be defined as having a 50% or greater 
reduction from baseline in HAM-D total score. Hamilton Rating Scale for Depression remission 
will be defined as having a HAM-D total score of ≤7. 
The HAM-D subject interview may be audio-recorded for independent quality control purposes. 
11.1.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive 
episodes in subjects with mood disorders. It was designed as an adjunct to the HAM-D that 
would be more sensitive than the Hamilton Scale to the changes brought on by antidepressants 
and other forms of treatment.  
Higher MADRS scores indicate more severe depression, and each item yields a score of 0 to 6. 
The overall score ranges from 0 to 60 (Williams 2008). 
The MADRS total score will be calculated as the sum of the ten individual item scores. 
The MADRS subject interview may be audio-recorded for independent quality control purposes. 
11.1.3. 
Clinical Global Impression (CGI) 
The CGI is a validated measure often utilized in clinical trials to allow clinicians to integrate 
several sources of information into a single rating of the subject’s condition. The CGI scale 
consists of 3 items. Only the first 2 items are being used in this study.  
The Clinical Global Impression - Severity (CGI-S) uses a 7-point Likert scale to rate the severity 
of the subject’s illness at the time of assessment, relative to the clinician’s past experience with 


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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 Clinical Global Impression - Improvement (CGI-I) employs a 7-point Likert scale to 
measure the overall improvement in the subject’s condition posttreatment. The Investigator will 
rate the subject’s total improvement whether or not it is due entirely to drug treatment. Response 
choices include: 0=not assessed, 1=very much improved, 2=much improved, 3=minimally 
improved, 4=no change, 5=minimally worse, 6=much worse, and 7=very much worse 
(Busner 2007b). The CGI-I is only rated at posttreatment assessments. By definition, all CGI-I 
assessments are evaluated against baseline conditions. CGI-I response will be defined as having 
a CGI-I score of “very much improved” or “much improved.”  
11.1.4. 
Insomnia Severity Index (ISI) 
The ISI is a validated questionnaire designed to assess the nature, severity, and impact of 
insomnia (Morin 2011). The ISI uses a 5-point Likert Scale to measure various aspects of 
insomnia severity (0 = none, 1 = mild, 2 = moderate; 3 = severe; 4 = very severe), satisfaction 
with current sleep pattern (0 = very satisfied, 1 = satisfied, 2 = moderately satisfied, 3 = 
dissatisfied, 4 = very dissatisfied), and various aspects of the impact of insomnia on daily 
functioning (0 = not at all, 1 = a little, 2 = somewhat, 3 = much, 4 = very much). A total score of 
0 to 7 = “no clinically significant insomnia,” 8 to 14 = subthreshold insomnia,” 15 to 21 = 
“clinical insomnia (moderate severity),” and 22 to 28 = “clinical insomnia (severe).”  


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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
The safety and tolerability of SAGE-217 will be assessed by the frequency and severity of AEs; 
changes from baseline in clinical laboratory measures, vital signs, and ECGs; suicidal ideation 
and behavior using the C-SSRS; and the YMRS. All assessments will be conducted according to 
the schedule of assessments (Table 1). 
12.1.1. 
Demographic/Medical History 
Demographic and baseline characteristics (age, race, gender, ethnicity, employment status, 
highest education level, marital/civil status) and a full medical history, including family 
psychiatric history, will be documented. The diagnosis of bipolar I or II disorder will be 
determined using the SCID-5-CT. 
12.1.2. 
Weight and Height 
Height (Screening only) and weight will be measured and documented.  
12.1.3. 
Physical Examination 
Physical examinations assessing body systems (eg, head, eye, ear, 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 physical examinations 
may also be conducted per the Investigator’s discretion. 
Any abnormality in physical examinations will be interpreted by the Investigator as abnormal, 
not clinically significant (NCS); or abnormal, clinically significant (CS) in source documents. 
New or worsening abnormalities that are judged to be clinically significant will be recorded as 
AEs, assessed according to Section 12.2.1.1. 
12.1.4. 
Vital Signs 
Vital signs comprise both supine and standing for systolic and diastolic blood pressure and heart 
rate measurements. Heart rate and blood pressure are to be collected in supine position after the 
subject has been resting for 5 minutes and then in the standing position. Respiratory rate, pulse 
oximetry and temperature are collected once, in either position. Vital signs will be documented. 
When vital signs are scheduled at the same time as blood draws, vital signs will be obtained first, 
with the blood sample collected as close to the scheduled time as possible. 
Any abnormality in vital signs will be interpreted by the Investigator as abnormal, NCS or 
abnormal, CS in source documents. New or worsening abnormalities that are judged to be 
clinically significant will be recorded as AEs, assessed according to Section 12.2.1.1. 
12.1.5. 
Electrocardiogram (ECG) 
Supine 12-lead ECGs will be performed in triplicate. The standard intervals (heart rate, PR, 
QRS, QT, and QTcF) as well as any rhythm abnormalities will be recorded. When ECG 
 
sample collection occur during the same visit, the ECGs will be conducted first. 


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Any abnormality in ECGs 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. 
Laboratory Assessments 
Samples will be collected in accordance with acceptable laboratory procedures detailed in the 
laboratory manual.   
The clinical laboratory tests to be performed are listed in Table 3. 
Table 3: 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Coagulation 
Red blood cell count 
Hemoglobin  
Hematocrit  
White blood cell count with 
differential  
Reticulocytes 
Platelet count 
Red blood cell morphology 
ALT 
Albumin 
Alkaline phosphatase 
AST 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
Total protein 
Creatinine 
Blood urea nitrogen 
Creatine kinase 
GGT 
Potassium 
Sodium 
Lactate dehydrogenase 
Glucose 
Chloride 
Bicarbonate 
Calcium 
Phosphorus 
Triglycerides 
pH 
Specific gravity 
Protein 
Glucose 
Red blood cells 
Nitrite 
Leukocyte 
esterase 
Ketones 
Bilirubin 
Urobilinogen 
Activated partial 
thromboplastin 
time 
Prothrombin 
time 
International 
normalized ratio 


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


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12.1.6.2. Pregnancy Screen 
A serum pregnancy test in women of child-bearing potential will be conducted at Screening and 
a urine pregnancy test will be conducted at all other scheduled timepoints (see Table 3).  
12.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011). This scale 
consists of a baseline evaluation that assesses the lifetime experience of the subject with suicidal 
ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last 
study visit. The C-SSRS includes ‘yes’ or ‘no’ responses for assessment of suicidal ideation and 
behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being 
the most severe).  
The “Baseline/Screening” C-SSRS form will be completed at screening (lifetime history and past 
24 months). The “Since Last Visit” C-SSRS form will be completed at all subsequent time 
points, as outlined in Table 1. 
12.1.8. 
Young Mania Rating Scale (YMRS) 
Manic symptoms will be assessed during the study using the YMRS (Young 1978). The 
clinician-administered scale is based on 11 items of core symptoms of mania. Four of the items 
(irritability, speech, thought content, and disruptive/aggressive behavior) are graded on a scale of 
0 to 8 (choices given as even numbers), with the remaining 7 items graded on a scale of 0 to 4. 
Scoring between the points given (whole or half points) is possible.  
12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Definition of Adverse Events 
12.2.1.1. Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the use of a 
medicinal (investigational) product whether or not related to the medicinal (investigational) 
product. In clinical studies, an AE can include an undesirable medical condition occurring at any 
time, including baseline or washout periods, even if no study treatment has been administered. 
A TEAE is an AE that occurs after the first administration of any study drug. The term study 
drug includes any Sage investigational product, a comparator, or a placebo administered in a 
clinical trial. 
An abnormal laboratory value will be considered an AE if the value represents a clinically 
significant change from baseline as determined by the Investigator.  
All AEs that occur after any subject has signed the informed consent form and throughout the 
duration of the study, whether or not they are related to the study, must be reported to Sage 
Therapeutics. 


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12.2.1.2. Serious Adverse Event (SAE) 
A serious adverse event is any untoward medical occurrence that at any dose: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
An SAE may also be any other medically important event that, in the opinion of the Investigator, 
may jeopardize the subject or may require medical intervention to prevent 1 of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization). 
All SAEs that occur after any subject has been enrolled and throughout the duration of the study, 
whether or not they are related to the study, must be recorded on the SAE form provided by Sage 
Therapeutics. 
12.3. 
Relationship to Study Drug 
The Investigator must make the determination of relationship to the study drug for each adverse 
event (not related, possibly related or probably related). The Investigator should decide whether, 
in his or her medical judgment, there is a reasonable possibility that the event may have been 
caused by the investigational product. If no valid reason exists for suggesting a relationship, then 
the adverse event should be classified as “not related.” If there is any valid reason, even if 
undetermined, for suspecting a possible cause-and-effect relationship between the investigational 
product and the occurrence of the adverse event, then the adverse event should be considered at 
least “possibly related.”  
Table 4: 
Relationship to Study Drug 
Relationship 
Definition 
Not Related: 
No relationship between the experience and the administration of study drug; related to 
other etiologies such as concomitant medications or subject’s clinical state. 
Possibly Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug.  
The reaction might have been produced by the subject’s clinical state or other modes of 
therapy administered to the subject, but this is not known for sure. 
Probably Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug.  
The reaction cannot be reasonably explained by the known characteristics of the subject’s 
clinical state or other modes of therapy administered to the subject. 
If the relationship between the adverse event/serious adverse event and the investigational 
product is determined to be “possible” or “probable”, the event will be considered related to the 
investigational product for the purposes of expedited regulatory reporting. 


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12.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. The AE term should be reported in standard medical terminology when 
possible. For each AE, the investigator will evaluate and report the onset (date and time), 
resolution (date and time), intensity, causality, action taken, serious outcome (if applicable), and 
whether or not it caused the subject to discontinue the study drug or withdraw early from the 
study. 
Intensity will be assessed according to the following scale: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities) 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.2.1.2. An AE of severe intensity 
may not be considered serious. 
Should a pregnancy occur, it must be reported and recorded on the Sage Therapeutics pregnancy 
notification form. Pregnancy in itself is not regarded as an AE unless there is a suspicion that an 
investigational product may have interfered with the effectiveness of a contraceptive medication. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented on the Sage Therapeutics 
pregnancy outcome form even if the subject was discontinued from the study. Reports of 
congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs.  
12.5. 
Reporting Serious Adverse Events 
All SAEs must be reported to Sage, or designee, immediately. A written account of the SAE 
must be sent to Sage, or designee, within 24 hours of the first awareness of the event by the 
investigator and/or his staff on the SAE report form. The Investigator must complete, sign and 
date the SAE pages, verify the accuracy of the information recorded on the SAE 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 CRF and/or study 
file. 
Any SAEs discovered by the Investigator after the designated follow up time for the study, 
should be promptly reported to Sage, or designee, according to the timelines noted above.  
Sage, or designee, is responsible for notifying the relevant regulatory authorities of certain 
events. It is the Principal Investigator’s responsibility to notify the ethics committee of all SAEs 
that occur at his or her site. Investigators will also be notified of all suspected, unexpected, 
serious, adverse reactions (SUSARs) that occur during the clinical study. Each site is responsible 


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for notifying its ethics committee of these SUSARs. In addition, appropriate Sponsor Drug 
Safety and Pharmacovigilance personnel, or designee, will unblind SUSARs for the purpose of 
regulatory reporting. The Sponsor, or designee, will submit SUSARs (in blinded or unblinded 
fashion) to regulatory agencies according to local law. The Sponsor, or designee, will submit 
SUSARs to investigators in a blinded fashion. 
12.6. 
Emergency Identification of Study Drug 
During the study, the blind is to be broken only when the safety of a subject is at risk and the 
treatment plan is dependent on the study treatment received. Unless a subject is at immediate 
risk, the Investigator must make diligent attempts to contact Sage prior to unblinding the study 
treatment administered to a subject. Any request from the Investigator about the treatment 
administered to study subjects must be discussed with Sage. If the unblinding occurs without 
Sage’s knowledge, the Investigator must notify Sage as soon as possible and no later than the 
next business morning. All circumstances surrounding a premature unblinding must be clearly 
documented in the source records. Unless a subject is at immediate risk, any request for the 
unblinding of individual subjects must be made in writing to Sage and approved by the 
appropriate Sage personnel, according to standard operating procedures. The blinding of the 
study will be broken after the database has been locked. Electronic copies of the randomization 
code will be made available to the laboratory performing the bioanalytical analyses in order to 
allow for limited analysis of samples from subjects receiving placebo. 
In the event of a medical emergency or pregnancy, the Investigator will discuss with the Medical 
Monitor if unblinding is warranted for medical management of the subject. If there is agreement 
to unblind treatment assignment, the unblinding procedure described in the Safety Management 
Plan for the study will be followed. If the Investigator is unable to contact the Medical Monitor 
in a medical emergency, and it is deemed clinically necessary by the Investigator, the treatment 
group for that subject may be unblinded in the IRT system. 
In all cases where the study drug allocation for a subject is unblinded, pertinent information 
(including the reason for unblinding) must be documented in the subject’s records and on the 
eCRF. If the subject or study center personnel have been unblinded, the subject will be 
permanently discontinued from the study. 


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13. 
STATISTICS 
A separate statistical analysis plan (SAP) for each part (Part A and Part B) will provide a detailed 
description of the analyses to be performed in the respective part of the study. The SAPs will be 
finalized and approved prior to database lock. Any deviations from or changes to the respective 
SAP following database lock will be described in detail in the clinical study report. 
13.1. 
Data Analysis Sets 
The Safety Set, defined as all subjects that received at least 1 dose of study drug, will be used to 
provide descriptive summaries of safety data.  
The Efficacy Set, defined as all subjects in the Safety Set that have at least 1 post-baseline 
HAM-D evaluation, will be used to analyze efficacy data, unless otherwise specified. 
 
  
Part B will also include a Randomized Set, defined as all subjects who are randomized. This 
analysis set will be used for all data listings in Part B. 
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 sets, using all non-missing data available. No imputation process will be used to 
estimate missing data.  
13.3. 
General Considerations 
For the purpose of all primary and secondary analyses where applicable, baseline is defined as 
the last measurement prior to receipt of study drug.  
Continuous endpoints will be summarized with number (n), mean, standard deviation (SD), 
median, minimum, and maximum. In addition, change from baseline values will be calculated at 
each time point and summarized descriptively. For categorical endpoints, descriptive summaries 
will include counts and percentages.  
13.4. 
Demographics and Baseline Characteristics 
Demographic data (see Section 12.1.1) and baseline characteristics, such as height, weight, and 
body mass index, will be summarized using the Safety Set.  
Pregnancy results will be listed but not summarized.  
Medical history will be listed by subject.  
13.5. 
Efficacy Analysis 
The primary efficacy endpoint, the change from baseline in HAM-D total score, will be analyzed 
using a mixed effects model for repeated measures (MMRM); the model will include center, 
treatment, baseline HAM-D total score, stratification factor, assessment time point, and time 
point-by-treatment as explanatory variables. All explanatory variables will be considered as fixed 


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effects and the subject effect will be considered random in the model. All post-baseline time 
points will be included in the model. The primary comparison will be between SAGE-217 and 
matching placebo at Day 25. Model-based point estimates (ie, least squares [LS] means, 95% 
confidence intervals, and p-values) will be reported. An unstructured covariance structure will be 
used to model the within-subject errors. In case of convergence issues, other covariance 
structures will be considered; this will be detailed in the statistical analyses plan. Other 
continuous endpoints will be analyzed using similar methods.  
Other efficacy analyses will be specified in the statistical analysis plan. In general, data will be 
analyzed using appropriate descriptive statistics or pre-specified statistical methods as 
applicable; subject listings will be provided for all efficacy data. Subjects will be analyzed 
according to randomized treatment for the purpose of efficacy unless otherwise specified. 
13.6. 
Safety Analyses 
Safety and tolerability of SAGE-217 will be assessed by the frequency and severity of AEs; 
changes from baseline in clinical laboratory measures, vital signs, and ECGs. Suicidal ideation 
and behavior will be evaluated using the C-SSRS. Mania will be evaluated using the YMRS. 
Safety data will be listed by subject and summarized by treatment group. All safety summaries 
will be performed on the Safety Set.  
13.6.1. 
Adverse Events 
The analysis of AEs will be based on the concept of TEAEs. The incidence of TEAEs will be 
summarized overall and by Medical Dictionary for Regulatory Activities (MedDRA) 
Version 20.1 or higher, system organ class (SOC), and preferred term (PT). 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 13.6.1).  
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 
Clinical laboratory results will be listed by subject and timing of collection. Mean changes from 
baseline in clinical laboratory measures will be evaluated.  
13.6.3. 
Physical Examinations 
Physical examination data will be listed by subject, but not summarized.  
13.6.4. 
Vital Signs 
Vital sign results will be listed by subject and timing of collection. Mean changes from baseline 
in vital signs will be evaluated by time point.  


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13.6.5. 
12-Lead Electrocardiogram 
The following ECG parameters will be listed for each subject: heart rate, PR, QRS, QT, and 
QTcF. Any clinically significant abnormalities or changes in ECGs should be listed as an AE. 
Electrocardiogram findings will be listed by subject and visit.  
13.6.6. 
Prior and Concomitant Medications 
Medications will be recorded at each study visit during the study and will be coded using World 
Health Organization-Drug dictionary (WHO-DD) September 2015, or later.  
Those medications taken prior to the initiation of the start of study drug will be denoted “Prior”. 
Those medications taken prior to the initiation of the study drug and continuing beyond the 
initiation of the study drug or those medications started at the same time or after the initiation of 
the study drug will be denoted “Concomitant” (ie, those with a start date on or after the first dose 
of study drug, or those with a start date before the first dose of study drug that are ongoing or 
with a stop date on or after the first dose of study drug).  
Medications will be presented according to whether they are “Prior” or “Concomitant” as 
defined above. If medication dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant.  
Details of prior and concomitant medications will be listed by subject, start date, and verbatim 
term.  
13.6.7. 
Columbia Suicide Severity Rating Scale 
Suicidality data collected on the C-SSRS at baseline and by visit will be summarized and listed 
for all subjects. Listings will include behavior type and/or category for Suicidal Ideation and 
Suicidal Behavior of the C-SSRS.  
13.6.8. 
Young Mania Rating Scale 
Mania data collected on the YMRS at baseline and by visit will be summarized and listed for all 
subjects.  
 
 
 
 
 
 
13.8. 
Determination of Sample Size 
Part A 
For Part A, the sample size of approximately 30 subjects was selected based on clinical and not 
statistical considerations. 


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Part B 
For Part B, assuming a two-sided alpha level of 0.05, a sample size of 112 total evaluable 
subjects (56 per treatment group) would provide 80% power to detect a placebo-adjusted 
treatment difference of approximately 4 points in the primary endpoint, change from baseline in 
HAM-D total score at Day 25, assuming standard deviation (SD) of 7.5 points.  
Assuming a 15% dropout rate, approximately 132 total randomized subjects will be required to 
obtain a total of 112 evaluable subjects. Evaluable subjects are defined as those randomized 
subjects who receive study drug and have a valid baseline and at least 1 post-baseline HAM-D 
assessment. Additional subjects may be randomized if the drop-out rate is higher than 15%. 


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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and the study site guarantee access to source documents by Sage Therapeutics 
or sponsor’s designee and by the IRB or IEC. 
All aspects of the study and its documentation will be subject to review by Sage Therapeutics or 
sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, study drug, subject medical records, informed consent documentation, and 
review of eCRFs and associated source documents. It is important that the investigator and other 
study personnel are available during the monitoring visits and that sufficient time is devoted to 
the process.  
14.2. 
Audits and Inspections 
Authorized representatives of Sage Therapeutics, a regulatory authority, an Independent Ethics 
Committee or an Institutional Review Board may visit the site to perform audits or inspections, 
including source data verification. The purpose of a Sage Therapeutics audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, Good Clinical Practice guidelines of the 
International Conference on Harmonization, and any applicable regulatory requirements. The 
investigator should contact Sage Therapeutics immediately if contacted by a regulatory agency 
about an inspection. 
14.3. 
Protocol Deviations 
Investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
Sage Therapeutics or sponsor’s designee (and IRB, as required) to determine the appropriate 
course of action. There will be no exemptions (a prospectively approved deviation) from the 
inclusion or exclusion criteria. 
14.4. 
Institutional Review Board (IRB) or Ethics Committee (EC) 
The Principal Investigator must obtain IRB (or EC) approval for the investigation. Initial IRB (or 
EC) approval, and all materials approved by the IRB (or EC) for this study including the subject 
consent form and recruitment materials must be maintained by the Investigator and made 
available for inspection. 


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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
Sage Therapeutics may conduct a quality assurance audit. Please see Section 14.2 for more 
details regarding the audit process. 
 


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


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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Inspection of Records 
Sage Therapeutics will be allowed to conduct site visits to the investigation facilities for the 
purpose of monitoring any aspect of the study. The Investigator agrees to allow the monitor to 
inspect the drug storage area, study drug stocks, drug accountability records, subject charts and 
study source documents, and other records relative to study conduct. 
17.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for the period 
outlined in the site contract, or for a period of 2 years after the last marketing application 
approval, whichever is longer. If not approved, documentation must be maintained for 2 years 
following the discontinuance of the test article for investigation. If it becomes necessary for Sage 
Therapeutics or the Regulatory Authority to review any documentation relating to the study, the 
Investigator must permit access to such records. 


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18. 
PUBLICATION POLICY 
All information concerning SAGE-217 is considered confidential and shall remain the sole 
property of Sage Therapeutics. The Investigator agrees to use this information only in conducting 
the study and shall not use it for any other purposes without written approval from Sage 
Therapeutics. No publication or disclosure of study results will be permitted except as specified 
in a separate, written, agreement between Sage Therapeutics and the Investigator. 


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19.
LIST OF REFERENCES
Begley CE, Annegers JF, Swann AC, Lewis C, Coan S, Schnapp WB, et al. The lifetime cost of 
bipolar disorder in the US: an estimate for new cases in 1998. Pharmacoeconomics. 2001;19(5 Pt 
1):483-95. 
Busner J, Targum S. CGI-S. (2007a), as adapted from Kay, Stanley R, Positive and Negative 
Symptoms in Schizophrenia:Assessment and Research.  Clinical and Experimental Psychiatry, 
Monograph No. 5.  Brunner/Mazel, 1991.  Modified from Guy W. Clinical Global Impressions: 
In ECDEU Assessment Manual for Psychopharmacology. 1976; 218-22. Revised DHEW Pub. 
(ADM) Rockville, MD: National Institute for Mental Health.   
Busner J, Targum S. CGI-I.  (2007b), as adapted from Spearing, et al.  Psychiatry Research, 
1997;73:159-71.  Modified from Guy W. Clinical Global Impressions: In ECDEU Assessment 
Manual for Psychopharmacology. 1976; 218-22. Revised DHEW Pub. (ADM) Rockville, MD: 
National Institute for Mental Health.   
Bowden CL, Anupama AK. Pharmacotherapy for bipolar depression: an economic assessment. 
Expert Opin Pharmacother. 2004 May;5(5):1101-7. 
DSM-5.  Diagnostic and statistical manual of mental disorders (5th ed.).  American Psychiatric 
Association 2013.  Arlington, VA: American Psychiatric Publishing. 
Ferrari AJ, Stockings E, Khoo JP, Erskine HE, Degenhardt L, Vos T, et al. The prevalence and 
burden of bipolar disorder: findings from the Global Burden of Disease Study 2013. Bipolar 
Disord. 2016 Aug;18(5):440-50. 
Gijsman HJ, Geddes JR, Rendell JM, Nolen WA, Goodwin GM. Antidepressants for bipolar 
depression: a systematic review of randomized, controlled trials. Am J Psychiatry 
2004;161:1537-1547. 
Judd LL, Akiskal HS, Maser JD, Zeller PJ, Endicott J, Coryell W, et al. A prospective 12-year 
study of subsyndromal and syndromal depressive symptoms in unipolar major depressive 
disorders. Arch Gen Psychiatry. 1998 Aug;55(8):694-700. 
Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA, et al. The long-term 
natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 
2002 Jun;59(6):530-7. 
Judd LL, Akiskal HS. Depressive episodes and symptoms dominate the longitudinal course of 
bipolar disorder. Curr Psychiatry Rep. 2003 Dec;5(6):417-8. 
Kessler RC, Akiskal HS, Ames M, Birnbaum H, Greenberg P, Hirschfeld RM, et al. Prevalence 
and effects of mood disorders on work performance in a nationally representative sample of U.S. 
workers. Am J Psychiatry. 2006 Sep;163(9):1561-8. 
Merikangas KR, Akiskal HS, Angst J, Greenberg PE, Hirschfeld RM, Petukhova M, et al. 
Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity 
Survey replication. Arch Gen Psychiatry. 2007 May;64(5):543-52. 
Morin CM, Belleville G, Bélanger L, Ivers H. The Insomnia Severity Index: Psychometric 
Indicators to Detect Insomnia Cases and Evaluate Treatment Response. Sleep. 2011;34(5):601-
608.


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Perlis RH, Ostacher MJ, Patel JK, Marangell LB, Zhang H, Wisniewski SR, et al. Predictors of 
recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement 
Program for Bipolar Disorder (STEP-BD). Am J Psychiatry. 2006 Feb;163(2):217-24. 
Posner K, Brown GK, Stanley B, et al. The Columbia–Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-77. 
Post RM, Leverich GS, Altshuler LL, Frye MA, Suppes TM, Keck PE Jr, et al. An overview of 
recent findings of the Stanley Foundation Bipolar Network (Part I). Bipolar Disord. 2003 
Oct;5(5):310-9. 
Rudolph U, Knoflach F. Beyond classical benzodiazepines: novel therapeutic potential of 
GABAA receptor subtypes. Nat Rev Drug Discov. 2011 Jul 29;10(9):685-97. 
Sachs GS, Nierenberg AA, Calabrese JR, Marangell LB, Wisniewski SR, Gyulai L, et al. 
Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 
2007 Apr 26;356(17):1711-22. Epub 2007 Mar 28. 
 
 
Williams JBW and Kobak KA. Development and reliability of a structured interview guide for 
the Montgomery-Asberg Depression Rating Scale (SIGMA). British Journal of Psychiatry. 
2008:192(1):52-58. 
Williams JBW.  SIGH-D 24hr: V1.3 – 24 HR Version. 2013a. 
Williams JBW.  SIGH-D Past week:  Past Week Version. 2013b. 
Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and 
sensitivity. Br J Psychiatry. 1978 Nov;133:429-35. 


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1.
TITLE PAGE
STUDY TITLE: A 2-PART STUDY (OPEN-LABEL 
FOLLOWED BY DOUBLE-BLIND, RANDOMIZED, 
PLACEBO-CONTROLLED, PARALLEL GROUP) OF 
THE SAFETY, TOLERABILITY, 
PHARMACOKINETICS, AND EFFICACY OF SAGE-217
IN THE TREATMENT OF SUBJECTS WITH 
BIPOLAR I/II DISORDER WITH A CURRENT MAJOR 
DEPRESSIVE EPISODE
PROTOCOL NUMBER: 217-BPD-201
Study Drug
SAGE-217 
Clinical Phase
Phase 2
Sponsor
Sage Therapeutics, Inc.
215 First Street
Cambridge, MA 02142 
Sponsor Contact
Tel:
email:
Sponsor Medical Monitor
, MD, MBA
Tel:
email:
Date of Original Protocol
Date of Amendment 1 
Version 1.0, 03 JUL 2018
Version 2.0, 13 SEP 2018
Confidentiality Statement
The confidential information in this document is provided to you as an Investigator or consultant for 
review by you, your staff, and the applicable Institutional Review Board/Independent Ethics Committee. 
Your acceptance of this document constitutes agreement that you will not disclose the information 
contained herein to others without written authorization from Sage Therapeutics, Inc.


Clinical Protocol 
217-BPD-201 v2.0 
Protocol Number: 
Study Drug: 
Study Phase: 
Sponsor: 
Protocol Date: 
Sponsor Approval 
 MD 
 
 MD, MBA 
MSHS 
Sage Therapeutics, Inc. 
217-BPD-201 
SAGE-217 
.Phase 2 
Sage Therapeutics, Inc. 
Version 2.0, 13 Sept 2018 
Date (DD/MMM/YYYY) 
Date (DD/MMM/YYYY) 
Date (DD/MMM/YYYY) 
Date (DD/MMM/YYYY) 
CONFIDENTIAL 
 PhD 
DVM, MS, MPH 
 PhD 
Date (DD/MMM/YYYY) 
Date (DDIMMMIYYYY) 
Date (DDIMMMIYYYY) 
2 


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INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for SAGE-217. I have read the 217-BPD-
201 clinical protocol and agree to conduct the study as outlined. I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
Date (DD Month YYYY) 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Sage Therapeutics 
Name of Investigational Product: 
SAGE-217 Capsule 
Name of Active Ingredient: 
SAGE-217 
Title of Study:  
A 2-Part Study (Open-label followed by Double-blind, Randomized, Placebo-controlled, Parallel 
Group) of the Safety, Tolerability, Pharmacokinetics, and Efficacy of SAGE-217 in the Treatment of 
Subjects with Bipolar I/II Disorder with a Current Major Depressive Episode 
Number of Sites and Study Location:  
Part A: Approximately 10 sites in the United States 
Part B: Approximately 40 sites in the United States 
Phase of Development: 2 
Planned Duration of participation: Up to 73 days (28-day Screening Period; 14-day Treatment 
Period, and 28-day [±3 days] Follow-up Period) 
Objectives: 
Part A Primary: 
• 
To evaluate the safety and tolerability of SAGE-217 in subjects with bipolar I or II disorder 
with a current major depressive episode (MDE). 
Part A Secondary:  
• 
To assess the efficacy of SAGE-217 in reducing depressive symptoms in subjects with bipolar 
I/II disorder with a current MDE. 
• 
To assess the effect of SAGE-217 on sleep.  
Part B Primary: 
• 
To assess the efficacy of SAGE-217 in reducing depressive symptoms in subjects with bipolar 
I/II disorder with a current MDE. 
Part B Secondary:  
• 
To evaluate the safety and tolerability of SAGE-217 in subjects with bipolar I/II disorder with 
a current MDE. 
• 
To assess the effect of SAGE-217 on sleep. 
 
 
 
 
 
 
 
 
 
 


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Endpoints:  
Part A Primary: 
• 
The safety and tolerability of SAGE-217 as assessed by the frequency and severity of adverse 
events; changes from baseline in clinical laboratory measures, vital signs, and 
electrocardiogram (ECGs); and suicidal ideation and behavior using the Columbia Suicide 
Severity Rating Scale (C-SSRS); and mania using the Young Mania Rating Scale (YMRS). 
Part A Secondary: 
• 
The reduction in depressive symptoms, as assessed by: 
o Change from baseline in the 17-item Hamilton Depression Rating Scale (HAM-D) 
total score at Day 15 and all other time points  
o HAM-D response at Day 15 and all other time points  
o HAM-D remission at Day 15 and all other time points  
o Change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) 
total score at Day 15 and all other time points  
o Change from baseline in HAM-D individual item scores at Day 15 and all other time 
points  
o The response to the Clinical Global Impression scale for severity and improvement 
(CGI-S and CGI-I, respectively) at Day 15 and all other time points. 
• 
The reduction in insomnia severity, as assessed by Insomnia Severity Index (ISI). 
Part B Primary: 
• 
The primary endpoint in Part B is the reduction in depressive symptoms with SAGE-217 
treatment, as assessed by the change from baseline in the HAM-D total score at Day 15. 
Part B Secondary: 
• 
The reduction in depressive symptoms, as assessed by: 
o Change from baseline in HAM-D total score at all other time points 
o HAM-D response at Day 15 and all other time points  
o HAM-D remission at Day 15 and all other time points  
o Change from baseline in the MADRS total score at Day 15 and all other time points  
o Change from baseline in HAM-D individual item scores at Day 15 and all other time 
points  
o CGI-S and CGI-I response at Day 15 and all other time points. 
• 
The safety and tolerability of SAGE-217 as assessed by the frequency and severity of adverse 
events; changes from baseline in clinical laboratory measures, vital signs, and ECGs; and 
suicidal ideation and behavior using the C-SSRS; and mania using the YMRS. 
• 
The reduction in insomnia severity, as assessed by ISI. 
 
 
 
 
 
 
 


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Study Description:   
This study will be conducted in 2 sequential parts: Part A (open-label) and Part B (randomized, double-
blind, placebo-controlled, parallel group). Part B will be initiated pending the review of Part A data. 
The methods of the 2 parts will be identical unless otherwise noted. Subjects who participate in Part A 
will not be allowed to participate in Part B. The study is designed to assess the safety, tolerability, 
 
and efficacy of SAGE-217 in adult subjects with bipolar I/II disorder, who are currently experiencing 
an MDE.  
The assessments are summarized in the Schedule of Events (Table 1). 
Screening begins with the signing of the informed consent form at the Screening Visit. The diagnosis 
of bipolar I or II disorder will be made using the Structured Clinical Interview for Diagnostic and 
Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) for clinical trials (SCID-5-CT) 
performed by a qualified healthcare professional.  
Beginning on Day 1, qualified subjects will self-administer the study drug once daily in the evening 
with food for 14 days. In Part A, all subjects will receive SAGE-217. For Part B, subjects will be 
randomized in a 1:1 ratio to receive SAGE-217 or placebo; randomization will be stratified based on 
use of mood stabilizers (Y/N). Subjects on antidepressants or mood stabilizers (lamotrigine, lithium, 
and valproic acid only) that have been taken at the same dose for at least 60 days prior to Day 1 are to 
continue the stable dose throughout the treatment period.  
If at any time, 30 mg is not tolerated, as assessed by the occurrence of a severe AE judged by the 
investigator to be related to study drug, the dose on the next day will be reduced to 20 mg and 
continued for the remainder of the treatment period. Dose adjustments related to moderate AEs will be 
judged by the Investigator. If a dose adjustment from 30 mg to 20 mg is deemed necessary by the 
Investigator, the subject will return to the site for the adjusted dose to be dispensed. Subjects who 
cannot tolerate the 20-mg dose at any time will be discontinued from study drug.  
If at any time during the study, a subject has a YMRS score of ≥13, the Investigator will clinically 
assess the subject for a manic or hypomanic switch. If the clinical assessment is consistent with 
hypomania or mania, the subject will be discontinued from study drug and treated as clinically 
appropriate. These incidents will be documented as AEs. 
Subjects will return to the study center during the treatment and follow-up periods as outlined in 
Table 1. 
Number of Subjects (planned):   
Part A: Approximately 30 subjects will be dosed. 
Part B: Approximately 132 subjects will be randomized and dosed to obtain a total of 112 evaluable 
subjects. 


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Eligibility criteria:  
Inclusion Criteria: 
1. Subject has signed an informed consent form (ICF) prior to the conduct of any study-specific 
procedures. 
2. Subject agrees to adhere to the study requirements, including use of prior, concomitant, and 
prohibited medications. 
3. Subject is an ambulatory man or woman, aged 18 to 65 years, inclusive, at Screening. 
4. 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. 
5. Subject has a documented history of hypomanic or manic episode (verified by medical records 
and/or treating healthcare professional) and a diagnosis of bipolar I or bipolar II disorder with 
a current MDE as per DSM-5 SCID-5-CT. 
6. Subject has a HAM-D score of ≥22 at Screening.  
7. Female subject agrees to use one of the following methods of contraception during 
participation in the study and for 30 days following the last dose of study drug, unless they are 
postmenopausal (defined as no menses for 12 months without an alternative medical cause and 
confirmed by follicle stimulating hormone [FSH] level ≥40 mIU/mL) and/or surgically sterile 
(hysterectomy or bilateral oophorectomy): 
• 
Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation. 
• 
Oral, injectable, or implantable progestogen-only hormonal contraception associated with 
inhibition of ovulation.  
• 
Intrauterine device. 
• 
Intrauterine hormone-releasing system. 
• 
Bilateral tubal ligation/occlusion. 
• 
Vasectomized partner. 
• 
Sexual abstinence (no sexual intercourse).  
8. Male subject agrees to use an acceptable method of effective contraception for the duration of 
study and for 5 days after receiving the last dose of the study drug. Acceptable methods of 
effective contraception for males includes sexual abstinence, vasectomy, or a condom with 
spermicide used together with highly effective female contraception methods (if the female 
partner is of child-bearing potential, see Inclusion Criteria #7 for acceptable method of 
contraception for females). 
9. 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. 
Exclusion Criteria: 
1. Subject has a history of suicide attempt within the last 2 years. 
2. Subject has current suicidal ideation with plans based on Investigator clinical assessment 
and/or the C-SSRS response at Screening or Day 1. 
3. Subject has a history of rapid cycling bipolar disorder as per DSM-5 SCID-5-CT. 


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4. Subject’s current depressive episode meets the DSM-5 specifier criteria for mixed features. 
5. Subject has ≥25% reduction in HAM-D score from Screening to Day 1. 
6. 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. 
7. Subject has abnormal liver function as shown by an abnormal liver function profile at 
screening (eg, repeated values of aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), or total bilirubin ≥2x the upper limit of normal). 
8. Subject has a clinically significant abnormal 12-lead ECG at the Screening or Day 1 visits. 
NOTE: mean QT interval calculated using the Fridericia method (QTcF) of >450 msec in male 
or >470 msec in female subjects will be the basis for exclusion from the study.  
9. Subject has a YMRS score ≥13 at Screening or Day 1. 
10. Subject presents for the study receiving a mood stabilizer other than lamotrigine, lithium, or 
valproic acid. 
11. Subject presents for the study receiving psychotropic medications, which have not been taken 
at the same dose for at least 60 days prior to Day 1. 
12. Subject that presents for the study receiving psychotropic medications and does not intend to 
continue the current treatment regimen during the treatment period.  
13. Subject is taking typical or atypical antipsychotics, monoamine oxidase inhibitors (MAOIs), 
benzodiazepines or GABA A modulators other than the allowed mood stabilizers at the 
Screening Visit.  
14. Subject has a history of severe rashes or Stevens-Johnson Syndrome associated with 
lamotrigine and is currently taking lamotrigine. 
15. Subject’s current depressive episode is treatment resistant; defined as persistent depressive 
symptoms despite treatment with adequate doses of antidepressants from two different classes 
for an adequate amount of time (ie, at least 4 weeks of treatment). This will be assessed using 
the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire. 
16. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds. 
17. Subject has a positive pregnancy test at the Screening Visit or on Day 1 (prior to 
administration of study drug) or, if she is breastfeeding at Screening or on Day 1 (prior to 
administration of study drug), she does not agree to temporarily cease giving breast milk to her 
child(ren) from just prior to receiving study drug on Day 1 until 7 days after the last dose of 
study drug. 
18. Subject has detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) and 
HCV viral load, or human immunodeficiency virus (HIV) antibody at screening. 
19. Subject has active psychosis per Investigator assessment. 


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20. Subject has a medical history of seizures. 
21. Subject has a medical history schizophrenia, and/or schizoaffective disorder. 
22. Subject has a history of mild, moderate, or severe substance use disorder diagnosed using 
DSM-5 criteria in the 12 months prior to screening. 
23. Subject has a positive drug and/or alcohol screen at screening or on Day 1 prior to dosing. 
24. Subject has had exposure to another investigational medication or device within 30 days prior 
to the Screening visit. 
25. Subject has been previously treated or randomized in any study using SAGE-217. Subjects 
who participate in Part A are not eligible to participate in Part B. 
26. Subject has used any known strong inhibitors of cytochrome P450 (CYP)3A4 within 28 days 
or five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, or Seville 
oranges, or products containing these within 14 days prior to receiving the first dose of study 
drug. 
27. Subject has used CYP inducers, such as rifampin, carbamazepine, ritonavir, enzalutamide, 
efavirenz, nevirapine, phenytoin, phenobarbital and St John’s Wort, within 28 days prior to the 
first dose of study drug. 
28. Subject plans to undergo elective surgery during participation in the study. 
SAGE-217 dosage and mode of administration:  
SAGE-217 is available as hard gelatin capsules containing a white to off-white powder. In addition to 
SAGE-217 Drug Substance, the SAGE-217 capsules contain croscarmellose sodium, mannitol, 
silicified microcrystalline cellulose (SMCC), colloidal silicon dioxide, and sodium stearyl fumarate as 
excipients. Colloidal silicon dioxide may be either a component of the SMCC or a standalone excipient 
in the formulation. Subjects will take the assigned dose orally once daily in the evening (approximately 
8:00 to 11:00 pm) with food. 
Reference therapy, dosage and mode of administration (Part B only):  
In Part B, placebo capsules are visually matched to the active capsules and are available as hard gelatin 
capsules containing only the excipients listed above for the active capsule treatment. Study drug will 
be administered orally once daily in the evening (approximately 8:00 to 11:00 pm) with food. 
Duration of Treatment: 14 days 
Statistical methods:   
A separate statistical analysis plan (SAP) for each part (Parts A and B) will provide a detailed 
description of the analyses to be performed in the respective part of the study. The SAPs will be 
finalized and approved prior to database lock. Any deviations from or changes to the SAP following 
database lock will be described in detail in the clinical study report. 
General: 
The data from Parts A and B will be analyzed separately. For the purpose of all safety and efficacy 
analyses where applicable, baseline is defined as the last available measurement prior to the start of 
study drug administration.  
Continuous endpoints will be summarized with n, mean, standard deviation, median, minimum, and 
maximum. In addition, change from baseline values will be calculated at each time point and 


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summarized descriptively. For categorical endpoints, descriptive summaries will include counts and 
percentages. 
Analysis Sets:  
Randomized set (Part B only) will be defined as all subjects who are randomized. This analysis set will 
be used of all data listings in Part B. Data listings for Part A will be based on Safety or Efficacy Set, as 
appropriate. 
The Safety Set, defined as all subjects received at least 1 dose of study drug, will be used to provide 
descriptive summaries of safety data.  
The Efficacy Set, defined as all subjects who are in Safety Set and have at least one post-baseline 
HAM-D evaluation, will be used to analyze efficacy data unless otherwise specified. 
 
Safety Analysis:  
The overall incidence of adverse events will be summarized by Medical Dictionary for Regulatory 
Activities (MedDRA) system organ class and preferred term. Data for vital signs, clinical laboratory 
measurements, ECG, and concomitant medication usage will also be summarized.  
Safety data will be summarized and examined for possible relationships between subject characteristics 
and plasma SAGE-217 concentrations, as appropriate. Suicidality data collected using the C-SSRS and 
evaluation of mania collected using the YMRS at baseline and at each visit during the active Treatment 
Period will be listed for all subjects. Out-of-range safety endpoints may be categorized as low or high, 
where applicable. Subjects will be summarized according to treatment received for the purpose of 
safety.  
Efficacy Analysis:  
The primary endpoint in Part B, the change from baseline in HAM-D total score, will be analyzed 
using a mixed effects model for repeated measures (MMRM); the model will include treatment, 
baseline HAM-D total score, stratification factor, assessment time point, and time point-by-treatment 
as explanatory variables. All explanatory variables will be considered as fixed effects and the subject 
effect will be considered random in the model. All post-baseline time points will be included in the 
model. The primary comparison will be between SAGE-217 and matching placebo at Day 15. Model-
based point estimates (ie, least squares [LS] means, 95% confidence intervals, and p-values) will be 
reported. An unstructured covariance structure will be used to model the within-subject errors. Other 
continuous endpoints will be analyzed using similar methods.  
Other efficacy analyses, including those in Part A, will be specified in the SAP. In general, data will be 
analyzed using appropriate descriptive statistics or pre-specified statistical methods as applicable; 
subject listings will be provided for all efficacy data. Subjects will be analyzed according to 
randomized treatment for the purpose of efficacy unless otherwise specified. 
 
 
 
 
 
Sample Size Calculation 
Part A: The sample size of approximately 30 subjects was selected based on clinical and not statistical 
considerations. 
Part B: Assuming a two-sided alpha level of 0.05, a sample size of 112 total evaluable subjects (56 per 
treatment group) would provide 80% power to detect a placebo-adjusted treatment difference of 


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approximately 4 points in the primary endpoint, change from baseline in HAM-D total score at Day 15, 
assuming standard deviation (SD) of 7.5 points.  
Assuming a 15% dropout rate, approximately 132 total randomized subjects will be required to obtain 
a total of 112 evaluable subjects. Evaluable subjects are defined as those randomized subjects who 
receive study drug and have a valid baseline and at least 1 post-baseline HAM-D assessment. 
Additional subjects may be randomized if the drop-out rate is higher than 15%.  
 


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Table 1: 
Schedule of Events 
Study Period 
Screening 
Period 
Treatment Period 
Follow-up Perioda 
Visit Day 
D-28 to  
D-1 
D1 
D3 
(+1d) 
D8 
(±1d) 
D12 
(±1d) 
D15 
(±1d)/EOTa 
D21 
(±3d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)/ 
ET 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical/Family History 
X 
 
 
 
 
 
 
 
 
 
SCID-5-CT 
X 
 
 
 
 
 
 
 
 
 
MGH-ATRQ 
X 
 
 
 
 
 
 
 
 
 
Serum FSH test 
X 
 
 
 
 
 
 
 
 
 
Randomization (Part B 
only) 
 
X 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
 
X 
 
 
 
X 
Body Weight/Heightc 
X 
 
 
 
 
X (wt only) 
 
 
 
X (wt 
only) 
Clinical Laboratory 
Assessmentsd 
X 
X 
 
X 
 
X 
X 
X 
 
X 
Drug & Alcohol Screene 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Testf 
X 
X 
 
 
 
X 
 
X 
 
X 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
Vital Signsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGj 
X 
X 
X 
 
 
X 
 
 
 
X 
C-SSRSk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAM-Dl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MADRSl 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-S 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
YMRSl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Table 1: 
Schedule of Events (Continued) 
Study Period 
Screening 
Period 
Treatment Period 
Follow-up Perioda 
Visit Day 
D-28 to  
D-1 
D1 
D3 
(+1d) 
D8 
(±1d) 
D12 
(±1d) 
D15 
(±1d)/EOTTa 
D21 
(±3d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)/ 
ET 
ISI 
 
X 
 
X 
 
X 
X 
X 
 
X 
Study Drug 
Dispensationo 
 
X 
 
X 
 
 
 
 
 
 
Study Drug 
Administration 
 
X (Day 1-14) 
 
 
 
 
 
Study Drug 
Accountability/Return 
 
 
X 
X 
X 
X 
 
 
 
 
Adverse Events/Serious 
Adverse Eventsp 
X 
Prior/Concomitant 
Medications/ 
Proceduresq 
X 
CGI-I = Clinical Global Impression - Improvement; CGI-S – Clinical Global Impression - Severity; C-SSRS = Columbia 
Suicide Severity Rating Scale; D = day; EOT = end of treatment; ECG = electrocardiogram; ET = early termination; 
 
 FSH = follicle stimulating hormone; HAM-D = Hamilton Rating Scale for Depression, 
17-item; HIV = human immunodeficiency virus; ISI = Insomnia Severity Index; MADRS = Montgomery-Åsberg Depression 
Rating Scale; MGH-ATRQ = Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; O = 
optional; 
; SCID-5-CT = Structured Clinical Interview for Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition for clinical trials; 
 
 
YMRS = Young Mania Rating Scale 
a Subjects who discontinue treatment early should return to the site for an EOT visit as soon as possible, preferably 
the day after treatment is discontinued. Follow-up visits should take place every 7 days after the last dose of 
treatment for a total of 4 follow-up visits. If at any time after the EOT visit, a subject decides to terminate the 
study, the subject should return for an ET visit. The EOT and ET visits can be on the same day if a subject 
discontinues study drug and terminates the study on the same day during a clinic visit; in this case, all events 
scheduled for both visits will be conducted.  
b A serum follicle stimulating hormone test will be conducted for female subjects at Screening to confirm whether a 
female subject with ≥12 months of spontaneous amenorrhea meets the protocol-defined criteria for being post-
menopausal. 
c Height measured at screening only 
d Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. Laboratory 
assessments are to be completed in the morning. 
e Urine toxicology for selected drugs of abuse, and breath test for alcohol (as per the standard procedures at each 
site).  
f For women of child-bearing potential, serum pregnancy test at screening and urine pregnancy test at all other 
scheduled timepoints. 
 
 
 
 
i Vital signs include oral temperature (°C), respiratory rate, heart rate, pulse oximetry, 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 in the standing position. Vital signs may be repeated at the 


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discretion of the Investigator as clinically indicated. When vital signs are scheduled at the same time as blood 
draws, vital signs will be obtained first.  
j Triplicate 12-lead ECGs will be performed with the subject in the supine position. When ECG 
 sample 
collection occur during the same visit, ECGs will be collected first. 
k 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. 
l For MADRS, HAM-D, and YMRS, the “Since Last Evaluation” forms will be completed at all subsequent time 
points following the initial assessment. 
 
 
 
 
o Additional unscheduled dispensation visits may be needed for dose reductions. 
p AEs/SAEs will be collected starting at the time of informed consent and throughout the duration of the subject’s 
participation in the study.  
q Prior medications will be collected at Screening and concomitant medications will be collected at each subsequent 
visit. All medications taken within 30 days prior to Screening through the duration of the study will be recorded. In 
addition, all psychotropic medications taken within 6 months prior to Screening will be recorded. 
 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............15 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................20 
5. 
INTRODUCTION ......................................................................................................22 
5.1. 
Background of Bipolar Disorders and Unmet Medical Need .....................................22 
5.2. 
SAGE-217 ...................................................................................................................23 
5.3. 
Potential Risks and Benefits .......................................................................................24 
5.4. 
Dose Justification ........................................................................................................24 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................25 
6.1. 
Study Objective ..........................................................................................................25 
6.1.1. 
Primary Objective .......................................................................................................25 
6.1.2. 
Secondary Objectives .................................................................................................25 
 
25 
6.2. 
Endpoints ....................................................................................................................26 
6.2.1. 
Primary Endpoint ........................................................................................................26 
6.2.2. 
Secondary Endpoints ..................................................................................................26 
 
27 
7. 
INVESTIGATIONAL PLAN .....................................................................................28 
7.1. 
Overall Study Design ..................................................................................................28 
7.2. 
Number of Subjects ....................................................................................................29 
7.3. 
Treatment Assignment ................................................................................................29 
7.4. 
Dose Adjustment Criteria ...........................................................................................29 
7.5. 
Study Termination ......................................................................................................30 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................31 
8.1. 
Subject Inclusion Criteria ...........................................................................................31 
8.2. 
Subject Exclusion Criteria ..........................................................................................32 
8.3. 
Subject Withdrawal Criteria .......................................................................................33 
8.3.1. 
Withdrawal from the Study or Discontinuation of Study Drug ..................................33 
8.3.2. 
Replacement of Subjects .............................................................................................34 
9. 
TREATMENT OF SUBJECTS ..................................................................................35 


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9.1. 
Study Drug ..................................................................................................................35 
9.2. 
Prior Medications, Concomitant Medications, and Restrictions ................................35 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................35 
9.2.2. 
Prohibited Medications ...............................................................................................35 
9.2.3. 
Other Restrictions .......................................................................................................35 
9.3. 
Treatment Adherence ..................................................................................................36 
9.4. 
Randomization and Blinding ......................................................................................36 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................37 
10.1. 
Description of Study Drug ..........................................................................................37 
10.2. 
Study Drug Packaging and Labeling ..........................................................................37 
10.3. 
Study Drug Storage .....................................................................................................37 
10.4. 
Study Drug Preparation ..............................................................................................37 
10.5. 
Study Drug Administration.........................................................................................37 
10.6. 
Study Drug Accountability .........................................................................................37 
10.7. 
Study Drug Handling and Disposal ............................................................................38 
11. 
ASSESSMENT OF EFFICACY 
 .............................39 
11.1. 
Efficacy Assessments .................................................................................................39 
11.1.1. 
Hamilton Rating Scale for Depression (HAM-D) ......................................................39 
11.1.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) ........................................39 
11.1.3. 
Clinical Global Impression (CGI) ..............................................................................39 
11.1.4. 
Insomnia Severity Index (ISI) ....................................................................................40 
 
40 
 
40 
 
41 
 
41 
 
41 
 
41 
 
41 
12. 
ASSESSMENT OF SAFETY .....................................................................................42 
12.1. 
Safety Parameters .......................................................................................................42 
12.1.1. 
Demographic/Medical History ...................................................................................42 
12.1.2. 
Weight and Height ......................................................................................................42 
12.1.3. 
Physical Examination .................................................................................................42 


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12.1.4. 
Vital Signs ..................................................................................................................42 
12.1.5. 
Electrocardiogram (ECG) ...........................................................................................42 
12.1.6. 
Laboratory Assessments .............................................................................................43 
12.1.6.1. 
Drugs of Abuse and Alcohol ......................................................................................44 
12.1.6.2. 
Pregnancy Screen ........................................................................................................44 
12.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................44 
12.1.8. 
Young Mania Rating Scale (YMRS) ..........................................................................45 
12.2. 
Adverse and Serious Adverse Events .........................................................................45 
12.2.1. 
Definition of Adverse Events .....................................................................................45 
12.2.1.1. 
Adverse Event (AE) ....................................................................................................45 
12.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................45 
12.3. 
Relationship to Study Drug ........................................................................................46 
12.4. 
Recording Adverse Events .........................................................................................46 
12.5. 
Reporting Serious Adverse Events .............................................................................47 
12.6. 
Emergency Identification of Study Drug ....................................................................48 
13. 
STATISTICS ..............................................................................................................49 
13.1. 
Data Analysis Sets ......................................................................................................49 
13.2. 
Handling of Missing Data ...........................................................................................49 
13.3. 
General Considerations ...............................................................................................49 
13.4. 
Demographics and Baseline Characteristics ...............................................................49 
13.5. 
Efficacy Analysis ........................................................................................................49 
13.6. 
Safety Analyses ..........................................................................................................50 
13.6.1. 
Adverse Events ...........................................................................................................50 
13.6.2. 
Clinical Laboratory Evaluations .................................................................................50 
13.6.3. 
Physical Examinations ................................................................................................50 
13.6.4. 
Vital Signs ..................................................................................................................50 
13.6.5. 
12-Lead Electrocardiogram ........................................................................................51 
13.6.6. 
Prior and Concomitant Medications ...........................................................................51 
13.6.7. 
Columbia Suicide Severity Rating Scale ....................................................................51 
13.6.8. 
Young Mania Rating Scale .........................................................................................51 
 
51 
13.8. 
Determination of Sample Size ....................................................................................51 
13.8.1. 
Part A ..........................................................................................................................51 


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13.8.2. 
Part B ..........................................................................................................................52 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................53 
14.1. 
Study Monitoring ........................................................................................................53 
14.2. 
Audits and Inspections ................................................................................................53 
14.3. 
Protocol Deviations ....................................................................................................53 
14.4. 
Institutional Review Board (IRB) or Ethics Committee (EC) ....................................53 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................54 
16. 
ETHICS ......................................................................................................................55 
16.1. 
Ethics Review .............................................................................................................55 
16.2. 
Ethical Conduct of the Study ......................................................................................55 
16.3. 
Written Informed Consent ..........................................................................................55 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................56 
17.1. 
Inspection of Records .................................................................................................56 
17.2. 
Retention of Records ..................................................................................................56 
18. 
PUBLICATION POLICY ..........................................................................................57 
19. 
LIST OF REFERENCES ............................................................................................58 
 


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LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................12 
Table 2: 
Abbreviations and specialist terms .............................................................................20 
Table 3: 
Clinical Laboratory Tests ...........................................................................................43 
Table 4: 
Relationship to Study Drug ........................................................................................46 
 
LIST OF FIGURES 
Figure 1: 
Study Design (Part A) .................................................................................................28 
Figure 2: 
Study Design (Part B) .................................................................................................29 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and specialist terms  
Abbreviation or specialist term 
Explanation 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CGI-I 
Clinical Global Impression scale for improvement 
CGI-S 
Clinical Global Impression scale for severity 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CYP 
cytochrome P450 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition 
EC 
ethics committee 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EOT 
end of treatment 
ET 
early termination 
 
 
FSH 
follicle-stimulating hormone 
GABA 
γ-aminobutyric acid 
HAM-D 
Hamilton Depression Rating Scale 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ID 
identification 
IRT 
interactive response technology 
ISI 
Insomnia Severity Index 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MDD 
major depressive disorder 
MDE 
major depressive episode 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGH-ATRQ 
Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire 


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Table 2: 
Abbreviations and specialist terms  (Continued) 
Abbreviation or specialist term 
Explanation 
MMRM 
mixed effects model for repeated measures 
PI 
Principal Investigator; the investigator who leads the study 
conduct at an individual study center. Every study center has a 
principal investigator. 
 
 
QTcF 
QT corrected according to Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCID-5-CT 
Structured Clinical Interview for Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition for clinical trials 
SD 
standard deviation 
 
 
 
 
TEAE 
treatment-emergent adverse event 
YMRS 
Young Mania Rating Scale 
 


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5. 
INTRODUCTION 
5.1. 
Background of Bipolar Disorders and Unmet Medical Need 
Bipolar disorder is a chronic and episodic illness that is associated with significant disability 
worldwide (Sachs 2007). The Global Burden of Disease Study revealed that in 2013, there were 
48.8 million cases of bipolar disorder globally (Ferrari 2016). Bipolar disorder accounted for 
9.9 million disability-adjusted life years (DALYs) globally, explaining 0.4% of total DALYs and 
1.3% of total years lived with disability.  
There are subtypes of bipolar disorder; this study includes the bipolar I and II subtypes. Bipolar I 
is characterized by a manic episode, whereas bipolar II is characterized by a hypomanic episode. 
The difference in the severity of the manic features relies on functional impairment that is caused 
by these episodes (DSM-5). The National Comorbidity Survey estimate of the lifetime 
prevalence of bipolar disorder is 2.1% in the US population when bipolar I disorder and 
bipolar II Disorder are combined (Merikangas 2007). 
While the manic or hypomanic episodes represent distinct departure from the baseline mood 
state and easily attract attention, evidence suggests that depressive episodes of both bipolar I and 
II are associated with more disability than any other aspect of the illness. A seminal long-term 
study of patients with bipolar I disorder demonstrated that over the 13-year follow-up period, 
patients were symptomatic about 47% of the time, and depressive symptoms were present in 
32% of the follow-up weeks vs manic features, which were present in 9% (Judd 2002). A similar 
analysis in patients with bipolar II disorder with a longer follow up of up to 20 years found that 
patients were symptomatic more than half of the time (54%) where depressive symptoms 
dominated the course at 50% of the follow-up weeks versus 1.3% for the hypomanic symptoms 
(Judd 2003). A study in patients with unipolar depression found a prevalence of depressive 
symptoms 47% of the time (Judd 1998), suggesting a comparable time spent with depressive 
symptoms in the bipolar spectrum. These naturalistic studies have also found that about half the 
time patients reported taking psychotropic medications. In another large-scale study with a 
follow-up period of up to 2 years, 58% of nearly 1500 patients with bipolar disorder who were 
symptomatic at study entry achieved recovery (Perlis 2006). Similarly, during the follow-up 
period, 49% of these individuals experienced recurrent episodes, where depressive episodes 
(38%) outweighed manic, hypomanic, or mixed episodes combined (13.8%). In the Stanley 
Foundation Bipolar Network Study, in which year-long, daily clinician ratings were included, 
despite treatment with an average of 4.1 psychotropic medications, patients with bipolar disorder 
spent 3 times as much time with depressive symptoms as manic symptoms (Post 2003). 
There are only 3 medications approved in the US for the treatment of bipolar depression, 
(lurasidone, olanzapine-fluoxetine combination, and quetiapine), all of which include atypical 
antipsychotics that are associated with significant adverse metabolic effects. None of the 
currently available antidepressants are indicated for bipolar depression due to their limited 
efficacy, and the possibility that their use may be associated with a manic switch and rapid 
cycling. While some studies reported varying levels of efficacy with antidepressants 
(Gijsman 2004), a large-scale, double-blind, placebo-controlled clinical trial sponsored by the 
National Institutes of Mental Health, The Systematic Treatment Enhancement Program for 
Bipolar Disorder (STEP-BD), found that only 23.5% of patients with bipolar depression 
receiving a mood stabilizer and adjunctive antidepressants versus 27.3% of those receiving a 


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mood stabilizer and placebo experienced a durable recovery, confirming the lack of effectiveness 
of antidepressants in bipolar depression (Sachs 2007). The tolerability profile of the approved 
atypical antipsychotics and limited efficacy of available antidepressants highlight the critical 
unmet need in the treatment of bipolar depression. 
In 1998, the lifetime cost of bipolar disorder in the US was estimated at $24 billion. The cost of a 
single manic episode was estimated at $11,720 to $624,785 for persons with 
nonresponsive/chronic episodes (Begley 1998); the cost of bipolar depression specifically, is less 
well studied, however, available estimates indicate a higher cost associated with bipolar 
depression than for mania (Bowden 2004). 
Kessler has studied the impact of mood disorders on work performance in a representative 
sample of over 3,000 US workers (Kessler 2006). Bipolar disorder and major depressive disorder 
were associated with 65.5 and 27.2 lost workdays per worker per year, respectively. Moreover, it 
was found that the increase in bipolar disorder was attributable to depressive symptoms rather 
than manic episodes in bipolar disorder. 
Taken together, these findings point to substantial predominance of depressive symptoms across 
the spectrum of bipolar disorder. In particular, they also highlight the importance of successful 
depressive symptom control, and an unmet need in the treatment of depressive episodes for both 
bipolar I and bipolar II disorder. 
5.2. 
SAGE-217 
SAGE-217 is a positive allosteric modulator of γ-aminobutyric acid (GABA)A 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. 
Data from an open-label portion of the Phase 2a study of SAGE-217 administered to subjects 
with moderate to severe major depressive disorder (MDD) showed clinically significant 
improvements from baseline in depression scale scores (HAM-D, Montgomery-Åsberg 
Depression Rating Scale [MADRS], and Clinical Global Impression – Improvement [CGI-I]) as 
early as Day 2 of the 14-day treatment period, with durable responses following the end of 
treatment. This result was further supported by the randomized, double-blind portion of this 
study (N=89) in which a rapid and substantial decrease in HAM-D scores was observed at 
Day 15 (primary endpoint), starting at Day 2. This response pattern was also observed with other 
efficacy scales, including MADRS and CGI-I. Statistically significant differences from the 
placebo group favoring the SAGE-217 arm were observed for 2 weeks in the follow-up period. 
SAGE-217 has been generally well tolerated in clinical studies to date. The most common 
treatment-emergent adverse events (TEAEs) were sedation, somnolence, and dizziness. Most 
AEs were reported as mild or moderate in intensity. Among the over 260 subjects exposed to 
SAGE-217 in clinical trials, there have been no deaths and only one subject with essential tremor 


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experienced a serious adverse event (SAE) of transient confusion leading to discontinuation of 
study drug. No other SAEs have been reported in any study of SAGE-217.  
Additional information on nonclinical and clinical data is provided in the Investigator’s 
Brochure.  
5.3. 
Potential Risks and Benefits 
Non-serious events of sedation, somnolence, and dizziness were the most commonly reported 
AEs with SAGE-217. Given the outcome of the Phase 2 study of SAGE-217 in subjects with 
MDD and the current significant unmet need in the treatment of depressive episodes associated 
with bipolar I/II disorders, a favorable risk-benefit balance and investigation of SAGE-217 in 
patients with bipolar I/II disorders are justified. 
5.4. 
Dose Justification 
The dose of SAGE-217 to be administered in this study (30 mg) was determined based on the 
maximum tolerated dose in the multiple ascending dose study of SAGE-217 in healthy subjects, 
and is the same dose level that has been used and generally well tolerated in clinical studies in 
various patient populations, including patients with MDD. Due to the observed improved 
tolerability of sedation/somnolence effects when taken in the evening in previous clinical studies, 
SAGE-217 will be administered in the evening in this study as well.  
With respect to the duration of treatment course, a 14-day study drug administration is planned. 
This is based on previous clinical trial data with SAGE-217, demonstrating substantial 
improvement in depressive symptoms in patients with MDD, starting within the first week of 
treatment. 


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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Study Objective 
6.1.1. 
Primary Objective 
Part A 
The primary objective of Part A of this study is to evaluate the safety and tolerability of 
SAGE-217 in subjects with bipolar I/II disorder with a current major depressive episode (MDE). 
Part B 
The primary objective of Part B of this study is to assess the efficacy of SAGE-217 in reducing 
depressive symptoms in subjects with bipolar I/II disorder with a current MDE. 
6.1.2. 
Secondary Objectives 
Part A 
Secondary objectives of Part A of this study are: 
• To assess the efficacy of SAGE-217 in reducing depressive symptoms in subjects 
with bipolar I/II disorder with a current MDE. 
• To assess the effect of SAGE-217 on sleep. 
Part B 
Secondary objectives of Part B of this study are: 
• To evaluate the safety and tolerability of SAGE-217 in subjects with bipolar I/II 
disorder with a current MDE. 
• To assess the effect of SAGE-217 on sleep. 
 
 
 
 
 
 
 
 
 
 
 
 


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6.2. 
Endpoints 
6.2.1. 
Primary Endpoint 
Part A 
The primary endpoint for Part A of this study is the safety and tolerability of SAGE-217, as 
assessed by the frequency and severity of adverse events (AEs); changes from baseline in clinical 
laboratory measures, vital signs, and electrocardiograms (ECGs); suicidal ideation and behavior 
using the Columbia Suicide Severity Rating Scale (C-SSRS); and mania using the Young Mania 
Rating Scale (YMRS). 
Part B 
The primary endpoint of Part B of this study is the reduction in depressive symptoms with 
SAGE-217 treatment, as assessed by the change from baseline in the 17-item HAM-D total score 
at Day 15. 
6.2.2. 
Secondary Endpoints 
Part A 
Secondary endpoints of Part A of this study are: 
• The reduction in depressive symptoms, as assessed by: 
− Change from baseline in the 17-item HAM-D total score at Day 15 and all other 
time points 
− HAM-D response at Day 15 and all other time points 
− HAM-D remission at Day 15 and all other time points  
− Change from baseline in the MADRS total score at Day 15 and all other time 
points  
− Change from baseline in HAM-D individual item scores at Day 15 and all other 
time points  
− The response to the CGI-S and CGI-I at Day 15 and all other time points. 
• The reduction in insomnia severity as assessed by the Insomnia Severity Index (ISI). 
Part B 
Secondary endpoints of Part B of this study are: 
• The reduction in depressive symptoms, as assessed by: 
− Change from baseline in total HAM-D score at all other time points 
− HAM-D response at Day 15 and all other time points  
− HAM-D remission at Day 15 and all other time points  


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− Change from baseline in the MADRS total score at Day 15 and all other time 
points  
− Change from baseline in HAM-D individual item scores at Day 15 and all other 
time points  
− CGI-S and CGI-I response at Day 15 and all other time points. 
• The safety and tolerability of SAGE-217 as assessed by the frequency and severity of 
AEs; changes from baseline in clinical laboratory measures, vital signs, and ECGs; 
and suicidal ideation and behavior using the C-SSRS, and the YMRS. 
• The reduction in insomnia severity, as assessed by the ISI. 
 
 
 
 
 
 
 
 
 
 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This study will be conducted in 2 sequential parts: Part A (open-label) and Part B (randomized, 
double-blind, placebo-controlled, parallel group). Part B will be initiated pending the review of 
Part A data.The methods of the 2 parts will be identical unless otherwise noted. The study is 
designed to assess the safety, tolerability, 
 and efficacy of SAGE-217 in adult subjects with 
bipolar I/II disorder, who are currently experiencing an MDE. 
Screening begins with the signing of the informed consent form (ICF) at the Screening Visit. The 
diagnosis of bipolar I or II disorder will be made using the Structured Clinical Interview for 
DSM-5 for clinical trials (SCID-5-CT) performed by a qualified healthcare professional. 
Subjects on antidepressants or mood stabilizers (lamotrigine, lithium, and valproic acid only) that 
have been taken at the same dose for at least 60 days prior to Day 1 are to continue the stable 
dose throughout the treatment period. 
Subjects will return to the study center during the treatment and follow-up periods as outlined in 
the Schedule of Events (Table 1). All assessments to be performed are summarized in Table 1. 
If at any time during the study, a subject has a YMRS score of ≥13, the Investigator will 
clinically assess the subject for a manic or hypomanic switch. If the clinical assessment is 
consistent with hypomania or mania, the subject will be discontinued from study drug and 
treated as clinically appropriate (see Section 8.3). 
Part A 
The study design for Part A is presented in Figure 1. In Part A, all subjects will receive  
SAGE-217. Beginning on Day 1, qualified subjects will self-administer 30-mg SAGE-217 once 
daily in the evening (approximately 8:00 to 11:00 pm) with food for 14 days. Dose adjustments 
based on study drug tolerability are permitted following the guidelines outlined in Section 7.4. 
 
Figure 1: 
Study Design (Part A) 
 
 
 
QD = once daily 
A dose adjustment to 20-mg SAGE-217 is permitted if the 30-mg dose is not tolerated at any time. 
 
Part B 
The study design for Part B is presented in Figure 2. In Part B, subjects will be randomized in a 
1:1 ratio to receive SAGE-217 or placebo; randomization will be stratified based on use of mood 
stabilizers (Y/N). Beginning on Day 1, qualified subjects will self-administer the study drug 
Day -28 to -1
Screening
Days 1 to 14
SAGE-217
30 mg QD (evening)
Days 21, 28, 35, 42
Follow-up Visits
Day 15/
EOT


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(30 mg SAGE-217 or placebo) once daily in the evening (approximately 8:00 to 11:00 pm) with 
food for 14 days. Dose adjustments based on study drug tolerability are permitted following the 
guidelines outlined in Section 7.4. 
 
Figure 2: 
Study Design (Part B) 
 
QD = once daily 
A dose adjustment to 20-mg SAGE-217 is permitted if the 30-mg dose is not tolerated at any time. 
7.2. 
Number of Subjects 
Part A 
Approximately 30 subjects will be dosed in Part A.  
Part B 
After review of Part A data, approximately 132 subjects will be randomized and dosed in Part B 
to obtain a total of 112 evaluable subjects (see Section 13.8). 
7.3. 
Treatment Assignment 
Part A 
In Part A, all subjects will receive SAGE-217 in an open-label manner.  
Part B 
In Part B, subjects will be randomized to a treatment group (SAGE-217 or placebo) in a 
1:1 ratio; randomization will be stratified based on use of mood stabilizers (Y/N).  
7.4. 
Dose Adjustment Criteria 
If at any time, 30 mg is not tolerated, as assessed by the occurrence of a severe AE judged by the 
investigator to be related to study drug, the dose on the next day will be reduced to 20 mg and 
continued for the remainder of the treatment period. Dose adjustments related to moderate AEs 
will be judged by the Investigator. If a dose adjustment from 30 mg to 20 mg is deemed 
Day -28 to -1
Screening
Day 1
Randomization
Days 1 to 14
Placebo QD (evening)
Days 1 to 14
SAGE-217
30 mg QD (evening)
Days 21, 28, 35, 42
Follow-up Visits
Day 15/
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necessary by the Investigator, the subject will return to the site for the adjusted dose to be 
dispensed. Subjects who cannot tolerate the 20-mg dose at any time will be discontinued from 
study drug (see Section 8.3).  
7.5. 
Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons including the occurrence of AEs or other findings suggesting unacceptable risk to 
subjects, or for administrative reasons. In the event of study termination, Sage Therapeutics will 
provide written notification to the Investigator. Investigational sites must promptly notify their 
ethics committee and initiate withdrawal procedures for participating subjects.  


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
Qualified subjects will meet all of the following criteria: 
1. Subject has signed an ICF prior to the conduct of any study-specific procedures. 
2. Subject agrees to adhere to the study requirements, including use of prior, concomitant, 
and prohibited medications. 
3. Subject is an ambulatory man or woman, aged 18 to 65 years, inclusive, at Screening. 
4. 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. 
5. Subject has a documented history of hypomanic or manic episode (verified by medical 
records and/or treating healthcare professional) and a diagnosis of bipolar I or bipolar II 
disorder with a current MDE as per DSM-5 SCID-5-CT. 
6. Subject has a HAM-D score of ≥22 at Screening.  
7. Female subject agrees to use one of the following methods of contraception during 
participation in the study and for 30 days following the last dose of study drug, unless 
they are postmenopausal (defined as no menses for 12 months without an alternative 
medical cause and confirmed by follicle stimulating hormone [FSH] level ≥40 mIU/mL) 
and/or surgically sterile (hysterectomy or bilateral oophorectomy): 
• Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation. 
• Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation.  
• Intrauterine device. 
• Intrauterine hormone-releasing system. 
• Bilateral tubal ligation/occlusion. 
• Vasectomized partner. 
• Sexual abstinence (no sexual intercourse).  
8. Male subject agrees to use an acceptable method of effective contraception for the 
duration of study and for 5 days after receiving the last dose of the study drug. 
Acceptable methods of effective contraception for males includes sexual abstinence, 
vasectomy, or a condom with spermicide used together with highly effective female 
contraception methods (if the female partner is of child-bearing potential, see Inclusion 
Criteria #7 for acceptable method of contraception for females). 
9. 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. 


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8.2. 
Subject Exclusion Criteria 
Subjects who meet any of the following criteria are disqualified from participation in this study: 
1. Subject has a history of suicide attempt within the last 2 years. 
2. Subject has current suicidal ideation with plans based on Investigator clinical assessment 
and/or the C-SSRS response at Screening or Day 1. 
3. Subject has a history of rapid cycling bipolar disorder as per DSM-5 SCID-5-CT. 
4. Subject’s current depressive episode meets the DSM-5 specifier criteria for mixed 
features. 
5. Subject has ≥25% reduction in HAM-D score from Screening to Day 1. 
6. 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. 
7. Subject has abnormal liver function as shown by an abnormal liver function profile at 
screening (eg, repeated values of aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), or total bilirubin ≥2x the upper limit of normal). 
8. Subject has a clinically significant abnormal 12-lead ECG at the Screening or Day 1 
visits. NOTE: mean QT interval calculated using the Fridericia method (QTcF) of 
>450 msec in male or >470 msec in female subjects will be the basis for exclusion from 
the study.  
9. Subject has a YMRS score ≥13 at Screening or Day 1. 
10. Subject presents for the study receiving a mood stabilizer other than lamotrigine, lithium, 
or valproic acid. 
11. Subject presents for the study receiving psychotropic medications, which have not been 
taken at the same dose for at least 60 days prior to Day 1. 
12. Subject that presents for the study receiving psychotropic medications and does not 
intend to continue the current treatment regimen during the treatment period.  
13. Subject is taking typical or atypical antipsychotics, monoamine oxidase inhibitors 
(MAOIs), benzodiazepines or GABA A modulators other than the allowed mood 
stabilizers at the Screening Visit.  
14. Subject has a history of severe rashes or Stevens-Johnson Syndrome associated with 
lamotrigine and is currently taking lamotrigine. 
15. Subject’s current depressive episode is treatment resistant; defined as persistent 
depressive symptoms despite treatment with adequate doses of antidepressants from two 
different classes for an adequate amount of time (ie, at least 4 weeks of treatment). This 
will be assessed using the Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire. 


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16. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds. 
17. Subject has a positive pregnancy test at the Screening Visit or on Day 1 (prior to 
administration of study drug) or, if she is breastfeeding at Screening or on Day 1 (prior to 
administration of study drug), she does not agree to temporarily cease giving breast milk 
to her child(ren) from just prior to receiving study drug on Day 1 until 7 days after the 
last dose of study drug. 
18. Subject has detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) 
and HCV viral load, or human immunodeficiency virus (HIV) antibody at screening. 
19. Subject has active psychosis per Investigator assessment. 
20. Subject has a medical history of seizures. 
21. Subject has a medical history schizophrenia, and/or schizoaffective disorder. 
22. Subject has a history of mild, moderate, or severe substance use disorder diagnosed using 
DSM-5 criteria in the 12 months prior to screening. 
23. Subject has a positive drug and/or alcohol screen at screening or on Day 1 prior to 
dosing. 
24. Subject has had exposure to another investigational medication or device within 30 days 
prior to the Screening visit. 
25. Subject has been previously treated or randomized in any study using SAGE-217. 
Subjects who participate in Part A are not eligible to participate in Part B. 
26. Subject has used any known strong inhibitors of cytochrome P450 (CYP)3A4 within 28 
days or five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, or 
Seville oranges, or products containing these within 14 days prior to receiving the first 
dose of study drug. 
27. Subject has used CYP inducers, such as rifampin, carbamazepine, ritonavir, 
enzalutamide, efavirenz, nevirapine, phenytoin, phenobarbital and St John’s Wort, within 
28 days prior to the first dose of study drug. 
28. Subject plans to undergo elective surgery during participation in the study. 
8.3. 
Subject Withdrawal Criteria 
8.3.1. 
Withdrawal from the Study or Discontinuation of Study Drug 
Subjects may discontinue study drug or withdraw from the study at any time for any reason. The 
Investigator may discontinue the subject from the study or study drug for any of the following 
reasons: 
• The subject is unwilling or unable to adhere to the protocol 
• The subject experiences an intolerable AE  
• Other medical or safety reason, at the discretion of the Investigator and/or the 
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In addition, if at any time during the study, a subject has a YMRS score of ≥13, the Investigator 
will clinically assess the subject for a manic or hypomanic switch. If the clinical assessment is 
consistent with hypomania or mania, the subject will be discontinued from study drug and 
treated as clinically appropriate. These incidents will be documented as AEs. 
The reasons for study drug discontinuation and/or subject withdrawal from the study must be 
recorded in the subject’s electronic case report form (eCRF). The Investigator must notify the 
Sponsor and/or the Medical Monitor immediately when a subject has discontinued or been 
withdrawn for any reason. 
Subjects who discontinue study drug early/withdraw during the treatment period should, if 
possible, have an end of treatment (EOT) visit, including the EOT assessments as summarized in 
the Schedule of Events (Table 1). The EOT visit should be scheduled as soon as possible, 
preferably the day after the subject’s last dose. All details of the EOT visit should be recorded in 
the subject’s medical source documents. For subjects that discontinue study drug early, follow-
up visits should take place every 7 days for 28 days. If at any time after the EOT visit, a subject 
decides to terminate the study early, the subject should return for an early termination (ET) visit. 
The EOT and ET visits can be on the same day if a subject discontinues study drug and 
terminates the study on the same day during a clinic visit; in this case, all events scheduled for 
both visits will be conducted only once.  
If the subject fails or refuses to return to the study center, an attempt must be made to contact the 
subject by telephone in order to assess as many safety and efficacy parameters as possible. All 
data collected over the telephone must be documented and kept in the subject’s record. A subject 
will be deemed lost to follow-up after 3 attempts at contact have been made and it has been at 
least 1 month since the last subject contact. The third attempt at contact must be a certified letter 
accompanied by a survey inquiring the reason for study discontinuation. All attempts at contact 
will be documented. 
Subjects who discontinue the study drug 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.  
If a subject failed to attend scheduled assessments during the course of the study, the 
Investigators must determine the reasons and the circumstances as completely and accurately as 
possible, and document this in the subject's source documents. 
8.3.2. 
Replacement of Subjects 
Part A 
In Part A, subjects will not be replaced. 
Part B 
In Part B, subjects will not be replaced. Additional subjects may be randomized if the drop-out 
rate is higher than anticipated (see Section 13.8). 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Study Drug 
Subjects will self-administer study drug orally once daily in the evening (approximately 8:00 to 
11:00 pm) with food for 14 days as outlined in Section 7.1.  
9.2. 
Prior Medications, Concomitant Medications, and Restrictions 
9.2.1. 
Prior and Concomitant Medications and/or Supplements 
The start and end dates, route of administration, dose/units, frequency, and indication for all 
medications and/or supplements taken within 30 days prior to Screening and throughout the 
duration of the study will be recorded. In addition, psychotropic drugs taken within 6 months 
prior to Screening will be recorded. 
Any concomitant medication determined necessary for the welfare of the subject may be given at 
the discretion of the Investigator at any time during the study under the guidance outlined in 
these sections.  
Antidepressants and mood stabilizers (lamotrigine, lithium, and valproic acid only) 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 throughout the treatment period. 
Medications intended for contraception are permitted for female subjects (see Section 8.1): 
9.2.2. 
Prohibited Medications 
The following specific classes of medications are prohibited at any time during the treatment 
period: 
• Benzodiazepines 
• GABA A modulators other than the allowed mood stabilizers 
• Typical or atypical antipsychotics 
• MAOIs 
• Any known strong inhibitors of CYP3A4 
• Use of CYP inducers, such as rifampin, carbamazepine, ritonavir, enzalutamide, 
efavirenz, nevirapine, phenytoin, phenobarbital and St John’s Wort. 
9.2.3. 
Other Restrictions 
The consumption of grapefruit juice, grapefruit, or Seville oranges, or products containing these 
is prohibited throughout the treatment period. 
Consumption of drugs of abuse and alcohol is discouraged throughout the duration of the study. 
Female subjects who are lactating or actively breastfeeding must stop giving breast milk to the 
baby(ies) starting on Day 1 until 7 days after the last dose of study drug following the treatment 
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9.3. 
Treatment Adherence 
SAGE-217 (Parts A and B) or placebo (Part B only) will be self-administered by subjects once 
every evening (approximately 8:00 to 11:00 pm) with food. Sites will dispense study drug to the 
subjects to take at home with instructions for use (Section 10.4).  
Administration of study drug will be monitored by a medication adherence monitoring platform 
used on smartphones to visually confirm medication ingestion. Subjects will receive a reminder 
within a predefined time window to take study drug while using the application. Subjects will 
follow a series of prescribed steps in front of the front-facing webcam to visually confirm their 
ingestion of the medication. The application will record the date and time of study drug 
administration by dose level, as well as missed doses. 
In addition, the subject will be instructed to bring their dosing kit to each visit during the 
treatment period, at which time the Investigator or designee will be responsible for ensuring the 
kit contains sufficient doses until the next scheduled dispensation. 
If the subject is persistently noncompliant with the study drug, the Investigator should discuss 
with Sage Therapeutics the potential discontinuation of the subject (Section 8.3). Dosing 
requirements will be reviewed with each subject during all study contacts. The authorized study 
personnel conducting the re-education must document the process in the subject source records. 
9.4. 
Randomization and Blinding 
Part A 
Part A is an open-label design in which all subjects will receive SAGE-217. 
Part B 
Part B is a randomized, double-blind, placebo-controlled, parallel group design. Subjects who 
meet the entrance criteria will be stratified based on use of mood stabilizers (Y/N) and randomly 
assigned within each stratum in a 1:1 ratio to receive SAGE-217 or matched placebo. Subjects, 
clinicians, and the study team will be blinded to treatment allocation. Randomization will be 
performed centrally via an interactive response technology (IRT) system. 
Randomization schedules will be generated by an independent statistician. The allocation to 
treatment group (SAGE-217 or placebo) will be based on the randomization schedule. The 
randomization schedules will be kept strictly confidential, accessible only to authorized 
personnel until the time of unblinding.  
During the study, the blind is to be broken only if the safety of a subject is at risk and the 
treatment plan is dependent on the study treatment received. See Section 12.6 for details of 
unblinding in the event of a medical emergency or pregnancy.  
In all cases where the study drug allocation for a subject is unblinded, pertinent information 
(including the reason for unblinding) must be documented in the subject’s records and on the 
eCRF. If the subject or study center personnel have been unblinded, the subject will be 
permanently discontinued from the study. 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Description of Study Drug 
SAGE-217 is available as hard gelatin capsules containing a white to off-white powder. In 
addition to the specified amount of SAGE-217 Drug Substance, active SAGE-217 Capsules 
contain croscarmellose sodium, mannitol, silicified microcrystalline cellulose (SMCC), colloidal 
silicon dioxide, and sodium stearyl fumarate as excipients. Colloidal silicon dioxide may be 
either a component of the SMCC or a standalone excipient in the formulation. Capsules will be 
available in 10-mg, 20-mg, and 30-mg strengths to achieve the target dose of 20 mg or 30 mg. 
Subjects will be administered 2 capsules per dose in Part A. Subjects will be administered 
1 capsule per dose in Part B.  
Matching placebo capsules are hard gelatin capsules containing only the excipients listed for the 
active capsule treatment.  
10.2. 
Study Drug Packaging and Labeling 
SAGE-217 and matched placebo will be provided to the clinic pharmacist and/or designated site 
staff responsible for dispensing the study drug in appropriately labeled, subject-specific kits each 
containing sealed unit doses. Each open-label unit dose for Part A consists of 2 capsules. Blinded 
unit doses for Part B will consist of 1 capsule each. 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 Code of Federal 
Regulations and Good Manufacturing Practices/Good Clinical Practices guidelines will be 
prepared by the clinical research organization. 
10.3. 
Study Drug Storage 
SAGE-217 and matched placebo are to be stored at room temperature, 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 in the evening (approximately 8:00 to 11:00 pm) with 
food. 
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 
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Site staff will access the IRT at the Screening Visit to obtain a subject identification (ID) number 
for each subject. On Day 1, site staff will access the IRT and provide the necessary subject-
identifying information, including the subject ID number assigned at Screening, to randomize the 
eligible subject into the study and obtain the medication ID number for the study drug to be 
dispensed to that subject. 
At the subsequent study drug-dispensing visit, the investigator or designee will access the IRT, 
providing the same subject ID number assigned at Screening, to obtain the medication ID 
number for the study drug to be dispensed at that visit. In the event of an unscheduled dose 
reduction (Section 7.4), a new subject-specific kit will be dispensed. 
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 medication 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 within usual 
business hours and with appropriate notice during or after completion of the study to perform 
drug accountability reconciliation. 
10.7. 
Study Drug Handling and Disposal 
At the end of the study, all used and unused study drug will be reconciled and returned to Sage 
Therapeutics for destruction or destroyed locally; disposition of study drug will be documented. 
A copy of the inventory record and a record of any clinical supplies that have been received, 
dispensed or destroyed must be documented by the site as directed. This documentation must 
include at least the information below:  
• the number of dispensed units 
• the number of unused units 
• the number of units destroyed at the end of the study 
• the date, method and location of destruction. 
 


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11. 
ASSESSMENT OF EFFICACY 
 
All assessments will be conducted according to the schedule of assessments (Table 1). 
11.1. 
Efficacy Assessments 
11.1.1. 
Hamilton Rating Scale for Depression (HAM-D) 
The primary outcome measure is the change from baseline in the 17-item HAM-D total score at 
Day 15.  
The 17-item HAM-D will be used to rate the severity of depression in subjects who are identified 
as experiencing an MDE (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. Every effort should be 
made for the same rater to perform all HAM-D assessments for an individual subject.  
The HAM-D total score will be calculated as the sum of the 17 individual item scores.  
In addition to the primary efficacy endpoint of change from baseline in HAM-D total score, 
several secondary efficacy endpoints will be derived for the HAM-D. Hamilton Rating Scale for 
Depression subscale scores will be calculated as the sum of the items comprising each subscale. 
Hamilton Rating Scale for Depression response will be defined as having a 50% or greater 
reduction from baseline in HAM-D total score. Hamilton Rating Scale for Depression remission 
will be defined as having a HAM-D total score of ≤7. 
The HAM-D subject interview may be audio-recorded for independent quality control purposes. 
11.1.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive 
episodes in subjects with mood disorders. It was designed as an adjunct to the HAM-D that 
would be more sensitive than the Hamilton Scale to the changes brought on by antidepressants 
and other forms of treatment.  
Higher MADRS scores indicate more severe depression, and each item yields a score of 0 to 6. 
The overall score ranges from 0 to 60 (Williams 2008). 
The MADRS total score will be calculated as the sum of the ten individual item scores. 
The MADRS subject interview may be audio-recorded for independent quality control purposes. 
11.1.3. 
Clinical Global Impression (CGI) 
The CGI is a validated measure often utilized in clinical trials to allow clinicians to integrate 
several sources of information into a single rating of the subject’s condition. The CGI scale 
consists of 3 items. Only the first 2 items are being used in this study.  
The Clinical Global Impression - Severity (CGI-S) uses a 7-point Likert scale to rate the severity 
of the subject’s illness at the time of assessment, relative to the clinician’s past experience with 


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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 Clinical Global Impression - Improvement (CGI-I) employs a 7-point Likert scale to 
measure the overall improvement in the subject’s condition posttreatment. The Investigator will 
rate the subject’s total improvement whether or not it is due entirely to drug treatment. Response 
choices include: 0=not assessed, 1=very much improved, 2=much improved, 3=minimally 
improved, 4=no change, 5=minimally worse, 6=much worse, and 7=very much worse 
(Busner 2007b). The CGI-I is only rated at posttreatment assessments. By definition, all CGI-I 
assessments are evaluated against baseline conditions. CGI-I response will be defined as having a 
CGI-I score of “very much improved” or “much improved.”  
11.1.4. 
Insomnia Severity Index (ISI) 
The ISI is a validated questionnaire designed to assess the nature, severity, and impact of 
insomnia (Morin 2011). The ISI uses a 5-point Likert Scale to measure various aspects of 
insomnia severity (0 = none, 1 = mild, 2 = moderate; 3 = severe; 4 = very severe), satisfaction 
with current sleep pattern (0 = very satisfied, 1 = satisfied, 2 = neutral, 3 = dissatisfied, 4 = very 
dissatisfied), and various aspects of the impact of insomnia on daily functioning (0 = not at all, 
1 = a little, 2 = somewhat, 3 = much, 4 = very much). A total score of 0 to 7 = “no clinically 
significant insomnia,” 8 to 14 = subthreshold insomnia,” 15 to 21 = “clinical insomnia (moderate 
severity),” and 22 to 28 = “clinical insomnia (severe).”  


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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
The safety and tolerability of SAGE-217 will be assessed by the frequency and severity of AEs; 
changes from baseline in clinical laboratory measures, vital signs, and ECGs; suicidal ideation 
and behavior using the C-SSRS; and the YMRS. All assessments will be conducted according to 
the schedule of assessments (Table 1). 
12.1.1. 
Demographic/Medical History 
Demographic and baseline characteristics (age, race, gender, ethnicity, employment status, 
highest education level, marital/civil status) and a full medical history, including family 
psychiatric history, will be documented. The diagnosis of bipolar I or II disorder will be 
determined using the SCID-5-CT. 
12.1.2. 
Weight and Height 
Height (Screening only) and weight will be measured and documented.  
12.1.3. 
Physical Examination 
Physical examinations assessing body systems (eg, head, eye, ear, 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 physical examinations 
may also be conducted per the Investigator’s discretion. 
Any abnormality in physical examinations will be interpreted by the Investigator as abnormal, 
not clinically significant (NCS); or abnormal, clinically significant (CS) in source documents. 
New or worsening abnormalities that are judged to be clinically significant will be recorded as 
AEs, assessed according to Section 12.2.1.1. 
12.1.4. 
Vital Signs 
Vital signs comprise both supine and standing for systolic and diastolic blood pressure and heart 
rate measurements. Heart rate and blood pressure are to be collected in supine position after the 
subject has been resting for 5 minutes and then in the standing position. Respiratory rate, pulse 
oximetry and temperature are collected once, in either position. Vital signs will be documented. 
When vital signs are scheduled at the same time as blood draws, vital signs will be obtained first, 
with the blood sample collected as close to the scheduled time as possible. 
Any abnormality in vital signs will be interpreted by the Investigator as abnormal, NCS or 
abnormal, CS in source documents. New or worsening abnormalities that are judged to be 
clinically significant will be recorded as AEs, assessed according to Section 12.2.1.1. 
12.1.5. 
Electrocardiogram (ECG) 
Supine 12-lead ECGs will be performed in triplicate. The standard intervals (heart rate, PR, 
QRS, QT, and QTcF) as well as any rhythm abnormalities will be recorded. When ECG 
 
sample collection occur during the same visit, the ECGs will be conducted first. 


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Any abnormality in ECGs 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. 
Laboratory Assessments 
Samples will be collected in accordance with acceptable laboratory procedures detailed in the 
laboratory manual.   
The clinical laboratory tests to be performed are listed in Table 3. 
Table 3: 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Coagulation 
Red blood cell count 
Hemoglobin  
Hematocrit  
White blood cell count with 
differential  
Platelet count 
Red blood cell morphology 
ALT 
Albumin 
Alkaline phosphatase 
AST 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
Total protein 
Creatinine 
Blood urea nitrogen 
Creatine kinase 
GGT 
Potassium 
Sodium 
Lactate dehydrogenase 
Glucose 
Chloride 
Bicarbonate 
Calcium 
Phosphorus 
Triglycerides 
pH 
Specific gravity 
Protein 
Glucose 
Red blood cells 
Nitrite 
Leukocyte esterase 
Ketones 
Bilirubin 
Urobilinogen 
Activated partial 
thromboplastin 
time 
Prothrombin time 
International 
normalized ratio 
Diagnostic Screening 
 
 
 
Serum 
Urine 
Breathalyzer 
 
Hepatitis B 
Hepatitis C 
HIV-1 and -2 
Female subjects of child bearing 
potential: serum human chorionic 
gonadotropin 
Female subjects, if menopause is 
suspected and not surgically sterile: 
FSH 
Drug screen including: 
amphetamines, barbiturates, 
benzodiazepines, 
cannabinoids, cocaine, 
opiates, phencyclidine, and 
propoxyphene 
Female subjects of child 
bearing potential: urine 
human chorionic 
gonadotropin 
Alcohol 
 


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The central laboratory will perform laboratory tests for hematology, serum chemistry, and 
urinalysis. The results of laboratory tests will be returned to the Investigator, who is responsible 
for reviewing and filing these results. All laboratory safety data will be transferred electronically 
to Sage Therapeutics or designee in the format requested by Sage Therapeutics.  
Laboratory reports must be signed and dated by the Investigator or subinvestigator indicating 
that the report has been reviewed and any abnormalities have been assessed for clinical 
significance. Any abnormalities identified prior to first dose will require clear and complete 
documentation in the source documents as to the investigator’s assessment of not clinically 
significant before proceeding with randomization.  
All clinical laboratory test results outside the central laboratory’s reference range will be 
interpreted by the Investigator as abnormal, 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. A 
clinically significant laboratory abnormality following subject randomization will be followed 
until the abnormality returns to an acceptable level or a satisfactory explanation has been 
obtained. 
Follicle stimulating hormone testing will be conducted at Screening to confirm whether a female 
subject with ≥12 months of spontaneous amenorrhea meets the protocol-defined criteria for 
being post-menopausal (Section 8.1). 
 
 
12.1.6.1. Drugs of Abuse and Alcohol 
Urine toxicology will be performed for selected drugs of abuse, and a breath test will be 
performed for alcohol (Table 1). 
12.1.6.2. Pregnancy Screen 
A serum pregnancy test in women of child-bearing potential will be conducted at Screening and 
a urine pregnancy test will be conducted at all other scheduled timepoints (Table 1).  
12.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011). This scale 
consists of a baseline evaluation that assesses the lifetime experience of the subject with suicidal 
ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last 
study visit. The C-SSRS includes ‘yes’ or ‘no’ responses for assessment of suicidal ideation and 
behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being 
the most severe).  
The “Baseline/Screening” C-SSRS form will be completed at screening (lifetime history and past 
24 months). The “Since Last Visit” C-SSRS form will be completed at all subsequent time 
points, as outlined in Table 1. 


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12.1.8. 
Young Mania Rating Scale (YMRS) 
Manic symptoms will be assessed during the study using the YMRS (Young 1978). The 
clinician-administered scale is based on 11 items of core symptoms of mania. Four of the items 
(irritability, speech, thought content, and disruptive/aggressive behavior) are graded on a scale of 
0 to 8 (choices given as even numbers), with the remaining 7 items graded on a scale of 0 to 4. 
Scoring between the points given (whole or half points) is possible.  
12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Definition of Adverse Events 
12.2.1.1. Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the use of a 
medicinal (investigational) product whether or not related to the medicinal (investigational) 
product. In clinical studies, an AE can include an undesirable medical condition occurring at any 
time, including baseline or washout periods, even if no study treatment has been administered. 
A TEAE is an AE that occurs after the first administration of any study drug. The term study 
drug includes any Sage investigational product, a comparator, or a placebo administered in a 
clinical trial. 
An abnormal laboratory value will be considered an AE if the value represents a clinically 
significant change from baseline as determined by the Investigator.  
All AEs that occur after any subject has signed the informed consent form and throughout the 
duration of the study, whether or not they are related to the study, must be reported to Sage 
Therapeutics. 
12.2.1.2. Serious Adverse Event (SAE) 
A serious adverse event is any untoward medical occurrence that at any dose: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
An SAE may also be any other medically important event that, in the opinion of the Investigator, 
may jeopardize the subject or may require medical intervention to prevent 1 of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
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All SAEs that occur after any subject has been enrolled and throughout the duration of the study, 
whether or not they are related to the study, must be recorded on the SAE form provided by Sage 
Therapeutics within 24 hours of first awareness (Section 12.5). All SAEs should to be followed 
until the event resolved, the condition stabilized, was no longer considered clinically significant 
or the subject was lost to follow-up. 
12.3. 
Relationship to Study Drug 
The Investigator must make the determination of relationship to the study drug for each adverse 
event (not related, possibly related or probably related). The Investigator should decide whether, 
in his or her medical judgment, there is a reasonable possibility that the event may have been 
caused by the investigational product. If no valid reason exists for suggesting a relationship, then 
the adverse event should be classified as “not related.” If there is any valid reason, even if 
undetermined, for suspecting a possible cause-and-effect relationship between the investigational 
product and the occurrence of the adverse event, then the adverse event should be considered at 
least “possibly related.”  
Table 4: 
Relationship to Study Drug 
Relationship 
Definition 
Not Related: 
No relationship between the experience and the administration of study drug; related to 
other etiologies such as concomitant medications or subject’s clinical state. 
Possibly Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug.  
The reaction might have been produced by the subject’s clinical state or other modes of 
therapy administered to the subject, but this is not known for sure. 
Probably Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug.  
The reaction cannot be reasonably explained by the known characteristics of the subject’s 
clinical state or other modes of therapy administered to the subject. 
If the relationship between the adverse event/serious adverse event and the investigational 
product is determined to be “possible” or “probable”, the event will be considered related to the 
investigational product for the purposes of expedited regulatory reporting. 
12.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. The AE term should be reported in standard medical terminology when 
possible. For each AE, the investigator will evaluate and report the onset (date and time), 
resolution (date and time), intensity, causality, action taken, serious outcome (if applicable), and 
whether or not it caused the subject to discontinue the study drug or withdraw early from the 
study. 
Intensity will be assessed according to the following scale: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 


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• Severe (incapacitating, with inability to perform normal activities) 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.2.1.2. An AE of severe intensity 
may not be considered serious. 
Should a pregnancy occur, it must be reported and recorded on the Sage Therapeutics pregnancy 
notification form. Pregnancy in itself is not regarded as an AE unless there is a suspicion that an 
investigational product may have interfered with the effectiveness of a contraceptive medication 
or a complication relating to the pregnancy occurs (eg, spontaneous abortion, which requires 
reporting as an SAE). All pregnancies occurring during this study are to be reported in the same 
time frame as SAEs (eg, within 24 hours of the site becoming aware of the pregnancy). 
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. Reports of 
congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs.  
If the pregnancy ends for any reason before the anticipated date, the Investigator should notify 
Sage Therapeutics, or designee. At the completion of the pregnancy, the Investigator will 
document the outcome of the pregnancy. 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), 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 on the SAE report form. 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 CRF and/or study 
file. 
Any SAEs discovered by the Investigator after the designated follow up time for the study, 
should be promptly reported to Sage, or designee, according to the timelines noted above. The 
contact information for reporting SAEs and/or pregnancies is located in the study reference 
manual.   
Sage, or designee, is responsible for notifying the relevant regulatory authorities of certain 
events. It is the Principal Investigator’s responsibility to notify the ethics committee of all SAEs 
that occur at his or her site. Investigators will also be notified of all suspected, unexpected, 
serious, adverse reactions (SUSARs) that occur during the clinical study. Each site is responsible 
for notifying its ethics committee of these SUSARs. In addition, appropriate SAGE Drug Safety 
and Pharmacovigilance personnel, or designee, will unblind SUSARs for the purpose of 


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regulatory reporting. SAGE, or designee, will submit SUSARs (in blinded or unblinded fashion) 
to regulatory agencies according to local law. SAGE, or designee, will submit SUSARs to 
investigators in a blinded fashion. 
12.6. 
Emergency Identification of Study Drug 
During the study, the blind is to be broken only when the safety of a subject is at risk and the 
treatment plan is dependent on the study treatment received. Unless a subject is at immediate 
risk, the Investigator must make diligent attempts to contact Sage prior to unblinding the study 
treatment administered to a subject. Any request from the Investigator about the treatment 
administered to study subjects must be discussed with Sage. If the unblinding occurs without 
Sage’s knowledge, the Investigator must notify Sage as soon as possible and no later than the 
next business morning. All circumstances surrounding a premature unblinding must be clearly 
documented in the source records. Unless a subject is at immediate risk, any request for the 
unblinding of individual subjects must be made in writing to Sage and approved by the 
appropriate Sage personnel, according to standard operating procedures. The blinding of the 
study will be broken after the database has been locked. Electronic copies of the randomization 
code will be made available to the laboratory performing the bioanalytical analyses in order to 
allow for limited analysis of samples from subjects receiving placebo. 
In the event of a medical emergency or pregnancy, the Investigator will discuss with the Medical 
Monitor if unblinding is warranted for medical management of the subject. If there is agreement 
to unblind treatment assignment, the unblinding procedure described in the Safety Management 
Plan for the study will be followed. If the Investigator is unable to contact the Medical Monitor 
in a medical emergency, and it is deemed clinically necessary by the Investigator, the treatment 
group for that subject may be unblinded in the IRT system. 
In all cases where the study drug allocation for a subject is unblinded, pertinent information 
(including the reason for unblinding) must be documented in the subject’s records and on the 
eCRF. If the subject or study center personnel have been unblinded, the subject will be 
permanently discontinued from the study. 


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13. 
STATISTICS 
A separate statistical analysis plan (SAP) for each part (Part A and B) will provide a detailed 
description of the analyses to be performed in the respective part of the study. The SAPs will be 
finalized and approved prior to database lock. Any deviations from or changes to the respective 
SAP following database lock will be described in detail in the clinical study report. 
13.1. 
Data Analysis Sets 
The Safety Set, defined as all subjects that received at least 1 dose of study drug, will be used to 
provide descriptive summaries of safety data.  
The Efficacy Set, defined as all subjects in the Safety Set that have at least 1 post-baseline 
HAM-D evaluation, will be used to analyze efficacy data, unless otherwise specified. 
 
 
Part B will also include a Randomized Set, defined as all subjects who are randomized. This 
analysis set will be used for all data listings in Part B. 
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 sets, using all non-missing data available. No imputation process will be used to 
estimate missing data.  
13.3. 
General Considerations 
For the purpose of all primary and secondary analyses where applicable, baseline is defined as 
the last measurement prior to receipt of study drug.  
Continuous endpoints will be summarized with number (n), mean, standard deviation (SD), 
median, minimum, and maximum. In addition, change from baseline values will be calculated at 
each time point and summarized descriptively. For categorical endpoints, descriptive summaries 
will include counts and percentages.  
13.4. 
Demographics and Baseline Characteristics 
Demographic data (Section 12.1.1) and baseline characteristics, such as height, weight, and body 
mass index, will be summarized using the Safety Set.  
Pregnancy results will be listed but not summarized.  
Medical history will be listed by subject.  
13.5. 
Efficacy Analysis 
The primary efficacy endpoint, the change from baseline in HAM-D total score, will be analyzed 
using a mixed effects model for repeated measures (MMRM); the model will include center, 
treatment, baseline HAM-D total score, stratification factor, assessment time point, and time 
point-by-treatment as explanatory variables. All explanatory variables will be considered as fixed 


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effects and the subject effect will be considered random in the model. All post-baseline time 
points will be included in the model. The primary comparison will be between SAGE-217 and 
matching placebo at Day 15. Model-based point estimates (ie, least squares [LS] means, 95% 
confidence intervals, and p values) will be reported. An unstructured covariance structure will be 
used to model the within-subject errors. In case of convergence issues, other covariance 
structures will be considered; this will be detailed in the statistical analyses plan. Other 
continuous endpoints will be analyzed using similar methods.  
Other efficacy analyses will be specified in the statistical analysis plan. In general, data will be 
analyzed using appropriate descriptive statistics or pre-specified statistical methods as 
applicable; subject listings will be provided for all efficacy data. Subjects will be analyzed 
according to randomized treatment for the purpose of efficacy unless otherwise specified. 
13.6. 
Safety Analyses 
Safety and tolerability of SAGE-217 will be assessed by the frequency and severity of AEs; 
changes from baseline in clinical laboratory measures, vital signs, and ECGs. Suicidal ideation 
and behavior will be evaluated using the C-SSRS. Mania will be evaluated using the YMRS. 
Safety data will be listed by subject and summarized by treatment group. All safety summaries 
will be performed on the Safety Set.  
13.6.1. 
Adverse Events 
The analysis of AEs will be based on the concept of TEAEs. The incidence of TEAEs will be 
summarized overall and by Medical Dictionary for Regulatory Activities (MedDRA) 
Version 20.1 or higher, system organ class (SOC), and preferred term (PT). 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 (Section 13.6.1).  
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 
Clinical laboratory results will be listed by subject and timing of collection. Mean changes from 
baseline in clinical laboratory measures will be evaluated.  
13.6.3. 
Physical Examinations 
Physical examination data will be listed by subject, but not summarized.  
13.6.4. 
Vital Signs 
Vital sign results will be listed by subject and timing of collection. Mean changes from baseline 
in vital signs will be evaluated by time point.  


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13.6.5. 
12-Lead Electrocardiogram 
The following ECG parameters will be listed for each subject: heart rate, PR, QRS, QT, and 
QTcF. Any clinically significant abnormalities or changes in ECGs should be listed as an AE. 
Electrocardiogram findings will be listed by subject and visit.  
13.6.6. 
Prior and Concomitant Medications 
Medications will be recorded at each study visit during the study and will be coded using World 
Health Organization-Drug dictionary (WHO-DD) September 2015, or later.  
Those medications taken prior to the initiation of the start of study drug will be denoted “Prior”. 
Those medications taken prior to the initiation of the study drug and continuing beyond the 
initiation of the study drug or those medications started at the same time or after the initiation of 
the study drug will be denoted “Concomitant” (ie, those with a start date on or after the first dose 
of study drug, or those with a start date before the first dose of study drug that are ongoing or 
with a stop date on or after the first dose of study drug).  
Medications will be presented according to whether they are “Prior” or “Concomitant” as 
defined above. If medication dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant.  
Details of prior and concomitant medications will be listed by subject, start date, and verbatim 
term.  
13.6.7. 
Columbia Suicide Severity Rating Scale 
Suicidality data collected on the C-SSRS at baseline and by visit will be summarized and listed 
for all subjects. Listings will include behavior type and/or category for Suicidal Ideation and 
Suicidal Behavior of the C-SSRS.  
13.6.8. 
Young Mania Rating Scale 
Mania data collected on the YMRS at baseline and by visit will be summarized and listed for all 
subjects.  
 
 
 
 
 
 
13.8. 
Determination of Sample Size 
13.8.1. 
Part A 
For Part A, the sample size of approximately 30 subjects was selected based on clinical and not 
statistical considerations. 


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13.8.2. 
Part B 
For Part B, assuming a two-sided alpha level of 0.05, a sample size of 112 total evaluable 
subjects (56 per treatment group) would provide 80% power to detect a placebo-adjusted 
treatment difference of approximately 4 points in the primary endpoint, change from baseline in 
HAM-D total score at Day 15, assuming standard deviation (SD) of 7.5 points.  
Assuming a 15% dropout rate, approximately 132 total randomized subjects will be required to 
obtain a total of 112 evaluable subjects. Evaluable subjects are defined as those randomized 
subjects who receive study drug and have a valid baseline and at least 1 post-baseline HAM-D 
assessment. Additional subjects may be randomized if the drop-out rate is higher than 15%. 


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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and the study site guarantee access to source documents by Sage Therapeutics 
or sponsor’s designee and by the IRB or IEC. 
All aspects of the study and its documentation will be subject to review by Sage Therapeutics or 
sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, study drug, subject medical records, informed consent documentation, and 
review of eCRFs and associated source documents. It is important that the investigator and other 
study personnel are available during the monitoring visits and that sufficient time is devoted to 
the process.  
14.2. 
Audits and Inspections 
Authorized representatives of Sage Therapeutics, a regulatory authority, an Independent Ethics 
Committee or an Institutional Review Board may visit the site to perform audits or inspections, 
including source data verification. The purpose of a Sage Therapeutics audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, Good Clinical Practice guidelines of the 
International Conference on Harmonization, and any applicable regulatory requirements. The 
investigator should contact Sage Therapeutics immediately if contacted by a regulatory agency 
about an inspection. 
14.3. 
Protocol Deviations 
Investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
Sage Therapeutics or sponsor’s designee (and IRB, as required) to determine the appropriate 
course of action. There will be no exemptions (a prospectively approved deviation) from the 
inclusion or exclusion criteria. 
14.4. 
Institutional Review Board (IRB) or Ethics Committee (EC) 
The Principal Investigator must obtain IRB (or EC) approval for the investigation. Initial IRB (or 
EC) approval, and all materials approved by the IRB (or EC) for this study including the subject 
consent form and recruitment materials must be maintained by the Investigator and made 
available for inspection. 


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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
Sage Therapeutics may conduct a quality assurance audit. Please see Section 14.2 for more 
details regarding the audit process. 
 


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


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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Inspection of Records 
Sage Therapeutics will be allowed to conduct site visits to the investigation facilities for the 
purpose of monitoring any aspect of the study. The Investigator agrees to allow the monitor to 
inspect the drug storage area, study drug stocks, drug accountability records, subject charts and 
study source documents, and other records relative to study conduct. 
17.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for the period 
outlined in the site contract, or for a period of 2 years after the last marketing application 
approval, whichever is longer. If not approved, documentation must be maintained for 2 years 
following the discontinuance of the test article for investigation. If it becomes necessary for Sage 
Therapeutics or the Regulatory Authority to review any documentation relating to the study, the 
Investigator must permit access to such records. 


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18. 
PUBLICATION POLICY 
All information concerning SAGE-217 is considered confidential and shall remain the sole 
property of Sage Therapeutics. The Investigator agrees to use this information only in conducting 
the study and shall not use it for any other purposes without written approval from Sage 
Therapeutics. No publication or disclosure of study results will be permitted except as specified 
in a separate, written, agreement between Sage Therapeutics and the Investigator. 


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19.
LIST OF REFERENCES
Begley CE, Annegers JF, Swann AC, Lewis C, Coan S, Schnapp WB, et al. The lifetime cost of 
bipolar disorder in the US: an estimate for new cases in 1998. Pharmacoeconomics. 2001;19(5 Pt 
1):483-95. 
Busner J, Targum S. CGI-S. (2007a), as adapted from Kay, Stanley R, Positive and Negative 
Symptoms in Schizophrenia:Assessment and Research.  Clinical and Experimental Psychiatry, 
Monograph No. 5.  Brunner/Mazel, 1991.  Modified from Guy W. Clinical Global Impressions: 
In ECDEU Assessment Manual for Psychopharmacology. 1976; 218-22. Revised DHEW Pub. 
(ADM) Rockville, MD: National Institute for Mental Health.   
Busner J, Targum S. CGI-I.  (2007b), as adapted from Spearing, et al.  Psychiatry Research, 
1997;73:159-71.  Modified from Guy W. Clinical Global Impressions: In ECDEU Assessment 
Manual for Psychopharmacology. 1976; 218-22. Revised DHEW Pub. (ADM) Rockville, MD: 
National Institute for Mental Health.   
Bowden CL, Anupama AK. Pharmacotherapy for bipolar depression: an economic assessment. 
Expert Opin Pharmacother. 2004 May;5(5):1101-7. 
DSM-5.  Diagnostic and statistical manual of mental disorders (5th ed.).  American Psychiatric 
Association 2013.  Arlington, VA: American Psychiatric Publishing. 
Ferrari AJ, Stockings E, Khoo JP, Erskine HE, Degenhardt L, Vos T, et al. The prevalence and 
burden of bipolar disorder: findings from the Global Burden of Disease Study 2013. Bipolar 
Disord. 2016 Aug;18(5):440-50. 
Gijsman HJ, Geddes JR, Rendell JM, Nolen WA, Goodwin GM. Antidepressants for bipolar 
depression: a systematic review of randomized, controlled trials. Am J Psychiatry 
2004;161:1537-1547. 
Judd LL, Akiskal HS, Maser JD, Zeller PJ, Endicott J, Coryell W, et al. A prospective 12-year 
study of subsyndromal and syndromal depressive symptoms in unipolar major depressive 
disorders. Arch Gen Psychiatry. 1998 Aug;55(8):694-700. 
Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA, et al. The long-term 
natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 
2002 Jun;59(6):530-7. 
Judd LL, Akiskal HS. Depressive episodes and symptoms dominate the longitudinal course of 
bipolar disorder. Curr Psychiatry Rep. 2003 Dec;5(6):417-8. 
Kessler RC, Akiskal HS, Ames M, Birnbaum H, Greenberg P, Hirschfeld RM, et al. Prevalence 
and effects of mood disorders on work performance in a nationally representative sample of U.S. 
workers. Am J Psychiatry. 2006 Sep;163(9):1561-8. 
Merikangas KR, Akiskal HS, Angst J, Greenberg PE, Hirschfeld RM, Petukhova M, et al. 
Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity 
Survey replication. Arch Gen Psychiatry. 2007 May;64(5):543-52. 
Morin CM, Belleville G, Bélanger L, Ivers H. The Insomnia Severity Index: Psychometric 
Indicators to Detect Insomnia Cases and Evaluate Treatment Response. Sleep. 2011;34(5):601-
608.


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Perlis RH, Ostacher MJ, Patel JK, Marangell LB, Zhang H, Wisniewski SR, et al. Predictors of 
recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement 
Program for Bipolar Disorder (STEP-BD). Am J Psychiatry. 2006 Feb;163(2):217-24. 
Posner K, Brown GK, Stanley B, et al. The Columbia–Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-77. 
Post RM, Leverich GS, Altshuler LL, Frye MA, Suppes TM, Keck PE Jr, et al. An overview of 
recent findings of the Stanley Foundation Bipolar Network (Part I). Bipolar Disord. 2003 
Oct;5(5):310-9. 
Rudolph U, Knoflach F. Beyond classical benzodiazepines: novel therapeutic potential of 
GABAA receptor subtypes. Nat Rev Drug Discov. 2011 Jul 29;10(9):685-97. 
Sachs GS, Nierenberg AA, Calabrese JR, Marangell LB, Wisniewski SR, Gyulai L, et al. 
Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007 
Apr 26;356(17):1711-22. Epub 2007 Mar 28. 
 
 
Williams JBW and Kobak KA. Development and reliability of a structured interview guide for 
the Montgomery-Asberg Depression Rating Scale (SIGMA). British Journal of Psychiatry. 
2008:192(1):52-58. 
Williams JBW.  SIGH-D 24hr: V1.3 – 24 HR Version. 2013a. 
Williams JBW.  SIGH-D Past week:  Past Week Version. 2013b. 
Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and 
sensitivity. Br J Psychiatry. 1978 Nov;133:429-35. 


217-BPD-201 Summary of Changes 
Sage Therapeutics 
Version 2.0, Amendment 1  
 
 
1 
Protocol 217-BPD-201, Amendment 1 
Date of Amendment: 13 September 2018 
A 2-PART STUDY (OPEN-LABEL FOLLOWED BY DOUBLE-BLIND, RANDOMIZED, 
PLACEBO-CONTROLLED, PARALLEL GROUP) OF THE SAFETY, 
TOLERABILITY, PHARMACOKINETICS, AND EFFICACY OF SAGE-217 IN THE 
TREATMENT OF SUBJECTS WITH BIPOLAR I/II DISORDER WITH A CURRENT 
MAJOR DEPRESSIVE EPISODE 
Rationale for Protocol Amendment 
Protocol 217-BPD-201 has been amended to limit SAGE-217 treatment to 30 mg per day for 2 weeks, 
consistent with experience using the same dose level and duration in other unipolar depression studies. 
Accordingly, the 20-mg dose titrations prior to and following treatment with 30 mg have been removed, 
and endpoint assessments have been adjusted; for example, from Day 29 to Day 15 (Note: dose reduction 
to 20 mg dose during the treatment period are still allowed). A number of sections have been updated to 
reflect this change. 
Additional changes were made as outlined below. 
• Additional information (regarding prohibited medication) was added to Exclusion 
#13. 
• Details related to breastfeeding were added to Exclusion #17. 
• Clarification of Exclusion #27 regarding CYP inducers. 
• Updated details regarding drug materials. 
• Updated language regarding reporting adverse events and serious adverse events. 
• Minor administrative changes have been made throughout the protocol to increase 
clarity on the procedures of the study including: 
− Alcohol testing to be conducted at each visit  
− All medications taken within 30 days prior to Screening through the duration of 
the study will be recorded 
− Insomnia Severity Index (ISI) scoring anchor error  
A detailed summary of changes is provided in Table 1. Corrections to typographical errors, 
punctuation, grammar, abbreviations, and formatting are not detailed. 
 


217-BPD-201 Summary of Changes 
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Version 2.0, Amendment 1  
 
 
2 
Table 1: 
Protocol Amendment 1 Detailed Summary of Changes 
The change in Protocol Amendment 1 is indicated. The corresponding related text has been revised throughout the protocol. Deleted 
text is indicated by strikeout; added text is indicated by bold font. 
Purpose: Updated dosing duration, including removal of up- and down-titration.  
The primary change occurs in Section 7, Investigational Plan, and Table 1, Schedule of Events. This change is reflected throughout the document 
as the end of treatment visit occurs on Day 15 (rather than Day 28). As there are multiple references to the length of the study and duration of 
study drug treatment. For ease of review, this change has not been outlined in this table for every occurrence. A tracked changes version of the 
protocol is available noting all edits made to incorporate this change throughout the document.  


217-BPD-201 Summary of Changes 
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Version 2.0, Amendment 1  
 
 
3 
Previous text: 
Part A 
The study design for Part A is presented in Figure 1. In Part A, all subjects will receive SAGE-217. Beginning on Day 1, 
qualified subjects will self-administer the study drug once daily in the evening with food for 28 days: 20 mg SAGE-217 
for 3 days, 30 mg SAGE-217 for 21 days, and then 20 mg-SAGE-217 for 4 days. Dose adjustments based on study drug 
tolerability are permitted following the guidelines outlined in Section 7.4. 
Figure 1: 
Study Design (Part A) 
 
QD = once daily 
*A dose adjustment to 20-mg SAGE-217 is permitted if the 30-mg dose is not tolerated at any time during Days 4 to 24. 
Part B 
The study design for Part B is presented in Figure 2. In Part B, subjects will be randomized in a 1:1 ratio to receive 
SAGE-217 or placebo; randomization will be stratified based on use of mood stabilizers (Y/N). Beginning on Day 1, 
qualified subjects will self-administer the study drug once daily in the evening with food for 28 days: 20 mg SAGE-217 
for 3 days, 30 mg SAGE-217 for 21 days, and then 20 mg-SAGE-217 for 4 days. Dose adjustments based on study drug 
tolerability are permitted following the guidelines outlined in Section 7.4. 
Figure 2: 
Study Design (Part B) 
 
QD = once daily 
*A dose adjustment to 20-mg SAGE-217 is permitted if the 30-mg dose is not tolerated at any time during Days 4 to 24. 
 
Day -28 to -1
Screening
Days 1 to 3
SAGE-217
20 mg QD
Days 4 to 24
SAGE-217
30 mg QD*
Days 25 to 28
SAGE-217
20 mg QD
Days 35, 42, 49, 56
Follow-up Visits
Day -28 to -1
Screening
Day 1
Randomization
Days 1 to 28
Placebo QD
Days 1 to 3
SAGE-217
20 mg QD
Days 4 to 24
SAGE-217
30 mg QD*
Days 25 to 28
SAGE-217
20 mg QD
Days 35, 42, 49, 56
Follow-up Visits


217-BPD-201 Summary of Changes 
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Version 2.0, Amendment 1  
 
 
4 
New text: 
Part A 
The study design for Part A is presented in Figure 1. In Part A, all subjects will receive SAGE-217. Beginning on Day 1, 
qualified subjects will self-administer 30-mg SAGE-217 once daily in the evening with food for 14 days. Dose 
adjustments based on study drug tolerability are permitted following the guidelines outlined in Section 7.4. 
Figure 3: 
Study Design (Part A) 
 
 
QD = once daily 
A dose adjustment to 20-mg SAGE-217 is permitted if the 30-mg dose is not tolerated at any time. 
Part B 
The study design for Part B is presented in Figure 2. In Part B, subjects will be randomized in a 1:1 ratio to receive 
SAGE-217 or placebo; randomization will be stratified based on use of mood stabilizers (Y/N). Beginning on Day 1, 
qualified subjects will self-administer the study drug (30 mg SAGE-217 or placebo) once daily in the evening with food 
for 14 days. Dose adjustments based on study drug tolerability are permitted following the guidelines outlined in 
Section 7.4. 
Figure 4: 
Study Design (Part B) 
QD = once 
daily 
A dose adjustment to 20-mg SAGE-217 is permitted if the 30-mg dose is not tolerated at any time. 
 
Day -28 to -1
Screening
Days 1 to 14
SAGE-217
30 mg QD (evening)
Days 21, 28, 35, 42
Follow-up Visits
Day 15/
EOT
Day -28 to -1
Screening
Day 1
Randomization
Days 1 to 14
Placebo QD (evening)
Days 1 to 14
SAGE-217
30 mg QD (evening)
Days 21, 28, 35, 42
Follow-up Visits
Day 15/
EOT


217-BPD-201 Summary of Changes 
Sage Therapeutics 
Version 2.0, Amendment 1  
 
 
5 
Purpose: Details regarding prohibited medications were added to Exclusion Criteria #13. 
The primary change occurs in Section 8.2, Subject Exclusion Criteria 
Added text: 
13. Subject is taking typical or atypical antipsychotics, MAOIs, and/or benzodiazepines at the Screening Visit.  
New text:  
13. Subject is taking typical or atypical antipsychotics, monoamine oxidase inhibitors (MAOIs), benzodiazepines or 
GABA A modulators other than the allowed mood stabilizers at the Screening Visit. 
Sections also affected by this change:   
• 
Synopsis  
• 
Section 9.2.2, Prohibited Medications 
Purpose: Details regarding breastfeeding were added to Exclusion Criteria #17. 
The primary change occurs in Section 8.2, Subject Exclusion Criteria 
Added text: 
17. Subject has a positive pregnancy test at the Screening Visit or on Day 1 (prior to administration of study drug) or, if 
she is breastfeeding at Screening or on Day 1 (prior to administration of study drug), she does not agree to temporarily 
cease giving breast milk to her child(ren) from just prior to receiving study drug on Day 1 until 7 days after the last 
dose of study drug. 
Sections also affected by this change:   
• 
Synopsis  
• 
Section 9.2.3, Other Restrictions 
Purpose: Details regarding CYP inhibitors were added to Exclusion Criteria #27. 
The primary change occurs in Section 8.2, Subject Exclusion Criteria 
Previous text: 
27. Subject has used any CYP inducer, such as such as rifampin, carbamazepine, ritonavir, enzalutamide, efavirenz, 
nevirapine, phenytoin, phenobarbital and St John’s Wort, within 28 days prior to the first dose of study drug. 
New text: 
27. Subject has used CYP inducers, such as rifampin, carbamazepine, ritonavir, enzalutamide, efavirenz, nevirapine, 
phenytoin, phenobarbital and St John’s Wort, within 28 days prior to the first dose of study drug. 
Sections also affected by this change:   
• 
Synopsis  
• 
Section 9.2.3, Other Restrictions 


217-BPD-201 Summary of Changes 
Sage Therapeutics 
Version 2.0, Amendment 1  
 
 
6 
Purpose: Updated details regarding drug materials. 
The primary change occurs in Section 10, Study Drug Materials and Management 
Added text: 
10.1 Description of Study Drug 
SAGE-217 is available as hard gelatin capsules containing a white to off-white powder. In addition to the specified 
amount of SAGE-217 Drug Substance, active SAGE-217 Capsules contain croscarmellose sodium, mannitol, silicified 
microcrystalline cellulose (SMCC), colloidal silicon dioxide, and sodium stearyl fumarate as excipients. Colloidal silicon 
dioxide may be either a component of the SMCC or a standalone excipient in the formulation. Capsules will be 
available in 10-mg, 20-mg, and 30-mg strengths to achieve the target dose of 20 mg or 30 mg. Subjects will be 
administered 2 capsules per dose in Part A. Subjects will be administered 1 capsule per dose in Part B. 
Matching placebo capsules are hard gelatin capsules containing only the excipients listed for the active capsule 
treatment.  
10.2. Study Drug Packaging and Labeling 
SAGE-217 and matched placebo will be provided to the clinic pharmacist and/or designated site staff responsible for 
dispensing the study drug in appropriately labeled, subject-specific kits each containing sealed unit doses. Each open-
label unit dose for Part A consists of 2 capsules. Blinded unit doses for Part B will consist of 1 capsule each. 
Section also affected by this change:   
• 
Synopsis  


217-BPD-201 Summary of Changes 
Sage Therapeutics 
Version 2.0, Amendment 1  
 
 
7 
Purpose: Updated language regarding reporting serious adverse events. 
The primary change occurs in Section 12.2.1.2, Serious Adverse Events (SAE). 
Added text: 
All SAEs that occur after any subject has been enrolled and throughout the duration of the study, whether or not they are 
related to the study, must be recorded on the SAE form provided by Sage Therapeutics within 24 hours of first 
awareness (Section 12.5). All SAEs should to be followed until the event resolved, the condition stabilized, was no 
longer considered clinically significant or the subject was lost to follow-up. 
Purpose: Adverse Event Language related to pregnancy was edited to align across program protocols. 
The primary change occurs in Section 12.4, Recording Adverse Events.  
Added text: 
Should a pregnancy occur, it must be reported and recorded on the Sage Therapeutics pregnancy notification form. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an investigational product may have 
interfered with the effectiveness of a contraceptive medication or a complication relating to the pregnancy occurs (eg, 
spontaneous abortion, which requires reporting as an SAE). All pregnancies occurring during this study are to be 
reported in the same time frame as SAEs (eg, within 24 hours of the site becoming aware of the pregnancy). 
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. Reports of congenital abnormalities/birth defects and spontaneous miscarriages should be 
reported and handled as SAEs.  
If the pregnancy ends for any reason before the anticipated date, the Investigator should notify Sage Therapeutics, or 
designee. At the completion of the pregnancy, the Investigator will document the outcome of the pregnancy. 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), the Investigator should follow the procedures 
for reporting an SAE. 
Sections also affected by this change:  
• 
Section 12.5, Reprting Serious Adverse Events 
 


Clinical Protocol
Sage Therapeutics, Inc.
217-BPD-201 v3.0
CONFIDENTIAL
1
1.
TITLE PAGE
A 2-PART STUDY (OPEN-LABEL FOLLOWED BY
DOUBLE-BLIND, RANDOMIZED, PLACEBO-
CONTROLLED, PARALLEL GROUP) OF THE SAFETY, 
TOLERABILITY, PHARMACOKINETICS, AND 
EFFICACY OF SAGE-217 IN THE TREATMENT OF 
SUBJECTS WITH BIPOLAR I/II DISORDER WITH A 
CURRENT MAJOR DEPRESSIVE EPISODE
PROTOCOL NUMBER: 217-BPD-201
Study Drug
SAGE-217
Clinical Phase
Phase 2
Sponsor
Sage Therapeutics, Inc.
215 First Street
Cambridge, MA 02142
Sponsor Contact
Tel:
email: 
Sponsor Medical Monitor
 MD, MBA
Tel:
email:
Date of Original Protocol
Date of Amendment 1
Date of Amendment 2
Version 1.0, 03 JUL 2018
Version 2.0, 13 SEP 2018
Version 3.0, 18 OCT 2018
Confidentiality Statement
The confidential information in this document is provided to you as an Investigator or consultant for 
review by you, your staff, and the applicable Institutional Review Board/Independent Ethics Committee.
Your acceptance of this document constitutes agreement that you will not disclose the information 
contained herein to others without written authorization from Sage Therapeutics, Inc.




Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-BPD-201 v3.0 
 
CONFIDENTIAL 
 
3 
 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for SAGE-217. I have read the 217-BPD-
201 clinical protocol and agree to conduct the study as outlined. I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
Date (DD Month YYYY) 
 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-BPD-201 v3.0 
 
CONFIDENTIAL 
 
4 
 
2. 
SYNOPSIS 
Name of Sponsor/Company: 
Sage Therapeutics 
Name of Investigational Product: 
SAGE-217 Capsule 
Name of Active Ingredient: 
SAGE-217 
Title of Study:  
A 2-Part Study (Open-label followed by Double-blind, Randomized, Placebo-controlled, Parallel 
Group) of the Safety, Tolerability, Pharmacokinetics, and Efficacy of SAGE-217 in the Treatment of 
Subjects with Bipolar I/II Disorder with a Current Major Depressive Episode 
Number of Sites and Study Location:  
Part A: Approximately 10 sites in the United States 
Part B: Approximately 40 sites in the United States 
Phase of Development: 2 
Planned Duration of participation: Up to 73 days (28-day Screening Period; 14-day Treatment 
Period, and 28-day [±3 days] Follow-up Period) 
Objectives: 
Part A Primary: 
• 
To evaluate the safety and tolerability of SAGE-217 in subjects with bipolar I or II disorder 
with a current major depressive episode (MDE). 
Part A Secondary:  
• 
To assess the efficacy of SAGE-217 in reducing depressive symptoms in subjects with bipolar 
I/II disorder with a current MDE. 
• 
To assess the effect of SAGE-217 on sleep.  
Part B Primary: 
• 
To assess the efficacy of SAGE-217 in reducing depressive symptoms in subjects with bipolar 
I/II disorder with a current MDE. 
Part B Secondary:  
• 
To evaluate the safety and tolerability of SAGE-217 in subjects with bipolar I/II disorder with 
a current MDE. 
• 
To assess the effect of SAGE-217 on sleep. 
 
 
 
 
 
 
 
 
 
 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-BPD-201 v3.0 
 
CONFIDENTIAL 
 
5 
 
Endpoints:  
Part A Primary: 
• 
The safety and tolerability of SAGE-217 as assessed by the frequency and severity of adverse 
events; changes from baseline in clinical laboratory measures, vital signs, and 
electrocardiogram (ECGs); and suicidal ideation and behavior using the Columbia Suicide 
Severity Rating Scale (C-SSRS); and mania using the Young Mania Rating Scale (YMRS). 
Part A Secondary: 
• 
The reduction in depressive symptoms, as assessed by: 
o Change from baseline in the 17-item Hamilton Depression Rating Scale (HAM-D) 
total score at Day 15 and all other time points  
o HAM-D response at Day 15 and all other time points  
o HAM-D remission at Day 15 and all other time points  
o Change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) 
total score at Day 15 and all other time points  
o Change from baseline in HAM-D individual item scores at Day 15 and all other time 
points  
o The response to the Clinical Global Impression scale for severity and improvement 
(CGI-S and CGI-I, respectively) at Day 15 and all other time points. 
• 
The reduction in insomnia severity, as assessed by Insomnia Severity Index (ISI). 
Part B Primary: 
• 
The primary endpoint in Part B is the reduction in depressive symptoms with SAGE-217 
treatment, as assessed by the change from baseline in the HAM-D total score at Day 15. 
Part B Secondary: 
• 
The reduction in depressive symptoms, as assessed by: 
o Change from baseline in HAM-D total score at all other time points 
o HAM-D response at Day 15 and all other time points  
o HAM-D remission at Day 15 and all other time points  
o Change from baseline in the MADRS total score at Day 15 and all other time points  
o Change from baseline in HAM-D individual item scores at Day 15 and all other time 
points  
o CGI-S and CGI-I response at Day 15 and all other time points. 
• 
The safety and tolerability of SAGE-217 as assessed by the frequency and severity of adverse 
events; changes from baseline in clinical laboratory measures, vital signs, and ECGs; and 
suicidal ideation and behavior using the C-SSRS; and mania using the YMRS. 
• 
The reduction in insomnia severity, as assessed by ISI. 
 
 
 
 
 
 
 
 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-BPD-201 v3.0 
 
CONFIDENTIAL 
 
6 
 
Study Description:   
This study will be conducted in 2 sequential parts: Part A (open-label) and Part B (randomized, double-
blind, placebo-controlled, parallel group). Part B will be initiated pending the review of Part A data. 
The methods of the 2 parts will be identical unless otherwise noted. Subjects who participate in Part A 
will not be allowed to participate in Part B. The study is designed to assess the safety, tolerability, 
 
and efficacy of SAGE-217 in adult subjects with bipolar I/II disorder, who are currently experiencing 
an MDE.  
The assessments are summarized in the Schedule of Events (Table 1). 
Screening begins with the signing of the informed consent form at the Screening Visit. The diagnosis 
of bipolar I or II disorder will be made using the Structured Clinical Interview for Diagnostic and 
Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) for clinical trials (SCID-5-CT) 
performed by a qualified healthcare professional.  
Beginning on Day 1, qualified subjects will self-administer the study drug once daily in the evening 
with food for 14 days. In Part A, all subjects will receive SAGE-217. For Part B, subjects will be 
randomized in a 1:1 ratio to receive SAGE-217 or placebo; randomization will be stratified based on 
use of mood stabilizers (Y/N). Subjects on antidepressants or mood stabilizers (lamotrigine, lithium, 
and valproic acid only) that have been taken at the same dose for at least 60 days prior to Day 1 are to 
continue the stable dose throughout the treatment period.  
If at any time, 30 mg is not tolerated, as assessed by the occurrence of a severe AE judged by the 
investigator to be related to study drug, the dose on the next day will be reduced to 20 mg and 
continued for the remainder of the treatment period. Dose adjustments related to moderate AEs will be 
judged by the Investigator. If a dose adjustment from 30 mg to 20 mg is deemed necessary by the 
Investigator, the subject will return to the site for the adjusted dose to be dispensed. Subjects who 
cannot tolerate the 20-mg dose at any time will be discontinued from study drug.  
If at any time during the study, a subject has a YMRS score of ≥13, the Investigator will clinically 
assess the subject for a manic or hypomanic switch. If the clinical assessment is consistent with 
hypomania or mania, the subject will be discontinued from study drug and treated as clinically 
appropriate. These incidents will be documented as AEs. 
Subjects will return to the study center during the treatment and follow-up periods as outlined in 
Table 1. 
Number of Subjects (planned):   
Part A: Approximately 30 subjects will be dosed. 
Part B: Approximately 132 subjects will be randomized and dosed to obtain a total of 112 evaluable 
subjects. 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-BPD-201 v3.0 
 
CONFIDENTIAL 
 
7 
 
Eligibility criteria:  
Inclusion Criteria: 
1. Subject has signed an informed consent form (ICF) prior to the conduct of any study-specific 
procedures. 
2. Subject agrees to adhere to the study requirements, including use of prior, concomitant, and 
prohibited medications. 
3. Subject is a man or woman, aged 18 to 65 years, inclusive, at Screening. 
4. 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. 
5. Subject has a documented history of hypomanic or manic episode (verified by medical records 
and/or treating healthcare professional) and a diagnosis of bipolar I or bipolar II disorder with 
a current MDE as per DSM-5 SCID-5-CT. 
6. Subject has a HAM-D score of ≥22 at Screening.  
7. Female subject agrees to use one of the following methods of contraception during 
participation in the study and for 30 days following the last dose of study drug, unless they are 
postmenopausal (defined as no menses for 12 months without an alternative medical cause and 
confirmed by follicle stimulating hormone [FSH] level ≥40 mIU/mL) and/or surgically sterile 
(hysterectomy or bilateral oophorectomy), or in sexual relationship(s) which do not carry a risk 
of pregnancy (eg, same-sex relationship(s)): 
• 
Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation. 
• 
Oral, injectable, or implantable progestogen-only hormonal contraception associated with 
inhibition of ovulation.  
• 
Intrauterine device. 
• 
Intrauterine hormone-releasing system. 
• 
Bilateral tubal ligation/occlusion. 
• 
Vasectomized partner. 
• 
Sexual abstinence (no sexual intercourse).  
8. Male subject agrees to use an acceptable method of effective contraception for the duration of 
study and for 5 days after receiving the last dose of the study drug, unless the subject is in 
sexual relationship(s) which do not carry a risk of pregnancy (eg, same-sex relationship(s)). 
Acceptable methods of effective contraception for males includes sexual abstinence, 
vasectomy, or a condom with spermicide used together with highly effective female 
contraception methods (if the female partner is of child-bearing potential, see Inclusion 
Criteria #7 for acceptable method of contraception for females). 
9. 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. 
Exclusion Criteria: 
1. Subject has a history of suicide attempt within the last 2 years. 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-BPD-201 v3.0 
 
CONFIDENTIAL 
 
8 
 
2. Subject has current suicidal ideation with plans based on Investigator clinical assessment 
and/or the C-SSRS response at Screening or Day 1. 
3. Subject has a history of rapid cycling bipolar disorder as per DSM-5 SCID-5-CT. 
4. Subject’s current depressive episode meets the DSM-5 specifier criteria for mixed features. 
5. Subject has ≥25% reduction in HAM-D score from Screening to Day 1. 
6. 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. 
7. Subject has abnormal liver function as shown by an abnormal liver function profile at 
screening (eg, repeated values of aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), or total bilirubin ≥2x the upper limit of normal). 
8. Subject has a clinically significant abnormal 12-lead ECG at the Screening or Day 1 visits. 
NOTE: mean QT interval calculated using the Fridericia method (QTcF) of >450 msec in male 
or >470 msec in female subjects will be the basis for exclusion from the study.  
9. Subject has a YMRS score ≥13 at Screening or Day 1. 
10. Subject presents for the study receiving a mood stabilizer other than lamotrigine, lithium, or 
valproic acid. 
11. Subject presents for the study receiving antidepressants and mood stabilizers, which have 
not been taken at the same dose for at least 60 days prior to Day 1. 
12. Subject that presents for the study receiving psychotropic medications and does not intend to 
continue the current treatment regimen during the treatment period.  
13. Subject is taking benzodiazepines or GABAA modulators/GABA-containing agents (eg, 
eszopiclone, zopiclone, zaleplon, and zolpidem) at Day -28. 
14. Subject has a history of severe rashes or Stevens-Johnson Syndrome associated with 
lamotrigine and is currently taking lamotrigine. 
15. Subject’s current depressive episode is treatment resistant; defined as persistent depressive 
symptoms despite treatment with adequate doses of antidepressants from two different classes 
for an adequate amount of time (ie, at least 4 weeks of treatment). This will be assessed using 
the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire. 
16. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds. 
17. Subject has a positive pregnancy test at the Screening Visit or on Day 1 (prior to 
administration of study drug) or, if she is breastfeeding at Screening or on Day 1 (prior to 
administration of study drug), she does not agree to temporarily cease giving breast milk to her 
child(ren) from just prior to receiving study drug on Day 1 until 7 days after the last dose of 
study drug. 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-BPD-201 v3.0 
 
CONFIDENTIAL 
 
9 
 
18. Subject has detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) and 
HCV viral load, or human immunodeficiency virus (HIV) antibody at screening. 
19. Subject has active psychosis per Investigator assessment. 
20. Subject has a medical history of seizures. 
21. Subject has a medical history schizophrenia, and/or schizoaffective disorder. 
22. Subject has a history of mild, moderate, or severe substance use disorder diagnosed using 
DSM-5 criteria in the 12 months prior to screening. 
23. Subject has a positive drug and/or alcohol screen at screening or on Day 1 prior to dosing. 
24. Subject has had exposure to another investigational medication or device within 30 days prior 
to the Screening visit. 
25. Subject has been previously treated or randomized in any study using SAGE-217. Subjects 
who participate in Part A are not eligible to participate in Part B. 
26. Subject has used any known strong inhibitors of cytochrome P450 (CYP)3A4 within 28 days 
or five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, or Seville 
oranges, or products containing these within 14 days prior to receiving the first dose of study 
drug. 
27. Subject has used CYP inducers, such as rifampin, carbamazepine, ritonavir, enzalutamide, 
efavirenz, nevirapine, phenytoin, phenobarbital and St John’s Wort, within 28 days prior to the 
first dose of study drug. 
28. Subject plans to undergo elective surgery during participation in the study. 
29. Subject is taking non-GABA anti-insomnia medications (eg, melatonin, Benadryl [anti-
histamines], trazodone, low-dose quetiapine, mirtazapine, etc) at Day -14 .  
SAGE-217 dosage and mode of administration:  
SAGE-217 is available as hard gelatin capsules containing a white to off-white powder. In addition to 
SAGE-217 Drug Substance, the SAGE-217 capsules contain croscarmellose sodium, mannitol, 
silicified microcrystalline cellulose (SMCC), colloidal silicon dioxide, and sodium stearyl fumarate as 
excipients. Colloidal silicon dioxide may be either a component of the SMCC or a standalone excipient 
in the formulation. Subjects will take the assigned dose orally once daily in the evening with food. 
Reference therapy, dosage and mode of administration (Part B only):  
In Part B, placebo capsules are visually matched to the active capsules and are available as hard gelatin 
capsules containing only the excipients listed above for the active capsule treatment. Study drug will 
be administered orally once daily in the evening  with food. 
Duration of Treatment: 14 days 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-BPD-201 v3.0 
 
CONFIDENTIAL 
 
10 
 
Statistical methods:   
A separate statistical analysis plan (SAP) for each part (Parts A and B) will provide a detailed 
description of the analyses to be performed in the respective part of the study. The SAPs will be 
finalized and approved prior to database lock. Any deviations from or changes to the SAP following 
database lock will be described in detail in the clinical study report. 
General: 
The data from Parts A and B will be analyzed separately. For the purpose of all safety and efficacy 
analyses where applicable, baseline is defined as the last available measurement prior to the start of 
study drug administration.  
Continuous endpoints will be summarized with n, mean, standard deviation, median, minimum, and 
maximum. In addition, change from baseline values will be calculated at each time point and 
summarized descriptively. For categorical endpoints, descriptive summaries will include counts and 
percentages. 
Analysis Sets:  
Randomized set (Part B only) will be defined as all subjects who are randomized. This analysis set will 
be used of all data listings in Part B. Data listings for Part A will be based on Safety or Efficacy Set, as 
appropriate. 
The Safety Set, defined as all subjects received at least 1 dose of study drug, will be used to provide 
descriptive summaries of safety data.  
The Efficacy Set, defined as all subjects who are in Safety Set and have at least one post-baseline 
HAM-D evaluation, will be used to analyze efficacy data unless otherwise specified. 
 
Safety Analysis:  
The overall incidence of adverse events will be summarized by Medical Dictionary for Regulatory 
Activities (MedDRA) system organ class and preferred term. Data for vital signs, clinical laboratory 
measurements, ECG, and concomitant medication usage will also be summarized.  
Safety data will be summarized and examined for possible relationships between subject characteristics 
and plasma SAGE-217 concentrations, as appropriate. Suicidality data collected using the C-SSRS and 
evaluation of mania collected using the YMRS at baseline and at each visit during the active Treatment 
Period will be listed for all subjects. Out-of-range safety endpoints may be categorized as low or high, 
where applicable. Subjects will be summarized according to treatment received for the purpose of 
safety.  
Efficacy Analysis:  
The primary endpoint in Part B, the change from baseline in HAM-D total score, will be analyzed 
using a mixed effects model for repeated measures (MMRM); the model will include treatment, 
baseline HAM-D total score, stratification factor, assessment time point, and time point-by-treatment 
as explanatory variables. All explanatory variables will be considered as fixed effects and the subject 
effect will be considered random in the model. All post-baseline time points will be included in the 
model. The primary comparison will be between SAGE-217 and matching placebo at Day 15. Model-
based point estimates (ie, least squares [LS] means, 95% confidence intervals, and p-values) will be 
reported. An unstructured covariance structure will be used to model the within-subject errors. Other 
continuous endpoints will be analyzed using similar methods.  
Other efficacy analyses, including those in Part A, will be specified in the SAP. In general, data will be 
analyzed using appropriate descriptive statistics or pre-specified statistical methods as applicable; 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-BPD-201 v3.0 
 
CONFIDENTIAL 
 
11 
 
subject listings will be provided for all efficacy data. Subjects will be analyzed according to 
randomized treatment for the purpose of efficacy unless otherwise specified. 
 
 
 
 
 
Sample Size Calculation 
Part A: The sample size of approximately 30 subjects was selected based on clinical and not statistical 
considerations. 
Part B: Assuming a two-sided alpha level of 0.05, a sample size of 112 total evaluable subjects (56 per 
treatment group) would provide 80% power to detect a placebo-adjusted treatment difference of 
approximately 4 points in the primary endpoint, change from baseline in HAM-D total score at Day 15, 
assuming standard deviation (SD) of 7.5 points.  
Assuming a 15% dropout rate, approximately 132 total randomized subjects will be required to obtain 
a total of 112 evaluable subjects. Evaluable subjects are defined as those randomized subjects who 
receive study drug and have a valid baseline and at least 1 post-baseline HAM-D assessment. 
Additional subjects may be randomized if the drop-out rate is higher than 15%.  
 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-BPD-201 v3.0 
 
CONFIDENTIAL 
 
12 
 
Table 1: 
Schedule of Events 
Study Period 
Screening 
Period 
Treatment Period 
Follow-up Perioda 
Visit Day 
D-28 to  
D-1 
D1 
D3 
(+1d) 
D8 
(±1d) 
D12 
(±1d) 
D15 
(±1d)/EOTa 
D21 
(±3d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)/ 
ET 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical/Family History 
X 
 
 
 
 
 
 
 
 
 
SCID-5-CT 
X 
 
 
 
 
 
 
 
 
 
MGH-ATRQ 
X 
 
 
 
 
 
 
 
 
 
Serum FSH test 
X 
 
 
 
 
 
 
 
 
 
Randomization (Part B 
only) 
 
X 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
 
X 
 
 
 
X 
Body Weight/Heightc 
X 
 
 
 
 
X (wt only) 
 
 
 
X (wt 
only) 
Clinical Laboratory 
Assessmentsd 
X 
X 
 
X 
 
X 
X 
X 
 
X 
Drug & Alcohol Screene 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Testf 
X 
X 
 
 
 
X 
 
X 
 
X 
Hepatitis & HIV 
Screen 
X 
 
 
 
 
 
 
 
 
 
Vital Signsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGj 
X 
X 
X 
 
 
X 
 
 
 
X 
C-SSRSk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAM-Dl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MADRSl 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-S 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
YMRSl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ISI 
 
X 
 
X 
 
X 
X 
X 
 
X 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-BPD-201 v3.0 
 
CONFIDENTIAL 
 
13 
 
Study Period 
Screening 
Period 
Treatment Period 
Follow-up Perioda 
Visit Day 
D-28 to  
D-1 
D1 
D3 
(+1d) 
D8 
(±1d) 
D12 
(±1d) 
D15 
(±1d)/EOTa 
D21 
(±3d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)/ 
ET 
Study Drug Dispensationo 
 
X 
 
X 
 
 
 
 
 
 
Study Drug Administration 
 
X (Day 1-14) 
 
 
 
 
 
Study Drug 
Accountability/Return 
 
 
X 
X 
X 
X 
 
 
 
 
Adverse Events/Serious 
Adverse Eventsp 
X 
Prior/Concomitant 
Medications/ Proceduresq 
X 
CGI-I = Clinical Global Impression - Improvement; CGI-S – Clinical Global Impression - Severity; C-SSRS = Columbia Suicide 
Severity Rating Scale; D = day; EOT = end of treatment; ECG = electrocardiogram; ET = early termination; 
 
 FSH = follicle stimulating hormone; HAM-D = Hamilton Rating Scale for Depression, 17-item; HIV = 
human immunodeficiency virus; ISI = Insomnia Severity Index; MADRS = Montgomery-Åsberg Depression Rating Scale; 
MGH-ATRQ = Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; O = optional; 
 
 SCID-5-CT = Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition for clinical trials; 
 
 YMRS = Young Mania 
Rating Scale 
a Subjects who discontinue treatment early should return to the site for an EOT visit as soon as possible, preferably 
the day after treatment is discontinued. Follow-up visits should take place every 7 days after the last dose of 
treatment for a total of 4 follow-up visits. If at any time after the EOT visit, a subject decides to terminate the 
study, the subject should return for an ET visit. The EOT and ET visits can be on the same day if a subject 
discontinues study drug and terminates the study on the same day during a clinic visit; in this case, all events 
scheduled for both visits will be conducted.  
b A serum follicle stimulating hormone test will be conducted for female subjects at Screening to confirm whether a 
female subject with ≥12 months of spontaneous amenorrhea meets the protocol-defined criteria for being post-
menopausal. 
c Height measured at screening only 
d Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. Laboratory 
assessments are to be completed in the morning. 
e Urine toxicology for selected drugs of abuse, and breath test for alcohol (as per the standard procedures at each 
site).  
f For women of child-bearing potential, serum pregnancy test at screening and urine pregnancy test at all other 
scheduled timepoints. 
 
 
 
 
i Vital signs include oral temperature (°C), respiratory rate, heart rate, pulse oximetry, 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 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 will be obtained first.  
j Triplicate 12-lead ECGs will be performed with the subject in the supine position. When ECG 
 sample 
collection occur during the same visit, ECGs will be collected first. 
k 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. 
l For MADRS, HAM-D, and YMRS, the “Since Last Evaluation” forms will be completed at all subsequent time 
points following the initial assessment. 


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o Additional unscheduled dispensation visits may be needed for dose reductions. 
p AEs/SAEs will be collected starting at the time of informed consent and throughout the duration of the subject’s 
participation in the study.  
q Prior medications will be collected at Screening and concomitant medications will be collected at each subsequent 
visit. All medications taken within 30 days prior to Screening through the duration of the study will be recorded. In 
addition, all psychotropic medications taken within 6 months prior to Screening will be recorded. 
 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............15 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................19 
5. 
INTRODUCTION ......................................................................................................21 
5.1. 
Background of Bipolar Disorders and Unmet Medical Need .....................................21 
5.2. 
SAGE-217 ...................................................................................................................22 
5.3. 
Potential Risks and Benefits .......................................................................................23 
5.4. 
Dose Justification ........................................................................................................23 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................24 
6.1. 
Study Objective ..........................................................................................................24 
6.1.1. 
Primary Objective .......................................................................................................24 
6.1.2. 
Secondary Objectives .................................................................................................24 
 
24 
6.2. 
Endpoints ....................................................................................................................25 
6.2.1. 
Primary Endpoint ........................................................................................................25 
6.2.2. 
Secondary Endpoints ..................................................................................................25 
 
26 
7. 
INVESTIGATIONAL PLAN .....................................................................................27 
7.1. 
Overall Study Design ..................................................................................................27 
7.2. 
Number of Subjects ....................................................................................................28 
7.3. 
Treatment Assignment ................................................................................................28 
7.4. 
Dose Adjustment Criteria ...........................................................................................28 
7.5. 
Study Termination ......................................................................................................29 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................30 
8.1. 
Subject Inclusion Criteria ...........................................................................................30 
8.2. 
Subject Exclusion Criteria ..........................................................................................31 
8.3. 
Subject Withdrawal Criteria .......................................................................................32 
8.3.1. 
Withdrawal from the Study or Discontinuation of Study Drug ..................................32 
8.3.2. 
Replacement of Subjects .............................................................................................33 
9. 
TREATMENT OF SUBJECTS ..................................................................................35 


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9.1. 
Study Drug ..................................................................................................................35 
9.2. 
Prior Medications, Concomitant Medications, and Restrictions ................................35 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................35 
9.2.2. 
Prohibited Medications ...............................................................................................35 
9.2.3. 
Other Restrictions .......................................................................................................36 
9.3. 
Treatment Adherence ..................................................................................................36 
9.4. 
Randomization and Blinding ......................................................................................36 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................38 
10.1. 
Description of Study Drug ..........................................................................................38 
10.2. 
Study Drug Packaging and Labeling ..........................................................................38 
10.3. 
Study Drug Storage .....................................................................................................38 
10.4. 
Study Drug Preparation ..............................................................................................38 
10.5. 
Study Drug Administration.........................................................................................38 
10.6. 
Study Drug Accountability .........................................................................................38 
10.7. 
Study Drug Handling and Disposal ............................................................................39 
11. 
ASSESSMENT OF EFFICACY 
 .............................40 
11.1. 
Efficacy Assessments .................................................................................................40 
11.1.1. 
Hamilton Rating Scale for Depression (HAM-D) ......................................................40 
11.1.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) ........................................40 
11.1.3. 
Clinical Global Impression (CGI) ..............................................................................40 
11.1.4. 
Insomnia Severity Index (ISI) ....................................................................................41 
 
41 
 
41 
 
42 
 
42 
 
42 
 
42 
 
42 
12. 
ASSESSMENT OF SAFETY .....................................................................................43 
12.1. 
Safety Parameters .......................................................................................................43 
12.1.1. 
Demographic/Medical History ...................................................................................43 
12.1.2. 
Weight and Height ......................................................................................................43 
12.1.3. 
Physical Examination .................................................................................................43 


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12.1.4. 
Vital Signs ..................................................................................................................43 
12.1.5. 
Electrocardiogram (ECG) ...........................................................................................43 
12.1.6. 
Laboratory Assessments .............................................................................................44 
12.1.6.1. 
Drugs of Abuse and Alcohol ......................................................................................45 
12.1.6.2. 
Pregnancy Screen ........................................................................................................46 
12.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................46 
12.1.8. 
Young Mania Rating Scale (YMRS) ..........................................................................46 
12.2. 
Adverse and Serious Adverse Events .........................................................................46 
12.2.1. 
Definition of Adverse Events .....................................................................................46 
12.2.1.1. 
Adverse Event (AE) ....................................................................................................46 
12.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................47 
12.3. 
Relationship to Study Drug ........................................................................................47 
12.4. 
Recording Adverse Events .........................................................................................48 
12.5. 
Reporting Serious Adverse Events .............................................................................48 
12.6. 
Emergency Identification of Study Drug ....................................................................49 
13. 
STATISTICS ..............................................................................................................51 
13.1. 
Data Analysis Sets ......................................................................................................51 
13.2. 
Handling of Missing Data ...........................................................................................51 
13.3. 
General Considerations ...............................................................................................51 
13.4. 
Demographics and Baseline Characteristics ...............................................................51 
13.5. 
Efficacy Analysis ........................................................................................................51 
13.6. 
Safety Analyses ..........................................................................................................52 
13.6.1. 
Adverse Events ...........................................................................................................52 
13.6.2. 
Clinical Laboratory Evaluations .................................................................................52 
13.6.3. 
Physical Examinations ................................................................................................52 
13.6.4. 
Vital Signs ..................................................................................................................52 
13.6.5. 
12-Lead Electrocardiogram ........................................................................................53 
13.6.6. 
Prior and Concomitant Medications ...........................................................................53 
13.6.7. 
Columbia Suicide Severity Rating Scale ....................................................................53 
13.6.8. 
Young Mania Rating Scale .........................................................................................53 
 
53 
13.8. 
Determination of Sample Size ....................................................................................53 
13.8.1. 
Part A ..........................................................................................................................53 


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13.8.2. 
Part B ..........................................................................................................................54 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................55 
14.1. 
Study Monitoring ........................................................................................................55 
14.2. 
Audits and Inspections ................................................................................................55 
14.3. 
Protocol Deviations ....................................................................................................55 
14.4. 
Institutional Review Board (IRB) or Ethics Committee (EC) ....................................55 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................56 
16. 
ETHICS ......................................................................................................................57 
16.1. 
Ethics Review .............................................................................................................57 
16.2. 
Ethical Conduct of the Study ......................................................................................57 
16.3. 
Written Informed Consent ..........................................................................................57 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................58 
17.1. 
Inspection of Records .................................................................................................58 
17.2. 
Retention of Records ..................................................................................................58 
18. 
PUBLICATION POLICY ..........................................................................................59 
19. 
LIST OF REFERENCES ............................................................................................60 
 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................12 
Table 2: 
Abbreviations and specialist terms .............................................................................19 
Table 3: 
Clinical Laboratory Tests ...........................................................................................44 
Table 4: 
Relationship to Study Drug ........................................................................................47 
 
LIST OF FIGURES 
Figure 1: 
Study Design (Part A) .................................................................................................27 
Figure 2: 
Study Design (Part B) .................................................................................................28 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and specialist terms  
Abbreviation or specialist term 
Explanation 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CGI-I 
Clinical Global Impression scale for improvement 
CGI-S 
Clinical Global Impression scale for severity 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CYP 
cytochrome P450 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition 
EC 
ethics committee 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EOT 
end of treatment 
ET 
early termination 
 
 
FSH 
follicle-stimulating hormone 
GABA 
γ-aminobutyric acid 
HAM-D 
Hamilton Depression Rating Scale 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ID 
identification 
IRT 
interactive response technology 
ISI 
Insomnia Severity Index 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MDD 
major depressive disorder 
MDE 
major depressive episode 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGH-ATRQ 
Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire 


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Table 2: 
Abbreviations and specialist terms  (Continued) 
Abbreviation or specialist term 
Explanation 
MMRM 
mixed effects model for repeated measures 
PI 
Principal Investigator; the investigator who leads the study 
conduct at an individual study center. Every study center has a 
principal investigator. 
 
 
QTcF 
QT corrected according to Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCID-5-CT 
Structured Clinical Interview for Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition for clinical trials 
SD 
standard deviation 
 
 
 
 
TEAE 
treatment-emergent adverse event 
YMRS 
Young Mania Rating Scale 
 


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5. 
INTRODUCTION 
5.1. 
Background of Bipolar Disorders and Unmet Medical Need 
Bipolar disorder is a chronic and episodic illness that is associated with significant disability 
worldwide (Sachs 2007). The Global Burden of Disease Study revealed that in 2013, there were 
48.8 million cases of bipolar disorder globally (Ferrari 2016). Bipolar disorder accounted for 
9.9 million disability-adjusted life years (DALYs) globally, explaining 0.4% of total DALYs and 
1.3% of total years lived with disability.  
There are subtypes of bipolar disorder; this study includes the bipolar I and II subtypes. Bipolar I 
is characterized by a manic episode, whereas bipolar II is characterized by a hypomanic episode. 
The difference in the severity of the manic features relies on functional impairment that is caused 
by these episodes (DSM-5). The National Comorbidity Survey estimate of the lifetime 
prevalence of bipolar disorder is 2.1% in the US population when bipolar I disorder and 
bipolar II Disorder are combined (Merikangas 2007). 
While the manic or hypomanic episodes represent distinct departure from the baseline mood 
state and easily attract attention, evidence suggests that depressive episodes of both bipolar I and 
II are associated with more disability than any other aspect of the illness. A seminal long-term 
study of patients with bipolar I disorder demonstrated that over the 13-year follow-up period, 
patients were symptomatic about 47% of the time, and depressive symptoms were present in 
32% of the follow-up weeks vs manic features, which were present in 9% (Judd 2002). A similar 
analysis in patients with bipolar II disorder with a longer follow up of up to 20 years found that 
patients were symptomatic more than half of the time (54%) where depressive symptoms 
dominated the course at 50% of the follow-up weeks versus 1.3% for the hypomanic symptoms 
(Judd 2003). A study in patients with unipolar depression found a prevalence of depressive 
symptoms 47% of the time (Judd 1998), suggesting a comparable time spent with depressive 
symptoms in the bipolar spectrum. These naturalistic studies have also found that about half the 
time patients reported taking psychotropic medications. In another large-scale study with a 
follow-up period of up to 2 years, 58% of nearly 1500 patients with bipolar disorder who were 
symptomatic at study entry achieved recovery (Perlis 2006). Similarly, during the follow-up 
period, 49% of these individuals experienced recurrent episodes, where depressive episodes 
(38%) outweighed manic, hypomanic, or mixed episodes combined (13.8%). In the Stanley 
Foundation Bipolar Network Study, in which year-long, daily clinician ratings were included, 
despite treatment with an average of 4.1 psychotropic medications, patients with bipolar disorder 
spent 3 times as much time with depressive symptoms as manic symptoms (Post 2003). 
There are only 3 medications approved in the US for the treatment of bipolar depression, 
(lurasidone, olanzapine-fluoxetine combination, and quetiapine), all of which include atypical 
antipsychotics that are associated with significant adverse metabolic effects. None of the 
currently available antidepressants are indicated for bipolar depression due to their limited 
efficacy, and the possibility that their use may be associated with a manic switch and rapid 
cycling. While some studies reported varying levels of efficacy with antidepressants 
(Gijsman 2004), a large-scale, double-blind, placebo-controlled clinical trial sponsored by the 
National Institutes of Mental Health, The Systematic Treatment Enhancement Program for 
Bipolar Disorder (STEP-BD), found that only 23.5% of patients with bipolar depression 
receiving a mood stabilizer and adjunctive antidepressants versus 27.3% of those receiving a 


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mood stabilizer and placebo experienced a durable recovery, confirming the lack of effectiveness 
of antidepressants in bipolar depression (Sachs 2007). The tolerability profile of the approved 
atypical antipsychotics and limited efficacy of available antidepressants highlight the critical 
unmet need in the treatment of bipolar depression. 
In 1998, the lifetime cost of bipolar disorder in the US was estimated at $24 billion. The cost of a 
single manic episode was estimated at $11,720 to $624,785 for persons with 
nonresponsive/chronic episodes (Begley 1998); the cost of bipolar depression specifically, is less 
well studied, however, available estimates indicate a higher cost associated with bipolar 
depression than for mania (Bowden 2004). 
Kessler has studied the impact of mood disorders on work performance in a representative 
sample of over 3,000 US workers (Kessler 2006). Bipolar disorder and major depressive disorder 
were associated with 65.5 and 27.2 lost workdays per worker per year, respectively. Moreover, it 
was found that the increase in bipolar disorder was attributable to depressive symptoms rather 
than manic episodes in bipolar disorder. 
Taken together, these findings point to substantial predominance of depressive symptoms across 
the spectrum of bipolar disorder. In particular, they also highlight the importance of successful 
depressive symptom control, and an unmet need in the treatment of depressive episodes for both 
bipolar I and bipolar II disorder. 
5.2. 
SAGE-217 
SAGE-217 is a positive allosteric modulator of γ-aminobutyric acid (GABA)A 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. 
Data from an open-label portion of the Phase 2a study of SAGE-217 administered to subjects 
with moderate to severe major depressive disorder (MDD) showed clinically significant 
improvements from baseline in depression scale scores (HAM-D, Montgomery-Åsberg 
Depression Rating Scale [MADRS], and Clinical Global Impression – Improvement [CGI-I]) as 
early as Day 2 of the 14-day treatment period, with durable responses following the end of 
treatment. This result was further supported by the randomized, double-blind portion of this 
study (N=89) in which a rapid and substantial decrease in HAM-D scores was observed at 
Day 15 (primary endpoint), starting at Day 2. This response pattern was also observed with other 
efficacy scales, including MADRS and CGI-I. Statistically significant differences from the 
placebo group favoring the SAGE-217 arm were observed for 2 weeks in the follow-up period. 
SAGE-217 has been generally well tolerated in clinical studies to date. The most common 
treatment-emergent adverse events (TEAEs) were sedation, somnolence, and dizziness. Most 
AEs were reported as mild or moderate in intensity. Among the over 260 subjects exposed to 
SAGE-217 in clinical trials, there have been no deaths and only one subject with essential tremor 


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experienced a serious adverse event (SAE) of transient confusion leading to discontinuation of 
study drug. No other SAEs have been reported in any study of SAGE-217.  
Additional information on nonclinical and clinical data is provided in the Investigator’s 
Brochure.  
5.3. 
Potential Risks and Benefits 
Non-serious events of sedation, somnolence, and dizziness were the most commonly reported 
AEs with SAGE-217. Given the outcome of the Phase 2 study of SAGE-217 in subjects with 
MDD and the current significant unmet need in the treatment of depressive episodes associated 
with bipolar I/II disorders, a favorable risk-benefit balance and investigation of SAGE-217 in 
patients with bipolar I/II disorders are justified. 
5.4. 
Dose Justification 
The dose of SAGE-217 to be administered in this study (30 mg) was determined based on the 
maximum tolerated dose in the multiple ascending dose study of SAGE-217 in healthy subjects, 
and is the same dose level that has been used and generally well tolerated in clinical studies in 
various patient populations, including patients with MDD. Due to the observed improved 
tolerability of sedation/somnolence effects when taken in the evening in previous clinical studies, 
SAGE-217 will be administered in the evening in this study as well.  
With respect to the duration of treatment course, a 14-day study drug administration is planned. 
This is based on previous clinical trial data with SAGE-217, demonstrating substantial 
improvement in depressive symptoms in patients with MDD, starting within the first week of 
treatment. 


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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Study Objective 
6.1.1. 
Primary Objective 
Part A 
The primary objective of Part A of this study is to evaluate the safety and tolerability of 
SAGE-217 in subjects with bipolar I/II disorder with a current major depressive episode (MDE). 
Part B 
The primary objective of Part B of this study is to assess the efficacy of SAGE-217 in reducing 
depressive symptoms in subjects with bipolar I/II disorder with a current MDE. 
6.1.2. 
Secondary Objectives 
Part A 
Secondary objectives of Part A of this study are: 
• To assess the efficacy of SAGE-217 in reducing depressive symptoms in subjects 
with bipolar I/II disorder with a current MDE. 
• To assess the effect of SAGE-217 on sleep. 
Part B 
Secondary objectives of Part B of this study are: 
• To evaluate the safety and tolerability of SAGE-217 in subjects with bipolar I/II 
disorder with a current MDE. 
• To assess the effect of SAGE-217 on sleep. 
 
 
 
 
 
 
 
 
 
 
 
 


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6.2. 
Endpoints 
6.2.1. 
Primary Endpoint 
Part A 
The primary endpoint for Part A of this study is the safety and tolerability of SAGE-217, as 
assessed by the frequency and severity of adverse events (AEs); changes from baseline in clinical 
laboratory measures, vital signs, and electrocardiograms (ECGs); suicidal ideation and behavior 
using the Columbia Suicide Severity Rating Scale (C-SSRS); and mania using the Young Mania 
Rating Scale (YMRS). 
Part B 
The primary endpoint of Part B of this study is the reduction in depressive symptoms with 
SAGE-217 treatment, as assessed by the change from baseline in the 17-item HAM-D total score 
at Day 15. 
6.2.2. 
Secondary Endpoints 
Part A 
Secondary endpoints of Part A of this study are: 
• The reduction in depressive symptoms, as assessed by: 
− Change from baseline in the 17-item HAM-D total score at Day 15 and all other 
time points 
− HAM-D response at Day 15 and all other time points 
− HAM-D remission at Day 15 and all other time points  
− Change from baseline in the MADRS total score at Day 15 and all other time 
points  
− Change from baseline in HAM-D individual item scores at Day 15 and all other 
time points  
− The response to the CGI-S and CGI-I at Day 15 and all other time points. 
• The reduction in insomnia severity as assessed by the Insomnia Severity Index (ISI). 
Part B 
Secondary endpoints of Part B of this study are: 
• The reduction in depressive symptoms, as assessed by: 
− Change from baseline in total HAM-D score at all other time points 
− HAM-D response at Day 15 and all other time points  
− HAM-D remission at Day 15 and all other time points  


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− Change from baseline in the MADRS total score at Day 15 and all other time 
points  
− Change from baseline in HAM-D individual item scores at Day 15 and all other 
time points  
− CGI-S and CGI-I response at Day 15 and all other time points. 
• The safety and tolerability of SAGE-217 as assessed by the frequency and severity of 
AEs; changes from baseline in clinical laboratory measures, vital signs, and ECGs; 
and suicidal ideation and behavior using the C-SSRS, and the YMRS. 
• The reduction in insomnia severity, as assessed by the ISI. 
 
 
 
 
 
 
 
 
 
 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This study will be conducted in 2 sequential parts: Part A (open-label) and Part B (randomized, 
double-blind, placebo-controlled, parallel group). Part B will be initiated pending the review of 
Part A data.The methods of the 2 parts will be identical unless otherwise noted. The study is 
designed to assess the safety, tolerability, 
 and efficacy of SAGE-217 in adult subjects with 
bipolar I/II disorder, who are currently experiencing an MDE. 
Screening begins with the signing of the informed consent form (ICF) at the Screening Visit. The 
diagnosis of bipolar I or II disorder will be made using the Structured Clinical Interview for 
DSM-5 for clinical trials (SCID-5-CT) performed by a qualified healthcare professional. 
Subjects on antidepressants or mood stabilizers (lamotrigine, lithium, and valproic acid only) that 
have been taken at the same dose for at least 60 days prior to Day 1 are to continue the stable 
dose throughout the treatment period. 
Subjects will return to the study center during the treatment and follow-up periods as outlined in 
the Schedule of Events (Table 1). All assessments to be performed are summarized in Table 1. 
If at any time during the study, a subject has a YMRS score of ≥13, the Investigator will 
clinically assess the subject for a manic or hypomanic switch. If the clinical assessment is 
consistent with hypomania or mania, the subject will be discontinued from study drug and 
treated as clinically appropriate (see Section 8.3). 
Part A 
The study design for Part A is presented in Figure 1. In Part A, all subjects will receive SAGE-
217. Beginning on Day 1, qualified subjects will self-administer 30-mg SAGE-217 once daily in 
the evening with food for 14 days. Dose adjustments based on study drug tolerability are 
permitted following the guidelines outlined in Section 7.4. 
 
Figure 1: 
Study Design (Part A) 
 
 
 
QD = once daily 
A dose adjustment to 20-mg SAGE-217 is permitted if the 30-mg dose is not tolerated at any time. 
 
Part B 
The study design for Part B is presented in Figure 2. In Part B, subjects will be randomized in a 
1:1 ratio to receive SAGE-217 or placebo; randomization will be stratified based on use of mood 
stabilizers (Y/N). Beginning on Day 1, qualified subjects will self-administer the study drug 
Day -28 to -1
Screening
Days 1 to 14
SAGE-217
30 mg QD (evening)
Days 21, 28, 35, 42
Follow-up Visits
Day 15/
EOT


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(30 mg SAGE-217 or placebo) once daily in the evening with food for 14 days. Dose 
adjustments based on study drug tolerability are permitted following the guidelines outlined in 
Section 7.4. 
 
Figure 2: 
Study Design (Part B) 
 
QD = once daily 
A dose adjustment to 20-mg SAGE-217 is permitted if the 30-mg dose is not tolerated at any time. 
7.2. 
Number of Subjects 
Part A 
Approximately 30 subjects will be dosed in Part A.  
Part B 
After review of Part A data, approximately 132 subjects will be randomized and dosed in Part B 
to obtain a total of 112 evaluable subjects (see Section 13.8). 
7.3. 
Treatment Assignment 
Part A 
In Part A, all subjects will receive SAGE-217 in an open-label manner.  
Part B 
In Part B, subjects will be randomized to a treatment group (SAGE-217 or placebo) in a 
1:1 ratio; randomization will be stratified based on use of mood stabilizers (Y/N).  
7.4. 
Dose Adjustment Criteria 
If at any time, 30 mg is not tolerated, as assessed by the occurrence of a severe AE judged by the 
investigator to be related to study drug, the dose on the next day will be reduced to 20 mg and 
continued for the remainder of the treatment period. Dose adjustments related to moderate AEs 
will be judged by the Investigator. If a dose adjustment from 30 mg to 20 mg is deemed 
Day -28 to -1
Screening
Day 1
Randomization
Days 1 to 14
Placebo QD (evening)
Days 1 to 14
SAGE-217
30 mg QD (evening)
Days 21, 28, 35, 42
Follow-up Visits
Day 15/
EOT


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necessary by the Investigator, the subject will return to the site for the adjusted dose to be 
dispensed. Subjects who cannot tolerate the 20-mg dose at any time will be discontinued from 
study drug (see Section 8.3).  
7.5. 
Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons including the occurrence of AEs or other findings suggesting unacceptable risk to 
subjects, or for administrative reasons. In the event of study termination, Sage Therapeutics will 
provide written notification to the Investigator. Investigational sites must promptly notify their 
ethics committee and initiate withdrawal procedures for participating subjects.  


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
Qualified subjects will meet all of the following criteria: 
1. Subject has signed an ICF prior to the conduct of any study-specific procedures. 
2. Subject agrees to adhere to the study requirements, including use of prior, concomitant, 
and prohibited medications. 
3. Subject is a man or woman, aged 18 to 65 years, inclusive, at Screening. 
4. 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. 
5. Subject has a documented history of hypomanic or manic episode (verified by medical 
records and/or treating healthcare professional) and a diagnosis of bipolar I or bipolar II 
disorder with a current MDE as per DSM-5 SCID-5-CT. 
6. Subject has a HAM-D score of ≥22 at Screening.  
7. Female subject agrees to use one of the following methods of contraception during 
participation in the study and for 30 days following the last dose of study drug, unless 
they are postmenopausal (defined as no menses for 12 months without an alternative 
medical cause and confirmed by follicle stimulating hormone [FSH] level ≥40 mIU/mL) 
and/or surgically sterile (hysterectomy or bilateral oophorectomy), or in sexual 
relationship(s) which do not carry a risk of pregnancy (eg, same-sex relationship(s)): 
• Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation. 
• Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation.  
• Intrauterine device. 
• Intrauterine hormone-releasing system. 
• Bilateral tubal ligation/occlusion. 
• Vasectomized partner. 
• Sexual abstinence (no sexual intercourse).  
8. Male subject agrees to use an acceptable method of effective contraception for the 
duration of study and for 5 days after receiving the last dose of the study drug, unless the 
subject is in sexual relationship(s) which do not carry a risk of pregnancy (eg, same-sex 
relationship(s)). Acceptable methods of effective contraception for males includes sexual 
abstinence, vasectomy, or a condom with spermicide used together with highly effective 
female contraception methods (if the female partner is of child-bearing potential, see 
Inclusion Criteria #7 for acceptable method of contraception for females). 


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9. 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. 
8.2. 
Subject Exclusion Criteria 
Subjects who meet any of the following criteria are disqualified from participation in this study: 
1. Subject has a history of suicide attempt within the last 2 years. 
2. Subject has current suicidal ideation with plans based on Investigator clinical assessment 
and/or the C-SSRS response at Screening or Day 1. 
3. Subject has a history of rapid cycling bipolar disorder as per DSM-5 SCID-5-CT. 
4. Subject’s current depressive episode meets the DSM-5 specifier criteria for mixed 
features. 
5. Subject has ≥25% reduction in HAM-D score from Screening to Day 1. 
6. 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. 
7. Subject has abnormal liver function as shown by an abnormal liver function profile at 
screening (eg, repeated values of aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), or total bilirubin ≥2x the upper limit of normal). 
8. Subject has a clinically significant abnormal 12-lead ECG at the Screening or Day 1 
visits. NOTE: mean QT interval calculated using the Fridericia method (QTcF) of 
>450 msec in male or >470 msec in female subjects will be the basis for exclusion from 
the study.  
9. Subject has a YMRS score ≥13 at Screening or Day 1. 
10. Subject presents for the study receiving a mood stabilizer other than lamotrigine, lithium, 
or valproic acid. 
11. Subject presents for the study receiving psychotropic medications, which have not been 
taken at the same dose for at least 60 days prior to Day 1. 
12. Subject that presents for the study receiving psychotropic medications and does not 
intend to continue the current treatment regimen during the treatment period.  
13. Subject is taking benzodiazepines or GABAA modulators/GABA-containing agents (eg, 
eszopiclone, zopiclone, zaleplon, and zolpidem) at Day -28. 
14. Subject has a history of severe rashes or Stevens-Johnson Syndrome associated with 
lamotrigine and is currently taking lamotrigine. 
15. Subject’s current depressive episode is treatment resistant; defined as persistent 
depressive symptoms despite treatment with adequate doses of antidepressants from two 
different classes for an adequate amount of time (ie, at least 4 weeks of treatment). This 


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will be assessed using the Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire. 
16. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds. 
17. Subject has a positive pregnancy test at the Screening Visit or on Day 1 (prior to 
administration of study drug) or, if she is breastfeeding at Screening or on Day 1 (prior to 
administration of study drug), she does not agree to temporarily cease giving breast milk 
to her child(ren) from just prior to receiving study drug on Day 1 until 7 days after the 
last dose of study drug. 
18. Subject has detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) 
and HCV viral load, or human immunodeficiency virus (HIV) antibody at screening. 
19. Subject has active psychosis per Investigator assessment. 
20. Subject has a medical history of seizures. 
21. Subject has a medical history schizophrenia, and/or schizoaffective disorder. 
22. Subject has a history of mild, moderate, or severe substance use disorder diagnosed using 
DSM-5 criteria in the 12 months prior to screening. 
23. Subject has a positive drug and/or alcohol screen at screening or on Day 1 prior to 
dosing. 
24. Subject has had exposure to another investigational medication or device within 30 days 
prior to the Screening visit. 
25. Subject has been previously treated or randomized in any study using SAGE-217. 
Subjects who participate in Part A are not eligible to participate in Part B. 
26. Subject has used any known strong inhibitors of cytochrome P450 (CYP)3A4 within 28 
days or five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, or 
Seville oranges, or products containing these within 14 days prior to receiving the first 
dose of study drug. 
27. Subject has used CYP inducers, such as rifampin, carbamazepine, ritonavir, 
enzalutamide, efavirenz, nevirapine, phenytoin, phenobarbital and St John’s Wort, within 
28 days prior to the first dose of study drug. 
28. Subject plans to undergo elective surgery during participation in the study. 
29. Subject is taking non-GABA anti-insomnia medications (eg, melatonin, Benadryl [anti-
histamines], trazodone, low dose quetiapine, mirtazapine, etc) at Day -14.  
8.3. 
Subject Withdrawal Criteria 
8.3.1. 
Withdrawal from the Study or Discontinuation of Study Drug 
Subjects may discontinue study drug or withdraw from the study at any time for any reason. The 
Investigator may discontinue the subject from the study or study drug 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, at the discretion of the Investigator and/or the 
Medical Monitor 
In addition, if at any time during the study, a subject has a YMRS score of ≥13, the Investigator 
will clinically assess the subject for a manic or hypomanic switch. If the clinical assessment is 
consistent with hypomania or mania, the subject will be discontinued from study drug and 
treated as clinically appropriate. These incidents will be documented as AEs. 
The reasons for study drug discontinuation and/or subject withdrawal from the study must be 
recorded in the subject’s electronic case report form (eCRF). The Investigator must notify the 
Sponsor and/or the Medical Monitor immediately when a subject has discontinued or been 
withdrawn for any reason. 
Subjects who discontinue study drug early/withdraw during the treatment period should, if 
possible, have an end of treatment (EOT) visit, including the EOT assessments as summarized in 
the Schedule of Events (Table 1). The EOT visit should be scheduled as soon as possible, 
preferably the day after the subject’s last dose. All details of the EOT visit should be recorded in 
the subject’s medical source documents. For subjects that discontinue study drug early, follow-
up visits should take place every 7 days for 28 days. If at any time after the EOT visit, a subject 
decides to terminate the study early, the subject should return for an early termination (ET) visit. 
The EOT and ET visits can be on the same day if a subject discontinues study drug and 
terminates the study on the same day during a clinic visit; in this case, all events scheduled for 
both visits will be conducted only once.  
If the subject fails or refuses to return to the study center, an attempt must be made to contact the 
subject by telephone in order to assess as many safety and efficacy parameters as possible. All 
data collected over the telephone must be documented and kept in the subject’s record. A subject 
will be deemed lost to follow-up after 3 attempts at contact have been made and it has been at 
least 1 month since the last subject contact. The third attempt at contact must be a certified letter 
accompanied by a survey inquiring the reason for study discontinuation. All attempts at contact 
will be documented. 
Subjects who discontinue the study drug 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.  
If a subject failed to attend scheduled assessments during the course of the study, the 
Investigators must determine the reasons and the circumstances as completely and accurately as 
possible, and document this in the subject's source documents. 
8.3.2. 
Replacement of Subjects 
Part A 
In Part A, subjects will not be replaced. 


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Part B 
In Part B, subjects will not be replaced. Additional subjects may be randomized if the drop-out 
rate is higher than anticipated (see Section 13.8). 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Study Drug 
Subjects will self-administer study drug orally once daily in the evening with food for 14 days as 
outlined in Section 7.1. Practical options include taking within 1 hour of dinner, or taking later in 
the evening with solid food. 
9.2. 
Prior Medications, Concomitant Medications, and Restrictions 
9.2.1. 
Prior and Concomitant Medications and/or Supplements 
The start and end dates, route of administration, dose/units, frequency, and indication for all 
medications and/or supplements taken within 30 days prior to Screening and throughout the 
duration of the study will be recorded. In addition, psychotropic drugs taken within 6 months 
prior to Screening will be recorded. 
Any concomitant medication determined necessary for the welfare of the subject may be given at 
the discretion of the Investigator at any time during the study under the guidance outlined in 
these sections.  
Antidepressants and mood stabilizers (lamotrigine, lithium, and valproic acid only) 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 throughout the treatment period. 
Medications intended for contraception are permitted for female subjects (see Section 8.1): 
• Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation 
• Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation. 
• Intrauterine device 
• Intrauterine hormone-releasing system 
9.2.2. 
Prohibited Medications 
The following specific classes of medications are prohibited at any time during the treatment 
period: 
• Initiation of new psychotropic medications at any time during the study 
• Initiation of new antidepressant therapy from 60 days prior to Day 1 through the 
duration of the study 
• Use of any benzodiazepines, GABAA modulators, GABAA-like acting drugs, or 
GABA-containing agents from Day -28 through the duration of the study 
• Use of any non-GABA anti-insomnia medications (eg, melatonin, Benadryl [anti-
histamines], trazodone, low dose quetiapine, mirtazapine, etc) from Day -14 through 
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• Exposure to another investigational medication or device from 30 days prior to 
Screening through the duration of the study 
• Any known strong inhibitors of CYP3A4 from Day -28 or 5 half-lives prior to Day 1 
(whichever is longer) through the duration of the study 
• Use of any CYP inducer, such as such as rifampin, carbamazepine, ritonavir, 
enzalutamide, efavirenz, nevirapine, phenytoin, phenobarbital and St John’s Wort 
from Day -28 through the duration of the study. 
9.2.3. 
Other Restrictions 
The consumption of grapefruit juice, grapefruit, or Seville oranges, or products containing these 
is prohibited throughout the treatment period. 
Consumption of drugs of abuse and alcohol is discouraged throughout the duration of the study. 
Female subjects who are lactating or actively breastfeeding must stop giving breast milk to the 
baby(ies) starting on Day 1 until 7 days after the last dose of study drug following the treatment 
period. 
Elective surgeries or procedures are prohibited during participation in the study. 
9.3. 
Treatment Adherence 
SAGE-217 (Parts A and B) or placebo (Part B only) will be self-administered by subjects once 
every evening with food. Sites will dispense study drug to the subjects to take at home with 
instructions for use (Section 10.4).  
Administration of study drug will be monitored by a medication adherence monitoring platform 
used on smartphones to visually confirm medication ingestion. Subjects will receive a reminder 
within a predefined time window to take study drug while using the application. Subjects will 
follow a series of prescribed steps in front of the front-facing webcam to visually confirm their 
ingestion of the medication. The application will record the date and time of study drug 
administration by dose level, as well as missed doses. 
In addition, the subject will be instructed to bring their dosing kit to each visit during the 
treatment period, at which time the Investigator or designee will be responsible for ensuring the 
kit contains sufficient doses until the next scheduled dispensation. 
If the subject is persistently noncompliant with the study drug, the Investigator should discuss 
with Sage Therapeutics the potential discontinuation of the subject (Section 8.3). Dosing 
requirements will be reviewed with each subject during all study contacts. The authorized study 
personnel conducting the re-education must document the process in the subject source records. 
9.4. 
Randomization and Blinding 
Part A 
Part A is an open-label design in which all subjects will receive SAGE-217. 


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Part B 
Part B is a randomized, double-blind, placebo-controlled, parallel group design. Subjects who 
meet the entrance criteria will be stratified based on use of mood stabilizers (Y/N) and randomly 
assigned within each stratum in a 1:1 ratio to receive SAGE-217 or matched placebo. Subjects, 
clinicians, and the study team will be blinded to treatment allocation. Randomization will be 
performed centrally via an interactive response technology (IRT) system. 
Randomization schedules will be generated by an independent statistician. The allocation to 
treatment group (SAGE-217 or placebo) will be based on the randomization schedule. The 
randomization schedules will be kept strictly confidential, accessible only to authorized 
personnel until the time of unblinding.  
During the study, the blind is to be broken only if the safety of a subject is at risk and the 
treatment plan is dependent on the study treatment received. See Section 12.6 for details of 
unblinding in the event of a medical emergency or pregnancy.  
In all cases where the study drug allocation for a subject is unblinded, pertinent information 
(including the reason for unblinding) must be documented in the subject’s records and on the 
eCRF. If the subject or study center personnel have been unblinded, the subject will be 
permanently discontinued from the study. 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Description of Study Drug 
SAGE-217 is available as hard gelatin capsules containing a white to off-white powder. In 
addition to the specified amount of SAGE-217 Drug Substance, active SAGE-217 Capsules 
contain croscarmellose sodium, mannitol, silicified microcrystalline cellulose (SMCC), colloidal 
silicon dioxide, and sodium stearyl fumarate as excipients. Colloidal silicon dioxide may be 
either a component of the SMCC or a standalone excipient in the formulation. Capsules will be 
available in 10-mg, 20-mg, and 30-mg strengths to achieve the target dose of 20 mg or 30 mg.  
Matching placebo capsules are hard gelatin capsules containing only the excipients listed for the 
active capsule treatment.  
10.2. 
Study Drug Packaging and Labeling 
SAGE-217 and matched placebo will be provided to the clinic pharmacist and/or designated site 
staff responsible for dispensing the study drug in appropriately labeled, subject-specific kits each 
containing sealed unit doses. Part A is open-label and Part B is blinded. 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 Code of Federal 
Regulations and Good Manufacturing Practices/Good Clinical Practices guidelines will be 
prepared by the clinical research organization. 
10.3. 
Study Drug Storage 
SAGE-217 and matched placebo are to be stored at room temperature, 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 in the evening with food. Practical options include taking 
within 1 hour of dinner, or taking later in the evening with solid food. 
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.  
Site staff will access the IRT at the Screening Visit to obtain a subject identification (ID) number 
for each subject. On Day 1, site staff will access the IRT and provide the necessary subject-
identifying information, including the subject ID number assigned at Screening, to randomize the 


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eligible subject into the study and obtain the medication ID number for the study drug to be 
dispensed to that subject. 
At the subsequent study drug-dispensing visit, the investigator or designee will access the IRT, 
providing the same subject ID number assigned at Screening, to obtain the medication ID 
number for the study drug to be dispensed at that visit. In the event of an unscheduled dose 
reduction (Section 7.4), a new subject-specific kit will be dispensed. 
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 medication 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 within usual 
business hours and with appropriate notice during or after completion of the study to perform 
drug accountability reconciliation. 
10.7. 
Study Drug Handling and Disposal 
At the end of the study, all used and unused study drug will be reconciled and returned to Sage 
Therapeutics for destruction or destroyed locally; disposition of study drug will be documented. 
A copy of the inventory record and a record of any clinical supplies that have been received, 
dispensed or destroyed must be documented by the site as directed. This documentation must 
include at least the information below:  
• the number of dispensed units 
• the number of unused units 
• the number of units destroyed at the end of the study 
• the date, method and location of destruction. 
 


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11. 
ASSESSMENT OF EFFICACY 
 
All assessments will be conducted according to the schedule of assessments (Table 1). 
11.1. 
Efficacy Assessments 
11.1.1. 
Hamilton Rating Scale for Depression (HAM-D) 
The primary outcome measure is the change from baseline in the 17-item HAM-D total score at 
Day 15.  
The 17-item HAM-D will be used to rate the severity of depression in subjects who are identified 
as experiencing an MDE (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. Every effort should be 
made for the same rater to perform all HAM-D assessments for an individual subject.  
The HAM-D total score will be calculated as the sum of the 17 individual item scores.  
In addition to the primary efficacy endpoint of change from baseline in HAM-D total score, 
several secondary efficacy endpoints will be derived for the HAM-D. Hamilton Rating Scale for 
Depression subscale scores will be calculated as the sum of the items comprising each subscale. 
Hamilton Rating Scale for Depression response will be defined as having a 50% or greater 
reduction from baseline in HAM-D total score. Hamilton Rating Scale for Depression remission 
will be defined as having a HAM-D total score of ≤7. 
The HAM-D subject interview may be audio-recorded for independent quality control purposes. 
11.1.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive 
episodes in subjects with mood disorders. It was designed as an adjunct to the HAM-D that 
would be more sensitive than the Hamilton Scale to the changes brought on by antidepressants 
and other forms of treatment.  
Higher MADRS scores indicate more severe depression, and each item yields a score of 0 to 6. 
The overall score ranges from 0 to 60 (Williams 2008). 
The MADRS total score will be calculated as the sum of the ten individual item scores. 
The MADRS subject interview may be audio-recorded for independent quality control purposes. 
11.1.3. 
Clinical Global Impression (CGI) 
The CGI is a validated measure often utilized in clinical trials to allow clinicians to integrate 
several sources of information into a single rating of the subject’s condition. The CGI scale 
consists of 3 items. Only the first 2 items are being used in this study.  
The Clinical Global Impression - Severity (CGI-S) uses a 7-point Likert scale to rate the severity 
of the subject’s illness at the time of assessment, relative to the clinician’s past experience with 


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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 Clinical Global Impression - Improvement (CGI-I) employs a 7-point Likert scale to 
measure the overall improvement in the subject’s condition posttreatment. The Investigator will 
rate the subject’s total improvement whether or not it is due entirely to drug treatment. Response 
choices include: 0=not assessed, 1=very much improved, 2=much improved, 3=minimally 
improved, 4=no change, 5=minimally worse, 6=much worse, and 7=very much worse 
(Busner 2007b). The CGI-I is only rated at posttreatment assessments. By definition, all CGI-I 
assessments are evaluated against baseline conditions. CGI-I response will be defined as having 
a CGI-I score of “very much improved” or “much improved.”  
11.1.4. 
Insomnia Severity Index (ISI) 
The ISI is a validated questionnaire designed to assess the nature, severity, and impact of 
insomnia (Morin 2011). The ISI uses a 5-point Likert Scale to measure various aspects of 
insomnia severity (0 = none, 1 = mild, 2 = moderate; 3 = severe; 4 = very severe), satisfaction 
with current sleep pattern (0 = very satisfied, 1 = satisfied, 2 = neutral, 3 = dissatisfied, 4 = very 
dissatisfied), and various aspects of the impact of insomnia on daily functioning (0 = not at all, 
1 = a little, 2 = somewhat, 3 = much, 4 = very much). A total score of 0 to 7 = “no clinically 
significant insomnia,” 8 to 14 = subthreshold insomnia,” 15 to 21 = “clinical insomnia (moderate 
severity),” and 22 to 28 = “clinical insomnia (severe).”  


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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
The safety and tolerability of SAGE-217 will be assessed by the frequency and severity of AEs; 
changes from baseline in clinical laboratory measures, vital signs, and ECGs; suicidal ideation 
and behavior using the C-SSRS; and the YMRS. All assessments will be conducted according to 
the schedule of assessments (Table 1). 
12.1.1. 
Demographic/Medical History 
Demographic and baseline characteristics (age, race, gender, ethnicity, employment status, 
highest education level, marital/civil status) and a full medical history, including family 
psychiatric history, will be documented. The diagnosis of bipolar I or II disorder will be 
determined using the SCID-5-CT. 
12.1.2. 
Weight and Height 
Height (Screening only) and weight will be measured and documented.  
12.1.3. 
Physical Examination 
Physical examinations assessing body systems (eg, head, eye, ear, 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 physical examinations 
may also be conducted per the Investigator’s discretion. 
Any abnormality in physical examinations will be interpreted by the Investigator as abnormal, 
not clinically significant (NCS); or abnormal, clinically significant (CS) in source documents. 
New or worsening abnormalities that are judged to be clinically significant will be recorded as 
AEs, assessed according to Section 12.2.1.1. 
12.1.4. 
Vital Signs 
Vital signs comprise both supine and standing for systolic and diastolic blood pressure and heart 
rate measurements. Heart rate and blood pressure are to be collected in supine position after the 
subject has been resting for 5 minutes and then in the standing position. Respiratory rate, pulse 
oximetry and temperature are collected once, in either position. Vital signs will be documented. 
When vital signs are scheduled at the same time as blood draws, vital signs will be obtained first, 
with the blood sample collected as close to the scheduled time as possible. 
Any abnormality in vital signs will be interpreted by the Investigator as abnormal, NCS or 
abnormal, CS in source documents. New or worsening abnormalities that are judged to be 
clinically significant will be recorded as AEs, assessed according to Section 12.2.1.1. 
12.1.5. 
Electrocardiogram (ECG) 
Supine 12-lead ECGs will be performed in triplicate. The standard intervals (heart rate, PR, 
QRS, QT, and QTcF) as well as any rhythm abnormalities will be recorded. When ECG 
 
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Any abnormality in ECGs 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. 
Laboratory Assessments 
Samples will be collected in accordance with acceptable laboratory procedures detailed in the 
laboratory manual.   
The clinical laboratory tests to be performed are listed in Table 3. 
Table 3: 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Coagulation 
Red blood cell count 
Hemoglobin  
Hematocrit  
White blood cell count with 
differential  
Platelet count 
Red blood cell morphology 
ALT 
Albumin 
Alkaline phosphatase 
AST 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
Total protein 
Creatinine 
Blood urea nitrogen 
Creatine kinase 
GGT 
Potassium 
Sodium 
Lactate dehydrogenase 
Glucose 
Chloride 
Bicarbonate 
Calcium 
Phosphorus 
Triglycerides 
pH 
Specific gravity 
Protein 
Glucose 
Red blood cells 
Nitrite 
Leukocyte 
esterase 
Ketones 
Bilirubin 
Urobilinogen 
Activated partial 
thromboplastin 
time 
Prothrombin 
time 
International 
normalized ratio 


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


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12.1.6.2. Pregnancy Screen 
A serum pregnancy test in women of child-bearing potential will be conducted at Screening and 
a urine pregnancy test will be conducted at all other scheduled timepoints (Table 1).  
12.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011). This scale 
consists of a baseline evaluation that assesses the lifetime experience of the subject with suicidal 
ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last 
study visit. The C-SSRS includes ‘yes’ or ‘no’ responses for assessment of suicidal ideation and 
behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being 
the most severe).  
The “Baseline/Screening” C-SSRS form will be completed at screening (lifetime history and past 
24 months). The “Since Last Visit” C-SSRS form will be completed at all subsequent time 
points, as outlined in Table 1. 
12.1.8. 
Young Mania Rating Scale (YMRS) 
Manic symptoms will be assessed during the study using the YMRS (Young 1978). The 
clinician-administered scale is based on 11 items of core symptoms of mania. Four of the items 
(irritability, speech, thought content, and disruptive/aggressive behavior) are graded on a scale of 
0 to 8 (choices given as even numbers), with the remaining 7 items graded on a scale of 0 to 4. 
Scoring between the points given (whole or half points) is possible.  
12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Definition of Adverse Events 
12.2.1.1. Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the use of a 
medicinal (investigational) product whether or not related to the medicinal (investigational) 
product. In clinical studies, an AE can include an undesirable medical condition occurring at any 
time, including baseline or washout periods, even if no study treatment has been administered. 
A TEAE is an AE that occurs after the first administration of any study drug. The term study 
drug includes any Sage investigational product, a comparator, or a placebo administered in a 
clinical trial. 
An abnormal laboratory value will be considered an AE if the value represents a clinically 
significant change from baseline as determined by the Investigator.  
All AEs that occur after any subject has signed the informed consent form and throughout the 
duration of the study, whether or not they are related to the study, must be reported to Sage 
Therapeutics. 


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12.2.1.2. Serious Adverse Event (SAE) 
A serious adverse event is any untoward medical occurrence that at any dose: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
An SAE may also be any other medically important event that, in the opinion of the Investigator, 
may jeopardize the subject or may require medical intervention to prevent 1 of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization). 
All SAEs that occur after any subject has been enrolled and throughout the duration of the study, 
whether or not they are related to the study, must be recorded on the SAE form provided by Sage 
Therapeutics within 24 hours of first awareness (Section 12.5). All SAEs should to be followed 
until the event resolved, the condition stabilized, was no longer considered clinically significant 
or the subject was lost to follow-up. 
12.3. 
Relationship to Study Drug 
The Investigator must make the determination of relationship to the study drug for each adverse 
event (not related, possibly related or probably related). The Investigator should decide whether, 
in his or her medical judgment, there is a reasonable possibility that the event may have been 
caused by the investigational product. If no valid reason exists for suggesting a relationship, then 
the adverse event should be classified as “not related.” If there is any valid reason, even if 
undetermined, for suspecting a possible cause-and-effect relationship between the investigational 
product and the occurrence of the adverse event, then the adverse event should be considered at 
least “possibly related.”  
Table 4: 
Relationship to Study Drug 
Relationship 
Definition 
Not Related: 
No relationship between the experience and the administration of study drug; related to 
other etiologies such as concomitant medications or subject’s clinical state. 
Possibly Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug.  
The reaction might have been produced by the subject’s clinical state or other modes of 
therapy administered to the subject, but this is not known for sure. 
Probably Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug.  
The reaction cannot be reasonably explained by the known characteristics of the subject’s 
clinical state or other modes of therapy administered to the subject. 


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If the relationship between the adverse event/serious adverse event and the investigational 
product is determined to be “possible” or “probable”, the event will be considered related to the 
investigational product for the purposes of expedited regulatory reporting. 
12.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. The AE term should be reported in standard medical terminology when 
possible. For each AE, the investigator will evaluate and report the onset (date and time), 
resolution (date and time), intensity, causality, action taken, serious outcome (if applicable), and 
whether or not it caused the subject to discontinue the study drug or withdraw early from the 
study. 
Intensity will be assessed according to the following scale: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities) 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.2.1.2. An AE of severe intensity 
may not be considered serious. 
If a female subject becomes pregnant during this study, pregnancy information must be collected 
and recorded on the Sage Therapeutics pregnancy form and submitted to the sponsor within 
24 hours of learning of the pregnancy. The Investigator will also attempt to collect pregnancy 
information on any male subject’s female partner who becomes pregnant while the male subject 
is participating in the study. After obtaining the necessary signed informed consent from the 
pregnant female partner directly, the investigator will follow the same pregnancy reporting 
procedures specified for pregnant female subjects. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) must be followed up and documented even if the subject was 
discontinued from the study. If the pregnancy ends for any reason before the anticipated date, the 
investigator should notify the sponsor. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that a study drug may 
have interfered with the effectiveness of a contraceptive medication or a complication relating to 
the pregnancy occurs (eg, spontaneous abortion). 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 on the SAE report form. The Investigator must complete, sign and 


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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 CRF and/or study 
file. 
Any SAEs discovered by the Investigator after the designated follow up time for the study, 
should be promptly reported to Sage, or designee, according to the timelines noted above.  
The contact information for reporting SAEs and/or pregnancies is located in the study reference 
manual.   
Sage, or designee, is responsible for notifying the relevant regulatory authorities of certain 
events. It is the Principal Investigator’s responsibility to notify the ethics committee of all SAEs 
that occur at his or her site. Investigators will also be notified of all suspected, unexpected, 
serious, adverse reactions (SUSARs) that occur during the clinical study. Each site is responsible 
for notifying its ethics committee of these SUSARs. In addition, appropriate SAGE Drug Safety 
and Pharmacovigilance personnel, or designee, will unblind SUSARs for the purpose of 
regulatory reporting. SAGE, or designee, will submit SUSARs (in blinded or unblinded fashion) 
to regulatory agencies according to local law. SAGE, or designee, will submit SUSARs to 
investigators in a blinded fashion. 
12.6. 
Emergency Identification of Study Drug 
During the study, the blind is to be broken only when the safety of a subject is at risk and the 
treatment plan is dependent on the study treatment received. Unless a subject is at immediate 
risk, the Investigator must make diligent attempts to contact Sage prior to unblinding the study 
treatment administered to a subject. Any request from the Investigator about the treatment 
administered to study subjects must be discussed with Sage. If the unblinding occurs without 
Sage’s knowledge, the Investigator must notify Sage as soon as possible and no later than the 
next business morning. All circumstances surrounding a premature unblinding must be clearly 
documented in the source records. Unless a subject is at immediate risk, any request for the 
unblinding of individual subjects must be made in writing to Sage and approved by the 
appropriate Sage personnel, according to standard operating procedures. The blinding of the 
study will be broken after the database has been locked. Electronic copies of the randomization 
code will be made available to the laboratory performing the bioanalytical analyses in order to 
allow for limited analysis of samples from subjects receiving placebo. 
In the event of a medical emergency or pregnancy, the Investigator will discuss with the Medical 
Monitor if unblinding is warranted for medical management of the subject. If there is agreement 
to unblind treatment assignment, the unblinding procedure described in the Safety Management 
Plan for the study will be followed. If the Investigator is unable to contact the Medical Monitor 
in a medical emergency, and it is deemed clinically necessary by the Investigator, the treatment 
group for that subject may be unblinded in the IRT system. 
In all cases where the study drug allocation for a subject is unblinded, pertinent information 
(including the reason for unblinding) must be documented in the subject’s records and on the 


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eCRF. If the subject or study center personnel have been unblinded, the subject will be 
permanently discontinued from the study. 


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13. 
STATISTICS 
A separate statistical analysis plan (SAP) for each part (Part A and B) will provide a detailed 
description of the analyses to be performed in the respective part of the study. The SAPs will be 
finalized and approved prior to database lock. Any deviations from or changes to the respective 
SAP following database lock will be described in detail in the clinical study report. 
13.1. 
Data Analysis Sets 
The Safety Set, defined as all subjects that received at least 1 dose of study drug, will be used to 
provide descriptive summaries of safety data.  
The Efficacy Set, defined as all subjects in the Safety Set that have at least 1 post-baseline 
HAM-D evaluation, will be used to analyze efficacy data, unless otherwise specified. 
 
 
Part B will also include a Randomized Set, defined as all subjects who are randomized. This 
analysis set will be used for all data listings in Part B. 
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 sets, using all non-missing data available. No imputation process will be used to 
estimate missing data.  
13.3. 
General Considerations 
For the purpose of all primary and secondary analyses where applicable, baseline is defined as 
the last measurement prior to receipt of study drug.  
Continuous endpoints will be summarized with number (n), mean, standard deviation (SD), 
median, minimum, and maximum. In addition, change from baseline values will be calculated at 
each time point and summarized descriptively. For categorical endpoints, descriptive summaries 
will include counts and percentages.  
13.4. 
Demographics and Baseline Characteristics 
Demographic data (Section 12.1.1) and baseline characteristics, such as height, weight, and body 
mass index, will be summarized using the Safety Set.  
Pregnancy results will be listed but not summarized.  
Medical history will be listed by subject.  
13.5. 
Efficacy Analysis 
The primary efficacy endpoint, the change from baseline in HAM-D total score, will be analyzed 
using a mixed effects model for repeated measures (MMRM); the model will include center, 
treatment, baseline HAM-D total score, stratification factor, assessment time point, and time 
point-by-treatment as explanatory variables. All explanatory variables will be considered as fixed 


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effects and the subject effect will be considered random in the model. All post-baseline time 
points will be included in the model. The primary comparison will be between SAGE-217 and 
matching placebo at Day 15. Model-based point estimates (ie, least squares [LS] means, 95% 
confidence intervals, and p values) will be reported. An unstructured covariance structure will be 
used to model the within-subject errors. In case of convergence issues, other covariance 
structures will be considered; this will be detailed in the statistical analyses plan. Other 
continuous endpoints will be analyzed using similar methods.  
Other efficacy analyses will be specified in the statistical analysis plan. In general, data will be 
analyzed using appropriate descriptive statistics or pre-specified statistical methods as 
applicable; subject listings will be provided for all efficacy data. Subjects will be analyzed 
according to randomized treatment for the purpose of efficacy unless otherwise specified. 
13.6. 
Safety Analyses 
Safety and tolerability of SAGE-217 will be assessed by the frequency and severity of AEs; 
changes from baseline in clinical laboratory measures, vital signs, and ECGs. Suicidal ideation 
and behavior will be evaluated using the C-SSRS. Mania will be evaluated using the YMRS. 
Safety data will be listed by subject and summarized by treatment group. All safety summaries 
will be performed on the Safety Set.  
13.6.1. 
Adverse Events 
The analysis of AEs will be based on the concept of TEAEs. The incidence of TEAEs will be 
summarized overall and by Medical Dictionary for Regulatory Activities (MedDRA) 
Version 20.1 or higher, system organ class (SOC), and preferred term (PT). 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 (Section 13.6.1).  
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 
Clinical laboratory results will be listed by subject and timing of collection. Mean changes from 
baseline in clinical laboratory measures will be evaluated.  
13.6.3. 
Physical Examinations 
Physical examination data will be listed by subject, but not summarized.  
13.6.4. 
Vital Signs 
Vital sign results will be listed by subject and timing of collection. Mean changes from baseline 
in vital signs will be evaluated by time point.  


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13.6.5. 
12-Lead Electrocardiogram 
The following ECG parameters will be listed for each subject: heart rate, PR, QRS, QT, and 
QTcF. Any clinically significant abnormalities or changes in ECGs should be listed as an AE. 
Electrocardiogram findings will be listed by subject and visit.  
13.6.6. 
Prior and Concomitant Medications 
Medications will be recorded at each study visit during the study and will be coded using World 
Health Organization-Drug dictionary (WHO-DD) September 2015, or later.  
Those medications taken prior to the initiation of the start of study drug will be denoted “Prior”. 
Those medications taken prior to the initiation of the study drug and continuing beyond the 
initiation of the study drug or those medications started at the same time or after the initiation of 
the study drug will be denoted “Concomitant” (ie, those with a start date on or after the first dose 
of study drug, or those with a start date before the first dose of study drug that are ongoing or 
with a stop date on or after the first dose of study drug).  
Medications will be presented according to whether they are “Prior” or “Concomitant” as 
defined above. If medication dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant.  
Details of prior and concomitant medications will be listed by subject, start date, and verbatim 
term.  
13.6.7. 
Columbia Suicide Severity Rating Scale 
Suicidality data collected on the C-SSRS at baseline and by visit will be summarized and listed 
for all subjects. Listings will include behavior type and/or category for Suicidal Ideation and 
Suicidal Behavior of the C-SSRS.  
13.6.8. 
Young Mania Rating Scale 
Mania data collected on the YMRS at baseline and by visit will be summarized and listed for all 
subjects.  
 
 
 
 
 
 
13.8. 
Determination of Sample Size 
13.8.1. 
Part A 
For Part A, the sample size of approximately 30 subjects was selected based on clinical and not 
statistical considerations.  


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13.8.2. 
Part B 
For Part B, assuming a two-sided alpha level of 0.05, a sample size of 112 total evaluable 
subjects (56 per treatment group) would provide 80% power to detect a placebo-adjusted 
treatment difference of approximately 4 points in the primary endpoint, change from baseline in 
HAM-D total score at Day 15, assuming standard deviation (SD) of 7.5 points.  
Assuming a 15% dropout rate, approximately 132 total randomized subjects will be required to 
obtain a total of 112 evaluable subjects. Evaluable subjects are defined as those randomized 
subjects who receive study drug and have a valid baseline and at least 1 post-baseline HAM-D 
assessment. Additional subjects may be randomized if the drop-out rate is higher than 15%. 


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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and the study site guarantee access to source documents by Sage Therapeutics 
or sponsor’s designee and by the IRB or IEC. 
All aspects of the study and its documentation will be subject to review by Sage Therapeutics or 
sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, study drug, subject medical records, informed consent documentation, and 
review of eCRFs and associated source documents. It is important that the investigator and other 
study personnel are available during the monitoring visits and that sufficient time is devoted to 
the process.  
14.2. 
Audits and Inspections 
Authorized representatives of Sage Therapeutics, a regulatory authority, an Independent Ethics 
Committee or an Institutional Review Board may visit the site to perform audits or inspections, 
including source data verification. The purpose of a Sage Therapeutics audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, Good Clinical Practice guidelines of the 
International Conference on Harmonization, and any applicable regulatory requirements. The 
investigator should contact Sage Therapeutics immediately if contacted by a regulatory agency 
about an inspection. 
14.3. 
Protocol Deviations 
Investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
Sage Therapeutics or sponsor’s designee (and IRB, as required) to determine the appropriate 
course of action. There will be no exemptions (a prospectively approved deviation) from the 
inclusion or exclusion criteria. 
14.4. 
Institutional Review Board (IRB) or Ethics Committee (EC) 
The Principal Investigator must obtain IRB (or EC) approval for the investigation. Initial IRB (or 
EC) approval, and all materials approved by the IRB (or EC) for this study including the subject 
consent form and recruitment materials must be maintained by the Investigator and made 
available for inspection. 


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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
Sage Therapeutics may conduct a quality assurance audit. Please see Section 14.2 for more 
details regarding the audit process. 
 


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


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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Inspection of Records 
Sage Therapeutics will be allowed to conduct site visits to the investigation facilities for the 
purpose of monitoring any aspect of the study. The Investigator agrees to allow the monitor to 
inspect the drug storage area, study drug stocks, drug accountability records, subject charts and 
study source documents, and other records relative to study conduct. 
17.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for the period 
outlined in the site contract, or for a period of 2 years after the last marketing application 
approval, whichever is longer. If not approved, documentation must be maintained for 2 years 
following the discontinuance of the test article for investigation. If it becomes necessary for Sage 
Therapeutics or the Regulatory Authority to review any documentation relating to the study, the 
Investigator must permit access to such records. 


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18. 
PUBLICATION POLICY 
All information concerning SAGE-217 is considered confidential and shall remain the sole 
property of Sage Therapeutics. The Investigator agrees to use this information only in conducting 
the study and shall not use it for any other purposes without written approval from Sage 
Therapeutics. No publication or disclosure of study results will be permitted except as specified 
in a separate, written, agreement between Sage Therapeutics and the Investigator. 


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19. 
LIST OF REFERENCES 
Begley CE, Annegers JF, Swann AC, Lewis C, Coan S, Schnapp WB, et al. The lifetime cost of 
bipolar disorder in the US: an estimate for new cases in 1998. Pharmacoeconomics. 2001;19(5 Pt 
1):483-95. 
Busner J, Targum S. CGI-S. (2007a), as adapted from Kay, Stanley R, Positive and Negative 
Symptoms in Schizophrenia:Assessment and Research.  Clinical and Experimental Psychiatry, 
Monograph No. 5.  Brunner/Mazel, 1991.  Modified from Guy W. Clinical Global Impressions: 
In ECDEU Assessment Manual for Psychopharmacology. 1976; 218-22. Revised DHEW Pub. 
(ADM) Rockville, MD: National Institute for Mental Health.   
Busner J, Targum S. CGI-I.  (2007b), as adapted from Spearing, et al.  Psychiatry Research, 
1997;73:159-71.  Modified from Guy W. Clinical Global Impressions: In ECDEU Assessment 
Manual for Psychopharmacology. 1976; 218-22. Revised DHEW Pub. (ADM) Rockville, MD: 
National Institute for Mental Health.   
Bowden CL, Anupama AK. Pharmacotherapy for bipolar depression: an economic assessment. 
Expert Opin Pharmacother. 2004 May;5(5):1101-7. 
DSM-5.  Diagnostic and statistical manual of mental disorders (5th ed.).  American Psychiatric 
Association 2013.  Arlington, VA: American Psychiatric Publishing. 
Ferrari AJ, Stockings E, Khoo JP, Erskine HE, Degenhardt L, Vos T, et al. The prevalence and 
burden of bipolar disorder: findings from the Global Burden of Disease Study 2013. Bipolar 
Disord. 2016 Aug;18(5):440-50. 
Gijsman HJ, Geddes JR, Rendell JM, Nolen WA, Goodwin GM. Antidepressants for bipolar 
depression: a systematic review of randomized, controlled trials. Am J Psychiatry 
2004;161:1537-1547. 
Judd LL, Akiskal HS, Maser JD, Zeller PJ, Endicott J, Coryell W, et al. A prospective 12-year 
study of subsyndromal and syndromal depressive symptoms in unipolar major depressive 
disorders. Arch Gen Psychiatry. 1998 Aug;55(8):694-700. 
Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA, et al. The long-term 
natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 
2002 Jun;59(6):530-7. 
Judd LL, Akiskal HS. Depressive episodes and symptoms dominate the longitudinal course of 
bipolar disorder. Curr Psychiatry Rep. 2003 Dec;5(6):417-8. 
Kessler RC, Akiskal HS, Ames M, Birnbaum H, Greenberg P, Hirschfeld RM, et al. Prevalence 
and effects of mood disorders on work performance in a nationally representative sample of U.S. 
workers. Am J Psychiatry. 2006 Sep;163(9):1561-8. 
Merikangas KR, Akiskal HS, Angst J, Greenberg PE, Hirschfeld RM, Petukhova M, et al. 
Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity 
Survey replication. Arch Gen Psychiatry. 2007 May;64(5):543-52. 
Morin CM, Belleville G, Bélanger L, Ivers H. The Insomnia Severity Index: Psychometric 
Indicators to Detect Insomnia Cases and Evaluate Treatment Response. Sleep. 2011;34(5):601-
608. 


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CONFIDENTIAL 
 
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Perlis RH, Ostacher MJ, Patel JK, Marangell LB, Zhang H, Wisniewski SR, et al. Predictors of 
recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement 
Program for Bipolar Disorder (STEP-BD). Am J Psychiatry. 2006 Feb;163(2):217-24. 
Posner K, Brown GK, Stanley B, et al. The Columbia–Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-77. 
Post RM, Leverich GS, Altshuler LL, Frye MA, Suppes TM, Keck PE Jr, et al. An overview of 
recent findings of the Stanley Foundation Bipolar Network (Part I). Bipolar Disord. 2003 
Oct;5(5):310-9. 
Rudolph U, Knoflach F. Beyond classical benzodiazepines: novel therapeutic potential of 
GABAA receptor subtypes. Nat Rev Drug Discov. 2011 Jul 29;10(9):685-97. 
Sachs GS, Nierenberg AA, Calabrese JR, Marangell LB, Wisniewski SR, Gyulai L, et al. 
Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007 
Apr 26;356(17):1711-22. Epub 2007 Mar 28. 
 
 
Williams JBW and Kobak KA. Development and reliability of a structured interview guide for 
the Montgomery-Asberg Depression Rating Scale (SIGMA). British Journal of Psychiatry. 
2008:192(1):52-58. 
Williams JBW.  SIGH-D 24hr: V1.3 – 24 HR Version. 2013a. 
Williams JBW.  SIGH-D Past week:  Past Week Version. 2013b. 
Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and 
sensitivity. Br J Psychiatry. 1978 Nov;133:429-35. 


Protocol 217-BPD-201, Summary of Changes 
Sage Therapeutics 
Version 3.0, Amendment 2  
 
CONFIDENTIAL 
 
 
1 
Protocol 217-BPD-201, Amendment 2 
Date of Amendment: 18 October 2018 
A 2-Part Study (Open-label followed by Double-blind, Randomized, Placebo-controlled, 
Parallel Group) of the Safety, Tolerability, Pharmacokinetics, and Efficacy of SAGE-217 in 
the Treatment of Subjects with Bipolar I/II Disorder with a Current Major Depressive 
Episode 
Rationale for Protocol Amendment 
The primary purpose for this protocol amendment is as follows: 
• Define exclusionary period for use of benzodiazepines and GABAA 
modulators/GABA-containing agents to avoid confounding by the natural resolution 
of prolonged mild GABAergic withdrawal symptoms 
• Removed number of capsules at each dose to allow for difference manufacturing 
processes. Specific instructions will be provided in the pharmacy manual. 
Additional changes are being implemented as outlined below: 
• Exclude subjects that have taken non-GABA anti-insomnia medications (eg 
melatonin, Benadryl [anti-histamines], trazodone, low dose quetiapine, mirtazapine, 
etc) within 14 days of initition of study drug. 
• Remove criterion that subjects must be ambulatory. 
• Include exception to contraception criteria for subjects in same-sex relationship(s) 
which do not carry a risk of pregnancy. 
• Remove specific timing of dosing and offer practical options for taking study drug 
with food in the evening 
• Reiterate exclusion criterion prohibiting elective surgeries. 
• Define timeframes for each type of prohibited medication. 
A detailed summary of changes is provided in Table 1. Corrections to typographical errors, 
punctuation, grammar, abbreviations, and formatting are not detailed. 
 


Protocol 217-BPD-201, Summary of Changes 
Sage Therapeutics 
Version 3.0, Amendment 2  
CONFIDENTIAL 
 
 
2 
Table 1: 
Protocol Amendment 2 Detailed Summary of Changes 
The primary section of the protocol affected by the changes in Protocol Amendment 2 is indicated. The corresponding related text has 
been revised throughout the protocol. Deleted text is indicated by strikeout; added text is indicated by bold font. 
Purpose: Remove criterion that subjects must be ambulatory. 
The primary change occurs in Section 8.1 Subject Inclusion Criteria 
Changed text: 
3. Subject is an ambulatory male or female between 18 and 65 years of age, inclusive, at Screening. 
Sections also affected by this change:  
• 
Synopsis 
Purpose: Include exception to contraception criteria for subjects in same-sex relationship(s) which do not carry a risk of pregnancy. 
The primary change occurs in Section 8.1. Subject Inclusion Criteria 
Changed text: 
7. Female subject agrees to use one of the following methods of contraception during participation in the study and for 
30 days following the last dose of study drug, unless they are postmenopausal (defined as no menses for 12 months 
without an alternative medical cause and confirmed by follicle stimulating hormone [FSH] >40 mIU/mL) and/or 
surgically sterile (hysterectomy or bilateral oophorectomy), or in sexual relationship(s) which do not carry a risk of 
pregnancy (eg, same-sex relationship(s)): 
• 
Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal hormonal contraception 
associated with inhibition of ovulation. 
• 
Oral, injectable, or implantable progestogen-only hormonal contraception associated with inhibition of ovulation.  
• 
Intrauterine device. 
• 
Intrauterine hormone-releasing system. 
• 
Bilateral tubal ligation/occlusion. 
• 
Vasectomized partner. 
• 
Sexual abstinence (no sexual intercourse). 
8. Male subject agrees to use an acceptable method of effective contraception for the duration of study and for 5 days 
after receiving the last dose of the study drug, unless the subject is in sexual relationship(s) which do not carry a risk 
of pregnancy (eg, same-sex relationship(s)). Acceptable methods of effective contraception for males includes sexual 
abstinence, vasectomy, or a condom with spermicide used together with highly effective female contraception methods if 
the female partner is of child-bearing potential (see Inclusion Criteria #7 for acceptable contraception methods). 


Protocol 217-BPD-201, Summary of Changes 
Sage Therapeutics 
Version 3.0, Amendment 2  
CONFIDENTIAL 
 
 
3 
Sections also affected by this change:  
• 
Synopsis 
Purpose: Define exclusionary period for use of benzodiazepines and GABAA modulators/GABA-containing agents to avoid confounding by the 
natural resolution of prolonged mild GABAergic withdrawal symptoms. 
The primary change occurs in Section 8.2 Subject Exclusion Criteria 
Changed text: 
13. Subject is taking typical or atypical antipsychotics, monoamine oxidase inhibitors (MAOIs), benzodiazepines or 
GABAA modulators/GABA-containing agents (eg, eszopiclone, zopiclone, zaleplon, and zolpidem) at Day -28 other 
than the allowed mood stablizers at the Screening Visit. 
Sections also affected by this change:  
• 
Synopsis, 9.2.2 Prohibited Medications 
Purpose: Exclude subjects that have taken non-GABA anti-insomnia medications (eg, melatonin, Benadryl [anti-histamines], trazodone, low dose 
quetiapine, mirtazapine, etc) within 14 days of initition of study drug. 
The primary change occurs in Section 8.2 Subject Exclusion Criteria 
Added text: 
29. Subject is taking non-GABA anti-insomnia medications (eg, melatonin, Benadryl [anti-histamines], 
trazodone, low dose quetiapine, mirtazapine, etc) at Day -14. 
Sections also affected by this change:  
• 
Synopsis, 9.2.2 Prohibited Medications 
Purpose: Offer practical options for taking study drug with food in the evening. 
The primary change occurs in Section 10.5 Study Drug Administration 
Added text: 
SAGE-217 is to be administered orally once daily in the evening with food. Practical options include taking SAGE-
217 within 1 hour of dinner or taking SAGE-217 later in the evening with solid food. If a subject misses a dose, the 
subject should skip that dose (ie, they should not take the dose in the morning) and take the next scheduled dose in the 
evening the next day. 
Sections also affected by this change:  
• 
Synopsis and Section 9.1 Study Drug 


Protocol 217-BPD-201, Summary of Changes 
Sage Therapeutics 
Version 3.0, Amendment 2  
CONFIDENTIAL 
 
 
4 
Purpose: Remove specific timing of dosing.  
The primary change occurs in Section 9.1 Study Drug 
Deleted text: 
(approximately 8:00 to 11:00 pm) 
Sections also affected by this change: 
• 
Synopsis, Section 7.1 Overall Study Design, 9.3 Treatment Adherence, 10.5 Study Drug Administration 
Purpose: Define timeframes for each type of prohibited medication. 
The primary change occurs in Section 9.2.2 Prohibited Medications 
Changed text: 
The following specific classes of medications are prohibited at any time during the treatment period: 
• 
Initiation of new psychotropic medications at any time during the study 
• 
Initiation of new antidepressant therapy from 60 days prior to Day 1 through the duration of the study 
• 
Use of any benzodiazepines, GABAA modulators, GABAA-like acting drugs, or GABA-containing agents 
from Day -28 through the duration of the study 
• 
Use of any non-GABA anti-insomnia medications (eg, melatonin, Benadryl [anti-histamines], trazodone, 
low dose quetiapine, mirtazapine, etc) from Day -14 through the duration of the study 
• 
Exposure to another investigational medication or device from 30 days prior to Screening through the 
duration of the study 
• 
Any known strong inhibitors of CYP3A4 from Day -28 or 5 half-lives prior to Day 1 (whichever is longer) 
through the duration of the study 
• 
Use of any CYP inducer, such as such as rifampin, carbamazepine, ritonavir, enzalutamide, efavirenz, 
nevirapine, phenytoin, phenobarbital and St John’s Wort from Day -28 through the duration of the study. 
• 
Benzodiazepines 
• 
GABA A modulators other than the allowed mood stabilizers 
• 
Typical or atypical antipsychotics 
• 
MAOIs 


Protocol 217-BPD-201, Summary of Changes 
Sage Therapeutics 
Version 3.0, Amendment 2  
CONFIDENTIAL 
 
 
5 
• 
Any known strong inhibitors of CYP3A4 
• 
Use of CYP inducers, such as rifampin, carbamazepine, ritonavir, enzalutamide, efavirenz, nevirapine, 
phenytoin, phenobarbital and St John’s Wort. 
Sections also affected by this change:  
• 
Not applicable 
Purpose: Reiterate exclusion criterion prohibiting elective surgeries.  
The primary change occurs in Section 9.2.3 Other Restriction  
Added text: 
Elective surgeries or procedures are prohibited during participation in the study. 
Sections also affected by this change: 
• 
Not applicable 
Purpose: Removed number of capsules at each dose. 
The primary change occurs in Section 10.1 Description of Study Drug 
Deleted text: 
Subjects will be administered 2 capsules per dose in Part A. Subjects will be administered 1 capsule per dose in Part B. 
Sections also affected by this change: 
• 
Section 10.2 Study Drug Packaging and Labeling 
Purpose: Correct typographical errors, punctuation, grammar, abbreviations, and formatting. 
These changes are not listed individually. 
 






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Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-BPD-201 v4.0 
 
CONFIDENTIAL 
 
3 
 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for SAGE-217. I have read the 217-BPD-
201 clinical protocol and agree to conduct the study as outlined. I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
Date (DD Month YYYY) 
 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-BPD-201 v4.0 
 
CONFIDENTIAL 
 
4 
 
2. 
SYNOPSIS 
Name of Sponsor/Company: 
Sage Therapeutics 
Name of Investigational Product: 
SAGE-217 Capsule 
Name of Active Ingredient: 
SAGE-217 
Title of Study:  
A 2-Part Study (Open-label followed by Double-blind, Randomized, Placebo-controlled, Parallel 
Group) of the Safety, Tolerability, Pharmacokinetics, and Efficacy of SAGE-217 in the Treatment of 
Subjects with Bipolar I/II Disorder with a Current Major Depressive Episode 
Number of Sites and Study Location:  
Part A: Approximately 10 sites in the United States 
Part B: Approximately 40 sites in the United States 
Phase of Development: 2 
Planned Duration of participation: Up to 73 days (28-day Screening Period; 14-day Treatment 
Period, and 28-day [±3 days] Follow-up Period) 
Objectives: 
Part A Primary: 
• 
To evaluate the safety and tolerability of SAGE-217 in subjects with bipolar I or II disorder 
with a current major depressive episode (MDE). 
Part A Secondary:  
• 
To assess the efficacy of SAGE-217 in reducing depressive symptoms in subjects with bipolar 
I/II disorder with a current MDE. 
• 
To assess the effect of SAGE-217 on sleep.  
Part B Primary: 
• 
To assess the efficacy of SAGE-217 in reducing depressive symptoms in subjects with bipolar 
I/II disorder with a current MDE. 
Part B Secondary:  
• 
To evaluate the safety and tolerability of SAGE-217 in subjects with bipolar I/II disorder with 
a current MDE. 
• 
To assess the effect of SAGE-217 on sleep. 
 
 
 
 
 
 
 
 
 
 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-BPD-201 v4.0 
 
CONFIDENTIAL 
 
5 
 
Endpoints:  
Part A Primary: 
• 
The safety and tolerability of SAGE-217 as assessed by the frequency and severity of adverse 
events; changes from baseline in clinical laboratory measures, vital signs, and 
electrocardiogram (ECGs); and suicidal ideation and behavior using the Columbia Suicide 
Severity Rating Scale (C-SSRS); and mania using the Young Mania Rating Scale (YMRS). 
Part A Secondary: 
• 
The reduction in depressive symptoms, as assessed by: 
o Change from baseline in the 17-item Hamilton Depression Rating Scale (HAM-D) 
total score at Day 15 
o HAM-D response at Day 15 
o HAM-D remission at Day 15 
o Change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) 
total score at Day 15 
o The response to the Clinical Global Impression scale for severity and improvement 
(CGI-S and CGI-I, respectively) at Day 15 
• 
The reduction in insomnia severity, as assessed by Insomnia Severity Index (ISI) at Day 15 
Part B Primary: 
• 
The primary endpoint in Part B is the reduction in depressive symptoms with SAGE-217 
treatment, as assessed by the change from baseline in the HAM-D total score. 
Part B Secondary: 
• 
The reduction in depressive symptoms, as assessed by: 
o Change from baseline in HAM-D total score at Day 15  
o HAM-D response at Day 15 
o HAM-D remission at Day 15 
o Change from baseline in the MADRS total score at Day 15 
o CGI-S and CGI-I response at Day 15 
• 
The safety and tolerability of SAGE-217 as assessed by the frequency and severity of adverse 
events; changes from baseline in clinical laboratory measures, vital signs, and ECGs; and 
suicidal ideation and behavior using the C-SSRS; and mania using the YMRS. 
• 
The reduction in insomnia severity, as assessed by ISI at Day 15 
 
 
 
 
 
 
 
 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-BPD-201 v4.0 
 
CONFIDENTIAL 
 
6 
 
Study Description:   
This study will be conducted in 2 sequential parts: Part A (open-label) and Part B (randomized, double-
blind, placebo-controlled, parallel group). Part B will be initiated pending the review of Part A data. 
The methods of the 2 parts will be identical unless otherwise noted. Subjects who participate in Part A 
will not be allowed to participate in Part B. The study is designed to assess the safety, tolerability, 
 
and efficacy of SAGE-217 in adult subjects with bipolar I/II disorder, who are currently experiencing 
an MDE.  
The assessments are summarized in the Schedule of Events (Table 1). 
Screening begins with the signing of the informed consent form at the Screening Visit. The diagnosis 
of bipolar I or II disorder will be made using the Structured Clinical Interview for Diagnostic and 
Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) for clinical trials (SCID-5-CT) 
performed by a qualified healthcare professional.  
Beginning on Day 1, qualified subjects will self-administer the study drug once daily in the evening 
with food for 14 days. In Part A, all subjects will receive SAGE-217. For Part B, subjects will be 
randomized in a 1:1 ratio to receive SAGE-217 or placebo; randomization will be stratified based on 
use of mood stabilizers (Y/N). Subjects on antidepressants or mood stabilizers (lamotrigine, lithium, 
and valproic acid only) that have been taken at the same dose for at least 60 days prior to Day 1 are to 
continue the stable dose throughout the treatment period.  
If at any time, 30 mg is not tolerated, as assessed by the occurrence of a severe AE judged by the 
investigator to be related to study drug, the dose on the next day will be reduced to 20 mg and 
continued for the remainder of the treatment period. Dose adjustments related to moderate AEs will be 
judged by the Investigator. If a dose adjustment from 30 mg to 20 mg is deemed necessary by the 
Investigator, the subject will return to the site for the adjusted dose to be dispensed. Subjects who 
cannot tolerate the 20-mg dose at any time will be discontinued from study drug.  
If at any time during the study, a subject has a YMRS score of ≥13, the Investigator will clinically 
assess the subject for a manic or hypomanic switch. If the clinical assessment is consistent with 
hypomania or mania, the subject will be discontinued from study drug and treated as clinically 
appropriate. These incidents will be documented as AEs. 
Subjects will return to the study center during the treatment and follow-up periods as outlined in 
Table 1. 
Number of Subjects (planned):   
Part A: Approximately 30 subjects will be dosed. 
Part B: Approximately 132 subjects will be randomized and dosed to obtain a total of 112 evaluable 
subjects. 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-BPD-201 v4.0 
 
CONFIDENTIAL 
 
7 
 
Eligibility criteria:  
Inclusion Criteria: 
1. Subject has signed an informed consent form (ICF) prior to the conduct of any study-specific 
procedures. 
2. Subject agrees to adhere to the study requirements, including use of prior, concomitant, and 
prohibited medications. 
3. Subject is a man or woman, aged 18 to 65 years, inclusive, at Screening. 
4. 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. 
5. Subject has a documented history of hypomanic or manic episode (verified by medical records 
and/or treating healthcare professional) and a diagnosis of bipolar I or bipolar II disorder with 
a current MDE as per DSM-5 SCID-5-CT. 
6. Subject has a HAM-D score of ≥22 at Screening.  
7. Female subject agrees to use one of the following methods of contraception during 
participation in the study and for 30 days following the last dose of study drug, unless they are 
postmenopausal (defined as no menses for 12 months without an alternative medical cause and 
confirmed by follicle stimulating hormone [FSH] level ≥40 mIU/mL) and/or surgically sterile 
(hysterectomy or bilateral oophorectomy), or does not engage in sexual relation(s) which carry 
a risk of pregnancy: 
• 
Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation. 
• 
Oral, injectable, or implantable progestogen-only hormonal contraception associated with 
inhibition of ovulation.  
• 
Intrauterine device. 
• 
Intrauterine hormone-releasing system. 
• 
Bilateral tubal ligation/occlusion. 
• 
Vasectomized partner. 
• 
Sexual abstinence (no sexual intercourse).  
8. 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 relation(s) which carry a risk of pregnancy. Acceptable methods of effective 
contraception for males includes sexual abstinence, vasectomy, or a condom with spermicide 
used together with highly effective female contraception methods (if the female partner is of 
child-bearing potential, see Inclusion Criteria #7 for acceptable method of contraception for 
females). 
9. 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. 
Exclusion Criteria: 
1. Subject has a history of suicide attempt within the last 2 years. 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-BPD-201 v4.0 
 
CONFIDENTIAL 
 
8 
 
2. Subject has current suicidal ideation with plans based on Investigator clinical assessment 
and/or the C-SSRS response at Screening or Day 1. 
3. Subject has a history of rapid cycling bipolar disorder as per DSM-5 SCID-5-CT. 
4. Subject’s current depressive episode meets the DSM-5 specifier criteria for mixed features. 
5. Subject has ≥25% reduction in HAM-D score from Screening to Day 1. 
6. 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. 
7. Subject has abnormal liver function as shown by an abnormal liver function profile at 
screening (eg, repeated values of aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), or total bilirubin ≥2x the upper limit of normal). 
8. Subject has a clinically significant abnormal 12-lead ECG at the Screening or Day 1 visits. 
NOTE: mean QT interval calculated using the Fridericia method (QTcF) of >450 msec in male 
or >470 msec in female subjects will be the basis for exclusion from the study.  
9. Subject has a YMRS score ≥13 at Screening or Day 1. 
10. Subject presents for the study receiving a mood stabilizer other than lamotrigine, lithium, or 
valproic acid. 
11. Subject presents for the study receiving antidepressants and mood stabilizers, which have 
not been taken at the same dose for at least 60 days prior to Day 1. 
12. Subject that presents for the study receiving psychotropic medications and does not intend to 
continue the current treatment regimen during the treatment period.  
13. Subject is taking benzodiazepines, barbituates, or GABAA modulators (eg, eszopiclone, 
zopiclone, zaleplon, and zolpidem) at Day -28, or subject has been using these agents on a 
daily or near-daily (≥4 times per week) for more than one year. 
14. Subject has a history of severe rashes or Stevens-Johnson Syndrome associated with 
lamotrigine and is currently taking lamotrigine. 
15. Subject’s current depressive episode is treatment resistant; defined as persistent depressive 
symptoms despite treatment with adequate doses of antidepressants from two different classes 
for an adequate amount of time (ie, at least 4 weeks of treatment). This will be assessed using 
the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire. 
16. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds. 
17. Subject has a positive pregnancy test at the Screening Visit or on Day 1 (prior to 
administration of study drug) or, if she is breastfeeding at Screening or on Day 1 (prior to 
administration of study drug), she does not agree to temporarily cease giving breast milk to her 
child(ren) from just prior to receiving study drug on Day 1 until 7 days after the last dose of 
study drug. 


Clinical Protocol 
 
Sage Therapeutics, Inc. 
217-BPD-201 v4.0 
 
CONFIDENTIAL 
 
9 
 
18. Subject has detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) and 
HCV viral load, or human immunodeficiency virus (HIV) antibody at screening. 
19. Subject has active psychosis per Investigator assessment. 
20. Subject has a medical history of seizures. 
21. Subject has a medical history schizophrenia, and/or schizoaffective disorder. 
22. Subject has a history of mild, moderate, or severe substance use disorder diagnosed using 
DSM-5 criteria in the 12 months prior to screening. 
23. Subject has a positive drug and/or alcohol screen at screening or on Day 1 prior to dosing. 
24. Subject has had exposure to another investigational medication or device within 30 days prior 
to the Screening visit. 
25. Subject has been previously treated or randomized in any study using SAGE-217. Subjects 
who participate in Part A are not eligible to participate in Part B. 
26. Subject has used any known strong inhibitors of cytochrome P450 (CYP)3A4 within 28 days 
or five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, or Seville 
oranges, or products containing these within 14 days prior to receiving the first dose of study 
drug. 
27. Subject has used strong CYP3A inducers, such as carbamazepine, enzalutamide, mitotane, 
phenytoin, rifampin, or St Johns Wort within 28 days prior to the first dose of study drug. 
28. Subject plans to undergo elective surgery during participation in the study. 
29. Subject is taking non-GABA anti-insomnia medications (eg, melatonin, Benadryl [anti-
histamines], trazodone, low-dose quetiapine, mirtazapine, etc) at Day -14 .  
30. Subject has been taking psychostimulants (eg, methylphenidate, amphetamine) or opioids 
regularly or as needed, at Day -28. 
SAGE-217 dosage and mode of administration:  
SAGE-217 (30 mg) will be administered orally once daily in the evening with food. 
Reference therapy, dosage and mode of administration (Part B only):  
Placebo capsules will only be used for Part B. Study drug placebo will be administered orally once 
daily in the evening  with food. 
Duration of Treatment: 14 days 


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Statistical methods:   
A separate statistical analysis plan (SAP) for each part (Parts A and B) will provide a detailed 
description of the analyses to be performed in the respective part of the study. The SAPs will be 
finalized and approved prior to database lock. Any deviations from or changes to the SAP following 
database lock will be described in detail in the clinical study report. 
General: 
The data from Parts A and B will be analyzed separately. For the purpose of all safety and efficacy 
analyses where applicable, baseline is defined as the last available measurement prior to the start of 
study drug administration.  
Continuous endpoints will be summarized with n, mean, standard deviation, median, minimum, and 
maximum. In addition, change from baseline values will be calculated at each time point and 
summarized descriptively. For categorical endpoints, descriptive summaries will include counts and 
percentages. 
Analysis Sets:  
Randomized set (Part B only) will be defined as all subjects who are randomized. This analysis set will 
be used of all data listings in Part B. Data listings for Part A will be based on Safety or Efficacy Set, as 
appropriate. 
The Safety Set, defined as all subjects received at least 1 dose of study drug, will be used to provide 
descriptive summaries of safety data.  
The Efficacy Set, defined as all subjects who are in Safety Set and have at least one post-baseline 
HAM-D evaluation, will be used to analyze efficacy data unless otherwise specified. 
 
Safety Analysis:  
The overall incidence of adverse events will be summarized by Medical Dictionary for Regulatory 
Activities (MedDRA) system organ class and preferred term. Data for vital signs, clinical laboratory 
measurements, ECG, and concomitant medication usage will also be summarized.  
Safety data will be summarized and examined for possible relationships between subject characteristics 
and plasma SAGE-217 concentrations, as appropriate. Suicidality data collected using the C-SSRS and 
evaluation of mania collected using the YMRS at baseline and at each visit during the active Treatment 
Period will be listed for all subjects. Out-of-range safety endpoints may be categorized as low or high, 
where applicable. Subjects will be summarized according to treatment received for the purpose of 
safety.  
Efficacy Analysis:  
The primary endpoint in Part B, the change from baseline in HAM-D total score, will be analyzed 
using a mixed effects model for repeated measures (MMRM); the model will include treatment, 
baseline HAM-D total score, stratification factor, assessment time point, and time point-by-treatment 
as explanatory variables. All explanatory variables will be considered as fixed effects and the subject 
effect will be considered random in the model. All post-baseline time points will be included in the 
model. The primary comparison will be between SAGE-217 and matching placebo at Day 15. Model-
based point estimates (ie, least squares [LS] means, 95% confidence intervals, and p-values) will be 
reported. An unstructured covariance structure will be used to model the within-subject errors. Other 
continuous endpoints will be analyzed using similar methods.  
Other efficacy analyses, including those in Part A, will be specified in the SAP. In general, data will be 
analyzed using appropriate descriptive statistics or pre-specified statistical methods as applicable; 


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subject listings will be provided for all efficacy data. Subjects will be analyzed according to 
randomized treatment for the purpose of efficacy unless otherwise specified. 
 
 
 
 
 
Sample Size Calculation 
Part A: The sample size of approximately 30 subjects was selected based on clinical and not statistical 
considerations. 
Part B: Assuming a two-sided alpha level of 0.05, a sample size of 112 total evaluable subjects (56 per 
treatment group) would provide 80% power to detect a placebo-adjusted treatment difference of 
approximately 4 points in the primary endpoint, change from baseline in HAM-D total score at Day 15, 
assuming standard deviation (SD) of 7.5 points.  
Assuming a 15% dropout rate, approximately 132 total randomized subjects will be required to obtain 
a total of 112 evaluable subjects. Evaluable subjects are defined as those randomized subjects who 
receive study drug and have a valid baseline and at least 1 post-baseline HAM-D assessment. 
Additional subjects may be randomized if the drop-out rate is higher than 15%.  
 


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Table 1: 
Schedule of Events 
Study Period 
Screening 
Period 
Treatment Period 
Follow-up Perioda 
Visit Day 
D-28 to  
D-1 
D1 
D3 
(+1d) 
D8 
(±1d) 
D12 
(±1d) 
D15 
(±1d)/
EOTa 
D21 
(±3d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)/ 
ET 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical/Family History 
X 
 
 
 
 
 
 
 
 
 
SCID-5-CT 
X 
 
 
 
 
 
 
 
 
 
MGH-ATRQ 
X 
 
 
 
 
 
 
 
 
 
Serum FSH testb 
X 
 
 
 
 
 
 
 
 
 
Randomization (Part B 
only) 
 
X 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
 
X 
 
 
 
X 
Body Weight/Heightc 
X 
 
 
 
 
X (wt 
only) 
 
 
 
X (wt 
only) 
Clinical Laboratory 
Assessmentsd 
X 
X 
 
X 
 
X 
X 
X 
 
X 
Drug & Alcohol Screene 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Testf 
X 
X 
 
 
 
X 
 
X 
 
X 
Hepatitis & HIV 
Screen 
X 
 
 
 
 
 
 
 
 
 
Vital Signsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGj 
X 
X 
X 
 
 
X 
 
 
 
X 
C-SSRSk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAM-Dl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MADRSl 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-S 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
YMRSl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Study Period 
Screening 
Period 
Treatment Period 
Follow-up Perioda 
Visit Day 
D-28 to  
D-1 
D1 
D3 
(+1d) 
D8 
(±1d) 
D12 
(±1d) 
D15 
(±1d)/
EOTa 
D21 
(±3d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)/ 
ET 
ISI 
 
X 
 
X 
 
X 
X 
X 
 
X 
Study Drug Dispensationo 
 
X 
 
X 
 
 
 
 
 
 
Study Drug 
Administration 
 
X (Day 1-14) 
 
 
 
 
 
Study Drug 
Accountability/Return 
 
 
X 
X 
X 
X 
 
 
 
 
Adverse Events/Serious 
Adverse Eventsp 
X 
Prior/Concomitant 
Medications/ Proceduresq 
X 
CGI-I = Clinical Global Impression - Improvement; CGI-S – Clinical Global Impression - Severity; C-SSRS = 
Columbia Suicide Severity Rating Scale; D = day; EOT = end of treatment; ECG = electrocardiogram; ET = early 
termination; 
 FSH = follicle stimulating hormone; HAM-D = Hamilton 
Rating Scale for Depression, 17-item; HIV = human immunodeficiency virus; ISI = Insomnia Severity Index; 
MADRS = Montgomery-Åsberg Depression Rating Scale; MGH-ATRQ = Massachusetts General Hospital 
Antidepressant Treatment Response Questionnaire; O = optional; 
 SCID-5-CT = Structured 
Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition for clinical trials; 
 
 YMRS = Young Mania Rating Scale 
a Subjects who discontinue treatment early should return to the site for an EOT visit as soon as possible, preferably 
the day after treatment is discontinued. Follow-up visits should take place every 7 days after the last dose of 
treatment for a total of 4 follow-up visits. If at any time after the EOT visit, a subject decides to terminate the 
study, the subject should return for an ET visit. The EOT and ET visits can be on the same day if a subject 
discontinues study drug and terminates the study on the same day during a clinic visit; in this case, all events 
scheduled for both visits will be conducted.  
b A serum follicle stimulating hormone test will be conducted for female subjects at Screening to confirm whether a 
female subject with ≥12 months of spontaneous amenorrhea and not surgically sterile meets the protocol-defined 
criteria for being post-menopausal. 
c Height measured at screening only 
d Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. Laboratory 
assessments are to be completed in the morning. 
e Urine toxicology for selected drugs of abuse, and breath test for alcohol (as per the standard procedures at each 
site).  
f For women of child-bearing potential, serum pregnancy test at screening and urine pregnancy test at all other 
scheduled timepoints. 
 
 
 
 
i Vital signs include oral temperature (°C), respiratory rate, heart rate, pulse oximetry, 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 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 will be obtained first.  
j Triplicate 12-lead ECGs will be performed with the subject in the supine position. When ECG 
 sample 
collection occur during the same visit, ECGs will be collected first. 
k 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. 


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l For MADRS, HAM-D, and YMRS, the “Since Last Evaluation” forms will be completed at all subsequent time 
points following the initial assessment. 
 
 
 
o Additional unscheduled dispensation visits may be needed for dose reductions. 
p AEs/SAEs will be collected starting at the time of informed consent and throughout the duration of the subject’s 
participation in the study.  
q Prior medications will be collected at Screening and concomitant medications will be collected at each subsequent 
visit. All medications taken within 30 days prior to Screening through the duration of the study will be recorded. In 
addition, all psychotropic medications taken within 12 months prior to Screening will be recorded. 
 


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3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF
FIGURES
1.
TITLE PAGE ................................................................................................................1 
2.
SYNOPSIS ...................................................................................................................4 
3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............15 
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................20 
5.
INTRODUCTION ......................................................................................................22 
5.1. 
Background of Bipolar Disorders and Unmet Medical Need .....................................22 
5.2. 
SAGE-217 ...................................................................................................................23 
5.3. 
Potential Risks and Benefits .......................................................................................24 
5.4. 
Dose Justification ........................................................................................................24 
6.
STUDY OBJECTIVES AND PURPOSE ..................................................................25 
6.1. 
Study Objective ..........................................................................................................25 
6.1.1. 
Primary Objective .......................................................................................................25 
6.1.2. 
Secondary Objectives .................................................................................................25 
 
25 
6.2. 
Endpoints ....................................................................................................................26 
6.2.1. 
Primary Endpoint ........................................................................................................26 
6.2.2. 
Secondary Endpoints ..................................................................................................26 
 
27 
7.
INVESTIGATIONAL PLAN .....................................................................................28 
7.1. 
Overall Study Design ..................................................................................................28 
7.2. 
Number of Subjects ....................................................................................................29 
7.3. 
Treatment Assignment ................................................................................................29 
7.4. 
Dose Adjustment Criteria ...........................................................................................29 
7.5. 
Study Termination ......................................................................................................30 
8.
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................31 
8.1. 
Subject Inclusion Criteria ...........................................................................................31 
8.2. 
Subject Exclusion Criteria ..........................................................................................32 
8.3. 
Subject Withdrawal Criteria .......................................................................................34 
8.3.1. 
Withdrawal from the Study or Discontinuation of Study Drug ..................................34 


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8.3.2. 
Replacement of Subjects .............................................................................................35 
9. 
TREATMENT OF SUBJECTS ..................................................................................36 
9.1. 
Study Drug ..................................................................................................................36 
9.2. 
Prior Medications, Concomitant Medications, and Restrictions ................................36 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................36 
9.2.2. 
Prohibited Medications ...............................................................................................36 
9.2.3. 
Other Restrictions .......................................................................................................37 
9.3. 
Treatment Adherence ..................................................................................................37 
9.4. 
Randomization and Blinding ......................................................................................37 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................39 
10.1. 
Description of Study Drug ..........................................................................................39 
10.2. 
Study Drug Packaging and Labeling ..........................................................................39 
10.3. 
Study Drug Storage .....................................................................................................39 
10.4. 
Study Drug Preparation ..............................................................................................39 
10.5. 
Study Drug Administration .........................................................................................39 
10.6. 
Study Drug Accountability .........................................................................................39 
10.7. 
Study Drug Handling and Disposal ............................................................................40 
11. 
ASSESSMENT OF EFFICACY 
 .............................41 
11.1. 
Efficacy Assessments .................................................................................................41 
11.1.1. 
Hamilton Rating Scale for Depression (HAM-D) ......................................................41 
11.1.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) ........................................41 
11.1.3. 
Clinical Global Impression (CGI) ..............................................................................41 
11.1.4. 
Insomnia Severity Index (ISI) ....................................................................................42 
 
42 
 
42 
 
43 
 
43 
 
43 
 
43 
 
43 
12. 
ASSESSMENT OF SAFETY .....................................................................................44 
12.1. 
Safety Parameters .......................................................................................................44 
12.1.1. 
Demographic/Medical History ...................................................................................44 


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12.1.2. 
Weight and Height ......................................................................................................44 
12.1.3. 
Physical Examination .................................................................................................44 
12.1.4. 
Vital Signs ..................................................................................................................44 
12.1.5. 
Electrocardiogram (ECG) ...........................................................................................44 
12.1.6. 
Laboratory Assessments .............................................................................................45 
12.1.6.1. 
Drugs of Abuse and Alcohol ......................................................................................46 
12.1.6.2. 
Pregnancy Screen ........................................................................................................46 
12.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................46 
12.1.8. 
Young Mania Rating Scale (YMRS) ..........................................................................47 
12.2. 
Adverse and Serious Adverse Events .........................................................................47 
12.2.1. 
Definition of Adverse Events .....................................................................................47 
12.2.1.1. 
Adverse Event (AE) ....................................................................................................47 
12.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................47 
12.3. 
Relationship to Study Drug ........................................................................................48 
12.4. 
Recording Adverse Events .........................................................................................48 
12.5. 
Reporting Serious Adverse Events .............................................................................49 
12.6. 
Emergency Identification of Study Drug ....................................................................50 
13. 
STATISTICS ..............................................................................................................51 
13.1. 
Data Analysis Sets ......................................................................................................51 
13.2. 
Handling of Missing Data ...........................................................................................51 
13.3. 
General Considerations ...............................................................................................51 
13.4. 
Demographics and Baseline Characteristics ...............................................................51 
13.5. 
Efficacy Analysis ........................................................................................................51 
13.6. 
Safety Analyses ..........................................................................................................52 
13.6.1. 
Adverse Events ...........................................................................................................52 
13.6.2. 
Clinical Laboratory Evaluations .................................................................................52 
13.6.3. 
Physical Examinations ................................................................................................52 
13.6.4. 
Vital Signs ..................................................................................................................52 
13.6.5. 
12-Lead Electrocardiogram ........................................................................................53 
13.6.6. 
Prior and Concomitant Medications ...........................................................................53 
13.6.7. 
Columbia Suicide Severity Rating Scale ....................................................................53 
13.6.8. 
Young Mania Rating Scale .........................................................................................53 
 
53 


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13.8. 
Determination of Sample Size ....................................................................................53 
13.8.1. 
Part A ..........................................................................................................................53 
13.8.2. 
Part B ..........................................................................................................................54 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................55 
14.1. 
Study Monitoring ........................................................................................................55 
14.2. 
Audits and Inspections ................................................................................................55 
14.3. 
Protocol Deviations ....................................................................................................55 
14.4. 
Institutional Review Board (IRB) or Ethics Committee (EC) ....................................55 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................56 
16. 
ETHICS ......................................................................................................................57 
16.1. 
Ethics Review .............................................................................................................57 
16.2. 
Ethical Conduct of the Study ......................................................................................57 
16.3. 
Written Informed Consent ..........................................................................................57 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................58 
17.1. 
Inspection of Records .................................................................................................58 
17.2. 
Retention of Records ..................................................................................................58 
18. 
PUBLICATION POLICY ..........................................................................................59 
19. 
LIST OF REFERENCES ............................................................................................60 
 


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LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................12 
Table 2: 
Abbreviations and specialist terms .............................................................................20 
Table 3: 
Clinical Laboratory Tests ...........................................................................................45 
Table 4: 
Relationship to Study Drug ........................................................................................48 
 
LIST OF FIGURES 
Figure 1: 
Study Design (Part A) .................................................................................................28 
Figure 2: 
Study Design (Part B) .................................................................................................29 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and specialist terms  
Abbreviation or specialist term 
Explanation 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
CGI-I 
Clinical Global Impression scale for improvement 
CGI-S 
Clinical Global Impression scale for severity 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CYP 
cytochrome P450 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition 
EC 
ethics committee 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EOT 
end of treatment 
ET 
early termination 
 
 
FSH 
follicle-stimulating hormone 
GABA 
γ-aminobutyric acid 
HAM-D 
Hamilton Depression Rating Scale 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ID 
identification 
IRT 
interactive response technology 
ISI 
Insomnia Severity Index 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MDD 
major depressive disorder 
MDE 
major depressive episode 
MedDRA 
Medical Dictionary for Regulatory Activities 


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Abbreviation or specialist term 
Explanation 
MGH-ATRQ 
Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire 
MMRM 
mixed effects model for repeated measures 
PI 
Principal Investigator; the investigator who leads the study 
conduct at an individual study center. Every study center has a 
principal investigator. 
 
 
QTcF 
QT corrected according to Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCID-5-CT 
Structured Clinical Interview for Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition for clinical trials 
SD 
standard deviation 
 
 
 
 
TEAE 
treatment-emergent adverse event 
YMRS 
Young Mania Rating Scale 
 


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5. 
INTRODUCTION 
5.1. 
Background of Bipolar Disorders and Unmet Medical Need 
Bipolar disorder is a chronic and episodic illness that is associated with significant disability 
worldwide (Sachs 2007). The Global Burden of Disease Study revealed that in 2013, there were 
48.8 million cases of bipolar disorder globally (Ferrari 2016). Bipolar disorder accounted for 
9.9 million disability-adjusted life years (DALYs) globally, explaining 0.4% of total DALYs and 
1.3% of total years lived with disability.  
There are subtypes of bipolar disorder; this study includes the bipolar I and II subtypes. Bipolar I 
is characterized by a manic episode, whereas bipolar II is characterized by a hypomanic episode. 
The difference in the severity of the manic features relies on functional impairment that is caused 
by these episodes (DSM-5). The National Comorbidity Survey estimate of the lifetime 
prevalence of bipolar disorder is 2.1% in the US population when bipolar I disorder and 
bipolar II Disorder are combined (Merikangas 2007). 
While the manic or hypomanic episodes represent distinct departure from the baseline mood 
state and easily attract attention, evidence suggests that depressive episodes of both bipolar I and 
II are associated with more disability than any other aspect of the illness. A seminal long-term 
study of patients with bipolar I disorder demonstrated that over the 13-year follow-up period, 
patients were symptomatic about 47% of the time, and depressive symptoms were present in 
32% of the follow-up weeks vs manic features, which were present in 9% (Judd 2002). A similar 
analysis in patients with bipolar II disorder with a longer follow up of up to 20 years found that 
patients were symptomatic more than half of the time (54%) where depressive symptoms 
dominated the course at 50% of the follow-up weeks versus 1.3% for the hypomanic symptoms 
(Judd 2003). A study in patients with unipolar depression found a prevalence of depressive 
symptoms 47% of the time (Judd 1998), suggesting a comparable time spent with depressive 
symptoms in the bipolar spectrum. These naturalistic studies have also found that about half the 
time patients reported taking psychotropic medications. In another large-scale study with a 
follow-up period of up to 2 years, 58% of nearly 1500 patients with bipolar disorder who were 
symptomatic at study entry achieved recovery (Perlis 2006). Similarly, during the follow-up 
period, 49% of these individuals experienced recurrent episodes, where depressive episodes 
(38%) outweighed manic, hypomanic, or mixed episodes combined (13.8%). In the Stanley 
Foundation Bipolar Network Study, in which year-long, daily clinician ratings were included, 
despite treatment with an average of 4.1 psychotropic medications, patients with bipolar disorder 
spent 3 times as much time with depressive symptoms as manic symptoms (Post 2003). 
There are only 3 medications approved in the US for the treatment of bipolar depression, 
(lurasidone, olanzapine-fluoxetine combination, and quetiapine), all of which include atypical 
antipsychotics that are associated with significant adverse metabolic effects. None of the 
currently available antidepressants are indicated for bipolar depression due to their limited 
efficacy, and the possibility that their use may be associated with a manic switch and rapid 
cycling. While some studies reported varying levels of efficacy with antidepressants 
(Gijsman 2004), a large-scale, double-blind, placebo-controlled clinical trial sponsored by the 
National Institutes of Mental Health, The Systematic Treatment Enhancement Program for 
Bipolar Disorder (STEP-BD), found that only 23.5% of patients with bipolar depression 
receiving a mood stabilizer and adjunctive antidepressants versus 27.3% of those receiving a 


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mood stabilizer and placebo experienced a durable recovery, confirming the lack of effectiveness 
of antidepressants in bipolar depression (Sachs 2007). The tolerability profile of the approved 
atypical antipsychotics and limited efficacy of available antidepressants highlight the critical 
unmet need in the treatment of bipolar depression. 
In 1998, the lifetime cost of bipolar disorder in the US was estimated at $24 billion. The cost of a 
single manic episode was estimated at $11,720 to $624,785 for persons with 
nonresponsive/chronic episodes (Begley 1998); the cost of bipolar depression specifically, is less 
well studied, however, available estimates indicate a higher cost associated with bipolar 
depression than for mania (Bowden 2004). 
Kessler has studied the impact of mood disorders on work performance in a representative 
sample of over 3,000 US workers (Kessler 2006). Bipolar disorder and major depressive disorder 
were associated with 65.5 and 27.2 lost workdays per worker per year, respectively. Moreover, it 
was found that the increase in bipolar disorder was attributable to depressive symptoms rather 
than manic episodes in bipolar disorder. 
Taken together, these findings point to substantial predominance of depressive symptoms across 
the spectrum of bipolar disorder. In particular, they also highlight the importance of successful 
depressive symptom control, and an unmet need in the treatment of depressive episodes for both 
bipolar I and bipolar II disorder. 
5.2. 
SAGE-217 
SAGE-217 is a positive allosteric modulator of γ-aminobutyric acid (GABA)A 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. 
Data from an open-label portion of the Phase 2a study of SAGE-217 administered to subjects 
with moderate to severe major depressive disorder (MDD) showed clinically significant 
improvements from baseline in depression scale scores (HAM-D, Montgomery-Åsberg 
Depression Rating Scale [MADRS], and Clinical Global Impression – Improvement [CGI-I]) as 
early as Day 2 of the 14-day treatment period, with durable responses following the end of 
treatment. This result was further supported by the randomized, double-blind portion of this 
study (N=89) in which a rapid and substantial decrease in HAM-D scores was observed at 
Day 15 (primary endpoint), starting at Day 2. This response pattern was also observed with other 
efficacy scales, including MADRS and CGI-I. Statistically significant differences from the 
placebo group favoring the SAGE-217 arm were observed for 2 weeks in the follow-up period. 
SAGE-217 has been generally well tolerated in clinical studies to date. The most common 
treatment-emergent adverse events (TEAEs) were sedation, somnolence, and dizziness. Most 
AEs were reported as mild or moderate in intensity. As of the Investigator’s Brochure cut-off 
date (24 September 2018), among the over 260 subjects exposed to SAGE-217 in clinical trials, 
there have been no deaths and only one subject with essential tremor experienced a serious 


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adverse event (SAE) of transient confusion leading to discontinuation of study drug. No other 
SAEs have been reported in any study of SAGE-217.  
Additional information on nonclinical and clinical data is provided in the Investigator’s 
Brochure.  
5.3. 
Potential Risks and Benefits 
Non-serious events of sedation, somnolence, and dizziness were the most commonly reported 
AEs with SAGE-217. Given the outcome of the Phase 2 study of SAGE-217 in subjects with 
MDD and the current significant unmet need in the treatment of depressive episodes associated 
with bipolar I/II disorders, a favorable risk-benefit balance and investigation of SAGE-217 in 
patients with bipolar I/II disorders are justified. 
5.4. 
Dose Justification 
The dose of SAGE-217 to be administered in this study (30 mg) was determined based on the 
maximum tolerated dose in the multiple ascending dose study of SAGE-217 in healthy subjects, 
and is the same dose level that has been used and generally well tolerated in clinical studies in 
various patient populations, including patients with MDD. Due to the observed improved 
tolerability of sedation/somnolence effects when taken in the evening in previous clinical studies, 
SAGE-217 will be administered in the evening in this study as well.  
With respect to the duration of treatment course, a 14-day study drug administration is planned. 
This is based on previous clinical trial data with SAGE-217, demonstrating substantial 
improvement in depressive symptoms in patients with MDD, starting within the first week of 
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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Study Objective 
6.1.1. 
Primary Objective 
Part A 
The primary objective of Part A of this study is to evaluate the safety and tolerability of 
SAGE-217 in subjects with bipolar I/II disorder with a current major depressive episode (MDE). 
Part B 
The primary objective of Part B of this study is to assess the efficacy of SAGE-217 in reducing 
depressive symptoms in subjects with bipolar I/II disorder with a current MDE. 
6.1.2. 
Secondary Objectives 
Part A 
Secondary objectives of Part A of this study are: 
• To assess the efficacy of SAGE-217 in reducing depressive symptoms in subjects 
with bipolar I/II disorder with a current MDE. 
• To assess the effect of SAGE-217 on sleep. 
Part B 
Secondary objectives of Part B of this study are: 
• To evaluate the safety and tolerability of SAGE-217 in subjects with bipolar I/II 
disorder with a current MDE. 
• To assess the effect of SAGE-217 on sleep. 
 
 
 
 
 
 
 
 
 
 
 
 


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6.2. 
Endpoints 
6.2.1. 
Primary Endpoint 
Part A 
The primary endpoint for Part A of this study is the safety and tolerability of SAGE-217, as 
assessed by the frequency and severity of adverse events (AEs); changes from baseline in clinical 
laboratory measures, vital signs, and electrocardiograms (ECGs); suicidal ideation and behavior 
using the Columbia Suicide Severity Rating Scale (C-SSRS); and mania using the Young Mania 
Rating Scale (YMRS). 
Part B 
The primary endpoint of Part B of this study is the reduction in depressive symptoms with 
SAGE-217 treatment, as assessed by the change from baseline in the 17-item HAM-D total 
score. 
6.2.2. 
Secondary Endpoints 
Part A 
Secondary endpoints of Part A of this study are: 
• The reduction in depressive symptoms, as assessed by: 
− Change from baseline in the 17-item HAM-D total score at Day 15 
− HAM-D response at Day 15 
− HAM-D remission at Day 15 
− Change from baseline in the MADRS total score at Day 15 
− The response to the CGI-S and CGI-I at Day 15 
• The reduction in insomnia severity as assessed by the Insomnia Severity Index (ISI) 
at Day 15 
Part B 
Secondary endpoints of Part B of this study are: 
• The reduction in depressive symptoms, as assessed by: 
− Change from baseline in total HAM-D score at Day 15 
− HAM-D response at Day 15 
− HAM-D remission at Day 15 
− Change from baseline in the MADRS total score at Day 15 
− CGI-S and CGI-I response at Day 15 


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• The safety and tolerability of SAGE-217 as assessed by the frequency and severity of 
AEs; changes from baseline in clinical laboratory measures, vital signs, and ECGs; 
and suicidal ideation and behavior using the C-SSRS, and the YMRS. 
• The reduction in insomnia severity, as assessed by the ISI at Day 15 
 
 
 
 
 
 
 
 
 
 
 


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7.
INVESTIGATIONAL PLAN
7.1. 
Overall Study Design
This study will be conducted in 2 sequential parts: Part A (open-label) and Part B (randomized, 
double-blind, placebo-controlled, parallel group). Part B will be initiated pending the review of 
Part A data.The methods of the 2 parts will be identical unless otherwise noted. The study is 
designed to assess the safety, tolerability, 
 and efficacy of SAGE-217 in adult subjects with 
bipolar I/II disorder, who are currently experiencing an MDE. 
Screening begins with the signing of the informed consent form (ICF) at the Screening Visit. The 
diagnosis of bipolar I or II disorder will be made using the Structured Clinical Interview for 
DSM-5 for clinical trials (SCID-5-CT) performed by a qualified healthcare professional. 
Subjects on antidepressants or mood stabilizers (lamotrigine, lithium, and valproic acid only) that 
have been taken at the same dose for at least 60 days prior to Day 1 are to continue the stable 
dose throughout the treatment period. 
Subjects will return to the study center during the treatment and follow-up periods as outlined in 
the Schedule of Events (Table 1). All assessments to be performed are summarized in Table 1. 
If at any time during the study, a subject has a YMRS score of ≥13, the Investigator will 
clinically assess the subject for a manic or hypomanic switch. If the clinical assessment is 
consistent with hypomania or mania, the subject will be discontinued from study drug and 
treated as clinically appropriate (see Section 8.3). 
Part A 
The study design for Part A is presented in Figure 1. In Part A, all subjects will receive 
SAGE-217. Beginning on Day 1, qualified subjects will self-administer 30-mg SAGE-217 once 
daily in the evening with food for 14 days. Dose adjustments based on study drug tolerability are 
permitted following the guidelines outlined in Section 7.4.
Figure 1: 
Study Design (Part A) 
QD = once daily 
A dose adjustment to 20-mg SAGE-217 is permitted if the 30-mg dose is not tolerated at any time. 
Part B 
The study design for Part B is presented in Figure 2. In Part B, subjects will be randomized in a 
1:1 ratio to receive SAGE-217 or placebo; randomization will be stratified based on use of mood 
stabilizers (Y/N). Beginning on Day 1, qualified subjects will self-administer the study drug 
Day -28 to -1
Screening
Days 1 to 14
SAGE-217
30 mg QD (evening)
Days 21, 28, 35, 42
Follow-up Visits
Day 15/
EOT


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(30 mg SAGE-217 or placebo) once daily in the evening with food for 14 days. Dose 
adjustments based on study drug tolerability are permitted following the guidelines outlined in 
Section 7.4. 
 
Figure 2: 
Study Design (Part B) 
 
QD = once daily 
A dose adjustment to 20-mg SAGE-217 is permitted if the 30-mg dose is not tolerated at any time. 
7.2. 
Number of Subjects 
Part A 
Approximately 30 subjects will be dosed in Part A.  
Part B 
After review of Part A data, approximately 132 subjects will be randomized and dosed in Part B 
to obtain a total of 112 evaluable subjects (see Section 13.8). 
7.3. 
Treatment Assignment 
Part A 
In Part A, all subjects will receive SAGE-217 in an open-label manner.  
Part B 
In Part B, subjects will be randomized to a treatment group (SAGE-217 or placebo) in a 
1:1 ratio; randomization will be stratified based on use of mood stabilizers (Y/N).  
7.4. 
Dose Adjustment Criteria 
If at any time, 30 mg is not tolerated, as assessed by the occurrence of a severe AE judged by the 
investigator to be related to study drug, the dose on the next day will be reduced to 20 mg and 
continued for the remainder of the treatment period. Dose adjustments related to moderate AEs 
will be judged by the Investigator. If a dose adjustment from 30 mg to 20 mg is deemed 
Day -28 to -1
Screening
Day 1
Randomization
Days 1 to 14
Placebo QD (evening)
Days 1 to 14
SAGE-217
30 mg QD (evening)
Days 21, 28, 35, 42
Follow-up Visits
Day 15/
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necessary by the Investigator, the subject will return to the site for the adjusted dose to be 
dispensed. Subjects who cannot tolerate the 20-mg dose at any time will be discontinued from 
study drug (see Section 8.3).  
7.5. 
Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons including the occurrence of AEs or other findings suggesting unacceptable risk to 
subjects, or for administrative reasons. In the event of study termination, Sage Therapeutics will 
provide written notification to the Investigator. Investigational sites must promptly notify their 
ethics committee and initiate withdrawal procedures for participating subjects.  


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
Qualified subjects will meet all of the following criteria: 
1. Subject has signed an ICF prior to the conduct of any study-specific procedures. 
2. Subject agrees to adhere to the study requirements, including use of prior, concomitant, 
and prohibited medications. 
3. Subject is a man or woman, aged 18 to 65 years, inclusive, at Screening. 
4. 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. 
5. Subject has a documented history of hypomanic or manic episode (verified by medical 
records and/or treating healthcare professional) and a diagnosis of bipolar I or bipolar II 
disorder with a current MDE as per DSM-5 SCID-5-CT. 
6. Subject has a HAM-D score of ≥22 at Screening.  
7. Female subject agrees to use one of the following methods of contraception during 
participation in the study and for 30 days following the last dose of study drug, unless 
they are postmenopausal (defined as no menses for 12 months without an alternative 
medical cause and confirmed by follicle stimulating hormone [FSH] level ≥40 mIU/mL) 
and/or surgically sterile (hysterectomy or bilateral oophorectomy), or does not engage in 
sexual relation(s) which carry a risk of pregnancy: 
• Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation. 
• Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation.  
• Intrauterine device. 
• Intrauterine hormone-releasing system. 
• Bilateral tubal ligation/occlusion. 
• Vasectomized partner. 
• Sexual abstinence (no sexual intercourse).  
8. 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 relation(s) which carry a risk of pregnancy. Acceptable 
methods of effective contraception for males includes sexual abstinence, vasectomy, or a 
condom with spermicide used together with highly effective female contraception 
methods (if the female partner is of child-bearing potential, see Inclusion Criteria #7 for 
acceptable method of contraception for females). 


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9. 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. 
8.2. 
Subject Exclusion Criteria 
Subjects who meet any of the following criteria are disqualified from participation in this study: 
1. Subject has a history of suicide attempt within the last 2 years. 
2. Subject has current suicidal ideation with plans based on Investigator clinical assessment 
and/or the C-SSRS response at Screening or Day 1. 
3. Subject has a history of rapid cycling bipolar disorder as per DSM-5 SCID-5-CT. 
4. Subject’s current depressive episode meets the DSM-5 specifier criteria for mixed 
features. 
5. Subject has ≥25% reduction in HAM-D score from Screening to Day 1. 
6. 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. 
7. Subject has abnormal liver function as shown by an abnormal liver function profile at 
screening (eg, repeated values of aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), or total bilirubin ≥2x the upper limit of normal). 
8. Subject has a clinically significant abnormal 12-lead ECG at the Screening or Day 1 
visits. NOTE: mean QT interval calculated using the Fridericia method (QTcF) of 
>450 msec in male or >470 msec in female subjects will be the basis for exclusion from 
the study.  
9. Subject has a YMRS score ≥13 at Screening or Day 1. 
10. Subject presents for the study receiving a mood stabilizer other than lamotrigine, lithium, 
or valproic acid. 
11. Subject presents for the study receiving psychotropic medications, which have not been 
taken at the same dose for at least 60 days prior to Day 1. 
12. Subject that presents for the study receiving psychotropic medications and does not 
intend to continue the current treatment regimen during the treatment period.  
13. Subject is taking benzodiazepines, barbituates, or GABAA modulators (eg, eszopiclone, 
zopiclone, zaleplon, and zolpidem) at Day -28, or subject has been using these agents on 
a daily or near-daily (≥4 times per week) for more than one year. 
14. Subject has a history of severe rashes or Stevens-Johnson Syndrome associated with 
lamotrigine and is currently taking lamotrigine. 
15. Subject’s current depressive episode is treatment resistant; defined as persistent 
depressive symptoms despite treatment with adequate doses of antidepressants from two 
different classes for an adequate amount of time (ie, at least 4 weeks of treatment). This 


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will be assessed using the Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire. 
16. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds. 
17. Subject has a positive pregnancy test at the Screening Visit or on Day 1 (prior to 
administration of study drug) or, if she is breastfeeding at Screening or on Day 1 (prior to 
administration of study drug), she does not agree to temporarily cease giving breast milk 
to her child(ren) from just prior to receiving study drug on Day 1 until 7 days after the 
last dose of study drug. 
18. Subject has detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV) 
and HCV viral load, or human immunodeficiency virus (HIV) antibody at screening. 
19. Subject has active psychosis per Investigator assessment. 
20. Subject has a medical history of seizures. 
21. Subject has a medical history schizophrenia, and/or schizoaffective disorder. 
22. Subject has a history of mild, moderate, or severe substance use disorder diagnosed using 
DSM-5 criteria in the 12 months prior to screening. 
23. Subject has a positive drug and/or alcohol screen at screening or on Day 1 prior to 
dosing. 
24. Subject has had exposure to another investigational medication or device within 30 days 
prior to the Screening visit. 
25. Subject has been previously treated or randomized in any study using SAGE-217. 
Subjects who participate in Part A are not eligible to participate in Part B. 
26. Subject has used any known strong inhibitors of cytochrome P450 (CYP)3A4 within 28 
days or five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, or 
Seville oranges, or products containing these within 14 days prior to receiving the first 
dose of study drug. 
27. Subject has used strong CYP3A inducers, such as carbamazepine, enzalutamide, 
mitotane, phenytoin, rifampin, or St Johns Wort within 28 days prior to the first dose of 
study drug. 
28. Subject plans to undergo elective surgery during participation in the study. 
29. Subject is taking non-GABA anti-insomnia medications (eg, melatonin, Benadryl [anti-
histamines], trazodone, low dose quetiapine, mirtazapine, etc) at Day -14.  
30. Subject has been taking psychostimulants (eg, methylphenidate, amphetamine) or opioids 
regularly or as needed, at Day -28. 


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8.3. 
Subject Withdrawal Criteria 
8.3.1. 
Withdrawal from the Study or Discontinuation of Study Drug 
Subjects may discontinue study drug or withdraw from the study at any time for any reason. The 
Investigator may discontinue the subject from the study or study drug for any of the following 
reasons: 
• The subject is unwilling or unable to adhere to the protocol 
• The subject experiences an intolerable AE  
• Other medical or safety reason, at the discretion of the Investigator and/or the 
Medical Monitor 
In addition, if at any time during the study, a subject has a YMRS score of ≥13, the Investigator 
will clinically assess the subject for a manic or hypomanic switch. If the clinical assessment is 
consistent with hypomania or mania, the subject will be discontinued from study drug and 
treated as clinically appropriate. These incidents will be documented as AEs. 
The reasons for study drug discontinuation and/or subject withdrawal from the study must be 
recorded in the subject’s electronic case report form (eCRF). The Investigator must notify the 
Sponsor and/or the Medical Monitor immediately when a subject has discontinued or been 
withdrawn for any reason. 
Subjects who discontinue study drug early/withdraw during the treatment period should, if 
possible, have an end of treatment (EOT) visit, including the EOT assessments as summarized in 
the Schedule of Events (Table 1). The EOT visit should be scheduled as soon as possible, 
preferably the day after the subject’s last dose. All details of the EOT visit should be recorded in 
the subject’s medical source documents. For subjects that discontinue study drug early, follow-
up visits should take place every 7 days for 28 days. If at any time after the EOT visit, a subject 
decides to terminate the study early, the subject should return for an early termination (ET) visit. 
The EOT and ET visits can be on the same day if a subject discontinues study drug and 
terminates the study on the same day during a clinic visit; in this case, all events scheduled for 
both visits will be conducted only once.  
If the subject fails or refuses to return to the study center, an attempt must be made to contact the 
subject by telephone in order to assess as many safety and efficacy parameters as possible. All 
data collected over the telephone must be documented and kept in the subject’s record. A subject 
will be deemed lost to follow-up after 3 attempts at contact have been made and it has been at 
least 1 month since the last subject contact. The third attempt at contact must be a certified letter 
accompanied by a survey inquiring the reason for study discontinuation. All attempts at contact 
will be documented. 
Subjects who discontinue the study drug 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.  
If a subject failed to attend scheduled assessments during the course of the study, the 
Investigators must determine the reasons and the circumstances as completely and accurately as 
possible, and document this in the subject's source documents. 


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8.3.2. 
Replacement of Subjects 
Part A 
In Part A, subjects will not be replaced. 
Part B 
In Part B, subjects will not be replaced. Additional subjects may be randomized if the drop-out 
rate is higher than anticipated (see Section 13.8). 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Study Drug 
Subjects will self-administer study drug orally once daily in the evening with food for 14 days as 
outlined in Section 7.1. Practical options include taking within 1 hour of dinner, or taking later in 
the evening with solid food. 
9.2. 
Prior Medications, Concomitant Medications, and Restrictions 
9.2.1. 
Prior and Concomitant Medications and/or Supplements 
The start and end dates, route of administration, dose/units, frequency, and indication for all 
medications and/or supplements taken within 30 days prior to Screening and throughout the 
duration of the study will be recorded. In addition, psychotropic drugs taken within 12 months 
prior to Screening will be recorded. 
Any concomitant medication determined necessary for the welfare of the subject may be given at 
the discretion of the Investigator at any time during the study under the guidance outlined in 
these sections.  
Antidepressants and mood stabilizers (lamotrigine, lithium, and valproic acid only) 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 throughout the treatment period. 
Medications intended for contraception are permitted for female subjects (see Section 8.1): 
• Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation 
• Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation. 
• Intrauterine device 
• Intrauterine hormone-releasing system 
9.2.2. 
Prohibited Medications 
The following specific classes of medications are prohibited at any time during the treatment 
period: 
• Initiation of new antidepressant therapy from 60 days prior to Day 1 through the end 
of treatment period 
• Use of any benzodiazepines, GABAA modulators, GABAA-like acting drugs, or 
GABA-containing agents from Day -28  
• Use of any non-GABA anti-insomnia medications (eg, melatonin, Benadryl [anti-
histamines], trazodone, low dose quetiapine, mirtazapine, etc) from Day -14  
• Exposure to another investigational medication or device from 30 days prior to 
Screening (throughout the treatment and follow-up periods). 


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• Any known strong inhibitors of CYP3A4 from Day -28 or 5 half-lives prior to Day 1 
(whichever is longer)  
• Use of strong CYP3A inducers, such as carbamazepine, enzalutamide, mitotane, 
phenytoin, rifampin, or St Johns Wort within 28 days prior to the first dose of study 
drug or 5 half-lives prior to Day 1 (whichever is longer)  
• Use of psychostimulants (eg, methylphenidate, amphetamine) or opioids regularly or 
as needed, from Day -28. 
9.2.3. 
Other Restrictions 
The consumption of grapefruit juice, grapefruit, or Seville oranges, or products containing these 
is prohibited throughout the treatment period. 
Consumption of drugs of abuse and alcohol is discouraged throughout the duration of the study. 
Female subjects who are lactating or actively breastfeeding must stop giving breast milk to the 
baby(ies) starting on Day 1 until 7 days after the last dose of study drug following the treatment 
period. 
Elective surgeries or procedures are prohibited during participation in the study. 
9.3. 
Treatment Adherence 
SAGE-217 (Parts A and B) or placebo (Part B only) will be self-administered by subjects once 
every evening with food. Sites will dispense study drug to the subjects to take at home with 
instructions for use (Section 10.4).  
Administration of study drug will be monitored by a medication adherence monitoring platform 
used on smartphones to visually confirm medication ingestion. Subjects will receive a reminder 
within a predefined time window to take study drug while using the application. Subjects will 
follow a series of prescribed steps in front of the front-facing webcam to visually confirm their 
ingestion of the medication. The application will record the date and time of study drug 
administration by dose level, as well as missed doses. 
In addition, the subject will be instructed to bring their dosing kit to each visit during the 
treatment period, at which time the Investigator or designee will be responsible for ensuring the 
kit contains sufficient doses until the next scheduled dispensation. 
If the subject is persistently noncompliant with the study drug, the Investigator should discuss 
with Sage Therapeutics the potential discontinuation of the subject (Section 8.3). Dosing 
requirements will be reviewed with each subject during all study contacts. The authorized study 
personnel conducting the re-education must document the process in the subject source records. 
9.4. 
Randomization and Blinding 
Part A 
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Part B 
Part B is a randomized, double-blind, placebo-controlled, parallel group design. Subjects who 
meet the entrance criteria will be stratified based on use of mood stabilizers (Y/N) and randomly 
assigned within each stratum in a 1:1 ratio to receive SAGE-217 or matched placebo. Subjects, 
clinicians, and the study team will be blinded to treatment allocation. Randomization will be 
performed centrally via an interactive response technology (IRT) system. 
Randomization schedules will be generated by an independent statistician. The allocation to 
treatment group (SAGE-217 or placebo) will be based on the randomization schedule. The 
randomization schedules will be kept strictly confidential, accessible only to authorized 
personnel until the time of unblinding.  
During the study, the blind is to be broken only if the safety of a subject is at risk and the 
treatment plan is dependent on the study treatment received. See Section 12.6 for details of 
unblinding in the event of a medical emergency or pregnancy.  
In all cases where the study drug allocation for a subject is unblinded, pertinent information 
(including the reason for unblinding) must be documented in the subject’s records and on the 
eCRF. If the subject or study center personnel have been unblinded, the subject will be 
permanently discontinued from the study. 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Description of Study Drug 
SAGE-217 is available as hard gelatin capsules containing a white to off-white powder. In 
addition to the specified amount of SAGE-217 Drug Substance, active SAGE-217 Capsules 
contain croscarmellose sodium, mannitol, silicified microcrystalline cellulose (SMCC), colloidal 
silicon dioxide, and sodium stearyl fumarate as excipients. Colloidal silicon dioxide may be 
either a component of the SMCC or a standalone excipient in the formulation. Capsules will be 
available in 10-mg, 20-mg, and 30-mg strengths to achieve the target dose of 20 mg or 30 mg.  
Matching placebo capsules are hard gelatin capsules containing only the excipients listed for the 
active capsule treatment.  
10.2. 
Study Drug Packaging and Labeling 
SAGE-217 and matched placebo will be provided to the clinic pharmacist and/or designated site 
staff responsible for dispensing the study drug in appropriately labeled, subject-specific kits each 
containing sealed unit doses. Part A is open-label and Part B is blinded. 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 Code of Federal 
Regulations and Good Manufacturing Practices/Good Clinical Practices guidelines will be 
prepared by the clinical research organization. 
10.3. 
Study Drug Storage 
SAGE-217 and matched placebo are to be stored at room temperature, 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 in the evening with food. Practical options include taking 
within 1 hour of dinner, or taking later in the evening with solid food. 
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.  
Site staff will access the IRT at the Screening Visit to obtain a subject identification (ID) number 
for each subject. On Day 1, site staff will access the IRT and provide the necessary subject-
identifying information, including the subject ID number assigned at Screening, to randomize the 


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eligible subject into the study and obtain the medication ID number for the study drug to be 
dispensed to that subject. 
At the subsequent study drug-dispensing visit, the investigator or designee will access the IRT, 
providing the same subject ID number assigned at Screening, to obtain the medication ID 
number for the study drug to be dispensed at that visit. In the event of an unscheduled dose 
reduction (Section 7.4), a new subject-specific kit will be dispensed. 
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 medication 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 within usual 
business hours and with appropriate notice during or after completion of the study to perform 
drug accountability reconciliation. 
10.7. 
Study Drug Handling and Disposal 
At the end of the study, all used and unused study drug will be reconciled and returned to Sage 
Therapeutics for destruction or destroyed locally; disposition of study drug will be documented. 
A copy of the inventory record and a record of any clinical supplies that have been received, 
dispensed or destroyed must be documented by the site as directed. This documentation must 
include at least the information below:  
• the number of dispensed units 
• the number of unused units 
• the number of units destroyed at the end of the study 
• the date, method and location of destruction. 
 


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11. 
ASSESSMENT OF EFFICACY 
 
All assessments will be conducted according to the schedule of assessments (Table 1). 
11.1. 
Efficacy Assessments 
11.1.1. 
Hamilton Rating Scale for Depression (HAM-D) 
The primary outcome measure is the change from baseline in the 17-item HAM-D total score at 
Day 15.  
The 17-item HAM-D will be used to rate the severity of depression in subjects who are identified 
as experiencing an MDE (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. Every effort should be 
made for the same rater to perform all HAM-D assessments for an individual subject.  
The HAM-D total score will be calculated as the sum of the 17 individual item scores.  
In addition to the primary efficacy endpoint of change from baseline in HAM-D total score, 
several secondary efficacy endpoints will be derived for the HAM-D. Hamilton Rating Scale for 
Depression subscale scores will be calculated as the sum of the items comprising each subscale. 
Hamilton Rating Scale for Depression response will be defined as having a 50% or greater 
reduction from baseline in HAM-D total score. Hamilton Rating Scale for Depression remission 
will be defined as having a HAM-D total score of ≤7. 
The HAM-D subject interview may be audio-recorded for independent quality control purposes. 
11.1.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive 
episodes in subjects with mood disorders. It was designed as an adjunct to the HAM-D that 
would be more sensitive than the Hamilton Scale to the changes brought on by antidepressants 
and other forms of treatment.  
Higher MADRS scores indicate more severe depression, and each item yields a score of 0 to 6. 
The overall score ranges from 0 to 60 (Williams 2008). 
The MADRS total score will be calculated as the sum of the ten individual item scores. 
The MADRS subject interview may be audio-recorded for independent quality control purposes. 
11.1.3. 
Clinical Global Impression (CGI) 
The CGI is a validated measure often utilized in clinical trials to allow clinicians to integrate 
several sources of information into a single rating of the subject’s condition. The CGI scale 
consists of 3 items. Only the first 2 items are being used in this study.  
The Clinical Global Impression - Severity (CGI-S) uses a 7-point Likert scale to rate the severity 
of the subject’s illness at the time of assessment, relative to the clinician’s past experience with 


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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 Clinical Global Impression - Improvement (CGI-I) employs a 7-point Likert scale to 
measure the overall improvement in the subject’s condition posttreatment. The Investigator will 
rate the subject’s total improvement whether or not it is due entirely to drug treatment. Response 
choices include: 0=not assessed, 1=very much improved, 2=much improved, 3=minimally 
improved, 4=no change, 5=minimally worse, 6=much worse, and 7=very much worse 
(Busner 2007b). The CGI-I is only rated at posttreatment assessments. By definition, all CGI-I 
assessments are evaluated against baseline conditions. CGI-I response will be defined as having 
a CGI-I score of “very much improved” or “much improved.”  
11.1.4. 
Insomnia Severity Index (ISI) 
The ISI is a validated questionnaire designed to assess the nature, severity, and impact of 
insomnia (Morin 2011). The ISI uses a 5-point Likert Scale to measure various aspects of 
insomnia severity (0 = none, 1 = mild, 2 = moderate; 3 = severe; 4 = very severe), satisfaction 
with current sleep pattern (0 = very satisfied, 1 = satisfied, 2 = neutral, 3 = dissatisfied, 4 = very 
dissatisfied), and various aspects of the impact of insomnia on daily functioning (0 = not at all, 
1 = a little, 2 = somewhat, 3 = much, 4 = very much). A total score of 0 to 7 = “no clinically 
significant insomnia,” 8 to 14 = subthreshold insomnia,” 15 to 21 = “clinical insomnia (moderate 
severity),” and 22 to 28 = “clinical insomnia (severe).”  


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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
The safety and tolerability of SAGE-217 will be assessed by the frequency and severity of AEs; 
changes from baseline in clinical laboratory measures, vital signs, and ECGs; suicidal ideation 
and behavior using the C-SSRS; and the YMRS. All assessments will be conducted according to 
the schedule of assessments (Table 1). 
12.1.1. 
Demographic/Medical History 
Demographic and baseline characteristics (age, race, gender, ethnicity, employment status, 
highest education level, marital/civil status) and a full medical history, including family 
psychiatric history, will be documented. The diagnosis of bipolar I or II disorder will be 
determined using the SCID-5-CT. 
12.1.2. 
Weight and Height 
Height (Screening only) and weight will be measured and documented.  
12.1.3. 
Physical Examination 
Physical examinations assessing body systems (eg, head, eye, ear, 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 physical examinations 
may also be conducted per the Investigator’s discretion. 
Any abnormality in physical examinations will be interpreted by the Investigator as abnormal, 
not clinically significant (NCS); or abnormal, clinically significant (CS) in source documents. 
New or worsening abnormalities that are judged to be clinically significant will be recorded as 
AEs, assessed according to Section 12.2.1.1. 
12.1.4. 
Vital Signs 
Vital signs comprise both supine and standing for systolic and diastolic blood pressure and heart 
rate measurements. Heart rate and blood pressure are to be collected in supine position after the 
subject has been resting for 5 minutes and then in the standing position. Respiratory rate, pulse 
oximetry and temperature are collected once, in either position. Vital signs will be documented. 
When vital signs are scheduled at the same time as blood draws, vital signs will be obtained first, 
with the blood sample collected as close to the scheduled time as possible. 
Any abnormality in vital signs will be interpreted by the Investigator as abnormal, NCS or 
abnormal, CS in source documents. New or worsening abnormalities that are judged to be 
clinically significant will be recorded as AEs, assessed according to Section 12.2.1.1. 
12.1.5. 
Electrocardiogram (ECG) 
Supine 12-lead ECGs will be performed in triplicate. The standard intervals (heart rate, PR, 
QRS, QT, and QTcF) as well as any rhythm abnormalities will be recorded. When ECG 
 
sample collection occur during the same visit, the ECGs will be conducted first. 


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Any abnormality in ECGs 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. 
Laboratory Assessments 
Samples will be collected in accordance with acceptable laboratory procedures detailed in the 
laboratory manual.   
The clinical laboratory tests to be performed are listed in Table 3. 
Table 3: 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Coagulation 
Red blood cell count 
Hemoglobin  
Hematocrit  
White blood cell count with 
differential  
Platelet count 
Red blood cell morphology 
ALT 
Albumin 
Alkaline phosphatase 
AST 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
Total protein 
Creatinine 
Blood urea nitrogen 
Creatine kinase 
GGT 
Potassium 
Sodium 
Lactate dehydrogenase 
Glucose 
Chloride 
Bicarbonate 
Calcium 
Phosphorus 
Triglycerides 
pH 
Specific gravity 
Protein 
Glucose 
Red blood cells 
Nitrite 
Leukocyte 
esterase 
Ketones 
Bilirubin 
Urobilinogen 
Activated partial 
thromboplastin 
time 
Prothrombin 
time 
International 
normalized ratio 
Diagnostic Screening 
 
 
 
Serum 
Urine 
Breathalyzer 
 
Hepatitis B 
Hepatitis C 
HIV-1 and -2 
Female subjects of child bearing 
potential: serum human 
chorionic gonadotropin 
Drug screen including: 
amphetamines, 
barbiturates, 
benzodiazepines, 
cannabinoids, cocaine, 
opiates, phencyclidine, and 
propoxyphene 
Alcohol 
 


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Female subjects, if menopause is 
suspected and not surgically 
sterile: FSH 
Female subjects of child 
bearing potential: urine 
human chorionic 
gonadotropin 
 
The central laboratory will perform laboratory tests for hematology, serum chemistry, and 
urinalysis. The results of laboratory tests will be returned to the Investigator, who is responsible 
for reviewing and filing these results. All laboratory safety data will be transferred electronically 
to Sage Therapeutics or designee in the format requested by Sage Therapeutics.  
Laboratory reports must be signed and dated by the Investigator or subinvestigator indicating 
that the report has been reviewed and any abnormalities have been assessed for clinical 
significance. Any abnormalities identified prior to first dose will require clear and complete 
documentation in the source documents as to the investigator’s assessment of not clinically 
significant before proceeding with randomization.  
All clinical laboratory test results outside the central laboratory’s reference range will be 
interpreted by the Investigator as abnormal, 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. A 
clinically significant laboratory abnormality following subject randomization will be followed 
until the abnormality returns to an acceptable level or a satisfactory explanation has been 
obtained. 
Follicle stimulating hormone testing will be conducted at Screening to confirm whether a female 
subject with ≥12 months of spontaneous amenorrhea and not surgically sterile meets the 
protocol-defined criteria for being post-menopausal (Section 8.1). 
 
 
12.1.6.1. Drugs of Abuse and Alcohol 
Urine toxicology will be performed for selected drugs of abuse, and a breath test will be 
performed for alcohol (Table 1). 
12.1.6.2. Pregnancy Screen 
A serum pregnancy test in women of child-bearing potential will be conducted at Screening and 
a urine pregnancy test will be conducted at all other scheduled timepoints (Table 1).  
12.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner 2011). This scale 
consists of a baseline evaluation that assesses the lifetime experience of the subject with suicidal 
ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last 
study visit. The C-SSRS includes ‘yes’ or ‘no’ responses for assessment of suicidal ideation and 
behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being 
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The “Baseline/Screening” C-SSRS form will be completed at screening (lifetime history and past 
24 months). The “Since Last Visit” C-SSRS form will be completed at all subsequent time 
points, as outlined in Table 1. 
12.1.8. 
Young Mania Rating Scale (YMRS) 
Manic symptoms will be assessed during the study using the YMRS (Young 1978). The 
clinician-administered scale is based on 11 items of core symptoms of mania. Four of the items 
(irritability, speech, thought content, and disruptive/aggressive behavior) are graded on a scale of 
0 to 8 (choices given as even numbers), with the remaining 7 items graded on a scale of 0 to 4. 
Scoring between the points given (whole or half points) is possible.  
12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Definition of Adverse Events 
12.2.1.1. Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the use of a 
medicinal (investigational) product whether or not related to the medicinal (investigational) 
product. In clinical studies, an AE can include an undesirable medical condition occurring at any 
time, including baseline or washout periods, even if no study treatment has been administered. 
A TEAE is an AE that occurs after the first administration of any study drug. The term study 
drug includes any Sage investigational product, a comparator, or a placebo administered in a 
clinical trial. 
An abnormal laboratory value will be considered an AE if the value represents a clinically 
significant change from baseline as determined by the Investigator.  
All AEs that occur after any subject has signed the informed consent form and throughout the 
duration of the study, whether or not they are related to the study, must be reported to Sage 
Therapeutics. 
12.2.1.2. Serious Adverse Event (SAE) 
A serious adverse event is any untoward medical occurrence that at any dose: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
An SAE may also be any other medically important event that, in the opinion of the Investigator, 
may jeopardize the subject or may require medical intervention to prevent 1 of the outcomes 


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listed above (examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization). 
All SAEs that occur after any subject has been enrolled and throughout the duration of the study, 
whether or not they are related to the study, must be recorded on the SAE form provided by Sage 
Therapeutics within 24 hours of first awareness (Section 12.5). All SAEs should to be followed 
until the event resolved, the condition stabilized, was no longer considered clinically significant 
or the subject was lost to follow-up. 
12.3. 
Relationship to Study Drug 
The Investigator must make the determination of relationship to the study drug for each adverse 
event (not related, possibly related or probably related). The Investigator should decide whether, 
in his or her medical judgment, there is a reasonable possibility that the event may have been 
caused by the investigational product. If no valid reason exists for suggesting a relationship, then 
the adverse event should be classified as “not related.” If there is any valid reason, even if 
undetermined, for suspecting a possible cause-and-effect relationship between the investigational 
product and the occurrence of the adverse event, then the adverse event should be considered at 
least “possibly related.”  
Table 4: 
Relationship to Study Drug 
Relationship 
Definition 
Not Related: 
No relationship between the experience and the administration of study drug; related to 
other etiologies such as concomitant medications or subject’s clinical state. 
Possibly Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug.  
The reaction might have been produced by the subject’s clinical state or other modes of 
therapy administered to the subject, but this is not known for sure. 
Probably Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug.  
The reaction cannot be reasonably explained by the known characteristics of the subject’s 
clinical state or other modes of therapy administered to the subject. 
If the relationship between the adverse event/serious adverse event and the investigational 
product is determined to be “possible” or “probable”, the event will be considered related to the 
investigational product for the purposes of expedited regulatory reporting. 
12.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. The AE term should be reported in standard medical terminology when 
possible. For each AE, the investigator will evaluate and report the onset (date and time), 
resolution (date and time), intensity, causality, action taken, serious outcome (if applicable), and 
whether or not it caused the subject to discontinue the study drug or withdraw early from the 
study. 
Intensity will be assessed according to the following scale: 


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• 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 the study. After obtaining the necessary signed informed consent from the 
pregnant female partner directly, the investigator will follow the same pregnancy reporting 
procedures specified for pregnant female subjects. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) must be followed up and documented even if the subject was 
discontinued from the study. If the pregnancy ends for any reason before the anticipated date, the 
investigator should notify the sponsor. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that a study drug may 
have interfered with the effectiveness of a contraceptive medication or a complication relating to 
the pregnancy occurs (eg, spontaneous abortion). 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 on the SAE report form. 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 CRF and/or study 
file. 
Any SAEs discovered by the Investigator after the designated follow up time for the study, 
should be promptly reported to Sage, or designee, according to the timelines noted above.  
The contact information for reporting SAEs and/or pregnancies is located in the study reference 
manual.   
Sage, or designee, is responsible for notifying the relevant regulatory authorities of certain 
events. It is the Principal Investigator’s responsibility to notify the ethics committee of all SAEs 
that occur at his or her site. Investigators will also be notified of all suspected, unexpected, 


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serious, adverse reactions (SUSARs) that occur during the clinical study. Each site is responsible 
for notifying its ethics committee of these SUSARs. In addition, appropriate SAGE Drug Safety 
and Pharmacovigilance personnel, or designee, will unblind SUSARs for the purpose of 
regulatory reporting. SAGE, or designee, will submit SUSARs (in blinded or unblinded fashion) 
to regulatory agencies according to local law. SAGE, or designee, will submit SUSARs to 
investigators in a blinded fashion. 
12.6. 
Emergency Identification of Study Drug 
During the study, the blind is to be broken only when the safety of a subject is at risk and the 
treatment plan is dependent on the study treatment received. Unless a subject is at immediate 
risk, the Investigator must make diligent attempts to contact Sage prior to unblinding the study 
treatment administered to a subject. Any request from the Investigator about the treatment 
administered to study subjects must be discussed with Sage. If the unblinding occurs without 
Sage’s knowledge, the Investigator must notify Sage as soon as possible and no later than the 
next business morning. All circumstances surrounding a premature unblinding must be clearly 
documented in the source records. Unless a subject is at immediate risk, any request for the 
unblinding of individual subjects must be made in writing to Sage and approved by the 
appropriate Sage personnel, according to standard operating procedures. The blinding of the 
study will be broken after the database has been locked. Electronic copies of the randomization 
code will be made available to the laboratory performing the bioanalytical analyses in order to 
allow for limited analysis of samples from subjects receiving placebo. 
In the event of a medical emergency or pregnancy, the Investigator will discuss with the Medical 
Monitor if unblinding is warranted for medical management of the subject. If there is agreement 
to unblind treatment assignment, the unblinding procedure described in the Safety Management 
Plan for the study will be followed. If the Investigator is unable to contact the Medical Monitor 
in a medical emergency, and it is deemed clinically necessary by the Investigator, the treatment 
group for that subject may be unblinded in the IRT system. 
In all cases where the study drug allocation for a subject is unblinded, pertinent information 
(including the reason for unblinding) must be documented in the subject’s records and on the 
eCRF. If the subject or study center personnel have been unblinded, the subject will be 
permanently discontinued from the study. 


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13. 
STATISTICS 
A separate statistical analysis plan (SAP) for each part (Part A and B) will provide a detailed 
description of the analyses to be performed in the respective part of the study. The SAPs will be 
finalized and approved prior to database lock. Any deviations from or changes to the respective 
SAP following database lock will be described in detail in the clinical study report. 
13.1. 
Data Analysis Sets 
The Safety Set, defined as all subjects that received at least 1 dose of study drug, will be used to 
provide descriptive summaries of safety data.  
The Efficacy Set, defined as all subjects in the Safety Set that have at least 1 post-baseline 
HAM-D evaluation, will be used to analyze efficacy data, unless otherwise specified. 
 
 
Part B will also include a Randomized Set, defined as all subjects who are randomized. This 
analysis set will be used for all data listings in Part B. 
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 sets, using all non-missing data available. No imputation process will be used to 
estimate missing data.  
13.3. 
General Considerations 
For the purpose of all primary and secondary analyses where applicable, baseline is defined as 
the last measurement prior to receipt of study drug.  
Continuous endpoints will be summarized with number (n), mean, standard deviation (SD), 
median, minimum, and maximum. In addition, change from baseline values will be calculated at 
each time point and summarized descriptively. For categorical endpoints, descriptive summaries 
will include counts and percentages.  
13.4. 
Demographics and Baseline Characteristics 
Demographic data (Section 12.1.1) and baseline characteristics, such as height, weight, and body 
mass index, will be summarized using the Safety Set.  
Pregnancy results will be listed but not summarized.  
Medical history will be listed by subject.  
13.5. 
Efficacy Analysis 
The primary efficacy endpoint, the change from baseline in HAM-D total score at Day 15, will 
be analyzed using a mixed effects model for repeated measures (MMRM); the model will 
include center, treatment, baseline HAM-D total score, stratification factor, assessment time 
point, and time point-by-treatment as explanatory variables. All explanatory variables will be 


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considered as fixed effects and the subject effect will be considered random in the model. All 
post-baseline time points will be included in the model. The primary comparison will be between 
SAGE-217 and matching placebo at Day 15. Model-based point estimates (ie, least squares [LS] 
means, 95% confidence intervals, and p values) will be reported. An unstructured covariance 
structure will be used to model the within-subject errors. In case of convergence issues, other 
covariance structures will be considered; this will be detailed in the statistical analyses plan. 
Other continuous endpoints will be analyzed using similar methods.  
Other efficacy analyses will be specified in the statistical analysis plan. In general, data will be 
analyzed using appropriate descriptive statistics or pre-specified statistical methods as 
applicable; subject listings will be provided for all efficacy data. Subjects will be analyzed 
according to randomized treatment for the purpose of efficacy unless otherwise specified. 
13.6. 
Safety Analyses 
Safety and tolerability of SAGE-217 will be assessed by the frequency and severity of AEs; 
changes from baseline in clinical laboratory measures, vital signs, and ECGs. Suicidal ideation 
and behavior will be evaluated using the C-SSRS. Mania will be evaluated using the YMRS. 
Safety data will be listed by subject and summarized by treatment group. All safety summaries 
will be performed on the Safety Set.  
13.6.1. 
Adverse Events 
The analysis of AEs will be based on the concept of TEAEs. The incidence of TEAEs will be 
summarized overall and by Medical Dictionary for Regulatory Activities (MedDRA) 
Version 20.1 or higher, system organ class (SOC), and preferred term (PT). 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 (Section 13.6.1).  
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 
Clinical laboratory results will be listed by subject and timing of collection. Mean changes from 
baseline in clinical laboratory measures will be evaluated.  
13.6.3. 
Physical Examinations 
Physical examination data will be listed by subject, but not summarized. 
13.6.4. 
Vital Signs 
Vital sign results will be listed by subject and timing of collection. Mean changes from baseline 
in vital signs will be evaluated by time point.  


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13.6.5. 
12-Lead Electrocardiogram 
The following ECG parameters will be listed for each subject: heart rate, PR, QRS, QT, and 
QTcF. Any clinically significant abnormalities or changes in ECGs should be listed as an AE. 
Electrocardiogram findings will be listed by subject and visit.  
13.6.6. 
Prior and Concomitant Medications 
Medications will be recorded at each study visit during the study and will be coded using World 
Health Organization-Drug dictionary (WHO-DD) September 2015, or later.  
Those medications taken prior to the initiation of the start of study drug will be denoted “Prior”. 
Those medications taken prior to the initiation of the study drug and continuing beyond the 
initiation of the study drug or those medications started at the same time or after the initiation of 
the study drug will be denoted “Concomitant” (ie, those with a start date on or after the first dose 
of study drug, or those with a start date before the first dose of study drug that are ongoing or 
with a stop date on or after the first dose of study drug).  
Medications will be presented according to whether they are “Prior” or “Concomitant” as 
defined above. If medication dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant.  
Details of prior and concomitant medications will be listed by subject, start date, and verbatim 
term.  
13.6.7. 
Columbia Suicide Severity Rating Scale 
Suicidality data collected on the C-SSRS at baseline and by visit will be summarized and listed 
for all subjects. Listings will include behavior type and/or category for Suicidal Ideation and 
Suicidal Behavior of the C-SSRS.  
13.6.8. 
Young Mania Rating Scale 
Mania data collected on the YMRS at baseline and by visit will be summarized and listed for all 
subjects.  
 
 
 
 
 
13.8. 
Determination of Sample Size 
13.8.1. 
Part A 
For Part A, the sample size of approximately 30 subjects was selected based on clinical and not 
statistical considerations.  


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13.8.2. 
Part B 
For Part B, assuming a two-sided alpha level of 0.05, a sample size of 112 total evaluable 
subjects (56 per treatment group) would provide 80% power to detect a placebo-adjusted 
treatment difference of approximately 4 points in the primary endpoint, change from baseline in 
HAM-D total score at Day 15, assuming standard deviation (SD) of 7.5 points.  
Assuming a 15% dropout rate, approximately 132 total randomized subjects will be required to 
obtain a total of 112 evaluable subjects. Evaluable subjects are defined as those randomized 
subjects who receive study drug and have a valid baseline and at least 1 post-baseline HAM-D 
assessment. Additional subjects may be randomized if the drop-out rate is higher than 15%. 


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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and the study site guarantee access to source documents by Sage Therapeutics 
or sponsor’s designee and by the IRB or IEC. 
All aspects of the study and its documentation will be subject to review by Sage Therapeutics or 
sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, study drug, subject medical records, informed consent documentation, and 
review of eCRFs and associated source documents. It is important that the investigator and other 
study personnel are available during the monitoring visits and that sufficient time is devoted to 
the process.  
14.2. 
Audits and Inspections 
Authorized representatives of Sage Therapeutics, a regulatory authority, an Independent Ethics 
Committee or an Institutional Review Board may visit the site to perform audits or inspections, 
including source data verification. The purpose of a Sage Therapeutics audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, Good Clinical Practice guidelines of the 
International Conference on Harmonization, and any applicable regulatory requirements. The 
investigator should contact Sage Therapeutics immediately if contacted by a regulatory agency 
about an inspection. 
14.3. 
Protocol Deviations 
Investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
Sage Therapeutics or sponsor’s designee (and IRB, as required) to determine the appropriate 
course of action. There will be no exemptions (a prospectively approved deviation) from the 
inclusion or exclusion criteria. 
14.4. 
Institutional Review Board (IRB) or Ethics Committee (EC) 
The Principal Investigator must obtain IRB (or EC) approval for the investigation. Initial IRB (or 
EC) approval, and all materials approved by the IRB (or EC) for this study including the subject 
consent form and recruitment materials must be maintained by the Investigator and made 
available for inspection. 


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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
Sage Therapeutics may conduct a quality assurance audit. Please see Section 14.2 for more 
details regarding the audit process. 
 


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


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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Inspection of Records 
Sage Therapeutics will be allowed to conduct site visits to the investigation facilities for the 
purpose of monitoring any aspect of the study. The Investigator agrees to allow the monitor to 
inspect the drug storage area, study drug stocks, drug accountability records, subject charts and 
study source documents, and other records relative to study conduct. 
17.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for the period 
outlined in the site contract, or for a period of 2 years after the last marketing application 
approval, whichever is longer. If not approved, documentation must be maintained for 2 years 
following the discontinuance of the test article for investigation. If it becomes necessary for Sage 
Therapeutics or the Regulatory Authority to review any documentation relating to the study, the 
Investigator must permit access to such records. 


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18. 
PUBLICATION POLICY 
All information concerning SAGE-217 is considered confidential and shall remain the sole 
property of Sage Therapeutics. The Investigator agrees to use this information only in conducting 
the study and shall not use it for any other purposes without written approval from Sage 
Therapeutics. No publication or disclosure of study results will be permitted except as specified 
in a separate, written, agreement between Sage Therapeutics and the Investigator. 


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19. 
LIST OF REFERENCES 
Begley CE, Annegers JF, Swann AC, Lewis C, Coan S, Schnapp WB, et al. The lifetime cost of 
bipolar disorder in the US: an estimate for new cases in 1998. Pharmacoeconomics. 2001;19(5 Pt 
1):483-95. 
Busner J, Targum S. CGI-S. (2007a), as adapted from Kay, Stanley R, Positive and Negative 
Symptoms in Schizophrenia:Assessment and Research.  Clinical and Experimental Psychiatry, 
Monograph No. 5.  Brunner/Mazel, 1991.  Modified from Guy W. Clinical Global Impressions: 
In ECDEU Assessment Manual for Psychopharmacology. 1976; 218-22. Revised DHEW Pub. 
(ADM) Rockville, MD: National Institute for Mental Health.   
Busner J, Targum S. CGI-I.  (2007b), as adapted from Spearing, et al.  Psychiatry Research, 
1997;73:159-71.  Modified from Guy W. Clinical Global Impressions: In ECDEU Assessment 
Manual for Psychopharmacology. 1976; 218-22. Revised DHEW Pub. (ADM) Rockville, MD: 
National Institute for Mental Health.   
Bowden CL, Anupama AK. Pharmacotherapy for bipolar depression: an economic assessment. 
Expert Opin Pharmacother. 2004 May;5(5):1101-7. 
DSM-5.  Diagnostic and statistical manual of mental disorders (5th ed.).  American Psychiatric 
Association 2013.  Arlington, VA: American Psychiatric Publishing. 
Ferrari AJ, Stockings E, Khoo JP, Erskine HE, Degenhardt L, Vos T, et al. The prevalence and 
burden of bipolar disorder: findings from the Global Burden of Disease Study 2013. Bipolar 
Disord. 2016 Aug;18(5):440-50. 
Gijsman HJ, Geddes JR, Rendell JM, Nolen WA, Goodwin GM. Antidepressants for bipolar 
depression: a systematic review of randomized, controlled trials. Am J Psychiatry 
2004;161:1537-1547. 
Judd LL, Akiskal HS, Maser JD, Zeller PJ, Endicott J, Coryell W, et al. A prospective 12-year 
study of subsyndromal and syndromal depressive symptoms in unipolar major depressive 
disorders. Arch Gen Psychiatry. 1998 Aug;55(8):694-700. 
Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA, et al. The long-term 
natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 
2002 Jun;59(6):530-7. 
Judd LL, Akiskal HS. Depressive episodes and symptoms dominate the longitudinal course of 
bipolar disorder. Curr Psychiatry Rep. 2003 Dec;5(6):417-8. 
Kessler RC, Akiskal HS, Ames M, Birnbaum H, Greenberg P, Hirschfeld RM, et al. Prevalence 
and effects of mood disorders on work performance in a nationally representative sample of U.S. 
workers. Am J Psychiatry. 2006 Sep;163(9):1561-8. 
Merikangas KR, Akiskal HS, Angst J, Greenberg PE, Hirschfeld RM, Petukhova M, et al. 
Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity 
Survey replication. Arch Gen Psychiatry. 2007 May;64(5):543-52. 
Morin CM, Belleville G, Bélanger L, Ivers H. The Insomnia Severity Index: Psychometric 
Indicators to Detect Insomnia Cases and Evaluate Treatment Response. Sleep. 2011;34(5):601-
608. 


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Perlis RH, Ostacher MJ, Patel JK, Marangell LB, Zhang H, Wisniewski SR, et al. Predictors of 
recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement 
Program for Bipolar Disorder (STEP-BD). Am J Psychiatry. 2006 Feb;163(2):217-24. 
Posner K, Brown GK, Stanley B, et al. The Columbia–Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-77. 
Post RM, Leverich GS, Altshuler LL, Frye MA, Suppes TM, Keck PE Jr, et al. An overview of 
recent findings of the Stanley Foundation Bipolar Network (Part I). Bipolar Disord. 2003 
Oct;5(5):310-9. 
Rudolph U, Knoflach F. Beyond classical benzodiazepines: novel therapeutic potential of 
GABAA receptor subtypes. Nat Rev Drug Discov. 2011 Jul 29;10(9):685-97. 
Sachs GS, Nierenberg AA, Calabrese JR, Marangell LB, Wisniewski SR, Gyulai L, et al. 
Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007 
Apr 26;356(17):1711-22. Epub 2007 Mar 28. 
 
 
Williams JBW and Kobak KA. Development and reliability of a structured interview guide for 
the Montgomery-Asberg Depression Rating Scale (SIGMA). British Journal of Psychiatry. 
2008:192(1):52-58. 
Williams JBW.  SIGH-D 24hr: V1.3 – 24 HR Version. 2013a. 
Williams JBW.  SIGH-D Past week:  Past Week Version. 2013b. 
Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and 
sensitivity. Br J Psychiatry. 1978 Nov;133:429-35. 


Protocol 217-BPD-201, Summary of Changes 
Sage Therapeutics 
Version 4.0, Amendment 3  
 
CONFIDENTIAL 
 
 
1 
Protocol 217-BPD-201, Amendment 3 
Date of Amendment: 16 January 2019 
A 2-Part Study (Open-label followed by Double-blind, Randomized, Placebo-controlled, 
Parallel Group) of the Safety, Tolerability, Pharmacokinetics, and Efficacy of SAGE-217 in 
the Treatment of Subjects with Bipolar I/II Disorder with a Current Major Depressive 
Episode 
Rationale for Protocol Amendment 
The primary purpose for this protocol amendment is as follows: 
• Updated Inclusion/Exclusion criteria to keep consistency within the SAGE-217 
program. This includes contraception use by subjects (and partners of subjects), 
clarification of use of benzodiazepines and GABAA modulator agents, and use of 
CYP3A inducers.  
• Addition of the following Exclusion criterion: Subject has been taking 
psychostimulants (eg, methylphenidate, amphetamine) or opioids regularly or as 
needed, at Day -28. 
Additional changes are being implemented as outlined below: 
• Updated sponsor contact 
• Updated secondary endpoints to be specific to one timepoint  
• Updated description of SAGE-217 and reference therapy dosage and mode of 
administration. 
• Changed collection period of prior psychotropic medications (from 6 to 12 months). 
• Added cut-off date for SAEs in SAGE-217 program. 
• Clarified details in the “Prohibited Medications” section for consistency with 
Inclusion/Exclusion criteria. 
• Added “or surgically sterile” regarding FSH assessment. 
A detailed summary of changes is provided in Table 1. Corrections to typographical errors, 
punctuation, grammar, abbreviations, and formatting are not detailed. 
 


Protocol 217-BPD-201, Summary of Changes 
Sage Therapeutics 
Version 3.0, Amendment 2  
CONFIDENTIAL 
 
 
2 
Table 1: 
Protocol Amendment 3 Detailed Summary of Changes 
The primary section of the protocol affected by the changes in Protocol Amendment 3 is indicated. The corresponding related text has 
been revised throughout the protocol. Deleted text is indicated by strikeout; added text is indicated by bold font. 
Purpose: Updated Inclusion/Exclusion criteria to keep consistency within the SAGE-217 program. This includes contraception use by subjects 
(and partners of subjects), clarification of use of benzodiazepines and GABAA modulator agents, and use of CYP3A inducers. 
The primary change occurs in Section 8.1 Subject Inclusion Criteria and 8.2 Subject Exclusion Criteria 


Protocol 217-BPD-201, Summary of Changes 
Sage Therapeutics 
Version 3.0, Amendment 2  
CONFIDENTIAL 
 
 
3 
Changed text: 
From Inclusion: 
7. Female subject agrees to use one of the following methods of contraception during participation in the study 
and for 30 days following the last dose of study drug, unless they are postmenopausal (defined as no menses 
for 12 months without an alternative medical cause and confirmed by follicle stimulating hormone [FSH] level 
≥40 mIU/mL) and/or surgically sterile (hysterectomy or bilateral oophorectomy), or does not engage in sexual 
relation(s)ship(s) which do not carry a risk of pregnancy (eg, same-sex relationship(s)): 
• 
Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal hormonal 
contraception associated with inhibition of ovulation. 
• 
Oral, injectable, or implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation.  
• 
Intrauterine device. 
• 
Intrauterine hormone-releasing system. 
• 
Bilateral tubal ligation/occlusion. 
• 
Vasectomized partner. 
• 
Sexual abstinence (no sexual intercourse).  
8. 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 is sexual 
relationship(s) which do not carry a risk of pregnancy (eg, same-sex relationship(s)). Acceptable methods of 
effective contraception for males includes sexual abstinence, vasectomy, or a condom with spermicide used 
together with highly effective female contraception methods (if the female partner is of child-bearing potential, 
see Inclusion Criteria #7 for acceptable method of contraception for females). 
From Exclusion Criteria: 
13. Subject is taking benzodiazepines, barbiturates, or GABAA modulators/GABA-containing agents (eg, 
eszopiclone, zopiclone, zaleplon, and zolpidem) at Day -28, or subject has been using these agents on a 
daily or near-daily (≥4 times per week) for more than one year. 
27. Subject has used strong CYP3A inducers, such as carbamazepine, enzalutamide, mitotane, phenytoin, 
rifampin, or St Johns wort within 28 days prior to the first dose of study drug.CYP inducers, such as 
rifampin, carbamazepine, ritonavir, enzalutamide, efavirenz, nevirapine, phenytoin, phenobarbital and St 
John’s Wort, within 28 days prior to the first dose of study drug 


Protocol 217-BPD-201, Summary of Changes 
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Version 3.0, Amendment 2  
CONFIDENTIAL 
 
 
4 
 
 
Sections also affected by this change:  
• 
Synopsis 
Purpose: Added exclusion related to psychostimulants and opioids. 
The primary change occurs in Section 8.2. Subject Exclusion Criteria 
Added text: 
30. Subject has been taking psychostimulants (eg, methylphenidate, amphetamine) or opioids regularly or 
as needed, at Day -28. 
 
Sections also affected by this change:  
• 
Synopsis 
Purpose: Updated sponsor contact. 
The primary change occurs on the Title Pahe 
Changed text: 
 
Tel:
email:
Tel:
email:
Purpose: Timing of assessments was removed as these will be defined in the Statistical Analysis Plan. 
The primary change occurs in Section 6.2 Endpoints 


Protocol 217-BPD-201, Summary of Changes 
Sage Therapeutics 
Version 3.0, Amendment 2  
CONFIDENTIAL 
 
 
5 
Changed text: 
Part A Secondary: 
• 
The reduction in depressive symptoms, as assessed by: 
o Change from baseline in the 17-item Hamilton Depression Rating Scale (HAM-D) total score at Day 
15 and all other time points  
o HAM-D response at Day 15 and all other time points  
o HAM-D remission at Day 15 and all other time points  
o Change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at 
Day 15 and all other time points  
o Change from baseline in HAM-D individual item scores at Day 15 and all other time points  
o The response to the Clinical Global Impression scale for severity and improvement (CGI-S and CGI-I, 
respectively) at Day 15 and all other time points. 
Part B Secondary: 
• 
The reduction in depressive symptoms, as assessed by: 
o Change from baseline in HAM-D total score at Day 15 at all other time points 
o HAM-D response at Day 15 and all other time points  
o HAM-D remission at Day 15 and all other time points  
o Change from baseline in the MADRS total score at Day 15 and all other time points  
o Change from baseline in HAM-D individual item scores at Day 15 and all other time points  
o CGI-S and CGI-I response at Day 15 and all other time points 
Sections also affected by this change:  
• 
Synopsis 
Purpose: Update description of SAGE-217 and reference therapy dosage and mode of administration. 
The primary change occurs in the synopsis 


Protocol 217-BPD-201, Summary of Changes 
Sage Therapeutics 
Version 3.0, Amendment 2  
CONFIDENTIAL 
 
 
6 
Changed text: 
SAGE-217 dosage and mode of administration:  
SAGE-217 is available as hard gelatin capsules containing a white to off-white powder. In addition to SAGE-217 Drug 
Substance, the SAGE-217 capsules contain croscarmellose sodium, mannitol, silicified microcrystalline cellulose 
(SMCC), colloidal silicon dioxide, and sodium stearyl fumarate as excipients. Colloidal silicon dioxide may be either a 
component of the SMCC or a standalone excipient in the formulation. Subjects will take the assigned dose SAGE-217 
(30 mg) will be administered orally once daily in the evening with food. 
 Reference therapy, dosage and mode of administration (Part B only): In Part B, placebo capsules are visually 
matched to the active capsules and are available as hard gelatin capsules containing only the excipients listed above for 
the active capsule treatment Placebo capsules will only be used for Part B. Study drug placebo will be administered 
orally once daily in the evening with food. 
Purpose: Changed collection period of prior psychotropic medications (from 6 to 12 months). 
The change occurs in Schedule of Events and Section 9.2.1 Prior and Concomitant Medications and/or Supplements 
Purpose: Added cut-off date for SAEs in SAGE-217 program to align with IB.  
The primary change occurs in Section 5.2 SAGE-217  
Changed text: 
As of the IB cut-off date (24 September 2018), among the over 260 subjects exposed to SAGE-217 in clinical trials, 
there have been no deaths and only one subject with essential tremor experienced a serious adverse event (SAE) of 
transient confusion leading to discontinuation of study drug. No other SAEs have been reported in any study of SAGE-
217.  
Purpose: Clarified details in the “Prohibited Medications” section for consistency with Inclusion/Exclusion criteria. 
The primary change occurs in Section 9.2.2 Prohibited Medications 
Changed text: 
The following specific classes of medications are prohibited at any time during the treatment period: 
• 
Initiation of new psychotropic medications at any time during the study 
• 
Initiation of new antidepressant therapy from 60 days prior to Day 1 through the duration of the study end 
of treatment period 
• 
Use of any benzodiazepines, GABAA modulators, GABAA-like acting drugs, or GABA-containing agents 
from Day -28. through the duration of the study 
• 
Use of any non-GABA anti-insomnia medications (eg, melatonin, Benadryl [anti-histamines], trazodone, 
low dose quetiapine, mirtazapine, etc) from Day -14 through the duration of the study 


Protocol 217-BPD-201, Summary of Changes 
Sage Therapeutics 
Version 3.0, Amendment 2  
CONFIDENTIAL 
 
 
7 
• 
Exposure to another investigational medication or device from 30 days prior to Screening through the 
duration of the study (throughout the treatment and follow-up periods) 
• 
Any known strong inhibitors of CYP3A4 from Day -28 or 5 half-lives prior to Day 1 (whichever is longer) 
through the duration of the study 
• 
Use of strong CYP3A inducers, such as carbamazepine, enzalutamide, mitotane, phenytoin, 
rifampin, or St Johns Wort within 28 days prior to the first dose of study drug Use of any CYP 
inducer, such as such as rifampin, carbamazepine, ritonavir, enzalutamide, efavirenz, nevirapine, 
phenytoin, phenobarbital and St John’s Wort from Day -28 through the duration of the study. or 5 half-
lives prior to Day 1 (whichever is longer) through the duration of the study 
• 
Use of psychostimulants (eg, methylphenidate, amphetamine) or opioids regularly or as needed, 
from Day -28. 
Purpose: Added “or surgically sterile” from FSH assessment. 
The primary change occurs in Section 12.1.6 Laboratory Assessments  
Changed text: 
Follicle stimulating hormone testing will be conducted at Screening to confirm whether a female subject with ≥12 
months of spontaneous amenorrhea and not surgically sterile meets the protocol-defined criteria for being post-
menopausal. 
Sections also affected by this change: 
• 
Schedule of Events  
Purpose: Correct typographical errors, punctuation, grammar, abbreviations, and formatting. 
These changes are not listed individually. 
 

SAP_001.pdf: 
Official Title: 
A 2-Part Study (Open-label Followed by Double-blind, Randomized, Placebo - 
Controlled, Parallel Group) of the Safety, Tolerability, Pharmacokinetics, and
Efficacy of SAGE-217 in the Treatment of Subjects With Bipolar I/II Disorder With
a Current Major Depressive Episode
NCT Number: 
NCT03692910
Document Date: 
SAP Version 1.0: 12 June 2019


Clinical Study Report 
 
217-BPD-201 
16.1 Study Information 
 
1 
 
 
  
 
9. 
DOCUMENTATION OF STATISTICAL METHODS 
Statistical Analysis Plan 


 Statistical Analysis Plan Methods 12 June 2019 Version 1.0 
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 Protocol Number: SAGE-217-BPD-201A 
Sage Therapeutics, Inc. 
Confidential Information 
SAGE THERAPEUTICS INCORPORATED 
Statistical Analysis Plan 
Methods 
Protocol Number SAGE-217-BPD-201 
A 2-PART STUDY (OPEN-LABEL FOLLOWED BY DOUBLE-BLIND, 
RANDOMIZED, PLACEBO-CONTROLLED, PARALLEL GROUP) OF THE 
SAFETY, TOLERABILITY, PHARMACOKINETICS, AND EFFICACY OF SAGE-
217 IN THE TREATMENT OF SUBJECTS WITH BIPOLAR I/II DISORDER 
WITH A CURRENT MAJOR DEPRESSIVE EPISODE 
Author of SAP: 
 
Version: Version 1.0 
Version Date of SAP: 12 JUN 2019 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, Massachusetts 02142 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Sage Therapeutics Incorporated is strictly prohibited except to the extent required under applicable 
laws or regulations.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them. 




 Statistical Analysis Plan Methods 12 June 2019 Version 1.0 
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 Protocol Number: SAGE-217-BPD-201A 
 
Sage Therapeutics Inc 
Confidential Information 
 
1 
TABLE OF CONTENTS 
1 
Table of Contents ............................................................................................................. 3 
2 
List of Abbreviations ....................................................................................................... 5 
3 
Introduction ...................................................................................................................... 7 
4 
Study Objectives .............................................................................................................. 7 
4.1 
Primary Objective ....................................................................................................... 7 
4.2 
Secondary Objective ................................................................................................... 7 
 
 7 
5 
Study Endpoints ............................................................................................................... 7 
5.1 
Primary Endpoint ........................................................................................................ 7 
5.2 
Secondary Endpoints .................................................................................................. 7 
 
 8 
6 
Study Design ..................................................................................................................... 8 
6.1 
Overall Design ............................................................................................................ 8 
6.2 
Sample Size and Power .............................................................................................. 9 
6.3 
Randomization ............................................................................................................ 9 
6.4 
Blinding and Unblinding ............................................................................................ 9 
7 
Modifications .................................................................................................................... 9 
7.1 
Modifications to the Approved Clinical Study Protocol ............................................ 9 
7.2 
Modifications to the Approved Statistical Analysis Plan ........................................... 9 
7.3 
Modifications to the Approved DMC Charter ............................................................ 9 
8 
Analysis Sets ..................................................................................................................... 9 
8.1 
Safety Set .................................................................................................................... 9 
8.2 
Efficacy Set ................................................................................................................ 9 
 
 9 
 
 10 
8.5 
Modified Safety Set .................................................................................................. 10 
8.6 
Modified Efficacy Set ............................................................................................... 10 
9 
Statistical Analysis ......................................................................................................... 10 
9.1 
General Considerations ............................................................................................ 10 
9.1.1 
Study Day Definition ........................................................................................ 10 
9.1.2 
Missing Data ..................................................................................................... 11 
9.2 
Background Characteristics ...................................................................................... 11 
9.2.1 
Subject Disposition ........................................................................................... 11 
9.2.2 
Protocol Deviations .......................................................................................... 11 
9.2.3 
Demographics and Baseline Characteristics ..................................................... 11 
9.2.4 
Medical/Surgical History .................................................................................. 12 
9.2.5 
Prior and Concomitant Medications / Concomitant Procedures ...................... 13 
9.2.6 
Study Drug Exposure ........................................................................................ 13 
9.2.7 
Study Drug Adherence ..................................................................................... 14 
9.3 
Efficacy Analysis ...................................................................................................... 14 
9.3.1 
Definition of Efficacy Variables ....................................................................... 14 
9.3.1.1 
Hamilton Rating Scale for Depression (HAM-D) ..................................... 14 
9.3.1.2 
Montgomery-Åsberg Depression Rating Scale (MADRS) ........................ 15 


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9.3.1.3 
Clinical Global Impression – Severity (CGI-S) ......................................... 15 
9.3.1.4 
Clinical Global Impression – Improvement (CGI-I) .................................. 15 
9.3.1.5 
Insomnia Severity Index (ISI) .................................................................... 15 
9.3.2 
Visit Windows .................................................................................................. 16 
9.3.3 
Analysis of Efficacy Variable(s) ...................................................................... 17 
9.4 
Safety Analysis ......................................................................................................... 17 
9.4.1 
Adverse Events ................................................................................................. 18 
9.4.2 
Clinical Laboratory ........................................................................................... 19 
9.4.3 
Vital Signs ........................................................................................................ 22 
9.4.4 
Electrocardiogram ............................................................................................ 22 
9.4.5 
Physical Examination ....................................................................................... 23 
9.4.6 
Columbia Suicide Severity Rating Scale (C-SSRS) ......................................... 23 
9.4.7 
Young Mania Rating Scale (YMRS) ................................................................ 24 
 
 24 
 
 24 
 
 25 
 
 25 
 
 25 
 
 25 
 
 26 
10 Summary of Interim and DMC Analyses .................................................................... 26 
11 References ....................................................................................................................... 27 
12 List of Appendices .......................................................................................................... 28 
12.1 Appendix A: Schedule of Assessments .................................................................... 28 
12.2 Appendix B: Handling of Missing Dates ................................................................. 31 
12.2.1  Adverse Events ................................................................................................... 31 
12.2.2 Prior and Concomitant Medications .................................................................... 32 
12.2.3 Dates in Disease History (Dates of diagnosis, current episode, first episode)..... 32 
12.3 Appendix D: List of Displays ................................................................................... 33 
12.3.1 Index of Tables ............................................................................................. 33 
12.3.2 Index of Listings .......................................................................................... 36 
12.3.3 Index of Figures ........................................................................................... 38 
 
 


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2 
LIST OF ABBREVIATIONS 
Abbreviation or specialist term 
Explanation 
ADaM 
Analysis Data Model 
AE 
adverse event 
ALP 
Alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
Anatomic Therapeutic Chemical Classification 
BLQ 
Below the Limit of Quantitation 
BUN 
Blood urea nitrogen 
C 
Celsius 
CGI-I 
Clinical Global Impression scale for improvement 
CGI-S 
Clinical Global Impression scale for severity 
C-SSRS 
Columbia Suicide Severity Rating Scale 
ECG 
Electrocardiogram 
EOT 
end of treatment 
ET 
early termination 
 
 
FSH 
follicle stimulating hormone 
GGT 
Gamma Glutamyl Transferase 
HAM-D 
Hamilton Rating Scale for Depression, 17-item 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ISI 
Insomnia Severity Index 
LFT 
Liver function tests 
LLOQ 
Lower Limit of Quantification 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MDD 
major depressive disorder 
MDE 
major depressive episode 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGH-ATRQ 
Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire 


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Abbreviation or specialist term 
Explanation 
PCS 
potentially clinically significant 
PCSC 
potentially clinically significant change 
 
 
PT 
Preferred term 
QTcF 
QT corrected according to Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCID-5-CT 
Structured Clinical Interview for Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition for clinical trials 
SD 
standard deviation 
 
 
SDTM 
Study Data Tabulation Model 
 
 
SI 
International System of Units 
SOC 
System organ class 
SpO2 
Pulse oximetry 
TEAE 
treatment-emergent adverse event 
ULN 
Upper limit of normal 
WBC 
White blood cell count 
WHO-DD 
World Health Organization-Drug dictionary 
YMRS 
Young Mania Rating Scale 


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3 
INTRODUCTION 
This statistical analysis plan (SAP) is for the final analysis and is based on the approved clinical study 
protocol, 217-BPD-201, dated 16 Jan 2019, version 4.0.  
Protocol 217-BPD-201 is an umbrella protocol that describes methods for two parts, referred to as 
Parts A and B (hereafter referred to as Study 217-BPD-201A and Study 217-BPD-201B, 
respectively).  These two parts will be conducted as two separate studies and will be analyzed and 
reported as such: Study 217-BPD-201A and Study 217-BPD-201B. 
The purpose of the SAP is to describe in detail the statistical methodology and the statistical analyses 
to be conducted for the above-mentioned protocol for Study 217-BPD-201A.  The SAP will be 
approved and finalized before Part A database lock. 
4 
STUDY OBJECTIVES  
4.1 Primary Objective 
The primary objective of Study 217-BPD-201A is to evaluate the safety and tolerability of SAGE-217 
in subjects with bipolar I/II disorder with a current major depressive episode (MDE). 
4.2 Secondary Objective 
The secondary objectives of Study 217-BPD-201A are: 
• 
To assess the efficacy of SAGE-217 in reducing depressive symptoms in subjects with 
bipolar I/II disorder with a current MDE. 
• 
To assess the effect of SAGE-217 on sleep. 
 
 
 
 
 
 
 
 
 
 
 
 
5 
STUDY ENDPOINTS 
5.1 Primary Endpoint 
• 
The primary endpoint for Study 217-BPD-201A is the safety and tolerability of SAGE-217 as 
assessed by the frequency and severity of adverse events (AEs); changes from baseline in 
clinical laboratory measures, vital signs, and electrocardiograms (ECGs); suicidal ideation 
and behavior using the Columbia Suicide Severity Rating Scale (C-SSRS); and mania using 
the Young Mania Rating Scale (YMRS). 
5.2 Secondary Endpoints 
Secondary endpoints of this study are:  


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• 
The reduction in depressive symptoms, as assessed by: 
o Change from baseline in the 17-item Hamilton Depression Rating Scale (HAM-D) 
total score at Day 15  
o HAM-D response at Day 15  
o HAM-D remission at Day 15  
o  Change from baseline in the Montgomery-Åsberg Depression Rating Scale 
(MADRS) total score at Day 15  
o Change from baseline in HAM-D individual item scores at Day 15 
o The response to the Clinical Global Impression scale for severity (CGI-S) and 
improvement (CGI-I) at Day 15. 
• 
The reduction in insomnia severity, as assessed by Insomnia Severity Index (ISI) at Day 15. 
 
 
  
 
 
 
 
 
 
 
 
6 
STUDY DESIGN  
6.1 Overall Design  
Study 217-BPD-201A is designed to assess the safety, tolerability, 
 and efficacy of SAGE-217 in 
adult subjects with bipolar I/II disorder, who are currently experiencing an MDE. 
Screening begins with the signing of the informed consent form (ICF) at the Screening Visit.  The 
diagnosis of bipolar I or II disorder will be made using the Structured Clinical Interview for 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition for clinical trials (SCID-5-CT) 
performed by a qualified healthcare professional.  Subjects on antidepressants or mood stabilizers 
(lamotrigine, lithium, and valproic acid only) that have been taken at the same dose for at least 60 
days prior to Day 1 are to continue the stable dose throughout the treatment period. 
Subjects will return to the study center during the treatment and follow-up periods as outlined in the 
Schedule of Events (Appendix A).  All assessments to be performed are summarized in Appendix A. 
If at any time during the study, a subject has a YMRS score of ≥13, the Investigator will clinically 
assess the subject for a manic or hypomanic switch.  If the clinical assessment is consistent with 
hypomania or mania, the subject will be discontinued from study drug and treated as clinically 
appropriate (see Clinical Protocol Section 8.3). 
The study design for 217-BPD-201A is presented in Figure 1.  All subjects will receive SAGE-217.  
Beginning on Day 1, qualified subjects will self-administer 30-mg SAGE-217 once daily in the 


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evening with food for 14 days.  Dose adjustments based on study drug tolerability are permitted 
following the guidelines outlined in Clinical Protocol Section 7.4. 
Figure 1: 
Study Design (217-BPD-201A) 
 
 
QD = once daily 
A dose adjustment to 20-mg SAGE-217 is permitted if the 30-mg dose is not tolerated at any time. 
 
6.2 Sample Size and Power 
The sample size of approximately 30 subjects was selected based on clinical and not statistical 
considerations. 
6.3 Randomization 
Study 217-BPD-201A is an open-label design, hence randomization does not apply.   
6.4 Blinding and Unblinding 
All subjects who receive any study drug in this part of the study, 217-BPD-201A, will receive SAGE-
217 in an open-label manner, hence blinding/unblinding does not apply.   
7 
MODIFICATIONS  
7.1 Modifications to the Approved Clinical Study Protocol 
There are no modifications from the clinical study protocol (version 4.0, dated 16 JAN 2019). 
7.2 Modifications to the Approved Statistical Analysis Plan 
This is the first version of the SAP for the final analysis. 
7.3 Modifications to the Approved DMC Charter 
Not applicable. 
8 
ANALYSIS SETS 
8.1 Safety Set 
The Safety Set is defined as all subjects that received at least 1 dose of study drug. 
8.2 Efficacy Set 
The Efficacy Set is defined as all subjects in the Safety Set that have at least 1 post-baseline HAM-D 
evaluation.  
 
 
 
 
 


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8.5 Modified Safety Set 
The Modified Safety Set is defined as all subjects in the Safety Set who have taken at least 14 
capsules over the first 7 days of planned treatment period for profill patients and at least 7 
capsules over the first 7 days of planned treatment period for autofill patients. [Profill and 
autofill patients are identified by the kit type used (Pro Kit Type for profill patients and Auto 
Kit Type for autofill patients).] 
8.6 Modified Efficacy Set 
The Modified Efficacy Set is defined as all subjects in the Efficacy Set who have taken at 
least 14 capsules over the first 7 days of planned treatment period for profill patients and at 
least 7 capsules over the first 7 days of planned treatment period for autofill patients. 
9 
STATISTICAL ANALYSIS 
9.1 General Considerations 
Unless otherwise specified, continuous endpoints will be summarized with n, mean, standard 
deviation (SD), median, minimum (min) and maximum (max).  If the measurements in the source 
(raw) data are integers, then the corresponding mean and median will be presented to 1 decimal place 
and the SD to 2 decimal places; if the measurements are obtained to 1 decimal place, then the mean 
and median will be presented to 2 decimal places and the SD to 3 decimal places; and so forth.  
Minimum and maximum will be displayed as reported in the source (raw) data.  In addition, change 
from baseline values (visit value – baseline value) will be calculated at each time point and 
summarized descriptively.  For categorical endpoints, descriptive summaries will include counts and 
percentages.  Percentages will be presented to 1 decimal place unless otherwise specified;  the 
denominator of percentages will be the number of subjects in the analysis set used unless specified 
otherwise.  
All analyses and summary outputs will be generated using SAS® 9.4 or higher. 
All subject data, including those derived, to support tables and figures will be presented in the subject 
data listings.  In general, the subject data listings will be sorted by subject number and assessment 
visit and date (and time, if applicable).  The summary tables will be presented descriptively in a 
pooled group for the analysis population.  
For the purpose of all safety and efficacy analyses, baseline is defined as the last non-missing 
measurement prior to the first dose of study drug. 
Last value on treatment is derived as the last value after the first dose of study drug and on or before 
last dose of study drug +1 day.  Last value on study is derived as the last value after the first dose of 
study drug. 
9.1.1 Study Day Definition 
Study day will be defined as follows:  
• 
The day of subject receiving the first dose of study drug is designated as Day 1. 


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• 
For visit days after Day 1, study day = visit date – Day 1 date + 1. 
• 
For visit days prior to Day 1, study day = visit date – Day 1 date.  Thus, study days for 
screening visit are negative numbers.  There is no “Day 0”. 
9.1.2 Missing Data 
Every attempt will be made to avoid missing data.  All subjects will be used in the analyses, as per the 
analysis sets, using all non-missing data available.  No imputation process will be used to estimate 
missing data.  Imputation of missing data in scoring of questionnaires are discussed in respective 
sections below. Handling of missing or incomplete dates have been discussed in Section 12.3, 
Appendix B. 
9.2 Background Characteristics  
9.2.1 Subject Disposition 
The analyses of subject disposition will use all subjects who provided written inform consent to the 
study. 
The summaries of subject disposition will include the number and percentage of subjects who 
received study drug, who completed the study, who prematurely withdrawn from the study, primary 
reasons for not completing the study, who discontinued treatment, and primary reasons for 
discontinuing treatment. In addition, the number and percentage of subjects who underwent a dose 
reduction to 20mg will be provided.  A completer for the study is defined as one who completed  the 
final follow up visit (Day 42), and is derived from the study conclusion CRF page with completion 
question answered Yes.  A subject who is marked as discontinuing treatment prematurely in the 
treatment discontinuation CRF page is considered prematurely discontinuing treatment; the main 
reason is provided in the same CRF page. 
The number and percentage of each analysis set will be provided. 
A separate data listing will be provided for all subjects who prematurely discontinued treatment or 
prematurely withdrew from the study with reasons, number of days on study drug, the number of days 
in each dose of study drug, etc. 
A data listing of screen failure subjects with date of informed consent, demographic information, any 
AE/serious adverse event (SAE) and eligibility criteria information will be provided. 
9.2.2 Protocol Deviations 
Protocol deviation analyses will use the Safety Set.  
Protocol deviations identified during site monitoring in consultation with Medical Monitor will be 
captured in a protocol deviation log and categorized as major and minor deviations. These deviations 
will be summarized by major-efficacy, major-safety, major-GCP, and minor.  
9.2.3 Demographics and Baseline Characteristics 
The following analyses will use the Safety Set. 
Demographic data (age, race, gender, ethnicity, employment status, highest education level, 
marital/civil status) and baseline characteristics, such as height, weight, and body mass index (BMI), 
will be summarized. Highest education level will be categorized in the summary tables as follows: 
Less than 12th grade  
12th grade diploma or GED 
Some college but no degree 
Associate degree 


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Bachelor’s degree 
Master’s degree 
Professional degree 
Doctoral degree 
Baseline subgroups will be summarized for the following categories: 
• 
Race (Black or African American, White, Other) 
• 
Age group (18-24, 25-50, 51-65 years)   
• 
Baseline antidepressant use (Yes, No) 
• 
Baseline use of mood stabilizer (Yes – Lamotrigine, Lithium, Valproic acid, No) 
• 
BMI (≤18.4, 18.5-24.9, 25-29.9, ≥30 kg/m2) 
Pregnancy results will be listed but not summarized.  
Diagnostic labs are part of screening; a data listing using Safety Set will be provided.    The following 
diagnostic screening test results will be included in this listing.  
 
Diagnostic Screening 
 
 
Serum 
Urine 
Breathalyzer 
Hepatitis B 
Hepatitis C 
HIV-1 and -2 
Female subjects of child bearing 
potential: serum human 
chorionic gonadotropin 
Female subjects, if menopause is 
suspected and not surgically 
sterile: FSH 
Drug screen including: amphetamines, 
barbiturates, benzodiazepines, 
cannabinoids, cocaine, opiates, 
phencyclidine, and propoxyphene 
Female subjects of child bearing 
potential: urine human chorionic 
gonadotropin 
Alcohol 
 
9.2.4 Medical/Surgical History 
The following analyses will use the Safety Set. 
Medical or surgical history collected at screening will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA), Version 21.0 or higher. 
Medical/surgical history data will be summarized by system organ class (SOC) and preferred term 
(PT).  
Detailed history of bipolar (type of bipolar, date of initial diagnosis, type of episode, etc.) will be 
collected.  Type of bipolar, years since initial diagnosis of bipolar, anti-depressant usage, etc. will be 
summarized.  Other psychiatric disorders (excluding bipolar) status and history will be listed and 
summarized separately from bipolar.  Family history of psychiatric disorders will be summarized.  
Years since initial diagnosis of bipolar, anti-depressant usage, etc. will be calculated using:   First 
dose date of the study drug – Date of interest. For imputation of incomplete dates in disease history, 
please see section 12.2.3. 


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9.2.5 Prior and Concomitant Medications / Concomitant Procedures 
The following analyses will use the Safety Set. 
All medications taken and procedures undergone during the study will be recorded; in addition, 
psychotropic medications taken within 6 months prior to screening, and non-psychotropic 
medications taken within 30 days prior to screening will also be collected.  All medications will be 
coded using World Health Organization-Drug dictionary (WHO-DD) March 2018 or later. 
Medications will be presented according to whether they are being taken prior to and/or during the 
study (concomitant).  Prior medications are defined as those taken prior to the initiation of the start of 
study drug.  Concomitant medications are defined as those with a start date on or after the first dose 
of study drug, or those with a start date before the first dose of study drug that are ongoing or with a 
stop date on or after the first dose of study drug.  If medication dates are incomplete and it is not clear 
whether the medication was concomitant, it will be assumed to be concomitant. 
• 
Concomitant medications will be further divided by usage period as follows (if time is 
missing, the date will be used for this algorithm): On treatment concomitant medications are 
those that have been used any time from start of first dose to the last dose of study drug. 
• 
Post-treatment concomitant medications are those that have been started after the last dose of 
study drug. 
 
Prior and concomitant non-psychotropic medication summaries will be performed by anatomical 
therapeutic chemical (ATC) level 1 and Generic Term.  Similar summary tables will be provided for 
psychotropic medications.  
Screening criteria for this study requires that if the patient is using a mood stabilizer before the first 
dose of the study drug, this must be one of the following three medications – Lamotrigine, Lithium, 
Valproic acid. If the patient started a mood stabilizer before the first dose of the study drug and 
continued the same dose after first dose, they will be considered as baseline users. Anti-depressant 
use is permitted for entry into the study as long as it is at stable dose for 60 days prior to the first dose 
of study.  Anti-depressant medications are identified by ATC3 level code of N06A. If the patient 
started anti-depressant medications prior to first dose of the study drug and continued after first dose, 
they will be considered as baseline users. A summary of anti-depressant use at baseline versus use of 
different mood stabilizers at baseline will be provided.  In addition, any change in these medications 
post-baseline (including the follow up period) will be summarized. 
Concomitant procedures will be presented in a listing by subject, and will not be summarized. 
9.2.6  Study Drug Exposure 
The following analyses will use the Safety Set 
Total drug exposure (in mg) is defined as the total study drug in mg that were taken during the study.  
Subjects on Profill capsules will be administered 2 capsules per dose.  If the subject takes one capsule 
instead of 2 in a day, the dose taken on that day is considered 30mg if this happened within Day 1 and 
Day 14 (both inclusive) without any dose reduction to 20mg before this day; otherwise the dose taken 
on that day is considered 10mg.  Subjects on Autofill capsules will be administered 1 capsule per 
dose.  If the patient skips dose on any of the days, the dose taken is 0mg.   
Total exposure duration to study drug (in days) is defined as total number of days treated with study 
drug during the study: Date of last dose – date of first dose + 1.  


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Percent of planned exposure received is defined as the total drug exposure, divided by planned 
exposure, times 100.  For subjects who complete the treatment period, planned exposure is 14 days of 
treatment planned, times 30 mg. For subjects who discontinue the treatment early, the planned 
exposure is (Last dose date – First dose date + 1), times 30 mg. 
Total drug exposure, total exposure duration and percent of planned exposure will be summarized 
descriptively. 
9.2.7 Study Drug Adherence 
The following analyses will use the Efficacy Set. 
Study drug adherence (%) is defined as the total number of capsules taken divided by total number of 
planned capsules, times 100. For autofill patients, planned dose is one capsule per day; for profill 
patients, planned dose is two capsules per day.  Number of planned capsules for study drug intake is 
defined as follows: 
1.     If the subject discontinues treatment within Day 2 and Day 14 (both inclusive), the planned 
number of capsules is the last dose day of study drug if the subject took autofill capsules,  and the last 
dose day of study drug, times 2, if the subject took profill capsules. 
2.    If the subject does not discontinue treatment, the planned number of capsules is 14 for autofill 
subjects and 28 for profill subjects. 
 
Study drug adherence will be descriptively summarized. 
9.3 Efficacy Analysis  
All efficacy analyses will be performed for the Efficacy Set unless otherwise specified. 
9.3.1 Definition of Efficacy Variables 
The efficacy variables are defined as follows: 
9.3.1.1  Hamilton Rating Scale for Depression (HAM-D) 
The 17-item HAM-D will be used to rate the severity of depression in subjects who are identified as 
experiencing an MDE.  HAM-D is collected during the clinic visit at Screening, Days 1, 3, 8, 12, 15, 
21, 28, 35, 42.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.  Each 
item is scored in a range of 0 to 2 or 0 to 4, with higher scores indicating a greater degree of 
depression.  The score for each item will be summed to compute a total score, which ranges from 0 to 
52.  If more than 3 individual items are missing, the HAM-D total score will not be calculated and 
will be left as missing.  If less than or equal to 3 individual item scores are missing, the missing item 
scores will be imputed by the mean of all other available item scores, or the maximum possible values 
for the missing responses, whichever is smaller, to calculate the HAM-D total score. 
HAM-D Response will be defined as a 50% or greater reduction from baseline in HAM-D total score.  
HAM-D Remission will be defined as a HAM-D total score of ≤7. The Core Subscale score is the 
sum of the following symptom scores: depressed mood, feelings of guilt, suicide, work and activities, 
and retardation. The Anxiety Subscale score is the sum of the following symptom scores: anxiety 
(psychic and somatic), somatic symptoms (gastrointestinal and general), hypochondriasis, and loss of 
weight. The Bech-6 Subscale score is the sum of the following symptom scores: depressed mood, 


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feelings of guilt, work and activities, retardation, anxiety psychic, and somatic symptoms 
general. The Meier Subscale score is the sum of the following symptom scores: depressed mood, 
feelings of guilt, work and activities, retardation, agitation, and anxiety psychic.  
9.3.1.2 
Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive 
episodes in subjects with mood disorders.  It was designed as an adjunct to the HAM-D that would be 
more sensitive than the Hamilton Scale to the changes brought on by antidepressants and other forms 
of treatment.  MADRS is collected during the clinic visit on Days 1, 3, 8, 12, 15, 21, 28, 35, and 42. 
Each MADRS item ranges from 0 to 6; higher MADRS scores indicate more severe depression.  The 
MADRS total score will be calculated as the sum of the 10 individual item scores, which ranges from 
0 to 60.  If more than two individual items are missing, the MADRS total score will not be calculated 
and will be left as missing.  If less than or equal to two individual item scores are missing, the missing 
item scores will be imputed by the mean of all other available item scores, to calculate the MADRS 
total score. 
9.3.1.3 
Clinical Global Impression – Severity (CGI-S) 
The Clinical Global Impression - Severity (CGI-S) uses a 7-point Likert scale to rate the severity of 
the subject’s illness at the time of assessment, relative to the clinician’s past experience with subjects 
who have the same diagnosis. Considering total clinical experience, a subject is assessed on severity 
of mental illness at the time of rating as 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly 
ill; 4=moderately ill; 5=markedly ill; 6=severely ill; and 7=extremely ill.  CGI-S is collected during 
the clinic visit on Days 1, 3, 8, 12, 15, 21, 28, 35, and 42. 
9.3.1.4 
Clinical Global Impression – Improvement (CGI-I) 
The Clinical Global Impression - Improvement (CGI-I) employs a 7-point Likert scale to measure the 
overall improvement in the subject’s condition post-treatment. The Investigator will rate the subject’s 
total improvement. Response choices include: 0=not assessed, 1=very much improved, 2=much 
improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, and 7=very 
much worse. The CGI-I is only rated at post-treatment assessments on Days 3, 8, 12, 15, 21, 28, 35, 
42.  By definition, all CGI-I assessments are evaluated against baseline conditions. CGI-I response 
will be defined as having a CGI-I score of “very much improved” or “much improved.” Missing CGI-
I at the visit will not be evaluated for response. 
9.3.1.5 
Insomnia Severity Index (ISI) 
The ISI is a validated, 7-item questionnaire designed to assess the nature, severity, and impact of 
insomnia.  It is collected during the clinic visit on Days 1, 8, 15, 21, 28, 42.  The ISI uses a 5-point 
Likert Scale to measure various aspects of insomnia severity (0 = none, 1 = mild, 2 = moderate; 3 = 
severe; 4 = very severe), satisfaction with current sleep pattern (0 = very satisfied, 1 = satisfied, 2 
=neutral, 3 = dissatisfied, 4 = very dissatisfied), and various aspects of the impact of insomnia on 
daily functioning (0 = not at all, 1 = a little, 2 = somewhat, 3 = much, 4 = very much).  The total score 
is derived as the sum of item scores.  If more than 1 individual items are missing, the ISI total score 
will not be calculated and will be left as missing.  If less than or equal to 1 individual item scores are 
missing, the missing item scores will be imputed by the mean of all other available item scores to 
calculate the ISI total score.  Total score is categorized as: 0 to 7 = “no clinically significant 
insomnia”, 8 to 14 = subthreshold insomnia”, 15 to 21 = “clinical insomnia (moderate severity)”, and 
22 to 28 = “clinical insomnia (severe).” Improvement since baseline is defined as a shift to a lower 
category compared to baseline. 


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9.3.2 Visit Windows 
The scheduled visits will not be windowed and will be used at nominal visit date value for analysis 
purposes. The unscheduled, end-of-treatment (EOT) and early termination (ET) visit will be mapped 
to a scheduled visit for analysis using the date of collection/assessment and Day 1 first dose date as a 
basis to determine study day and then study day will be mapped to the intended visit according to the 
visit windows specified in the table below. Unscheduled visits after EOT visit date, including ET 
visit, will be windowed using relative days since last dose date; the mapping will follow the table 
below. In order to accommodate as much as data as possible into analysis, these windows have been 
widened compared to protocol-specified operational window, to have no gap between them; these 
windows are used for analyses purpose only.   
Once analysis visit windows are assigned, all visits, including scheduled visits, unscheduled visits, 
and EOT/ET visits will be eligible for being flagged as the “analyzed record” within the analysis 
window, a subject’s individual analysis visit window could potentially contain more than 1 visit.  In 
the event of multiple visits falling within an analysis window or in case of a tie, the following rules 
will be used in sequence to determine the “analyzed record” for the analysis visit window: 
• 
If there is a scheduled visit/day for the analysis visit window, then the scheduled visit/day 
data will be used.  
• 
If there is no scheduled visit/day for the analysis visit window, the data closest to the 
scheduled day/time will be used.  
• 
If there is no scheduled visit/day for the analysis visit window and there is a tie between the 
data in the number of days/hours before and after the scheduled day, the later data will be 
used.  
The summary by visit will use “analyzed records” only ---at most one per subject.  However, any time 
post-baseline PCS values or last value on treatment/study will use all analyzed records as well as any 
other record available in the respective time frame. 
An unscheduled visit that does not fall under any window (e.g. in case one is available after Day 45) 
will remain in the database and will be included in the listings.  The data not flagged as the “analyzed 
record” will be included in subject listings. Table 1 displays windows for efficacy analysis.  
Table 1: Visit Windows for Efficacy Analysis 
Scheduled Visit 
Study Day of Expected Visit 
Study Day Window for Visit 
Screening 
Day -1 
Days (-28) to (-1) 
First Dose 
Day 1 (pre-dose) 
Day 1 (pre-dose) 
Day 3 (+1 day) 
Day 3 
Day 2 - Day 5 
Day 8 (±1 day) 
Day 8 
Day 6- Day 9 
Day 12 (±1 day) 
Day 12 
Day 10 - Day 13 
Day 15 (±1 day) 
Day 15 
Day 14 - Day 17 
Day 21/last dose +7 days (±3 
day)  
Day 21/ (last dose +7 days) 
Day 18 - Day 24 (last dose 
day+4 days, +10 days) 
Day 28/last dose +14 days (±3 
day)  
Day 28/ (last dose +14 days) 
Day 25 - Day 31(last dose day 
+11days, +17 days) 
Day 35/last dose +21 days (±3 
days) 
Day 35(/last dose +21 days) 
Day 32 – 38 (last dose date+ 18 
days, +24 days) 


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Day 42/last dose+28 days (±3 
days) 
Day 42(/last dose+28 days) 
Day 39 – 45 (last dose date+25 
days, +31 days) 
Note: Parenthesized study day and study day window are for unscheduled, EOT or ET visits  
that occur at least 4 days after the last dose date. 
9.3.3 Analysis of Efficacy Variable(s) 
The Efficacy Set will be used for all efficacy summary tables. 
The following efficacy endpoints will be summarized descriptively by scheduled assessment time 
point (including last value on treatment and last value on study, separately):  
• 
HAM-D total score – observed, change from baseline, percent change from baseline 
• 
HAM-D individual item score -– observed, change from baseline, percent change from 
baseline 
• 
MADRS total score – observed, change from baseline, percent change from baseline -  
• 
MADRS individual item score – observed, change from baseline, percent change from 
baseline 
• 
ISI total score – observed (including categories) including any shift toward improvement 
from baseline 
• 
CGI-I score – observed 
• 
CGI-S score – observed and change from baseline 
• 
HAM-D response 
• 
HAM-D remission 
• 
CGI-I response 
If the Modified Efficacy Set is less than 90% of the Efficacy Set, a sensitivity analysis of the HAM-D 
change from baseline in total score, response and remission, and MADRS change from baseline in 
total score will be performed on the Modified Efficacy Set. 
The HAM-D change from baseline in total score, response and remission, and MADRS change from 
baseline total score will be presented by the subgroups of the following variable (subgroup definitions 
are provided in Section 9.2.3): 
1. Age group   
2. Race 
3. Gender 
4. Baseline antidepressant use 
5. Baseline use of mood stabilizer 
Change from baseline in HAM-D and MADRS total score over time will be presented graphically. 
9.4 Safety Analysis 
The primary objective is to evaluate the safety and tolerability of SAGE-217 as assessed by the 
frequency and severity of adverse events; changes from baseline in clinical laboratory measures, vital 
signs, and ECGs; and suicidal ideation and behavior using the C-SSRS; and mania using the YMRS. 
Safety analyses will be conducted using the Safety Set, unless specified otherwise.  
The safety endpoints and variables considered in the summary tables for this study are summarized in 
Table 2.  


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Table 2: Safety endpoints and variables in the summary tables 
Safety 
Evaluation 
Incidence 
Obser
ved 
Value 
Change from 
Baseline 
Abnormality/Clinic
al Significance (CS) 
Potentially Clinical 
Significance (PCS) 
AEs 
X 
 
 
 
 
Labs 
 
X 
X  
Z 
X 
ECGs 
 
X 
X 
Z 
X 
Vital Signs 
 
X 
X  
 
X 
C-SSRS 
X 
 
 
 
 
YMRS 
 
X 
X 
 
 
Note: PCS criteria are outlined in sections 9.4.2-9.4.4 
X = to be summarized in tables 
Z = to be presented in listings only 
The visit windows used for safety endpoints are the same as the visit windows used for efficacy 
endpoints, as outlined in Table 1, in Section 9.3.2. 
9.4.1 Adverse Events  
Adverse events are collected starting at the time of informed consent and throughout the duration of a 
subject’s participation in the study.  A treatment-emergent adverse event (TEAE) is defined as an 
adverse event with onset after the start of study drug.  
An on-treatment TEAE is defined as an adverse event with onset after the start of study drug but on or 
before 7 days since the last dose of study drug. A post-treatment TEAE is defined as an adverse event 
with onset after 7 days from the last dose of study drug. 
If the date of an adverse event is incomplete and an unambiguous determination could not be made 
with respect to its onset time versus the first dose of study drug and/or last dose of study drug, the 
adverse event will be assumed to be a TEAE and on-treatment.  For imputation of missing AE dates, 
please refer to Appendix B.  
 
All adverse events will be coded using MedDRA version 21.0 or higher. An overview summary table 
of AEs will present the number and percentage of subjects as well as the number of events for the 
following: 
• 
TEAE 
•     On-treatment TEAE and Post-treatment TEAE   
• 
TEAEs by maximum severity (severe>moderate>mild) 
• 
TEAE leading to discontinuation of study drug 
• 
TEAE leading to withdrawal from the study 
• 
Death 
• 
SAE 


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Incidence of TEAEs in following categories will be provided by SOC and PT.  A subject is counted 
only once under each SOC and PT in case of multiple occurrences of the same AE.  
• 
TEAEs 
•     On-treatment TEAE 
•     Post-treatment TEAE 
• 
TEAEs by maximum Severity 
• 
TEAEs by relationship to study drug 
• 
Serious TEAEs 
• 
TEAEs leading to discontinuation of study drug 
• 
TEAEs leading to withdrawal from the study  
•     TEAEs leading to dose reduction (from 30mg to 20mg) 
•     TEAEs leading to dose interruption of the study drug 
Most common TEAEs are defined as those, which occur in more than 5% of the safety population.  
A summary of most common TEAE by preferred term where the incidence is more than 5% will be 
provided, sorted by decreasing frequency.  
For maximum severity, subjects will be counted only once within each SOC and PT at the maximum 
severity in the following order: severe> moderate> mild; an AE with missing severity will be omitted 
from severity presentation.  For relationship to study drug, subjects will be counted only once within 
each SOC and PT at the strongest relationship to study drug in the following order: probably related > 
possibly related > not related.  ‘Related’ is defined as relationship being “possible” or “probable” or 
missing. The incidences will be presented by descending frequency of SOC and then, within a SOC, 
by descending frequency of PT based on the subject count, and in alphabetical order of PT if the 
incidence within a PT is a tie. Adverse events with onset before the first dose of study drug will be 
provided in a separate listing.  Separate data listing for deaths and non-fatal SAEs will be provided. 
TEAEs will be classified by the last dose taken before the onset of AE.  A summary of TEAEs by 
SOC/PT and by last dose taken before the onset of AE will be provided. 
If the Modified Safety Set is less than 90% of the Safety Set, a summary of TEAE by SOC/PT for the 
Modified Safety Set will be provided.  TEAE summary by SOC/PT will also be presented by the 
following subgroups (subgroup definitions are provided in Section 9.2.3): 
 
1. Age group 
2. Race 
3. Gender 
4. Baseline antidepressant use 
5. Baseline use of mood stabilizer 
 
9.4.2 Clinical Laboratory 
The clinical laboratory tests to be performed for monitoring of safety are listed in Table 3.  They are 
collected during the clinic visits at Screening, Days 1, 8, 15, 21, 28, and 42. 


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Table 1:  Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Coagulation 
Red blood cell count 
Hemoglobin  
Hematocrit  
White blood cell count with 
differential  
Platelet count 
Red blood cell morphology 
Alanine aminotransferase 
(ALT) 
Albumin 
Alkaline phosphatase 
(ALP) 
Aspartate 
aminotransferase (AST) 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
Total protein 
Creatinine 
Blood urea nitrogen 
(BUN) 
Creatine kinase 
Gamma Glutamyl 
Transferase (GGT) 
Potassium 
Sodium 
Lactate dehydrogenase 
Glucose 
Chloride 
Bicarbonate 
Calcium 
Phosphorus 
Triglycerides 
pH 
Specific gravity 
Protein 
Glucose 
Red blood cells 
Nitrite 
Leukocyte 
esterase 
Ketones 
Bilirubin 
Urobilinogen 
Activated partial 
thromboplastin 
time 
Prothrombin 
time 
International 
normalized ratio 
 
Diagnostic screening labs as outlined in the protocol are excluded from safety analysis; the results 
will be listed by subject for safety population as part of baseline characteristics. 
All parameters will be converted to consistent units according to the International System of Units 
(SI) before summarization.  Listing will provide the results in SI units; the results reported in original 
unit will reside in the database. For the laboratory results that is “< or <= x”, where x is a number as 
collected in the data, the numeric part of the result will be used in calculation in the summary 
tables.  Same is true if the result is presented as BLQ and a LLOQ value is provided – LLOQ value 
will be used for calculation in the summary tables.  The actual results as collected will be displayed in 
the listings. 
Summary tables on safety will include descriptive statistics for the observed values and changes from 
baseline by scheduled assessment timepoint (as well as for last value on treatment and last value on 
study) in hematology, serum chemistry, coagulation and quantitative urinalysis test results.  If a 
normal range is provided for the parameter, out-of-range values will be flagged as low or high, where 
applicable, in the subject data listings.  A shift table for these parameters from baseline to each 
scheduled assessment time point will be provided.  This table will also include the shift from normal 
to high or low at any time during treatment (>Day 1, <= last day of treatment), any time post-baseline 
during the study and at the end of study (i.e. the last available value in the database). 


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Qualitative urinalysis parameters will be summarized descriptively. The number and percentage of 
subjects with PCS values will be provided in separate displays in hematology and serum chemistry 
provided for such occurrence any time post-baseline (irrespective whether it happens in scheduled or 
unscheduled assessments). Potentially clinically significant values will be identified for specific 
laboratory parameters as outlined in the following table. 
Laboratory 
Parameter 
Gender 
Units 
Criteria for PCS Values (Observed values) 
High  
Low  
Hematology 
 
 
 
 
Hemoglobin 
Male 
g/L  
>185  
<115 
 
Female 
g/L  
>170 
<100 
Hematocrit 
Male 
Fraction of 1 
>0.55  
<0.385 
 
Female 
Fraction of 1 
>0.49 
<0.345 
Platelet count 
 
10^9/L  
>600 
<125 
WBC  
 
10^9/L  
>15  
<2.5  
Basophils 
 
10^9/L  
>0.5 
NA 
Eosinophils 
 
10^9/L  
>1.5 
NA 
Neutrophils 
 
10^9/L  
NA  
<1.5  
Lymphocytes 
 
10^9/L  
>6.0  
<0.5  
Monocytes  
 
10^9/L  
>1.4 
NA 
Serum Chemistry 
 
 
 
 
Albumin  
 
g/L  
>70  
<28  
Blood urea nitrogen 
 
mmol/L 
>10.71 
 
Calcium 
 
mmol/L 
>2.75 
<2.0 
Creatinine 
 
μmol/L  
>3 x ULN or >3 x 
Baseline 
NA  
Phosphorus 
 
 mmol/L 
>1.94 
<0.61 
Sodium  
 
mmol/L  
>150  
<132  
Bicarbonate  
 
mmol/L  
>34  
<18  
Potassium  
 
mmol/L  
>5.4  
<3.3  
Chloride  
 
mmol/L  
>120  
<90  
Protein 
 
g/L 
 
<45 
Glucose 
 
mmol/L 
>13.9 
<2.8 
GGT 
 
 
>3 x ULN 
 
Liver Function Tests 
(LFT) 
 
 
 
 
Bilirubin  
 
μ/L  
>2xULN  
NA  
Aspartate 
Aminotransferase  
 
U/L  
>3xULN  
NA  
Alanine Aminotransferase   
U/L  
>3xULN  
NA  
Alkaline Phosphatase  
 
U/L  
>1.5xULN  
NA  
 
Liver function tests will be monitored closely for potentially clinically significant values, and will be 
summarized for occurrence any time post-baseline for the following parameters for these PCS 
threshold (for condition involving more than one parameter, the results need to be from the same 
timepoint): 
Alanine Aminotransferase: >3xULN, >5xULN, >10xULN 
Aspartate Aminotransferase: >3xULN, >5xULN, >10xULN 


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Alanine Aminotransferase or Aspartate Aminotransferase: >3xULN, >5xULN, >10xULN 
Alkaline Phosphatase: >1.5xULN, >2xULN 
Total Bilirubin: >1.5xULN, >2xULN 
Total Bilirubin > 2xULN AND (Alanine Aminotransferase or Aspartate Aminotransferase >3xULN) 
Total Bilirubin >2xULN AND Alkaline Phosphatase >2xULN AND (Alanine Aminotransferase or  
Aspartate Aminotransferase >3xULN) 
Any lab results considered clinically significant by the investigator will be captured as adverse events, 
hence will show up in AE displays. 
9.4.3 Vital Signs 
Vitals for the following parameters - respiratory rate (breaths/minute), oral temperature (degrees C), 
supine heart rate (beats/minute), supine systolic blood pressure (mmHg), supine diastolic blood 
pressure (mmHg), standing heart rate (beats/minute), standing systolic blood pressure (mmHg), 
standing diastolic blood pressure (mmHg), and pulse oximetry (SpO2, %) – are collected during the 
clinic visits at Screening, Days 1, 3, 8, 12, 15, 21, 28, 35, 42.  Descriptive summaries of observed 
values and changes from baseline will be provided for vital sign parameters - by scheduled 
assessment time point as well as for last value on treatment and last value on study 
Additionally, the number and percentage of subjects with PCS and potentially clinically significant 
change (PCSC) values will be summarized for such occurrence any time post-baseline. Potentially 
clinically significant values will be identified for vital sign parameters as outlined in the following 
table. 
Vital Sign 
Units 
Criteria for PCS 
Values (Observed 
values) 
Criteria for PCSC values 
(Change from Baseline values) 
 
 
High  
Low  
Increase  
Decrease  
Heart rate (supine and 
standing) 
Beats/min  >120  
<40  
NA 
NA 
Systolic Blood Pressure 
(supine and standing)  
mmHg  
>180 
<90  
≥30 
≥30 
Diastolic Blood 
pressure (supine and 
standing)  
mmHg  
>110 
<50  
≥20 
≥20  
Orthostatic Systolic 
Blood Pressure Change 
mmHg 
≥20 
 
 
 
Orthostatic Diastolic 
Blood Pressure Change 
mmHg 
≥10 
 
 
 
Orthostatic BP = Supine - Standing 
The change from supine to standing (Supine – Standing) vital signs – heart rate, systolic and diastolic 
blood pressure – will be summarized by scheduled assessment timepoint. 
Any vital signs results considered clinically significant by the investigator will be captured as adverse 
events, hence will show up in AE displays. 
 
9.4.4 Electrocardiogram 
Supine 12-lead ECGs will be performed in triplicate, and are collected during the clinic visits at 
Screening, Days 1, 3, 15, and 42.  The following ECG parameters will be listed for each subject: heart 
rate (beats per minute), PR (msec), QRS (msec), QT (msec), and QTcF (msec).     


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The average of the triplicate values will be used in the summary, including baseline ECG values.  The 
observed value at each time point and change from baseline at each post-baseline scheduled time 
point will be summarized.  Each ECG is evaluated as ‘normal’, ‘abnormal, not clinically significant’ 
and ‘abnormal, clinically significant’; the number and percentage of subjects with at least one of the 
triplicate values in the categories of ‘abnormal, clinically significant’ and ‘abnormal, not clinically 
significant’ will be provided at baseline and each post-baseline scheduled assessment time point. 
ECG vendor information on normal/abnormal/clinically significant/not clinically significant will 
reside in the database, but will not be summarized or listed.  
Additionally, the number and percentage of subjects with PCS and PCSC values will be summarized 
for such occurrence any time post-baseline.  Potentially clinically significant values will be identified 
for ECG parameters as outlined in the following table.  This analysis includes triplicate values 
individually, and is not based on average value.   
ECG 
Units 
Criteria for PCS Values (Observed values) 
Criteria for PCSC values 
(Change from Baseline) 
 
 
High  
Low  
Increase  
Decrease  
QTcF  
Interval 
msec  
females: >450 to 480, male: >450 to 470 
females: >480 to 500, male: >470 to 500  
>500 
NA  
>=30 to 60 
>60 
 
NA  
 
9.4.5 Physical Examination  
Physical examination is scheduled for Screening, Days 1, 15, 42.  Only clinically significant 
abnormalities are captured in the database – for post-baseline observations, these will be reported as 
adverse events, hence these will be included in AE displays; for pre-baseline observations, these will 
be reported as medical history, hence these will be included in Medical History displays.  No further 
display for physical examination will be provided. 
9.4.6 Columbia Suicide Severity Rating Scale (C-SSRS) 
Suicidality data collected on the C-SSRS is collected during the clinical visits at Screening, Days 1, 3, 
8, 12, 15, 21, 28, 35, and 42.   The C-SSRS includes ‘yes’ or ‘no’ responses for assessment of suicidal 
ideation and behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 
5 being the most severe).  The subject’s non-suicidal self-injurious behaviors is also assessed 
separately as part of C-SSRS. The “Baseline/Screening” C-SSRS form will be completed at screening 
(lifetime history and past 24 months). The “Since Last Visit” C-SSRS form will be completed at all 
subsequent time points.  
 
The assessments for suicidal ideation is ranked as follows with 5 being the worst: 
1. Wish to be dead 
2. Non-specific active suicidal thoughts 
3. Active suicidal ideation with any methods 
4. Active suicidal ideation with some intent 
5. Active suicidal ideation with specific plan 
The assessments for suicidal behavior is ranked as follows with 5 being the worst: 
1. Preparatory acts or behavior 
2. Aborted attempt 
3. Interrupted attempt 
4. Actual attempt (non-fatal) 
5. Completed suicide 


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Suicidal behavior is considered worse than suicidal ideation.   
 
Baseline for each question is defined as the worst of the assessments done before the first dose of 
study drug, excluding the lifetime version.  This will typically include the ‘past 24-month ‘version 
from screening and ‘since last visit version’ from Day 1; any Yes will make the baseline value as Yes. 
 
Summary of shift from baseline in C-SSRS suicidal ideation and suicidal behavior will be presented 
for the following categories (no suicidal ideation/behavior, suicidal ideation, suicidal behavior) for 
each scheduled assessment time point.  If the answer to all 5 assessments in suicidal ideation and all 5 
assessments in suicidal behavior is ‘No’ then the category for the table is considered as ‘No suicidal 
ideation/behavior’.  If any of the assessments in suicidal behavior is Yes, the category is considered 
as ‘Suicidal behavior’.  If any of the assessments in suicidal ideation is Yes but all assessments in 
suicidal behavior is No, the category is considered as ‘Suicidal ideation’. 
The number and percentage of subjects with at least one response of ‘Yes’ to any C-SSRS suicidal 
ideation or suicidal behavior item, as well as for Subject’s non-suicidal self-injurious behavior, will 
be summarized for baseline and any time post-baseline. 
In addition, summary of shift in suicidal ideation from baseline maximum rank score for any time 
post-baseline maximum rank score will be presented.  Maximum score 0 refers to all No for all 
assessments in the desired period for all 5 questions on suicidal ideation.   
 
9.4.7 Young Mania Rating Scale (YMRS) 
YMRS is collected during the clinical visits at Screening, Days 1, 3, 8, 12, 15, 21, 28, 35, and 42.  
The clinician-administered scale is based on 11 items of core symptoms of mania.  Four of the items 
(irritability, speech, thought content, and disruptive/aggressive behavior) are graded on a scale of 0 to 
8 (choices given as even numbers), with the remaining 7 items graded on a scale of 0 to 4.  Scoring 
between the points given (whole or half points) is possible.  The total score ranges from 0 to 60.  If 
more than 2 individual items are missing, the YMRS total score will not be calculated and will be left 
as missing.  If less than or equal to 2 individual item scores are missing, the missing item scores will 
be imputed by the mean of all other available item scores or the maximum possible values for the 
missing responses, whichever is smaller, to calculate the YMRS total score.  A higher total score 
indicates a greater degree of mania. 
Observed values and changes from baseline will be summarized for YMRS total score by each 
scheduled assessment time point (as well as the last value on treatment and last value on study).  In 
addition, a summary will be provided by the use of antidepressant and mood stabilizer at baseline. 


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10 SUMMARY OF INTERIM AND DMC ANALYSES 
Not applicable 


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11 REFERENCES 
Clinical Study Protocol: Version 4.0 (16 January 2019), Company: Sage Therapeutics Inc. 


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12 LIST OF APPENDICES 
12.1 Appendix A: Schedule of Assessments 
Study Period 
Screening 
Period 
Treatment Period 
Follow-up Perioda 
Visit Day 
D-28 to  
D-1 
D1 
D3 
(+1d) 
D8 
(±1d) 
D12 
(±1d) 
D15 
(±1d)/EOTa 
D21 
(±3d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)/ET 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical/Family History 
X 
 
 
 
 
 
 
 
 
 
SCID-5-CT 
X 
 
 
 
 
 
 
 
 
 
MGH-ATRQ 
X 
 
 
 
 
 
 
 
 
 
Serum FSH test 
X 
 
 
 
 
 
 
 
 
 
Randomization (Part B only) 
 
X 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
 
X 
 
 
 
X 
Body Weight/Heightc 
X 
 
 
 
 
X (wt only) 
 
 
 
X (wt only) 
Clinical Laboratory Assessmentsd 
X 
X 
 
X 
 
X 
X 
X 
 
X 
Drug & Alcohol Screene 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Testf 
X 
X 
 
 
 
X 
 
X 
 
X 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 


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Study Period 
Screening 
Period 
Treatment Period 
Follow-up Perioda 
Visit Day 
D-28 to  
D-1 
D1 
D3 
(+1d) 
D8 
(±1d) 
D12 
(±1d) 
D15 
(±1d)/EOTa 
D21 
(±3d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)/ET 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Vital Signsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGj 
X 
X 
X 
 
 
X 
 
 
 
X 
C-SSRSk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HAM-Dl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MADRSl 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-S 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
YMRSl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ISI 
 
X 
 
X 
 
X 
X 
X 
 
X 
Study Drug Dispensationo 
 
X 
 
X 
 
 
 
 
 
 
Study Drug Administration 
 
X (Day 1 – Day 14) 
 
 
 
 
Study Drug Accountability/Return 
 
 
X 
X 
X 
X 
 
 
 
 
Adverse Events/Serious Adverse 
Eventsp 
X 
Prior/Concomitant Medications/ 
X 


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Study Period 
Screening 
Period 
Treatment Period 
Follow-up Perioda 
Visit Day 
D-28 to  
D-1 
D1 
D3 
(+1d) 
D8 
(±1d) 
D12 
(±1d) 
D15 
(±1d)/EOTa 
D21 
(±3d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d)/ET 
Visit Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Proceduresq 
CGI-I = Clinical Global Impression - Improvement; CGI-S – Clinical Global Impression - Severity; C-SSRS = Columbia Suicide Severity Rating Scale; D = day; EOT = end 
of treatment; ECG = electrocardiogram; ET = early termination; 
 FSH = follicle stimulating hormone; HAM-D = Hamilton 
Rating Scale for Depression, 17-item; HIV = human immunodeficiency virus; ISI = Insomnia Severity Index; MADRS = Montgomery-Åsberg Depression Rating Scale; 
MGH-ATRQ = Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; O = optional; 
 SCID-5-CT = Structured Clinical 
Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition for clinical trials; 
 
 
YMRS = Young Mania Rating Scale 
a Subjects who discontinue treatment early should return to the site for an EOT visit as soon as possible, preferably the day after treatment is discontinued. 
Follow-up visits should take place every 7 days after the last dose of treatment for a total of 4 follow-up visits. If at any time after the EOT visit, a subject 
decides to terminate the study, the subject should return for an ET visit. The EOT and ET visits can be on the same day if a subject discontinues study drug 
and terminates the study on the same day during a clinic visit; in this case, all events scheduled for both visits will be conducted. 
b A serum follicle stimulating hormone test will be conducted for female subjects at Screening to confirm whether a female subject with ≥12 months of 
spontaneous amenorrhea and not surgically sterile meets the protocol-defined criteria for being post-menopausal. 
c Height measured at screening only 
d Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. Laboratory assessments are to be completed in the morning. 
e Urine toxicology for selected drugs of abuse, and breath test for alcohol (as per the standard procedures at each site).  
f For women of child-bearing potential, serum pregnancy test at screening and urine pregnancy test at all other scheduled timepoints. 
 
 
 
 
i Vital signs include oral temperature (°C), respiratory rate, heart rate, pulse oximetry 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 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 will be obtained first. 
j Triplicate 12-lead ECGs will be performed with the subject in the supine position. When ECG 
 sample collection occur during the same visit, ECGs 
will be collected first. 
k 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. 
l For MADRS, HAM-D, and YMRS, the “Since Last Evaluation” forms will be completed at all subsequent time points following the initial assessment. 
 
 
 
 
 


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o Additional unscheduled dispensation visits may be needed for dose reductions. 
p AEs/SAEs will be collected starting at the time of informed consent and throughout the duration of the subject’s participation in the study.  
q Prior medications will be collected at Screening and concomitant medications will be collected at each subsequent visit. All medications taken within 30 
days prior to Screening through the duration of the study will be recorded. In addition, all psychotropic medications taken within 12 months prior to 
Screening will be recorded. 
12.2 Appendix B: Handling of Missing Dates 
Dates missing the day or both the day and month of the year will adhere to the following conventions in order to classify TEAEs and to 
classify prior and concomitant medications.  
In general, listings will present the actual partial or missing values rather than the imputed values that may be used in derivation. In instances 
where imputed values will be presented, imputed values will be flagged.  
 
12.2.1  Adverse Events 
If the AE start date is completely missing, do not impute a date but consider it as TEAE, unless the AE end date is before the 
initiation of treatment, in which case the AE will be considered prior. 
For partial AE start dates: 
• When the year is known, but the month and day is unknown, then: 
o If the year matches the year of first dose date and the end date (if present) is after first dose date, or AE is ongoing, then impute 
as the month and day of the first dose date + 1 day 
o If the year of AE onset < year of initiation of the treatment, then the month and day will be set to December 31st .  
o If the year of AE onset > the year of initiation of treatment, then the month and day will be set to January 1st. 
 
• If the year and month are known, but the day is unknown, then: 
o If the year of AE onset = the year of initiation of the treatment and: 
 the month of AE onset = the month of initiation of the treatment, then the day will be set to the day of the first dose 
date + 1 day 
 the month of AE onset < the month of initiation of the treatment, then the day will be set to the last day of month. 
 if the month of AE onset > the month of initiation of the treatment, then the day will be set to the 1st day of month. 
o If the year of AE onset < the year of initiation of the treatment, then the day will be set to the last day of month. 


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o If the year of AE onset > the year of initiation of the treatment, then the day will be set to the 1st day of month. 
 If the imputed AE onset date is after the AE stop date, then the onset date will be set to the stop date. 
 
• When the year and day are present and the month is missing, treat it as if the day is missing, and only year is present.  Follow the 
imputation rules for “year is known, but the month and day is unknown”. 
• When the year is missing, but the month and/or day is known, treat this date as missing; do not impute. 
 
12.2.2 Prior and Concomitant Medications 
If the conmed start date is completely missing, do not impute a date but consider it as a concomitant medication, unless the 
conmed end date is before the initiation of treatment, in which case the conmed will be considered prior. 
 
For the partial start date of medication: 
o If the year is present and the month and day are missing, then the month and day will be set to January 1. 
o If the year and day are present and the month is missing, then treat it as if the day is also missing.  Set the month and day to be 
January 1. 
o If the year and month are present and the day is missing, then the day will be set to the 1st day of month. 
o If the imputed start date of medication is after the non-imputed end date of medication, then the start date will be set to the end date 
of medication. 
For the partial end date of medication: 
o If the year is present and the month and day are missing, then the month and day will be set to December 31. 
o If the year and month are present and the day is missing, then the day will be set to the last day of the month. 
o If the year and day are present and the month is missing, then treat it as if the day is also missing.  Set the month and day to be 
December 31.   
12.2.3 Dates in Disease History (Dates of diagnosis, current episode, first episode) 
o If the year is present and the month and day are missing, then the month and day will be set to January 1. 
o If the year and month are present and the day is missing, then the day will be set to the 1st day of month. 
o If the year and day are present and the month is missing, then treat it as if the day is also missing.  Set the month and day 
to be January 1. 


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12.3 Appendix D: List of Displays 
12.3.1 Index of Tables 
Number 
Title 
Analysis Set 
Table 14.1.1.1 
Summary of Subject Disposition 
All Subjects 
Table 14.1.1.2 
Protocol Deviations 
Safety Set 
Table 14.1.2.1.1 
Summary of Demographics and Baseline Characteristics 
Safety Set 
Table 14.1.2.1.2 
Summary of Baseline Subgroups 
Safety Set 
Table 14.1.3.1 
Summary of Medical and Surgical History 
Safety Set 
Table 14.1.3.2.1 
Summary of Prior Psychotropic Medications 
Safety Set 
Table 14.1.3.2.2 
Summary of Concomitant Psychotropic Medications 
Safety Set 
Table 14.1.3.2.3 
Summary of On-treatment Psychotropic Medications 
Safety Set 
Table 14.1.3.2.4 
Summary of Post-treatment Psychotropic Medications 
Safety Set 
Table 14.1.3.3.1 
Summary of Prior Non-Psychotropic Medications 
Safety Set 
Table 14.1.3.3.2 
Summary of Concomitant Non-Psychotropic Medications 
Safety Set 
Table 14.1.3.3.3 
Summary of On-treatment Concomitant Non-Psychotropic Medications 
Safety Set 
Table 14.1.3.3.4 
Summary of Post-treatment Concomitant Non-Psychotropic Medications 
Safety Set 
Table 14.1.3.4 
Summary of Use of Antidepressant and Mood Stabilizer at Baseline 
Safety Set 
Table 14.1.4 
Summary of Bipolar History 
Safety Set 
Table 14.1.5 
Summary of History of Psychiatric Disorders (excluding Bipolar) 
Safety Set 
Table 14.1.6 
Summary of Family History of Psychiatric Disorders 
Safety Set 
Table 14.1.7 
Summary of Study Drug Exposure 
Safety Set 
Table 14.1.8 
Summary of Study Drug Adherence 
Efficacy Set 
Table 14.2.1.1.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Study Visit  
Efficacy Set 
Table 14.2.1.1.1a 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Study Visit  
Modified Efficacy 
Set 
Table 14.2.1.1.2 
Summary of Hamilton Rating Scale for Depression (HAM-D) Individual Item Score by Study 
Visit  
Efficacy Set 
Table 14.2.1.1.3 
Summary of Hamilton Rating Scale for Depression (HAM-D) Response by Study Visit  
Efficacy Set 
Table 14.2.1.1.3a 
Summary of Hamilton Rating Scale for Depression (HAM-D) Response by Study Visit  
Modified Efficacy 


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Set 
Table 14.2.1.1.4 
Summary of Hamilton Rating Scale for Depression (HAM-D) Remission by Study Visit  
Efficacy Set 
Table 14.2.1.1.4a 
Summary of Hamilton Rating Scale for Depression (HAM-D) Remission by Study Visit  
Modified Efficacy 
Set 
Table 14.2.1.1.5 
Summary of HAM-D Total Score (Change from Baseline, Response, Remission) by Study 
Visit, Anti-depressant and Mood Stabilizer Use at Baseline 
Efficacy Set 
Table 14.2.1.1.6 
Summary of HAM-D Total Score (Change from Baseline, Response, Remission) by Study 
Visit and Age Group 
Efficacy Set 
Table 14.2.1.1.7 
Summary of HAM-D Total Score (Change from Baseline, Response, Remission) by Study 
Visit and Gender  
Efficacy Set 
Table 14.2.1.1.8 
Summary of HAM-D Total Score (Change from Baseline, Response, Remission) by Study 
Visit and Race Group 
Efficacy Set 
Table 14.2.1.2.1 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Total Score by Study 
Visit  
Efficacy Set 
Table 14.2.1.2.1a 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Total Score by Study 
Visit  
Modified Efficacy 
Set 
Table 14.2.1.2.2 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Individual Item Score 
by Study Visit 
Efficacy Set 
Table 14.2.1.2.3 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Total Score (Change 
from Baseline) by Study Visit, Anti-depressant and Mood Stabilizer Use at Baseline 
Efficacy Set 
Table 14.2.1.2.4 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Total Score (Change 
from Baseline) by Study Visit and Age Group 
Efficacy Set 
Table 14.2.1.2.5 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Total Score (Change 
from Baseline) by Study Visit and Gender 
Efficacy Set 
Table 14.2.1.2.6 
Summary of Montgomery-Asberg Depression Rating Scale (MADRS) Total Score (Change 
from Baseline) by Study Visit and Race Group 
Efficacy Set 
Table 14.2.1.3.1 
Summary of Clinical Global Impression (CGI) – Severity by Study Visit 
Efficacy Set 
Table 14.2.1.3.2 
Summary of Clinical Global Impression (CGI) – Improvement by Study Visit  
Efficacy Set 
Table 14.2.1.3.3 
Summary of Clinical Global Impression (CGI) - Improvement Response by Study Visit  
Efficacy Set 
Table 14.2.1.4.1 
Summary of Insomnia Sleep Index (ISI)  by Study Visit  
Efficacy Set 
 
  
 
 
  
 
 
 
 


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Table 14.3.1.1 
Overview of Treatment Emergent Adverse Events 
Efficacy Set 
Table 14.3.1.2.1.1 
Summary of Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
Efficacy Set 
Table 14.3.1.2.1.2 
Summary of On-Treatment Treatment Emergent Adverse Events by System Organ Class and 
Preferred Term 
Efficacy Set 
Table 14.3.1.2.1.3 
Summary of Post-Treatment Treatment Emergent Adverse Events by System Organ Class and 
Preferred Term 
Safety Set 
Table 14.3.1.2.2 
Summary of Treatment Emergent Adverse Events by System Organ Class and Preferred 
Term, and Use of Anti-Depressant and Mood Stabilizer at Baseline 
Safety Set 
Table 14.3.1.2.3 
Summary of Treatment Emergent Adverse Events by System Organ Class, Preferred Term 
and Age Group 
Safety Set 
Table 14.3.1.2.4 
Summary of Treatment Emergent Adverse Events by System Organ Class, Preferred Term 
and Gender Group  
Safety Set 
Table 14.3.1.2.5 
Summary of Treatment Emergent Adverse Events by System Organ Class, Preferred Term 
and Race Group  
Safety Set 
Table 14.3.1.2.6 
Summary of Treatment Emergent Adverse Events by System Organ Class, Preferred Term 
Modified Safety Set 
Table 14.3.1.3 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, 
and Maximum Severity 
Safety Set 
Table 14.3.1.4 
Summary of Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, 
and Relationship to Study Drug 
Safety Set 
Table 14.3.1.5 
Summary of Treatment Emergent Adverse Events Leading to Discontinuation of Study Drug 
by System Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.6 
Summary of Treatment Emergent Adverse Events leading to Withdrawal from the Study by 
System Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.7 
Summary of Treatment Emergent Serious Adverse Events by System Organ Class and 
Preferred Term 
Safety Set 
Table 14.3.1.8 
Summary of Treatment Emergent Adverse Events Leading to Dose Reduction (from 30mg to 
20 mg) 
Safety Set 
Table 14.3.1.9 
Summary of Treatment Emergent Adverse Events Leading to Dose Interruption of Study 
Drug by System Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.10 
Summary of Treatment Emergent Adverse Events by System Organ Class and Preferred 
Term, and the Last Dose Before the Onset of AE 
Safety Set 
Table 14.3.1.11 
Summary of Most Common Treatment Emergent Adverse Events by Preferred Term  
Safety Set 
Table 14.3.4.1.1 
Summary of Serum Chemistry Results by Study Visit 
Safety Set 


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Table 14.3.4.1.2 
Summary of Shift in Serum Chemistry Results During the Study 
Safety Set 
Table 14.3.4.1.3 
Summary of Potentially Clinically Significant Liver Function Tests Any Time Post-Baseline 
Safety Set 
Table 14.3.4.1.4 
Summary of Potentially Clinically Significant Serum Chemistry (excluding LFT) Results Any 
Time Post-Baseline 
Safety Set 
Table 14.3.4.2.1 
Summary of Hematology Results by Study Visit 
Safety Set 
Table 14.3.4.2.2 
Summary of Shift in Hematology Results During the Study  
Safety Set 
Table 14.3.4.2.3 
Summary of Potentially Clinically Significant Hematology Results Any Time Post-Baseline 
Safety Set 
Table 14.3.4.3.1 
Summary of Urinalysis by Study Visit – Quantitative Results  
Safety Set 
Table 14.3.4.3.2 
Summary of Urinalysis by Study Visit – Qualitative Results  
Safety Set 
Table 14.3.4.4.1 
Summary of Coagulation Results by Study Visit  
Safety Set 
Table 14.3.4.5.1 
Summary of Vital Signs by Study Visit  
Safety Set 
Table 14.3.4.5.2 
Summary of Potentially Clinically Significant Vital Signs Any Time Post-Baseline 
Safety Set 
Table 14.3.4.5.3 
Difference in Supine to Standing Vital Signs (Supine minus Standing) by Study Visit  
Safety Set 
Table 14.3.4.6.1 
Summary of ECG Data by Study Visit 
Safety Set 
Table 14.3.4.6.2 
Summary of Abnormal ECG by Investigator’s Assessment by Study Visit 
Safety Set 
Table 14.3.4.6.3 
Summary of Potentially Clinically Significant QTcF in ECG Data Any Time Post-Baseline 
Safety Set 
Table 14.3.4.7.1 
Summary of Shift from Baseline in Columbia Suicide Rating Scale (C-SSRS) Suicidal 
Ideation and Suicidal Behavior Data by Study Visit 
Safety Set 
Table 14.3.4.7.2 
Summary of Columbia-Suicide Severity Rating Scale (C-SSRS) on Suicidal Ideation and 
Suicidal Behavior Data 
Safety Set 
Table 14.3.4.7.3 
Summary of Shift from Baseline in C-SSRS Maximum Severity Score in Suicidal Ideation 
Any Time Post-Baseline 
Safety Set 
Table 14.3.4.8.1 
Summary of Young Mania Rating Scale (YMRS) Score 
Safety Set 
Table 14.3.4.8.2 
Summary of Young Mania Rating Scale (YMRS) Score by Study Visit and Use of Anti-
Depressant and Mood Stabilizer at Baseline  
Safety Set 
12.3.2 Index of Listings 
Number 
Title 
Analysis Set 
Listing 16.2.1.1 
Subject Disposition 
Safety Set 
Listing 16.2.1.2 
Premature Withdrawal from Study or Premature Discontinuation from Study Drug 
Safety Set 
Listing 16.2.1.3 
Analysis Sets 
Safety Set 


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Listing 16.2.1.4 
Protocol Deviations 
All Subjects 
Listing 16.2.1.5 
Screen Failure 
All Subjects 
Listing 16.2.2.1 
Demographics and Baseline Characteristics 
Safety Set 
Listing 16.2.3.1 
Prior and Concomitant Psychotropic Medications 
Safety Set 
Listing 16.2.3.2 
Prior and Concomitant Non-Psychotropic Medications 
Safety Set 
Listing 16.2.4.1 
Bipolar History 
Safety Set 
Listing 16.2.4.2 
History of Psychiatric Disorders (excluding Bipolar) 
Safety Set 
Listing 16.2.4.3 
Family History of Psychiatric Disorders 
Safety Set 
Listing 16.2.4.4 
Medical and Surgical History 
Safety Set 
Listing 16.2.4.5 
Concomitant Procedures 
Safety Set 
Listing 16.2.5.1 
Study Drug Administration 
Safety Set 
Listing 16.2.5.2 
Study Drug Compliance 
Efficacy Set 
Listing 16.2.6.3 
Study Drug Exposure 
Safety Set 
Listing 16.2.6.1 
Hamilton Rating Scale for Depression (HAM-D) 
Efficacy Set 
Listing 16.2.6.2 
Montgomery-Asberg Depression Rating Scale (MADRS)  
Efficacy Set 
Listing 16.2.6.3 
Clinical Global Impression (CGI) – Severity 
Efficacy Set 
Listing 16.2.6.4 
Clinical Global Impression (CGI) – Improvement     
Efficacy Set 
Listing 16.2.6.5 
Insomnia Sleep Index (ISI)  
Efficacy Set 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 16.2.7.1 
Treatment Emergent Adverse Events 
Safety Set 
Listing 16.2.7.2 
Non-fatal Serious Adverse Events  
Safety Set 
Listing 16.2.7.3 
Adverse Events Leading to Death  
Safety Set 
Listing 16.2.7.4 
Adverse Events With Onset Prior to First Dose of Study Drug  
Safety Set 
Listing 16.2.7.5 
Adverse events leading to Premature Discontinuation of Study Drug  
Safety Set 
Listing 16.2.7.6 
Adverse events leading to Premature Withdrawal from the Study 
Safety Set 


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Listing 16.2.8.1 
Serum Chemistry Data 
Safety Set 
Listing 16.2.8.2 
Hematology Data  
Safety Set 
Listing 16.2.8.3 
Urinalysis Data 
Safety Set 
Listing 16.2.8.4 
Coagulation Data  
Safety Set 
Listing 16.2.8.5 
Pregnancy Test 
Safety Set 
Listing 16.2.8.6 
Diagnostic Screening Laboratory Tests 
Safety Set 
Listing 16.2.9.1 
Vital Signs 
Safety Set 
Listing 16.2.10.1 
ECG data 
Safety Set 
Listing 16.2.11.1 
Columbia-Suicide Severity Rating Scale (C-SSRS) – Suicidal Ideation  
Safety Set 
Listing 16.2.11.2 
Columbia-Suicide Severity Rating Scale (C-SSRS) – Suicidal Behavior 
Safety Set 
Listing 16.2.12.1 
Young Mania Rating Scale (YMRS) Scores 
Safety Set 
 
12.3.3 Index of Figures 
Figure 14.2.1.1 
Mean (±SD) Change from Baseline in Hamilton Rating Scale for Depression (HAM-D) Total 
Score Over Time 
Efficacy Set 
Figure 14.2.1.2 
Mean (±SD) Change from Baseline in Montgomery-Åsberg Depression Rating Scale 
(MADRS) Total Score Over Time 
Efficacy Set