Conditions: Major Depression
Keywords: Depression
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 102
Healthy volunteers: no

Brief summary:
This is a two-part (open-label followed by double-blind) study evaluating the safety, tolerability, pharmacokinetics, and efficacy of SAGE-217 in 102 participants diagnosed with moderate to severe Major Depressive Disorder.

Detailed description:
Part A of the study is an open-label design with dosing of SAGE-217 for 14 days.

Part B of the study is a randomized, double-blind, parallel-group, placebo-controlled design. Eligible participants were randomized to SAGE-217 or placebo for 14 days.

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

Arms:
arm 1: Participants received SAGE-217, 30 milligrams (mg), oral solution, once daily for 14 days, as tolerated. arm 2: Eligible participants received matching placebo capsules once daily for 14 days. arm 3: Eligible participants received SAGE-217, 30 mg, oral capsules, once daily for 14 days.

Interventions: intervention 1: SAGE-217 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 




Protocol 217-MDD-201 
 
Sage Therapeutics 
Version 2.0 13 January 2017 
 
3 
 
 
  
 
INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for SAGE-217.  I have read the Clinical 
Protocol 217-MDD-201 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 
 


Protocol 217-MDD-201 
 
Sage Therapeutics 
Version 2.0 13 January 2017 
 
4 
 
 
  
 
CONTACTS IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Clinical Research Organization 
 
 
 
 
USA 
 
 
 


Protocol 217-MDD-201 
 
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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Sage Therapeutics 
215 First Street  
Cambridge, MA  02142 
Name of Investigational Product: 
SAGE-217 Oral Solution 
Name of Active Ingredient: 
SAGE-217  
Title of Study: A Phase 2, Two-Part (Open-Label Followed by Double-Blind) Study Evaluating the 
Safety, Tolerability, Pharmacokinetics, and Efficacy of SAGE-217 in the Treatment of Adult Subjects 
With Moderate to Severe Major Depressive Disorder 
Study centers: Approximately 3 sites in Part A and approximately 15 sites in Part B 
Phase of development: 2a 
Methodology:  
This study will assess the safety, tolerability, pharmacokinetics (PK), and efficacy of SAGE-217 Oral 
Solution in adult subjects diagnosed with moderate to severe major depressive disorder (MDD).   
There are two parts to the study: 
Part A:  Open-label dosing with SAGE-217 Oral Solution (14 days) 
All subjects will receive a 30 mg SAGE-217 Oral Solution dose administered at 8:00 PM 
(±15 minutes) with food on Day 1 to Day 14 as tolerated.   
Part B:  Randomized, double-blind, parallel-group, placebo-controlled (14 days) 
Based on the results of Part A, eligible subjects will be stratified based on use of antidepressant 
treatment (current/stable or not treated/withdrawn ≥30 days) and randomized within each stratum in a 
1:1 fashion to receive SAGE-217 Oral Solution 30 mg or matching placebo for 14 days beginning on 
Day 1 as tolerated.  All doses of study drug will be administered at 8:00 PM (±15 minutes) with food.   
Dose adjustments based on tolerability are detailed in Section 9.3.   
Separate cohorts of subjects will be enrolled in Part A and Part B; subjects participating in Part A 
cannot enroll in Part B.  Part B may be initiated and enrollment into Part A stopped if there is a clear 
signal of activity based on the 17-item Hamilton Rating Scale for Depression (HAM-D) scores and/or 
other scales being assessed.   
Both parts of the study will consist of an up to 7-day Screening Period (Days -7 to -1), a 14-day 
Treatment Period, and a 2-week Follow-up Period.  During the study Treatment Period, subjects must 
remain inpatient for the first 7 days at minimum and per Investigator’s judgement thereafter.   
Screening Period: The Screening Period begins with the signing of the informed consent form (ICF) 
at the Screening Visit, which can occur on any two consecutive calendar days of the 7-day window 
(from Day -7 through Day -1).  The diagnosis of MDD must be made according to Structured Clinical 
Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Axis I 
Disorders (SCID-I) performed by a qualified healthcare professional.  Subjects will undergo 
preliminary screening procedures at the Screening Visit to determine eligibility, including completion 
of the HAM-D, Hamilton Anxiety Rating Scale (HAM-A), Clinical Global Impression - Severity 
(CGI-S), and Montgomery-Åsberg Depression Rating Scale (MADRS).  The Screening Period 
assessments will be conducted on an outpatient basis.  Most eligibility criteria are the same for both 
parts of the study.   


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Treatment Period:  
Part A – Once subjects are confirmed as eligible, they will receive a 30 mg dose of study drug at 
8:00 PM (±15 minutes) with food for 14 days (Day 1 to Day 14) as tolerated.  Subjects who cannot 
tolerate 30 mg will receive 20 mg for the rest of the Treatment Period.  Subjects who cannot tolerate 
20 mg will be terminated from the study.  The following assessments will be performed: HAM-D, 
HAM-A, and MADRS total scores and Clinical Global Impression – Improvement (CGI-I).   
Enrollment into Part A may be stopped and Part B initiated if there is a clear signal of activity based on 
the HAM-D scores and/or other scales being assessed.  Alternatively, upon completion of Part A, 
Part B may begin.  The study may be terminated if there is clear lack of activity based on HAM-D 
scores during Part A.  Separate cohorts of subjects will be enrolled in Part A and Part B; subjects 
participating in Part A cannot enroll in Part B.   
Part B - Based on the results of Part A, eligible subjects will be stratified based on use of antidepressant 
treatment (current/stable or not treated/withdrawn ≥30 days) and randomized within each stratum to 
one of two treatment groups (SAGE-217 Oral Solution 30 mg or matching placebo) in a 1:1 ratio.  
Subjects will be administered study drug at 8:00 PM (±15 minutes) with food for 14 days.  Subjects 
who cannot tolerate 30 mg will receive 20 mg for the rest of the Treatment Period.  Subjects who 
cannot tolerate 20 mg will be terminated from the study.   
In both parts of the study, subjects may be discharged after a minimum 7-day inpatient stay, following 
completion of the Day 7 assessments.  If their clinical condition does not allow discharge, the 
Investigator may keep the subjects as inpatients for a longer period of time.   
In both parts of the study, subjects discharged from the inpatient unit may receive treatment with study 
drug for the remainder of the 14-day Treatment Periods as outpatients.  The outpatient phase treatment 
may be provided at the clinical site or, if suitable arrangements can be made, via home administration.  
Home administration of study drug will be performed according to a site-specific plan by a healthcare 
professional trained on the protocol and delivery of the study drug. 
With the exception of subjects permitted to use current stable antidepressant treatment, initiation of 
psychotropic medications and other medications that may potentially have an impact on efficacy or 
safety endpoints will not be allowed between screening and completion of the Day 15 assessments 
(Parts A and B).  Psychotropic medications, which must have been initiated at least 14 days prior to 
screening, must remain at a stable dose until completion of the Day 15 assessments (Parts A and B).   
Efficacy and safety assessments will be performed periodically during the study, and blood samples 
will be collected for analysis of SAGE-217 as outlined in the Schedule of Events (Table 2 and Table 3).  
Follow-up Period: Follow-up visits will be conducted on an outpatient basis.  Follow-up visits for 
Parts A and B will be conducted at 1 week (21±1 day) and 2 weeks (28±3 days) after the last dose of 
study drug.   
Objectives:  
Part A:  
Primary:  
The primary objective of the study is to evaluate the safety and tolerability of SAGE-217 Oral Solution 
30 mg.   
Secondary: 
The secondary objective of Part A is to determine if treatment with SAGE-217 Oral Solution 30 mg for 
14 days reduces depressive symptoms.   


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Part B:  
Primary:  
The primary objective of the study is to evaluate the safety and tolerability of SAGE-217 Oral Solution 
30 mg.   
Secondary: 
The secondary efficacy objective for Part B of the study is to determine if treatment with SAGE-217 
Oral Solution 30 mg reduces depressive symptoms in subjects with moderate to severe MDD compared 
to matching placebo.   
Endpoints: 
Part A:  
Primary:  
The primary endpoint is 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 
electrocardiograms (ECGs); Stanford Sleepiness Scale (SSS) score; physical examination; and suicidal 
ideation using the Columbia-Suicide Severity Rating Scale (C-SSRS).   
Secondary: 
Reduction in depressive symptoms as assessed by the following: 
• 
Change from baseline in HAM-D total score at all time points;  
• 
HAM-D response;  
• 
HAM-D remission;  
• 
Change from baseline in the MADRS total score at all time points; 
• 
Change from baseline in HAM-D subscale and individual item scores at all time points; and  
• 
CGI-I response. 
Part B:  
Primary:  
The primary endpoint is 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; SSS score; physical examination; and suicidal ideation using the C-SSRS.   
Secondary: 
Reduction in depressive symptoms, compared to placebo, as assessed by the following:   
• 
Change from baseline in the 17-item HAM-D total score at all time points;  
• 
HAM-D response;  
• 
HAM-D remission;  
• 
Change from baseline in the MADRS total score at all time points; 
• 
Change from baseline in HAM-D subscale and individual item scores at all time points;  
• 
CGI-I response; and 
• 
36-item short form survey (SF-36) and fatigue associated with depression (FAs-D) patient-reported 
outcome.   
Pharmacokinetic: 
The PK objective of Part A and Part B is:  
• 
To assess the PK profile of SAGE-217 Oral Solution in plasma samples.   


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Number of subjects (planned):  
Approximately ten subjects will be enrolled in Part A.  Up to 52 subjects may be randomized in Part B. 
Diagnosis and main criteria for inclusion:  
Inclusion criteria: 
1. Subject has signed an ICF prior to any study-specific procedures being performed. 
2. Subject is an ambulatory male or female between 18 and 65 years of age, inclusive. 
3. Subject is in good physical health and has no clinically significant findings, as determined by 
the Investigator, on physical examination, 12-lead ECG, or clinical laboratory tests. 
4. Subject agrees to adhere to the study requirements.   
5. Subject has a diagnosis of MDD that has been present for at least a 4-week period as diagnosed 
by SCID-I.   
6. Subject has a HAM-D total score of ≥22 at screening and Day 1 (prior to dosing).   
7. Subject has a HAM-A total score of ≥20 at screening and Day 1 (prior to dosing) (Part B only).   
8. Subject is willing to delay start of other antidepressant or antianxiety medications and any new 
pharmacotherapy regimens, including as-needed benzodiazepine anxiolytics, during the 
screening and treatment periods.   
9. Subject agrees to practice an acceptable method of highly effective birth control at screening 
and throughout study participation.  Highly effective methods of birth control include sexual 
abstinence (for males and females); vasectomy; or a condom with spermicide in combination 
with a highly effective female partner’s method (for males); and hormonal methods of 
contraception (ie, established use of oral, implantable, injectable, or transdermal hormones); 
placement of an intrauterine device; placement of an intrauterine system; and 
mechanical/barrier method of contraception (ie, condom or occlusive cap [diaphragm or 
cervical/vault cap] in conjunction with spermicide [foam, gel, film, cream, or suppository]) (for 
females). 
Exclusion criteria: 
1. Subject has a history of suicide attempt.   
2. Subject has a recent history or active clinically significant manifestations of metabolic, hepatic, 
renal, hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, 
dermatological, urogenital, neurological, or eyes, ears, nose, and throat disorders, or any other 
acute or chronic condition that, in the Investigator's opinion, would limit the subject's ability to 
complete or participate in this clinical study.   
3. Subject has a history of treatment-resistant depression, defined as persistent depressive 
symptoms despite treatment with adequate doses of antidepressants from two different classes 
for an adequate amount of time (ie, at least 4 weeks of treatment).   
4. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds.   
5. Subject has a positive pregnancy test at screening or on Day 1 prior to the start of study drug 
administration.   
6. Subject has detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV), or 
human immunodeficiency virus (HIV) antibody at screening.   
7. Subject has active psychosis per Investigator assessment.   
8. Subject has a medical history of seizures.   
9. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder.   


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10. Subject has a history of alcohol or drug dependence (including benzodiazepines) in the 
12 months prior to screening.   
11. Subject has had exposure to another investigational medication or device within 30 days prior 
to screening.   
12. Subject has been treated or randomized in this study (eg, Part A) or any other study employing 
SAGE-217 previously (ie, subject may not have received study drug and then re-enroll).   
13. Subject has had administration of psychotropics that have been initiated within 14 days prior to 
screening and/or are not being taken at a stable dose.   
14. Use of any known strong inhibitors and/or inducers of cytochrome P450 (CYP)3A4 within the 
14 days or five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, 
Seville oranges, or St. John's Wort or products containing these within 30 days prior to 
receiving the first dose of study drug.   
15. Subject has a positive drug and/or alcohol screen at screening or on Day 1 prior to dosing. 
Investigational product, dosage and mode of administration:  
SAGE-217 Oral Solution is available as a 6 mg/mL stock aqueous solution of SAGE-217 Drug 
Substance containing 40% hydroxypropyl-β-cyclodextrin (HPβCD) and 0.0025% sucralose, which is 
further diluted with Sterile Water for Injection to achieve the selected dose.   
Duration of participation:   
Part A:  Up to 38 days (14 days of treatment) 
Part B:  Up to 38 days (14 days of treatment) 
Reference therapy, dosage and mode of administration:  
Reference therapy is taste-matched placebo.   
Randomization: 
Subjects participating in Part A of the study will be administered study drug (SAGE-217 Oral Solution) 
in an open-label manner.  Subjects in Part B will be randomized within each antidepressant treatment 
stratum to receive SAGE-217 Oral Solution or matching placebo oral solution in a 1:1 ratio.  Subjects, 
clinicians, and the study team will be blinded to treatment allocation.  The pharmacist and/or 
designated pharmacy staff, who will prepare the oral solutions according to the randomization 
schedule, will be unblinded.   
Dose Adjustment for Safety/Tolerability Reasons: 
During the Treatment Period, subjects will be able to receive study drug as long as there are no 
dose-limiting safety/tolerability concerns.  Subjects who experience moderate or severe adverse events 
that according to the clinical judgement of the Investigator are related to study drug while receiving the 
30 mg dose of study drug will receive 20 mg for the remaining of the Treatment Period.  Subjects who 
experience moderate or severe related adverse events while receiving the 20 mg dose of study drug 
may not be able to continue receiving study drug based on the evaluation and clinical judgment of the 
Investigator, and may be terminated from the study.  Dosing may also be modified based on tolerability 
as assessed with SSS scores.   
Enrollment into Part A may be stopped and Part B initiated if there is a clear signal of activity based on 
the HAM-D scores and/or other scales being assessed.  The study may be terminated if there is clear 
lack of activity based on HAM-D scores during Part A.  A Data Review Team will assess the HAM-D 
and other data on an ongoing basis during Part A.   


Protocol 217-MDD-201 
 
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Inpatient Length of Stay and Discharge Instructions 
The minimum length of inpatient stay in both parts of this study is 7 days.  It is the Investigator’s 
responsibility to assess whether the subject can safely be discharged home and continue taking study 
drug administered by a healthcare professional trained on the protocol and delivery of the study drug 
for the rest of the treatment days (Days 8 to 14 for Parts A and B) or by returning to the clinic daily.  
The Investigator may decide to extend the subject’s inpatient stay to maximize safety oversight.  In 
making this assessment, the Investigator may consider not only the drug tolerability but also clinical 
factors including, but not limited to, availability of social support, transportation, severity of symptoms, 
and suicidality.   
Discharge instructions must include warnings about avoiding activities for which sedative effects of the 
study drug may impair performance, such as driving a motor vehicle and operating machinery.   
Criteria for evaluation: 
Efficacy: 
Reduction of depressive symptoms will be assessed by the change from baseline at various time points 
in HAM-D total score; HAM-D response; HAM-D remission; change from baseline in the MADRS 
total score; CGI-I response; change from baseline in HAM-D subscale and individual item scores; 
change from baseline in HAM-A total score; change from baseline in SF-36; and change from baseline 
in FAs-D.   
Pharmacokinetics: 
Plasma samples will be collected to assay for concentrations of SAGE-217.  The following PK 
parameters will be derived from the plasma concentrations (where evaluable): area under the 
concentration-time curve (AUC), AUC from time zero to infinity (AUC∞), maximum (peak) plasma 
concentration (Cmax), time at maximum (peak) plasma concentration (tmax), steady-state drug 
concentration in the plasma during oral intake (Css), and in the plasma at steady state during a dosing 
interval. 
Safety: 
The safety and tolerability of SAGE-217 Oral Solution will be evaluated by frequency, type, and 
severity of adverse events; mean changes from baseline in clinical laboratory measures, vital signs, and 
ECGs; SSS score; physical examination; and suicidal ideation using the C-SSRS during both Part A 
and Part B.   
Statistical methods: 
General 
For the purpose of all safety and efficacy analyses where applicable, baseline is defined as the last 
measurement prior to the start of study drug administration.   
Continuous endpoints will be summarized with 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.   


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Analysis Populations and Methods:  
The Safety Population (for both Part A and Part B), defined as all subjects administered study drug, 
will be used to provide descriptive summaries of safety data.  Adverse events will be classified by type, 
incidence, severity, and causality.  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, physical examinations, 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 at baseline and at each visit during the active Treatment 
Period will be listed for all subjects.  The C-SSRS listings will include behavior type and/or category 
for suicidal ideation and suicidal behavior of the C-SSRS.  Out-of-range safety endpoints may be 
categorized as low or high, where applicable.  Subjects will be summarized according to treatment 
received.   
The Efficacy Population (for both Part A and Part B), defined as all subjects in the Safety Population 
who complete at least 1 day of dosing of study drug and have at least one post-baseline efficacy 
evaluation, will be used to analyze efficacy data.  Efficacy data will be analyzed using appropriate 
descriptive statistics and pre-specified statistical methods, as well as other data presentation methods 
where applicable; subject listings will be provided for all efficacy data.  For (the open-label) Part A, 
efficacy data will be summarized descriptively.  For Part B, subjects will be analyzed according to 
randomized treatment.   
For 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, 
antidepressant use strata, assessment time point, and time point-by-treatment as explanatory variables.  
All post-baseline time points will be included in the model.  The primary comparison will be between 
SAGE-217 Oral Solution and matching placebo at the 15-day time point.  Model-based point estimates 
(ie, least squares [LS] means), 95% confidence intervals, and p-values will be reported.  An 
unstructured covariance structure will be used to model the within-subject errors.  Continuous variables 
will be analyzed using similar methods.   
Binary efficacy endpoints, including responder and remission endpoints, will be analyzed using logistic 
regression model.   
The PK Population will consist of all subjects in the Safety Population with sufficient plasma 
concentrations for PK evaluations, and will be used to summarize PK data.  PK parameters will be 
summarized using appropriate descriptive statistics and listed by subject.  The PK parameters to be 
summarized where possible will include AUC∞, Cmax, tmax, t½, and Css.   
Sample Size Calculation 
The sample size of ten subjects for Part A was selected based on clinical and not statistical 
considerations.   
For Part B, assuming a two-sided t-test at an alpha level of 0.10, a sample size of 23 subjects per group 
would provide 80% power to detect an effect size of 0.75 between the SAGE-217 Oral Solution and 
matching placebo groups with regard to the secondary efficacy outcome variable of change from 
baseline in HAM-D total score.  An effect size of 0.75 corresponds to a matching placebo-adjusted 
difference of 7.5 points in the change from baseline in HAM-D total score at 15 days with an assumed 
SD of 10 points.  By including two treatment groups and using a 1:1 randomization, a total of 
46 subjects are required.  Assuming a non-evaluability rate of 10%, up to 52 subjects will be 
randomized.   


Protocol 217-MDD-201 
Sage Therapeutics  
Version 2.0  13 January 2017 
 
12  
 
  
 
Table 2: 
Schedule of Events (Part A) 
 
Screening Period 
Open-Label Treatment Period 
Follow-up Period 
Visits 
OUTPATIENT 
INPATIENT 
INPATIENT or OUTPATIENT
a 
OUTPATIENT 
Visit Days 
D-7 to D-1 
D1* 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
D15/ 
ET 
D21 
(+1d) 
D28 
(±3d) 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Family History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCID-I 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confinement 
 
X 
(X) 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
Body Weight/Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X (wt 
only) 
X (wt 
only) 
X (wt 
only) 
Clinical Laboratory 
Assessments
b 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
Drug & Alcohol Screen
c 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test
d 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
e 
 
X 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Sample
f 
O 
 
 
 
 
 
 
 
O 
 
 
 
 
 
 
O 
 
 
Genetic Sample
g 
O 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs
h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse Oximetry 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
12-Lead ECG
i 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
C-SSRS
j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-S
k 
X 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 


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Version 2.0  13 January 2017 
 
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Screening Period 
Open-Label Treatment Period 
Follow-up Period 
Visits 
OUTPATIENT 
INPATIENT 
INPATIENT or OUTPATIENT
a 
OUTPATIENT 
Visit Days 
D-7 to D-1 
D1* 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
D15/ 
ET 
D21 
(+1d) 
D28 
(±3d) 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CGI-Ik 
 
 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
HAM-Ak 
X 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
HAM-Dk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
MADRSk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
SSS
l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Plasma PK
m 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
 
 
Study Drug 
Administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse Events 
X 
Prior/Concomitant 
Medications
n 
X 
CGI-I = Clinical Global Impression - Improvement; CGI-S – Clinical Global Impression - Severity; C-SSRS = Columbia Suicide Severity Rating Scale; D = day; ET = early 
termination; ECG = electrocardiogram; HAM-A = Hamilton Anxiety Rating Scale; HAM-D = Hamilton Rating Scale for Depression, 17-item; HIV = human immunodeficiency 
virus; MADRS = Montgomery-Åsberg Depression Rating Scale; PK = pharmacokinetic; SCID-I = Structured Clinical Interview for Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition Axis I Disorders; SSS = Stanford Sleepiness Scale 
*D1 procedures are to be completed prior to dosing 
a Outpatient visits may take place at the subject’s residence or in the clinic. 
b Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis.  Laboratory assessments are to be completed in the morning on Days 8 and 15 and 
during the follow-up visits on Day 21 and Day 28.  
c Urine toxicology for selected drugs of abuse and serum or breath test for alcohol.   
d Serum pregnancy test at screening and urine pregnancy test at Day 1 and Day 28.   
e Female subjects who prematurely discontinue will have a pregnancy test performed at the ET visit. 
f An optional blood sample for hormone and exploratory biochemistry testing, where consent is given.   
g An optional genetic sample for biomarker testing, where consent is given. 
h Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing).  Vital signs will be obtained within ±5 minutes of the scheduled 
time point through 0.5 hours after dosing and ±30 minutes of the scheduled time point from 1 hour after dosing and greater, unless the subject is asleep between the hours of 
23:00 h and 06:00 h.  From Day 1 through Day 7, vital signs will be completed at the following time points: predose, 0.25, 0.5, 1, 2, and 12 hours after dosing.  During the 
outpatient treatment period, vital signs will be completed prior to dosing and 1 hour after dosing.  Vital signs may be repeated at the discretion of the Investigator or Visiting 
Home Healthcare Provider as clinically indicated.   
i Will be performed 1 hour ±15 minutes after dosing on Days 1, 2, 7, and 14, and during the follow-up visit on Day 21. 


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j 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.   
k To be completed to be completed at 8:00 AM (±30 minutes) at each scheduled time point during the Treatment Period, and in the morning on Day 15, Day 21, and Day 28.  The 
assessment timeframe for HAM-D and HAM-A scales will refer to the past 7 days (1 week) on Screening, Day 1, Day 15/ET, Day 21, and Day 28 visits, and the past 24 hours 
on visits occurring on Days 2 through 8. 
l To be completed within ±5 minutes of the scheduled time point through 0.5 hours after dosing and ±15 minutes of the scheduled time point from 1 hour after dosing and greater, 
unless the subject is asleep between 23:00 h and 06:00 h during the inpatient treatment period.  From Day 1 through Day 7, SSS will be completed at the following time points: 
predose, 0.25, 0.5, 1, and 2 hours after dosing.  During the outpatient treatment period, SSS will be completed prior to dosing and 1 hour after dosing. 
m Plasma samples for PK analysis in Part A and Part B will be collected predose on Days 2, 3, 4, 5, and 6, predose and 0.25, 0.5, 1, 2, 10, and 12 hours postdose on Day 7 (within 
±5 minutes of the scheduled time point through 0.5 hours after dosing and ±15 minutes of the scheduled time point from 1 hour after dosing and greater), prior to discharge on 
Day 8 for subjects being discharged or 16 hours postdose for subjects remaining as inpatients, predose on Day 14, and in the morning on Day 15.  The time of study drug 
administration is time zero and all post-dosing sampling times are relative to this time.  In the event of a dose adjustment, an unscheduled PK sample should be collected just 
prior to the dose change.  Plasma samples for PK analysis will be collected per protocol and subjects may need to be awoken for sample collection.   
n To include those taken within 30 days prior to informed consent and throughout the study. 
 


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Table 3: 
Schedule of Events (Part B) 
 
Screening Period 
Double-Blind, Placebo-Controlled Treatment Period 
Follow-up Period 
Visits 
OUTPATIENT 
INPATIENT 
INPATIENT or OUTPATIENT
a 
OUTPATIENT 
Visit Days 
D-7 to D-1 
D1* 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
D15/ 
ET 
D21 
(+1d) 
D28 
(±3d) 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Family History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCID-I 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confinement 
 
X 
(X) 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
Body Weight/Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X (wt 
only) 
X (wt 
only) 
X (wt 
only) 
Clinical Laboratory 
Assessments
b 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
Drug & Alcohol Screen
c 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test
d 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
e 
 
X 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Sample
f 
O 
 
 
 
 
 
 
 
O 
 
 
 
 
 
 
O 
 
 
Genetic Sample
g 
O 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs
h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse Oximetry 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
12-Lead ECG
i 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
C-SSRS
j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Screening Period 
Double-Blind, Placebo-Controlled Treatment Period 
Follow-up Period 
Visits 
OUTPATIENT 
INPATIENT 
INPATIENT or OUTPATIENT
a 
OUTPATIENT 
Visit Days 
D-7 to D-1 
D1* 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
D15/ 
ET 
D21 
(+1d) 
D28 
(±3d) 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CGI-S
k 
X 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
CGI-Ik 
 
 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
HAM-Ak 
X 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
HAM-Dk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
MADRSk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
SF-36k 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
FAs-Dk 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
SSS
l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Plasma PK
m 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
 
 
Study Drug 
Administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse Events 
X 
Prior/Concomitant 
Medications
n 
X 
CGI-I = Clinical Global Impression - Improvement; CGI-S – Clinical Global Impression - Severity; C-SSRS = Columbia Suicide Severity Rating Scale; D = day; ET = early 
termination; ECG = electrocardiogram; FAs-D = fatigue associated with depression; HAM-A = Hamilton Anxiety Rating Scale; HAM-D = Hamilton Rating Scale for Depression, 
17-item; HIV = human immunodeficiency virus; MADRS = Montgomery-Åsberg Depression Rating Scale; PK = pharmacokinetic; SCID-I = Structured Clinical Interview for 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition Axis I Disorders; SF-36 = 36-item short form survey; SSS = Stanford Sleepiness Scale 
*D1 procedures are to be completed prior to dosing 
a Outpatient visits may take place at the subject’s residence or in the clinic. 
b Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis.  Laboratory assessments are to be completed in the morning on Days 8 and 15 and 
during the follow-up visits on Day 21 and Day 28.  
c Urine toxicology for selected drugs of abuse and serum or breath test for alcohol.   
d Serum pregnancy test at screening and urine pregnancy test at Day 1 and Day 28.   
e Female subjects who prematurely discontinue will have a pregnancy test performed at the ET visit. 
f An optional blood sample for hormone and exploratory biochemistry testing, where consent is given.   
g An optional genetic sample for biomarker testing, where consent is given. 


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h Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing).  Vital signs will be obtained within ±5 minutes of the scheduled 
time point through 0.5 hours after dosing and ±30 minutes of the scheduled time point from 1 hour after dosing and greater, unless the subject is asleep between the hours of 
23:00 h and 06:00 h.  From Day 1 through Day 7, vital signs will be completed at the following time points: predose, 0.25, 0.5, 1, 2, and 12 hours after dosing.  During the 
outpatient treatment period, vital signs will be completed prior to dosing and 1 hour after dosing.  Vital signs may be repeated at the discretion of the Investigator or Visiting 
Home Healthcare Provider as clinically indicated.   
i Will be performed 1 hour ±15 minutes after dosing on Days 1, 2, 7, and 14, and during the follow-up visit on Day 21. 
j 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.   
k To be completed at 8:00 AM (±30 minutes) at each scheduled time point during the Treatment Period, and in the morning on Day 15, Day 21, and Day 28.  The assessment 
timeframe for HAM-D and HAM-A scales will refer to the past 7 days (1 week) on Screening, Day 1, Day 15/ET, Day 21, and Day 28 visits, and the past 24 hours on visits 
occurring on Days 2 through 8. 
l To be completed within ±5 minutes of the scheduled time point through 0.5 hours after dosing and ±15 minutes of the scheduled time point from 1 hour after dosing and greater, 
unless the subject is asleep between 23:00 h and 06:00 h during the inpatient treatment period.  From Day 1 through Day 7, SSS will be completed at the following time points: 
predose, 0.25, 0.5, 1, and 2 hours after dosing.  During the outpatient treatment period, SSS will be completed prior to dosing and 1 hour after dosing. 
m Plasma samples for PK analysis in Part A and Part B will be collected predose on Days 2, 3, 4, 5, and 6, predose and 0.25, 0.5, 1, 2, 10, and 12 hours postdose on Day 7 (within 
±5 minutes of the scheduled time point through 0.5 hours after dosing and ±15 minutes of the scheduled time point from 1 hour after dosing and greater), prior to discharge on 
Day 8 for subjects being discharged or 16 hours postdose for subjects remaining as inpatients, predose on Day 14, and in the morning on Day 15.  The time of study drug 
administration is time zero and all post-dosing sampling times are relative to this time.  In the event of a dose adjustment, an unscheduled PK sample should be collected just 
prior to the dose change.  Plasma samples for PK analysis will be collected per protocol and subjects may need to be awoken for sample collection.   
n To include those taken within 30 days prior to informed consent and throughout the study. 
 
 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............18 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................23 
5. 
INTRODUCTION ......................................................................................................25 
5.1. 
Background of Major Depressive Disorders and Unmet Medical Need ....................25 
5.2. 
SAGE-217 Oral Solution ............................................................................................26 
5.3. 
Summary of Nonclinical and Clinical Experience with SAGE-217 ..........................26 
5.3.1. 
Nonclinical Studies with SAGE-217 ..........................................................................26 
. 
26 
 
28 
5.5. 
Dose Justification ........................................................................................................28 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................29 
6.1. 
Part A ..........................................................................................................................29 
6.1.1. 
Primary Objective .......................................................................................................29 
6.1.2. 
Secondary Objective ...................................................................................................29 
6.2. 
Part B ..........................................................................................................................29 
6.2.1. 
Primary Objective .......................................................................................................29 
6.2.2. 
Secondary Objective ...................................................................................................29 
6.3. 
Pharmacokinetic Objective .........................................................................................29 
6.4. 
Endpoints ....................................................................................................................29 
6.4.1. 
Part A ..........................................................................................................................29 
6.4.1.1. 
Primary .......................................................................................................................29 
6.4.1.2. 
Secondary ...................................................................................................................29 
6.4.2. 
Part B ..........................................................................................................................30 
6.4.2.1. 
Primary .......................................................................................................................30 
6.4.2.2. 
Secondary ...................................................................................................................30 
7. 
INVESTIGATIONAL PLAN .....................................................................................31 


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7.1. 
Overall Study Design ..................................................................................................31 
7.2. 
Blinding and Randomization ......................................................................................32 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................34 
8.1. 
Subject Inclusion Criteria ...........................................................................................34 
8.2. 
Subject Exclusion Criteria ..........................................................................................34 
8.3. 
Subject Withdrawal Criteria .......................................................................................35 
8.3.1. 
Study Drug Withdrawal ..............................................................................................36 
8.3.2. 
Criteria for Study Termination ...................................................................................36 
9. 
TREATMENT OF SUBJECTS ..................................................................................37 
9.1. 
Number of Subjects ....................................................................................................37 
9.2. 
Treatment Assignment ................................................................................................37 
9.2.1. 
Part A ..........................................................................................................................37 
9.2.2. 
Part B ..........................................................................................................................37 
9.3. 
Dose Adjustment Criteria ...........................................................................................37 
9.4. 
Prior/Concomitant Medications ..................................................................................38 
9.4.1. 
Prior/Concomitant Medications ..................................................................................38 
9.4.2. 
Restricted Medications ...............................................................................................38 
9.5. 
Treatment Compliance ................................................................................................39 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................40 
10.1. 
Study Drug ..................................................................................................................40 
10.2. 
Batch Formula for Stock SAGE-217 Oral Solution 6 mg/mL ...................................40 
10.3. 
Study Drug Packaging and Labeling ..........................................................................40 
10.4. 
Study Drug Storage .....................................................................................................41 
10.5. 
Administration and Study Drug Accountability .........................................................41 
10.5.1. 
Study Drug Administration.........................................................................................42 
10.5.2. 
Study Drug Accountability .........................................................................................42 
10.6. 
Study Drug Handling and Disposal ............................................................................42 
11. 
ASSESSMENT OF EFFICACY ................................................................................43 
11.1. 
Hamilton Rating Scale for Depression (HAM-D) ......................................................43 
11.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) ........................................43 
11.3. 
Hamilton Anxiety Rating Scale (HAM-A) .................................................................44 
11.4. 
Clinical Global Impression (CGI) ..............................................................................44 


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11.5. 
Short Form-36 (SF-36) ...............................................................................................45 
11.6. 
The Fatigue Associated With Depression (FAs-D) Patient-Reported 
Outcome (PRO) ..........................................................................................................45 
12. 
PHARMACOKINETICS ...........................................................................................46 
12.1. 
Blood Sample Collection ............................................................................................46 
12.2. 
Storage and Shipment of Pharmacokinetic Samples ..................................................46 
12.3. 
Sample Analysis .........................................................................................................46 
13. 
ASSESSMENT OF SAFETY .....................................................................................47 
13.1. 
Safety Parameters .......................................................................................................47 
13.1.1. 
Demographic/Medical History ...................................................................................47 
13.1.2. 
Vital Signs ..................................................................................................................47 
13.1.3. 
Weight and Height ......................................................................................................47 
13.1.4. 
Physical Examination .................................................................................................47 
13.1.5. 
Electrocardiogram (ECG) ...........................................................................................47 
13.1.6. 
Laboratory Assessments .............................................................................................47 
13.1.6.1. 
Hematology .................................................................................................................48 
13.1.6.2. 
Blood Chemistry .........................................................................................................48 
13.1.6.3. 
Urinalysis ....................................................................................................................48 
13.1.6.4. 
Hormones and Exploratory Biochemistry ..................................................................48 
13.1.6.5. 
Virus Serology ............................................................................................................48 
13.1.6.6. 
Pregnancy Test ............................................................................................................49 
13.1.6.7. 
Genetic Testing ...........................................................................................................49 
13.1.6.8. 
Drugs of Abuse and Alcohol ......................................................................................49 
13.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................49 
13.1.8. 
Stanford Sleepiness Scale (SSS) .................................................................................50 
13.2. 
Adverse and Serious Adverse Events .........................................................................50 
13.2.1. 
Definition of Adverse Events .....................................................................................50 
13.2.1.1. 
Adverse Event .............................................................................................................50 
13.2.1.2. 
Suspected Adverse Reaction .......................................................................................50 
13.2.1.3. 
Serious Adverse Event ................................................................................................50 
13.3. 
Relationship to Study Drug ........................................................................................51 
13.4. 
Recording Adverse Events .........................................................................................51 
13.5. 
Reporting Adverse Events ..........................................................................................52 


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13.6. 
Emergency Identification of Study Drug ....................................................................52 
14. 
STATISTICS ..............................................................................................................54 
14.1. 
Data Analysis Sets ......................................................................................................54 
14.1.1. 
Analysis Populations and Methods .............................................................................54 
14.2. 
Handling of Missing Data ...........................................................................................54 
14.3. 
General Considerations ...............................................................................................54 
14.4. 
Demographics and Baseline Characteristics ...............................................................54 
14.5. 
Efficacy Analyses .......................................................................................................54 
14.6. 
Safety Analyses ..........................................................................................................55 
14.6.1. 
Adverse Events ...........................................................................................................56 
14.6.2. 
Clinical Laboratory Evaluations .................................................................................56 
14.6.3. 
Physical Examinations ................................................................................................56 
14.6.4. 
Vital Signs ..................................................................................................................56 
14.6.5. 
12-Lead Electrocardiogram ........................................................................................56 
14.6.6. 
Prior and Concomitant Medications ...........................................................................56 
14.6.7. 
Columbia Suicide Severity Rating Scale ....................................................................57 
14.6.8. 
Stanford Sleepiness Scale ...........................................................................................57 
14.7. 
Pharmacokinetic Analyses ..........................................................................................57 
14.8. 
Determination of Sample Size ....................................................................................57 
14.9. 
Changes From Protocol Specified Analyses ...............................................................57 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................58 
15.1. 
Study Monitoring ........................................................................................................58 
15.2. 
Audits and Inspections ................................................................................................58 
15.3. 
Institutional Review Board (IRB) ...............................................................................59 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................60 
17. 
ETHICS ......................................................................................................................61 
17.1. 
Ethics Review .............................................................................................................61 
17.2. 
Ethical Conduct of the Study ......................................................................................61 
17.3. 
Written Informed Consent ..........................................................................................61 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................62 
18.1. 
Inspection of Records .................................................................................................62 
18.2. 
Retention of Records ..................................................................................................62 


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18.3. 
Confidentiality ............................................................................................................62 
19. 
PUBLICATION POLICY ..........................................................................................64 
20. 
LIST OF REFERENCES ............................................................................................65 
21. 
APPENDICES ............................................................................................................67 
APPENDIX 1. HAMILTON RATING SCALE FOR DEPRESSION, 17-ITEM 
(HAM-D) ....................................................................................................................68 
APPENDIX 2. MONTGOMERY-ÅSBERG DEPRESSION RATING SCALE 
(MADRS) ...................................................................................................................85 
APPENDIX 3. HAMILTON ANXIETY RATING SCALE (HAM-A) .....................................97 
APPENDIX 4. CLINICAL GLOBAL IMPRESSION–IMPROVEMENT SCALE 
(CGI-I) AND SEVERITY SCALE (CGI-S) ............................................................122 
APPENDIX 5. SHORT-FORM 36 (SF-36) ..............................................................................125 
APPENDIX 6. THE FATIGUE ASSOCIATED WITH DEPRESSION (FAS-D) 
PATIENT-REPORTED OUTCOME (PRO) ...........................................................130 
APPENDIX 7. COLUMBIA - SUICIDE SEVERITY RATING SCALE (C-SSRS)...............132 
APPENDIX 8. STANFORD SLEEPINESS SCALE (SSS) .....................................................140 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Schedule of Events (Part A) .......................................................................................12 
Table 3: 
Schedule of Events (Part B) ........................................................................................15 
Table 4: 
Abbreviations and Specialist Terms ...........................................................................23 
Table 5: 
Batch Formula for 125 mL of Stock SAGE-217 Oral Solution 6 mg/mL..................40 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 4: 
Abbreviations and Specialist Terms 
Abbreviation or Specialist Term Explanation 
AUC 
area under the concentration-time curve 
AUC∞ 
area under the concentration-time curve from time zero to infinity 
BMI 
body mass index 
CGI-I 
Clinical Global Impression - Improvement 
CGI-S 
Clinical Global Impression - Severity 
Cmax 
maximum (peak) plasma concentration 
CS 
clinically significant  
Css 
steady-state drug concentration in the plasma during oral intake 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP450 
cytochrome P450 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EP 
European Pharmacopeia 
FAs-D  
fatigue associated with depression 
GABA 
γ-aminobutyric acid 
GABAA 
γ-aminobutyric acid-ligand gated chloride channel 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HAM-A 
Hamilton Anxiety Rating Scale 
HAM-D 
17-item Hamilton Rating Scale for Depression 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HPβCD 
hydroxypropyl-β-cyclodextrin 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 


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Abbreviation or Specialist Term Explanation 
IRB 
Institutional Review Board 
MAD 
multiple-ascending dose 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDD 
major depressive disorders 
MMRM 
mixed effects model for reported measures 
MTD 
maximum tolerated dose 
n 
number 
NCS 
not clinically significant  
NF 
National Formulary 
PK 
pharmacokinetic(s) 
PPD 
postpartum depression 
SAD 
single-ascending dose 
SCID-I 
Structured Clinical Interview for DSM-5 Axis I Disorders 
SD 
standard deviation 
SF-36 
36-item short form survey 
SOC 
system organ class 
SRC 
Safety Review Committee 
SSS 
Stanford Sleepiness Scale 
TEAE 
treatment-emergent adverse event  
tmax 
time at maximum (peak) plasma concentration 
USP 
United States Pharmacopeia 
WHO 
World Health Organization 
WHO-DD 
World Health Organization-Drug Dictionary 
 


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5.
INTRODUCTION
5.1.
Background of Major Depressive Disorders and Unmet Medical
Need
World Health Organization (WHO) has identified depression as the leading cause of disability 
worldwide, and a major contributor to the overall global burden of disease 
(http://www.who.int/mediacentre/factsheets/fs369/en/).  Globally, depression has been estimated 
to affect 350 million people.  
In DSM-5, depression refers to an overarching set of diagnoses, including disruptive mood 
dysregulation disorder, major depressive disorder, persistent depressive disorder (dysthymia), 
premenstrual dysphoric disorder, substance/medication-induced depressive disorder, depressive 
disorder due to another medical condition, other specified depressive disorder, and unspecified 
depressive disorder.   
In the US, the economic burden of depression, including workplace costs, direct costs and 
suicide-related costs, was estimated to be $210.5 billion in 2010 (Greenberg 2015).  As per 
WHO statistics, over 800,000 people die due to suicide every year, and suicide is the second 
leading cause of death in 15- to 29-year-olds.  In the US, an estimated 10% to 15% of individuals 
with depression commit suicide (Angst 1999).   
Antidepressants are mainstay of pharmacological treatment for depressive disorders.  Selective 
serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic 
antidepressants, monoamine oxidase inhibitors, and other compounds that affect monoaminergic 
neurotransmission, such as mirtrazapine and bupropion, represent the major classes of 
antidepressants.  While antidepressants are widely used, large scale studies have demonstrated 
their limited efficacy.  For example, in the STAR*D trial where over 2800 patients were treated 
in “real world” settings, the HAM-D remission rate was 28% following 14 weeks of treatment 
with citalopram, a typical selective serotonin reuptake inhibitor (Trivedi 2006).  Recent studies 
have shown a number of symptoms that remain untreated, such as cognitive impairment, sleep 
disturbances and anxiety, even in patients that are in remission over a long period of time after 
treatment (Conradi 2011; Romera 2013).  A close examination of randomized placebo-controlled 
trials of antidepressants approved by the Food and Drug Administration in the treatment of both 
major or minor depressive disorders demonstrated Cohen’s d effect sizes below 0.2 and high 
placebo response rates (Kirsch 2008; Fournier 2010), emphasizing the challenges in assessing 
antidepressant drug efficacy and the unmet need in the treatment of depression.   
Converging preclinical and clinical evidence (Gerner 1981; Honig 1988; Drugan 1989; 
Luscher 2011; Mann 2014) implicates deficits in GABAergic neurotransmission in the 
pathophysiology of depressive disorders including MDD and PPD.  Furthermore, several pieces 
of experimental data implicate deficiencies in the normal regulation of endogenous neuroactive 
steroids in depressive disorders (Maguire 2008; Maguire 2009).  The neuroactive steroid class of 
compounds includes the endogenous neuroactive steroid, allopregnanolone.  Allopregnanolone is 
a positive allosteric modulator of both synaptic and extrasynaptic GABAA receptors – the 
prominent inhibitory transmitter system in the brain.  Depressed patients show low levels of 
GABA in the brain and of neurosteroids in the CSF and plasma, and antidepressant therapy 








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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Part A 
6.1.1. 
Primary Objective 
The primary objective of the study is to evaluate the safety and tolerability of SAGE-217 Oral 
Solution 30 mg.   
6.1.2. 
Secondary Objective 
The secondary objective of Part A is to determine if treatment with SAGE-217 Oral Solution 
30 mg for 14 days reduces depressive symptoms.   
6.2. 
Part B 
6.2.1. 
Primary Objective 
The primary objective of the study is to evaluate the safety and tolerability of SAGE-217 Oral 
Solution 30 mg.   
6.2.2. 
Secondary Objective 
The secondary efficacy objective for Part B of the study is to determine if treatment with 
SAGE-217 Oral Solution 30 mg reduces depressive symptoms in subjects with moderate to 
severe MDD compared to matching placebo.   
6.3. 
Pharmacokinetic Objective 
The PK objective of Part A and Part B is to assess the PK profile of SAGE-217 Oral Solution in 
plasma samples.   
6.4. 
Endpoints 
6.4.1. 
Part A 
6.4.1.1. 
Primary 
The primary endpoint is 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 electrocardiograms (ECGs); Stanford Sleepiness Scale (SSS) score; physical examination; 
and suicidal ideation using the Columbia-Suicide Severity Rating Scale (C-SSRS).   
6.4.1.2. 
Secondary 
Reduction in depressive symptoms as assessed by the following: 
• Change from baseline in HAM-D total score at all time points;  


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• HAM-D response (defined as having a 50% or greater reduction from baseline in 
HAM-D total score);  
• HAM-D remission (defined as having a HAM-D total score of ≤7);  
• Change from baseline in the Montgomery-Åsberg Depression Rating Scale 
(MADRS) total score at all time points; 
• Change from baseline in HAM-D subscale and individual item scores at all time 
points;  
• Change from baseline in Hamilton Anxiety Rating Scale (HAM-A) total score at all 
time points; and  
• Clinical Global Impression – Improvement (CGI-I) response (defined as a CGI-I 
score of “very much improved” or “much improved”).   
6.4.2. 
Part B 
6.4.2.1. 
Primary 
The primary endpoint is 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; SSS score; physical examination; and suicidal ideation using the C-SSRS.   
6.4.2.2. 
Secondary 
Reduction in depressive symptoms, compared to placebo, as assessed by the following: 
• Change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D) 
total score at all time points;  
• HAM-D response;  
• HAM-D remission;  
• Change from baseline in the MADRS total score at all time points; 
• Change from baseline in HAM-D subscale and individual item scores at all time 
points;  
• Change from baseline in HAM-A total score at all time points;  
• CGI-I response; and 
• 36-item short form survey (SF-36) and fatigue associated with depression (FAs-D) 
patient-reported outcome.   


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This study is a two-part, multicenter, Phase 2a study to evaluate the safety, tolerability, PK, and 
efficacy of SAGE-217 Oral Solution in approximately 62 adult subjects with MDD.  Part A of 
the study is an open-label design with SAGE-217 Oral Solution dosing for 14 days.  Part B of the 
study is a randomized, double-blind, parallel-group, placebo-controlled design with SAGE-217 
Oral Solution or matching placebo dosing for 14 days.  Separate cohorts of subjects will be 
enrolled in Part A and Part B; subjects participating in Part A cannot enroll in Part B.   
Parts A and B of the study will consist of an up to 7-day Screening Period (Days -7 to -1), a 
14-day Treatment Period, and a 2-week Follow-up Period (through Day 28).   
During the Screening Period (Day -7 to Day -1), after signing the informed consent form (ICF), 
subjects will be assessed for study eligibility, and the severity of each subject’s MDD will be 
evaluated using HAM-D.  The Screening Period assessments will be conducted on an outpatient 
basis.   
If applicable, standard of care data collected prior to obtaining informed consent may also be 
included as screening data, if appropriate, such as laboratory tests, ECG, physical examination, 
and vital signs conducted within the preceding 48 hours, as long as the requirement for the 
screening assessment to be collected retrospectively is met in full.  If applicable, to ensure 
protocol compliance, any standard of care data eligible for inclusion as screening data must 
include the precise nature and timing of data collection.   
During the 14-day study Treatment Period of Parts A and B, subjects must remain inpatient for 
the first 7 days at minimum and per Investigator’s judgement thereafter.  The Follow-up Period 
assessments will be conducted on an outpatient basis.   
The study will be conducted in two parts: 
• Part A:  Beginning on Day 1, subjects will receive open-label SAGE-217 Oral 
Solution at 8:00 PM (±15 minutes) with food (as outlined in Section 9.2.1).  Subjects 
will receive SAGE-217 Oral Solution 30 mg from Day 1 to Day 14 as tolerated.   
• Part B:  Based on the results of Part A, eligible subjects will be stratified based on use 
of antidepressant treatment (current/stable or not treated/withdrawn ≥30 days) and 
randomized within each stratum in a 1:1 fashion to receive SAGE-217 Oral Solution 
or matching placebo for 14 days beginning on Day 1 as tolerated.  All doses of study 
drug will be administered at 8:00 PM (±15 minutes) with food as outlined in 
Section 9.2.2.   
Enrollment into Part A may be stopped and Part B initiated if there is a clear signal of activity 
based on the HAM-D scores and/or other scales being assessed.  Alternatively, upon completion 
of Part A, Part B may begin.  The study may be terminated if there is clear lack of activity based 
on HAM-D scores during Part A.   
In Part A and Part B, study drug (SAGE-217 Oral Solution or matching placebo) will be 
administered at the study center for at least the first 7 days of the Treatment Period, which 


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includes Day 1 of study drug administration through completion of study drug administration on 
Day 14.  Subjects may be discharged after a minimum 7-day inpatient stay, following completion 
of the Day 7 assessments.  If their clinical condition does not allow discharge, the Investigator 
may keep the subjects as inpatients for a longer period of time.  Subjects discharged from the 
inpatient unit may receive treatment with study drug for the remainder of the 14-day Treatment 
Period as outpatients.  For the outpatient phase, dosing will be done at the clinical site or, if 
suitable arrangements can be made, via home administration where local regulations allow.  
Home administration of study drug will be performed according to a site-specific plan by a 
healthcare professional trained on the protocol and delivery of the study drug.   
Subjects will be monitored for safety during the Treatment and Follow-up Periods including 
monitoring for adverse events/serious adverse events, routine clinical laboratory assessments, 
physical examination, vital signs, and ECG. 
During the Treatment Period, subjects will be able to receive study drug as long as there are no 
dose-limiting safety/tolerability concerns.  Subjects who experience moderate or severe adverse 
events that according to the clinical judgement of the Investigator are related to study drug while 
receiving the 30 mg dose of study drug will receive 20 mg for the remaining of the Treatment 
Period.  Subjects who experience moderate or severe related adverse events while receiving the 
20 mg dose of study drug may not be able to continue receiving study drug based on the 
evaluation and clinical judgment of the Investigator, and may be terminated from the study.   
Dosing may also be modified based on tolerability as assessed with SSS scores.  Any SSS score 
of ≥6 will be reassessed within 10 minutes.  If a subject is receiving the 30 mg dose of study 
drug and has an SSS score of ≥6 that is confirmed on repeat assessment during normal waking 
hours, the dose will be decreased to 20 mg for the rest of the Treatment Period.  If a subject is 
receiving the 20 mg dose of study drug and has an SSS score of ≥6 that is confirmed on repeat 
assessment during normal waking hours, then study drug will be discontinued and the subject 
will be terminated from the study.   
7.2. 
Blinding and Randomization 
Part A is open-label with no control group; therefore, there will be no randomization or blinding.   
Part B is a double-blind, placebo-controlled study.  Subjects who meet the entrance criteria will 
be stratified based on use of antidepressant treatment (current/stable or not treated/withdrawn 
≥30 days) and randomly assigned within each stratum in a 1:1 ratio to receive SAGE-217 Oral 
Solution or taste-matched placebo according to a computer-generated randomization schedule.  
Once it has been determined that a subject meets eligibility criteria, the subject will be 
sequentially assigned a subject number from the randomization schedule provided to the 
unblinded pharmacist.  Subject identification numbers will consist of the site number (eg, “01”) 
followed by numbering starting with double zero (eg, 01-001, 01-002, 01-003 through 01-062).   
The randomization schedule will be generated using SAS V9.2 or later.  Only the clinic 
pharmacist or designated pharmacy staff, who is responsible for preparing the solutions, will be 
given a copy of the randomization schedule.  In the event of a medical emergency, the 
pharmacist may reveal actual solution contents to the Investigator, who should also alert Sage of 
the emergency (see Section 13.6 for more details related to unblinding).  In all cases where the 
study drug allocation for a subject is unblinded, pertinent information (including the reason for 


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unblinding) must be documented in the subject’s records and on the electronic case report form 
(eCRF).  If the subject or study center personnel (other than pharmacist) have been unblinded, 
the subject will be terminated from the study.  In addition, an unblinded Monitor will perform 
drug accountability during the study.   


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
The following inclusion criteria must be met for individuals to be eligible for the study.   
1. Subject has signed an ICF prior to any study-specific procedures being performed. 
2. Subject is an ambulatory male or female between 18 and 65 years of age, inclusive. 
3. Subject is in good physical health and has no clinically significant findings, as 
determined by the Investigator, on physical examination, 12-lead ECG, or clinical 
laboratory tests. 
4. Subject agrees to adhere to the study requirements.   
5. Subject has a diagnosis of MDD that has been present for at least a 4-week period as 
diagnosed by Structured Clinical Interview for Diagnostic and Statistical Manual of 
Mental Disorders, Fifth Edition (DSM-5) Axis I Disorders (SCID-I).   
6. Subject has a HAM-D total score of ≥22 at screening and Day 1 (prior to dosing).   
7. Subject has a HAM-A total score of ≥20 at screening and Day 1 (prior to dosing) (Part B 
only).   
8. Subject is willing to delay start of other antidepressant or antianxiety medications and 
any new pharmacotherapy regimens, including as-needed benzodiazepine anxiolytics, 
during the screening and treatment periods.   
9. Subject agrees to practice an acceptable method of highly effective birth control at 
screening and throughout study participation.  Highly effective methods of birth control 
include sexual abstinence (for males and females); vasectomy; or a condom with 
spermicide in combination with a highly effective female partner’s method (for males); 
and hormonal methods of contraception (ie, established use of oral, implantable, 
injectable, or transdermal hormones); placement of an intrauterine device; placement of 
an intrauterine system; and mechanical/barrier method of contraception (ie, condom or 
occlusive cap [diaphragm or cervical/vault cap] in conjunction with spermicide [foam, 
gel, film, cream, or suppository]) (for females).   
8.2. 
Subject Exclusion Criteria 
Subjects will be excluded if they meet any of the following exclusion criteria.   
1. Subject has a history of suicide attempt.   
2. Subject has a recent history or active clinically significant manifestations of metabolic, 
hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, 
musculoskeletal, dermatological, urogenital, neurological, or eyes, ears, nose, and throat 
disorders, or any other acute or chronic condition that, in the Investigator's opinion, 
would limit the subject's ability to complete or participate in this clinical study.   


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3. Subject has a history of treatment-resistant depression, defined as persistent depressive 
symptoms despite treatment with adequate doses of antidepressants from two different 
classes for an adequate amount of time (ie, at least 4 weeks of treatment).   
4. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds.   
5. Subject has a positive pregnancy test at screening or on Day 1 prior to the start of study 
drug administration.   
6. Subject has detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV), 
or human immunodeficiency virus (HIV) antibody at screening. 
7. Subject has active psychosis per Investigator assessment.   
8. Subject has a medical history of seizures.   
9. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder.   
10. Subject has a history of alcohol or drug dependence (including benzodiazepines) in the 
12 months prior to screening.   
11. Subject has had exposure to another investigational medication or device within 30 days 
prior to screening.   
12. Subject has been treated or randomized in this study (eg, Part A) or any other study 
employing SAGE-217 previously (ie, subject may not have received study drug and then 
re-enroll).   
13. Subject has had administration of psychotropics that have been initiated within 14 days 
prior to screening and/or are not being taken at a stable dose.   
14. Use of any known strong inhibitors and/or inducers of CYP3A4 within the 14 days or 
five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, Seville 
oranges, or St. John's Wort or products containing these within 30 days prior to receiving 
the first dose of study drug.   
15. Subject has a positive drug and/or alcohol screen at screening or on Day 1 prior to 
dosing. 
8.3. 
Subject Withdrawal Criteria 
If there is an adverse event or medical reason for the withdrawal, the subject should be followed 
medically until the condition has either resolved or is stable.  Details of the reason for 
withdrawal should be recorded in the subject’s eCRF.   
Subjects who withdraw should, if possible, have a follow-up examination, including a physical 
examination, the appropriate investigations, vital signs, and clinical laboratory tests (including 
pregnancy tests), as outlined for the Day 15 visit (Table 2 and Table 3).  All details of this 
follow-up examination should be recorded in the subject’s medical source documents.   


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8.3.1. 
Study Drug Withdrawal 
Participation in the study is strictly voluntary.  Subjects are free to discontinue the study at any 
time without giving their reason(s).   
A subject must be withdrawn from the study treatment in the event of any of the following: 
• Withdrawal of the subject’s consent; 
• New onset of a condition that would have met exclusion criterion, is clinically 
relevant and affects the subject’s safety, and discontinuation is considered necessary 
by the Investigators and/Sponsor; 
• Occurrence of intolerable adverse events;  
• Occurrence of pregnancy;  
• Intake of nonpermitted concomitant medication; 
• Subject noncompliance;  
• Significant protocol deviation determined in consultation with the Medical Monitor. 
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.   
Subjects may be withdrawn from the study if there is concern for the subject’s safety or it is 
determined that the subject is no longer a qualified participant.  Subjects who withdraw should, if 
possible, have a follow-up examination, including a physical examination, the appropriate 
investigations, vital signs, and clinical laboratory tests (including pregnancy tests), as outlined 
for the Day 15 visit (Table 2 and Table 3).  All details of this follow-up examination should be 
recorded in the subject’s medical source documents.   
Subjects who withdraw or are withdrawn from the study will be replaced only if they withdraw 
prior to dosing.  Subjects who are withdrawn from the study, fail to return or are no longer 
qualified will not be replaced.   
8.3.2. 
Criteria for Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons, including the occurrence of adverse events or other findings suggesting unacceptable 
risk to subjects, or for administrative reasons.  In the event of study termination, Sage 
Therapeutics will provide written notification to the Investigator.  Investigational sites must 
promptly notify their Institutional Review Board (IRB) and initiate withdrawal procedures for 
participating subjects.   
 
 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Number of Subjects 
Approximately ten subjects with MDD will be enrolled into Part A of the study.  Up to 
52 subjects may be randomized in Part B to ensure at least 46 evaluable subjects for Part B.  
Evaluable subjects are defined as those subjects receiving study drug with at least one post-
baseline HAM-D assessment.   
9.2. 
Treatment Assignment 
Study drug will be administered with food in both the inpatient and outpatient treatment periods.  
Food intake will be standardized as specified by the Sponsor.   
9.2.1. 
Part A 
Subjects participating in Part A of the study will take study drug (SAGE-217) in an open-label 
manner.  Subjects will be administered a 30 mg dose of study drug at 8:00 PM (±15 minutes) 
with food for 14 days (Day 1 to Day 14) as tolerated.   
9.2.2. 
Part B 
Subjects participating in the randomized, double-blind, placebo-controlled portion of the study 
(Part B) will be randomly assigned to receive SAGE-217 Oral Solution 30 mg or matching 
placebo solution on a 1:1 basis according to a computer-generated randomization schedule; the 
randomization schedule will be stratified to allow for treatment balance within each use of 
antidepressant stratum.   
Subjects, clinicians, and study team will be blinded to treatment allocation.  The pharmacist, who 
will prepare the oral solutions according to the randomization schedule, and an unblinded 
Monitor, who will perform drug accountability during the study, will be unblinded.  
9.3. 
Dose Adjustment Criteria 
During the Treatment Period, subjects will be able to receive study drug as long as there are no 
dose-limiting safety/tolerability concerns.   
In both Part A and Part B, subjects who experience moderate or severe adverse events that 
according to the clinical judgement of the Investigator are related to study drug while receiving 
the 30 mg dose of study drug will receive 20 mg for the remaining of the Treatment Period.  
Subjects who experience moderate or severe related adverse events while receiving the 20 mg 
dose of study drug may not be able to continue receiving study drug based on the evaluation and 
clinical judgment of the Investigator, and may be terminated from the study.   
Dosing may also be modified based on tolerability as assessed with SSS scores.  Any SSS score 
of ≥6 will be reassessed within 10 minutes.  If a subject is receiving the 30 mg dose of study 
drug and has an SSS score of ≥6 that is confirmed on repeat assessment during normal waking 
hours, the dose will be decreased to 20 mg for the rest of the Treatment Period.  If a subject is 
receiving the 20 mg dose of study drug and has an SSS score of ≥6 that is confirmed on repeat 


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assessment during normal waking hours, then study drug will be discontinued and the subject 
will be terminated from the study.   
Enrollment into Part A may be stopped and Part B initiated if there is a clear signal of activity 
based on the HAM-D scores and/or other scales being assessed.  The study may be terminated if 
there is clear lack of activity based on HAM-D scores during Part A.  A Data Review Team will 
assess the HAM-D and other data on an ongoing basis during Part A.   
9.4.
Prior/Concomitant Medications 
9.4.1.
Prior/Concomitant Medications 
Subjects will receive standard of care for adult patients diagnosed with moderate to severe MDD. 
Psychotropic medications, which must have been initiated at least 14 days prior to screening, 
must remain at a stable dose until completion of the Day 15 assessments (Parts A and B).   
Eligible subjects will be stratified based on use of antidepressant treatment (current/stable or not 
treated/withdrawn ≥30 days) and randomly assigned within each stratum in a 1:1 ratio to receive 
SAGE-217 Oral Solution or taste-matched placebo.   
In this study, psychotropic medications refer to central nervous system active medications taken 
to help depressive symptoms, and include antidepressants, benzodiazepines, and hypnotic agents. 
Subjects presenting to the study on antidepressants may be eligible to participate if they have 
been on a stable dose for at least 14 days.  Those subjects on benzodiazepines and hypnotic 
agents may be considered for eligibility based on specific discussions between the Investigator 
and the Sponsor to ensure safety.  Subjects on other psychotropic medications, including 
stimulants, antipsychotics, and mood stabilizers, are not eligible to participate in this study.   
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 
Section 9.4.2.  In both Part A and Part B, all medications should be documented throughout the 
study from 30 days prior to signing the ICF through Day 28 (±3 days) and recorded on the eCRF. 
Prior medications (ie, those taken prior to signing of ICF) that required washout for study entry 
will also be documented.   
9.4.2. 
Restricted Medications 
Restrictions on specific classes of medications include the following: 
•
Initiation of new antidepressant therapy is prohibited upon admission to the study
center for those eligible subjects who desire study participation.  Those subjects
already taking an antidepressant at the time of study entry (and meeting all study
inclusion criteria) will be permitted to remain on the pre-existing antidepressant at
their current dose if they were on this medication for at least 14 days prior to study
enrollment.
•
Benzodiazepines are to be avoided as much as possible.  Eligible subjects taking a
stable dose of benzodiazepine for at least 14 days prior to the study will be discussed
on a case-by-case basis with the Sponsor to determine eligibility.  Subjects may be
permitted to continue to take their current dose of the benzodiazepine (to prevent


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acute withdrawal), but no new benzodiazepine use will be permitted during the course 
of the study.   
• The use of hypnotics for sleep/insomnia such as Ambien® and trazodone is to be 
avoided; use of hypnotics will be discussed on a case-by-case basis with the Sponsor.   
• Anticonvulsants and atypical antipsychotics are prohibited.   
9.5. 
Treatment Compliance 
Investigational product will be prepared by the site pharmacist.  The Investigator(s) or designee 
will record the time and dose of study drug administration in the source documents.  Any reasons 
for noncompliance will also be documented, including: 
• Missed visits;  
• Interruptions in the schedule of administration; and 
• Nonpermitted medications. 
The time at which study procedures are conducted should follow the protocol timelines as 
closely as possible.   
 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT
10.1. 
Study Drug 
SAGE-217 Oral Solution is available as a 6 mg/mL stock aqueous solution of SAGE-217 Drug 
Substance containing 40% HPβCD and 0.0025% sucralose, which is further diluted with Sterile 
Water for Injection to achieve the selected dose.  The 6 mg/mL stock SAGE-217 Oral Solution 
will be compounded from SAGE-217 Drug Substance Powder in the Bottle and Excipient (s) in 
the Bottle (manufactured under current Good Manufacturing Practice [GMP] conditions  
) and further admixed at the clinical site in preparation for dosing.   
A matching placebo oral solution will be prepared for administration without the active 
ingredient, but including the HPβCD and sucralose, as well as three taste-masking components to 
preserve the blinding.  Detailed instructions for study drug (SAGE-217 Oral Solution 30 mg and 
matching placebo) preparation will be provided in the Pharmacy Manual.   
10.2. 
Batch Formula for Stock SAGE-217 Oral Solution 6 mg/mL 
Each bottle of SAGE-217 Oral Solution 6 mg/mL will be compounded at the clinical pharmacy 
from components manufactured 
 and supplied by the Sponsor per the directions 
provided in the Pharmacy Manual.  The batch formula for a 125 mL solution of the 6 mg/mL 
stock solution is shown in Table 5.   
Table 5: 
Batch Formula for 125 mL of Stock SAGE-217 Oral Solution 6 mg/mL 
Ingredient 
Compendia Specification Concentration (mg/mL) 
Amount (mg/Bottle) 
SAGE-217 
not applicable 
6 
750 
HPβCD
USP/EP 
457 
57,100 
Sucralose 
USP/NF 
0.025 
3.124 
Water for Injection 
USP 
not applicable 
85,650 
Abbreviations:  EP = European Pharmacopeia; HPβCD = hydroxypropyl-β-cyclodextrin; NF = National Formulary; 
USP = United States Pharmacopeia 
Additional excipients will be utilized in matching placebo to match the taste of SAGE-217 Oral 
Solution.  They include sucrose octaacetate, tannic acid, and ammonium glycyrrhizate.  The 
quantities of these excipients will vary depending on the dose of SAGE-217 to match the taste of 
each individual dose.   
10.3. 
Study Drug Packaging and Labeling 
The composition and pharmaceutical quality of the investigational product will be maintained 
according to the current GMP and Good Clinical Practice (GCP) guidelines and available for 
review in the study medication documentation.  Study drug will be provided to the site as powder 
in the bottle and excipient(s) in the bottle units to be compounded in the pharmacy at a volume of 
125 mL of a 6 mg/mL stock solution and then further diluted to approximately 40 mL at the 
identified doses.  The taste-matching excipients will be provided to the clinical pharmacies via 


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suitable suppliers or can be ordered directly by the clinical pharmacies.  Study drug labels with 
all required information and conforming to all applicable Code of Federal Regulations and 
GMP/GCP guidelines will be prepared by the clinical research organization.   
10.4. 
Study Drug Storage 
Upon receipt of study drug, the Investigator or designee will inspect the materials and complete 
and return the acknowledgment of receipt form enclosed with the parcel.  A copy of the signed 
receipt will be kept in the study files.  
The study drug materials must be carefully stored at the temperature specified in the Pharmacy 
Manual (eg, clinical dosing solutions stored at approximately 2 to 8°C for 11 days with room 
temperature excursions allowed for up to 24 hours after preparation), safely and separately from 
other drugs.  The study drug may not be used for any purpose other than the present study.  After 
the study is completed, all unused study drug must be retained, returned as directed, or destroyed 
on site per the Sponsor’s instructions.   
The Investigator or designee will be responsible for ensuring appropriate storage, compounding, 
dispensing, inventory, and accountability of all clinical supplies.  An accurate, timely record of 
the disposition of all clinical supplies must be maintained.  The supplies and inventory must be 
available for inspection by the designated representatives of the Sponsor or the Sponsor’s 
representatives on request, and must include the information below: 
• The identification of the subject to whom the drug was dispensed; 
• The date(s) and quantity of the drug dispensed to the subject; and 
• The product lot/batch number. 
The preparation of the study drugs must be documented on a ‘Drug Preparation and Dispensing 
Log Form’ or similar form. 
The drug inventory and any clinical supplies that have been destroyed must be documented.  
This documentation must include at least the information below or as agreed with the Sponsor: 
• The number of prepared units; 
• The number of administered units; 
• The number of unused units; 
• The number of units destroyed at the end of the study; 
• The date, method, and location of destruction. 
10.5. 
Administration and Study Drug Accountability 
Doses will be prepared as an approximate 40 mL oral solution to be swallowed all at once, 
followed by approximately 200 mL of water that has been used to rinse the dosing bottle.  The 
start time of swallowing the approximately 40 mL oral solution is time zero for all assessments.  
Subjects may have assistance from the clinic staff when taking the study drug.   


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10.5.1. 
Study Drug Administration 
While confined in the clinical unit (at least Day 1 through Day 7 of Part A and Part B), subjects 
will receive study drug at 8:00 PM (±15 minutes) with food.   
Food intake will be standardized as specified by the Sponsor.  Subjects who experience moderate 
or severe related adverse events while receiving study drug may not be able to continue receiving 
study drug based on the evaluation and clinical judgment of the Investigator, and may be 
terminated from the study.   
Subjects may be discharged after a minimum 7-day inpatient stay, following completion of the 
Day 7 assessments.  If their clinical condition does not allow discharge, the Investigator may 
keep the subjects as inpatients for a longer period of time.   
For non-confinement days (Days 8 through 14 of Parts A and B), dosing will be done at the 
clinical site or, if suitable arrangements can be made, via home administration where local 
regulations allow.  Home administration of study drug will be performed according to a site-
specific plan by a healthcare professional trained on the protocol and delivery of the study drug.   
10.5.2. 
Study Drug Accountability 
The study drug provided is for use only as directed in this protocol.   
The Investigator or designee must maintain a record of all study drug received, used, and 
discarded.  It must be clear from the records which subject received which dose of active or 
matching placebo treatment.   
The Sponsor 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.  Only unblinded personnel will be able to access the study drug and 
accountability documentation from first dosing through database hard lock.   
10.6. 
Study Drug Handling and Disposal 
The pharmacist or designee for drug accountability is to document the date and time of initial 
compounding, subsequent admixture of dosing solutions, administration of test article, and for 
which subject the study drug was intended (ie, record subject initials and birth date or other 
unique identifier).   
At the end of the study, any unused study drug will be retained or returned to the Sponsor for 
destruction or destroyed locally per the Sponsor’s directions.  The disposition of study drug will 
be documented.   


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11. 
ASSESSMENT OF EFFICACY 
11.1. 
Hamilton Rating Scale for Depression (HAM-D) 
The primary outcome measure in Part B will be the change from baseline in 17-item HAM-D 
total score at the end of the Treatment Period (Day 15).  The HAM-D will be administered 
before, during, and after the administration of open-label (Part A) and blinded (Part B) study 
drug.   
The 17-item HAM-D will be used to rate the severity of depression in subjects who are already 
diagnosed as depressed (Williams 2013a; Williams 2013b).  The 17-item HAM-D comprises 
individual ratings related to the following symptoms: depressed mood (sadness, hopeless, 
helpless, worthless), feelings of guilt, suicide, insomnia (early, middle, late), work and activities, 
retardation (slowness of thought and speech; impaired ability to concentrate; decreased motor 
activity), agitation, anxiety (psychic and somatic), somatic symptoms (gastrointestinal and 
general), genital symptoms, hypochondriasis, loss of weight, and insight.  The HAM-D 
assessments are to be completed at 8:00 AM (±30 minutes) at each scheduled time point during 
the Treatment Period, and in the morning on Day 15, Day 21, and Day 28.  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.  Item 16 
can be rated according to history (item 16A) or actual weight change (item 16B).  The item 16 
score is calculated as the item 16 response that is not equal to 3 (ie, “Not assessed”).   
In addition to the primary efficacy endpoint of change from baseline in HAM-D total score 
(Part B), 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.  A copy of the HAM-D is 
provided in Appendix 1.   
11.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item diagnostic questionnaire that psychiatrists use to measure the severity 
of depressive episodes in subjects with mood disorders.  It was designed as an adjunct to the 
HAM-D that would be more sensitive to the changes brought on by antidepressants and other 
forms of treatment than the Hamilton Scale.   
The MADRS assessments are to be completed at 8:00 AM (±30 minutes) at each scheduled time 
point during the Treatment Period, and in the morning on Day 15, Day 21, and Day 28.   
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 questionnaire includes questions on the following symptoms:   
1. Apparent sadness  
2. Reported sadness  


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3. Inner tension  
4. Reduced sleep  
5. Reduced appetite  
6. Concentration difficulties  
7. Lassitude  
8. Inability to feel  
9. Pessimistic thoughts  
10. Suicidal thoughts 
The MADRS total score will be calculated as the sum of the 10 individual item scores.  A copy 
of the MADRS is provided in Appendix 2.   
11.3. 
Hamilton Anxiety Rating Scale (HAM-A) 
The 14-item HAM-A will be used to rate the severity of symptoms of anxiety (Williams 2013c; 
Williams 2013d).  Each of the 14 items is defined by a series of symptoms, and measures both 
psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical 
complaints related to anxiety).  Scoring for HAM-A is calculated by assigning scores of 0 (not 
present) to 4 (very severe), with a total score range of 0 to 56, where <17 indicates mild severity, 
18 to 24 mild to moderate severity, and 25 to 30 moderate to severe severity.   
The HAM-A assessments are to be completed at 8:00 AM (±30 minutes) at each scheduled time 
point during the Treatment Period, and in the morning on Day 15, Day 21, and Day 28.  Every 
effort should be made for the same rater to perform all HAM-A assessments for an individual 
subject.   
The HAM-A total score will be calculated as the sum of the 14 individual item scores.  A copy of 
the HAM-A is provided in Appendix 3.   
11.4. 
Clinical Global Impression (CGI) 
The CGI is a validated measure often utilized in clinical trials to allow clinicians to integrate 
several sources of information into a single rating of the subject’s condition.  The CGI scale 
consists of 3 items.  Only the first 2 items are being used in this study.   
The 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 (Busner 2007a).  The CGI-S assessments are to be completed at 8:00 AM (±30 
minutes) at each scheduled time point during the Treatment Period, and in the morning on 
Day 15, Day 21, and Day 28.   
The CGI-I employs a 7-point Likert scale to measure the overall improvement in the subject’s 
condition posttreatment.  The Investigator will rate the subject’s total improvement whether or 


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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.”  The CGI-I assessments are to be completed at 8:00 AM (±30 minutes) at 
each scheduled time point during the Treatment Period, and in the morning on Day 15, Day 21, 
and Day 28.  A copy of the CGI is provided in Appendix 4.   
11.5. 
Short Form-36 (SF-36) 
The SF-36® Health Survey is a subject-reported 36-item instrument for measuring functional 
health and well-being in eight dimensions (physical functioning, role physical, bodily pain, 
general health, vitality, social functioning, role emotional, and mental health) (Ware 2007).  
Scores are provided for each of the eight dimensions and are totaled into a Physical Component 
Summary and a Mental Component Summary.  Higher SF-36 scores indicate a better state of 
health.  The SF-36 requires approximately 10 minutes to complete, and can be self-administered 
or completed by interview in person or by telephone.  In Part B, the SF-36 assessments are to be 
completed at 8:00 AM (±30 minutes) at each scheduled time point during the Treatment Period, 
and in the morning on Day 15, Day 21, and Day 28.   
A copy of the SF-36 is provided in Appendix 5.   
11.6. 
The Fatigue Associated With Depression (FAs-D) Patient-Reported 
Outcome (PRO) 
Fatigue is one of the most common symptoms of MDD.  The Fatigue Associated with 
Depression Questionnaire (FAs-D) was developed to assess fatigue and its impact in patients 
with MDD.  The 13-item patient-reported questionnaire was designed to assess fatigue 
associated with depression in the past week.  Three scores are computed: a six-item fatigue 
experience subscale (fatigued, tired, exhausted, lack of energy, physically weak, and feeling like 
everything requires too much effort), a seven-item fatigue impact subscale (impact on household 
chores; family relationships; enjoyable activities; social activities with friends; self-care; intimate 
relationships; and productivity at work or school), and a total score (all 13 items) (Matza 2015).  
Items 12 (impact on intimate relationships) and 13 (impact on productivity at work or school) are 
not applicable to all subjects, so these items are not answered in some cases.  The fatigue 
experience items are rated on a five-point scale with response options of “never,” “rarely,” 
“sometimes,” “often,” and “always.”  The impact items are rated on a five-point scale with 
response options of “not at all,” “a little,” “somewhat,” “quite a bit,” and “very much.”  The two 
subscales and the total score are computed as the mean of all answered items within each scale, 
and each scale score has a possible range of 1 to 5, with higher scores representing greater 
fatigue.  In Part B, the FAs-D assessments are to be completed at 8:00 AM (±30 minutes) at each 
scheduled time point during the Treatment Period, and in the morning on Day 15, Day 21, and 
Day 28.   
A copy of the FAs-D is provided in Appendix 6.   


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12. 
PHARMACOKINETICS 
12.1. 
Blood Sample Collection 
Plasma samples for PK analysis in Part A and Part B will be collected predose on Days 2, 3, 4, 5, 
and 6, predose and 0.25, 0.5, 1, 2, 10, and 12 hours postdose on Day 7 (within ±5 minutes of the 
scheduled time point through 0.5 hours after dosing and ±15 minutes of the scheduled time point 
from 1 hour after dosing and greater), prior to discharge on Day 8 for subjects being discharged 
or 16 hours postdose for subjects remaining as inpatients, predose on Day 14, and in the morning 
on Day 15.  The time of study drug administration is time zero and all post-dosing sampling 
times are relative to this time.  The Investigator or designee will arrange to have the plasma 
samples processed, stored, and transported as directed for bioanalysis.   
In the event of a dose adjustment, an unscheduled PK sample should be collected just prior to the 
dose change.  An additional PK sample may be collected at any time if clinically indicated and at 
the discretion of the Investigator (eg, for unusual or severe adverse events).   
Each sample will be marked with unique identifiers such as the study number, subject number, 
and the nominal sample time.  The date and actual time that the blood sample was taken will be 
recorded on the CRF or electronically with a bar code or other method.   
12.2. 
Storage and Shipment of Pharmacokinetic Samples 
The plasma samples should be kept frozen at approximately -70 to -80°C until analyzed.  They 
should be packed as directed to avoid breakage during transit and with sufficient dry ice to 
prevent thawing for at least 72 hours.  A specimen-identification form must be completed and 
sent to the laboratory with each set of samples.  The clinical site will arrange to have the plasma 
samples transported as directed for bioanalysis as detailed in the PK instructions.   
12.3. 
Sample Analysis 
Bioanalysis of plasma samples for the determination of SAGE-217 will be performed utilizing a 
validated liquid chromatography-tandem mass spectrometry method at a qualified laboratory.   
 


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13. 
ASSESSMENT OF SAFETY 
13.1. 
Safety Parameters 
Safety and tolerability of study drug will be evaluated in Parts A and B by vital signs 
measurements, clinical laboratory measures, physical examination, ECGs, concomitant 
medication usage, C-SSRS, SSS, and adverse event reporting.   
13.1.1. 
Demographic/Medical History 
Age, race, and ethnic origin will be recorded at the Screening visit.  The diagnosis of MDD will 
be determined using the SCID-I.   
13.1.2. 
Vital Signs 
Vital signs include respiratory rate, oral temperature, and supine (for at least 5 minutes prior to 
the measurement) and standing systolic and diastolic blood pressure and heart rate.  Vital signs 
will be obtained within ±5 minutes of the scheduled time point through 0.5 hours after dosing 
and ±30 minutes of the scheduled time point from 1 hour after dosing and greater, unless the 
subject is asleep between the hours of 23:00 h and 06:00 h.   
From Day 1 through Day 7, vital signs and pulse oximetry will be performed at screening (vital 
signs only) and at the following time points: predose, 0.25, 0.5, 1, 2, and 12 hours after dosing.  
During the outpatient treatment period, vital signs will be completed prior to dosing and 1 hour 
after dosing.  Vital signs may be repeated at the discretion of the Investigator or Visiting Home 
Healthcare Provider as clinically indicated.   
13.1.3. 
Weight and Height 
Body weight and height will be measured at the Screening visit; weight will also be measured on 
in the morning on Day 15, and during the follow-up visits on Days 21 and 28.   
13.1.4. 
Physical Examination 
A physical examination of all major body systems will be undertaken and recorded at the 
Screening visit, Day 8, Day 15, and Day 21, with a brief physical examination on Day 28.   
13.1.5. 
Electrocardiogram (ECG) 
A 12-lead ECG will be assessed at the Screening visit and 1 hour ±15 minutes after dosing on 
Days 1, 2, 7, and 14 and during the follow-up visit on Day 21.  All time points are relative to the 
time of dosing.  The standard intervals as well as any abnormalities will be recorded.   
13.1.6. 
Laboratory Assessments 
Blood and urine samples will be collected for hematology, serum chemistry, coagulation, select 
hormone parameters, and urinalysis at the Screening visit, and in the morning on Days 8 and 15 
and during the follow-up visits on Days 21 and 28.  Where consent is given, an optional blood 
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Day 8 and Day 15 and an optional genetic sample for biomarker testing will be collected at the 
Screening visit.   
Serum and urine samples for pregnancy tests will also be collected.  These assessments should be 
performed as outlined below.   
All required samples in Part A will be analyzed at local laboratories.  All samples in Part B will 
be analyzed at the central laboratory.  Subjects may be considered eligible for the study based on 
local laboratory results; however, screening samples in Part B must also be sent to the central 
laboratory.   
All clinical laboratory test results outside the reference range will be interpreted by the 
Investigator as abnormal, not clinically significant (NCS) or abnormal, clinically significant 
(CS).  Screening results considered abnormal, CS recorded at the Screening visit may make the 
subject ineligible for the study pending review by the Medical Monitor.  Clinical laboratory 
results that are abnormal, CS during the study but within normal range at baseline and/or indicate 
a worsening from baseline will be considered adverse events, assessed according to 
Section 13.2.1, and recorded in the eCRF.   
13.1.6.1. Hematology 
Hematology tests will include complete blood count, including red blood cells, white blood cells 
with differentiation, hemoglobin, hematocrit, reticulocytes, and platelets.  The coagulation panel 
will include activated partial thromboplastin time, prothrombin time, and international 
normalized ratio.   
13.1.6.2. Blood Chemistry 
Serum chemistry tests will include serum electrolytes; renal function tests, including creatinine, 
blood urea nitrogen, bicarbonate or total carbon dioxide; liver function tests, including alkaline 
phosphatase, total bilirubin, aspartate aminotransferase, and alanine aminotransferase; total 
protein; albumin; and thyroid stimulating hormone.   
13.1.6.3. Urinalysis 
Urinalysis will include assessment of protein, blood, glucose, ketones, bile, urobilinogen, 
hemoglobin, leukocyte esterase, nitrites, color, turbidity, pH, and specific gravity.   
13.1.6.4. Hormones and Exploratory Biochemistry 
Optional blood samples will be collected and may be analyzed for stress hormone levels, 
kynurenine biochemistry, and markers of inflammation.  Future research may suggest other 
biochemical pathways as candidates for influencing not only response to SAGE-217 but also 
susceptibility to disorders for which SAGE-217 may be evaluated.  Thus, the exploratory 
biochemistry may involve study of additional unnamed molecular pathways, but only as related 
to disease susceptibility and drug action.   
13.1.6.5. Virus Serology 
Subjects will be screened for hepatitis (HBsAg and anti-HCV) and HIV prior to being enrolled in 
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13.1.6.6. Pregnancy Test 
Females of childbearing potential will be tested for pregnancy by serum pregnancy test at the 
Screening visit and by urine pregnancy test on Day 1 (predose) and at the follow-up visit on 
Day 28.  In addition, female subjects who prematurely discontinue before Day 28 will have a 
pregnancy test performed at the early termination visit. 
13.1.6.7. Genetic Testing 
Where consent is given, an optional genetic sample for biomarker testing will be collected at the 
Screening visit.   
The objective of this research is to collect and store blood samples for possible DNA extraction 
and exploratory research into how genes or specific genetic variation may influence response (ie, 
distribution, safety, tolerability, and efficacy) to SAGE-217.  Specific genetic variations of 
interest include but are not limited to: classes of metabolizing enzymes (eg, cytochrome P450 
supra-family genes), genes encoding enzymes involved in the production and metabolism of 
SAGE-217 (eg, AKR1C4 [3α-hydroxysteroid dehydrogenase]), genes associated with the 
γ-aminobutyric acid (GABA) receptor (eg, GABRA1-A6, GABRB1-B3, GABRD, GABRE, 
GABRG1-3), and genes associated with the production and degradation of GABA.   
Future research may suggest other genes or gene categories as candidates for influencing not 
only response to SAGE-217 but also susceptibility to disorders for which SAGE-217 may be 
evaluated.  Thus, the genetic research may involve study of additional unnamed genes or gene 
categories, but only as related to disease susceptibility and drug action.   
13.1.6.8. Drugs of Abuse and Alcohol 
A urine sample for assessment of selected drugs of abuse (including amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, opiates, phencyclidine, and propoxyphene) and a serum 
or breath sample for alcohol screen will be collected at screening and predose on Day 1.  Use of 
benzodiazepines at screening is not necessarily exclusionary, as subjects will be allowed to take 
psychotropics that have been initiated at least 14 days prior to admission to the study center at a 
stable dose following discussion with the Sponsor (see Section 9.3).   
13.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS.  This scale consists of a 
baseline evaluation that assesses the lifetime experience of the subject with suicidal ideation and 
behavior (Posner 2008a), and a post-baseline evaluation that focuses on suicidality since the last 
study visit (Posner 2008b).  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).   
If, in the opinion of the Investigator, the subject is showing clinically meaningful changes in 
suicidality, no further study drug will be administered and the subject will be referred to a 
psychologist or psychiatrist for further evaluation.  This information will be tracked.   
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 any time of day at all 


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subsequent time points, as outlined in Table 2 and Table 3.  The C-SSRS is provided in 
Appendix 7.   
13.1.8. 
Stanford Sleepiness Scale (SSS) 
The SSS is subject-rated scale designed to quickly assess how alert a subject is feeling.  Degrees 
of sleepiness and alertness are rated on a scale of 1 to 7, where the lowest score of ‘1’ indicates 
the subject is ‘feeling active, vital, alert, or wide awake’ and the highest score of ‘7’ indicates the 
subject is ‘no longer fighting sleep, sleep onset soon; having dream-like thoughts’ 
(Hoddes 1973).   
In both Part A and Part B, from Day 1 through Day 7, SSS will be completed at the following 
time points: predose, 0.25, 0.5, 1, and 2 after dosing.  The scale is to be completed within 
±5 minutes of the scheduled time point through 0.5 hours after dosing and ±15 minutes of the 
scheduled time point from 1 hour after dosing and greater, unless the subject is asleep between 
23:00 h and 06:00 h during the inpatient treatment period.  During the outpatient treatment 
period, SSS will be completed prior to dosing and 1 hour after dosing.  All time points are 
relative to the time of dosing.  The SSS is provided in Appendix 8.   
13.2. 
Adverse and Serious Adverse Events 
13.2.1. 
Definition of Adverse Events 
13.2.1.1. Adverse Event 
An adverse event is the development of an undesirable medical condition or the deterioration of 
a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  In clinical studies, an adverse event 
can include an undesirable medical condition occurring at any time, including baseline or 
washout periods, even if no study treatment has been administered.   
13.2.1.2. Suspected Adverse Reaction 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event.  For the purposes of Investigational New Drug safety 
reporting, “reasonable possibility” means there is evidence to suggest a causal relationship 
between the drug and the adverse event.  Suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a drug.   
13.2.1.3. Serious Adverse Event 
A serious adverse event is an adverse event occurring during any study phase and at any dose of 
the investigational product, comparator or placebo, that fulfils one or more of the following: 
• It results in death 
• It is immediately life-threatening 
• It requires inpatient hospitalization or prolongation of existing hospitalization 
• It results in persistent or significant disability or incapacity 


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• It results in a congenital abnormality or birth defect 
• It is an important medical event that may jeopardize the subject or may require 
medical intervention to prevent one of the outcomes listed above. 
All serious adverse events that occur after any subject has been enrolled, whether or not they are 
related to the study, must be recorded for the duration of the study on forms provided by Sage 
Therapeutics or designee.   
13.3. 
Relationship to Study Drug 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each adverse event (unrelated, 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 “unrelated.”  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 “related.”   
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 to be related 
to the investigational product for the purposes of expedited regulatory reporting.   
13.4. 
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.  Clinically significant changes in laboratory values, blood pressure, and 
pulse need not be reported as adverse events unless they prompt corrective medical action by the 
Investigator, constitute a serious adverse event, or lead to discontinuation of administration of 
study drug.   
Information about adverse events will be collected from the signing of the ICF until the final 
visit of the study for that subject.  Adverse events that occur after the first administration of study 
drug will be denoted TEAEs.   
All adverse events will be followed until they are resolved or have reached a clinical plateau with 
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The adverse event term should be reported in standard medical terminology when possible.  For 
each adverse event, the Investigator will evaluate and report the onset (date and time), resolution 
or clinical plateau (date and time), severity, causality, action taken, outcome, and whether or not 
it caused the subject to discontinue the study.   
Severity 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) 
13.5. 
Reporting Adverse Events 
All serious adverse events (regardless of causality) will be recorded from the signing of the ICF 
until the Day 28 follow-up visit.  Any serious adverse events considered possibly or probably 
related to the investigational product and discovered by the Investigator at any time after the 
study should be reported.  All serious adverse events must be reported to the Sponsor or 
Sponsor’s designee immediately by phone and in writing within 24 hours of the first awareness 
of the event.  The Investigator must complete, sign and date the serious adverse event pages, 
verify the accuracy of the information recorded on the serious adverse event pages with the 
corresponding source documents, and send a copy to Sage Therapeutics or designee.   
Additional follow-up information, if required or available, should be sent to Sage Therapeutics 
or designee within 24 hours of receipt; a follow-up serious adverse event form should be 
completed and placed with the original serious adverse event information and kept with the 
appropriate section of the study file.   
Sage Therapeutics or designee is responsible for notifying the relevant regulatory authorities of 
certain events.  It is the Principal Investigator’s responsibility to notify the IRB of all serious 
adverse events that occur at his or her site if applicable per the IRB’s requirements.  Investigators 
will also be notified of all unexpected, serious, drug-related events (7-/15-Day Safety Reports) 
that occur during the clinical study.  Each site is responsible for notifying its IRB of these 
additional serious adverse events.   
13.6. 
Emergency Identification of Study Drug 
Part B of the study is double-blind.  The pharmacist responsible for preparing the solutions will 
be unblinded and will retain an official paper copy of the randomization schedule.  In addition, 
an unblinded Monitor will perform drug accountability during the study.   
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 the Sponsor 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 the Sponsor.  If the unblinding occurs 
without the Sponsor’s knowledge, the Investigator must notify the Sponsor 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 


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risk, any request for the unblinding of individual subjects must be made in writing to the Sponsor 
and approved by the appropriate Sponsor 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 matching 
placebo.   
In all cases where the study drug allocation for a subject is unblinded, pertinent information must 
be documented in the subject’s records and on the eCRF.  If the subject or study center personnel 
(other than pharmacist) have been unblinded, the subject will be terminated from the study.   


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14. 
STATISTICS 
14.1. 
Data Analysis Sets 
14.1.1. 
Analysis Populations and Methods 
The Safety Population (for both Part A and Part B), defined as all subjects administered study 
drug, will be used to provide descriptive summaries of safety data.   
The Efficacy Population (for both Part A and Part B), defined as all subjects in the Safety 
Population who complete at least 1 day of dosing of study drug and have at least one post-
baseline efficacy evaluation, will be used to analyze efficacy data.   
The PK Population will consist of all subjects in the Safety Population with sufficient plasma 
concentrations for PK evaluations, and will be used to summarize PK data.   
14.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data.  All subjects will be used in the analyses, as 
per the analysis populations, using all non-missing data available.  No imputation process will be 
used to estimate missing data.  A sensitivity analysis will be used to investigate the impact of 
missing data if ≥5% of subjects have missing data.   
14.3. 
General Considerations 
For the purpose of all safety and efficacy analyses where applicable, baseline is defined as the 
last measurement prior to the start of study drug administration.   
Continuous endpoints will be summarized with 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.   
14.4. 
Demographics and Baseline Characteristics 
Demographic data, such as age, race, and ethnicity, and baseline characteristics, such as height, 
weight, and body mass index (BMI), will be summarized using the Safety Population.   
Hepatitis, HIV, drug and alcohol, and pregnancy screening results will be listed, but not 
summarized as they are considered part of the inclusion/exclusion criteria.   
Medical/family history will be listed by subject.   
14.5. 
Efficacy Analyses 
Efficacy data will be summarized using appropriate descriptive statistics and other data 
presentation methods where applicable; subject listings will be provided for all efficacy data.  
For (the open-label) Part A, efficacy data will be summarized descriptively.  For Part B, subjects 
will be analyzed according to randomized treatment.   


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An analysis of ten subjects completing Part A is planned to inform Part B study conduct. 
For Part B of the study, change from baseline to each assessment in HAM-D total score will be 
analyzed using a mixed effects model for repeated measures (MMRM); the model will include 
center, treatment, baseline HAM-D total score, antidepressant use strata, assessment time point, 
and time point-by-treatment as explanatory variables.  Center will be treated as a random effect 
while all other explanatory variables will be treated as fixed effects.  All post-baseline time 
points will be included in the model.  The main comparison will be between SAGE-217 Oral 
Solution and matching placebo at the 15-day time point.  Model-based point estimates (ie, least 
squares [LS] means), 95% confidence intervals, and p-values) will be reported where applicable.  
An unstructured covariance structure will be used to model the within-subject errors.  Compound 
symmetry covariance structure will be used if there is a convergence issue with the unstructured 
covariance model.   
Descriptive statistics for HAM-D total score and change from baseline values will be presented 
by assessment time point for Part A.  Summaries will include n, mean, SD, median, minimum, 
and maximum.   
Similar to those methods described above for Part B, an MMRM will be used for the analysis of 
the following variables: changes from baseline in MADRS total score and HAM-A total score, 
and select individual item and subscale scores.  For each model, the comparison of interest will 
be between SAGE-217 Oral Solution and matching placebo at the 15-day time point.  
Model-based point estimates (ie, LS means), 95% confidence intervals, and p-values will be 
reported.   
Logistic regression methods will be used for the analysis of the following binary variables: 
HAM-D response (defined as ≥50% reduction from baseline in HAM-D total score), HAM-D 
remission (defined as HAM-D total score of ≤7.0), and CGI-I response.  Logistic regression 
models will include terms for center, treatment, antidepressant use strata, and baseline score.  
The comparison of interest will be the difference between SAGE-217 Oral Solution and 
matching placebo at the 15-day time point in Part B.  Model-based point estimates (ie, odds 
ratios), 95% confidence intervals, and p-values will be reported.  For the CGI-I response 
analysis, baseline CGI-S score will be included in the model.   
For all scores, descriptive statistics, change from baseline values, and response variables will be 
presented by treatment and assessment time point.  Summaries will include n, mean, SD, median, 
minimum, and maximum.   
Similar to the main comparison of HAM-D total score in Part B, descriptive summary statistics 
will be provided and an MMRM model will be used to analyze the change from baseline in 
SF-36 and FAs-D.   
14.6. 
Safety Analyses 
Safety and tolerability of study drug will be evaluated by adverse events, concomitant 
medication usage, changes from baseline in physical examination, vital signs, clinical laboratory 
evaluations, and 12-lead ECG.  Suicidality will be monitored by the C-SSRS.  Sedation will be 
assessed using the SSS.  Safety data will be listed by subject and summarized by treatment 
group.  All safety summaries will be performed on the Safety Population.   


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14.6.1. 
Adverse Events 
The analysis of adverse events will be based on the concept of TEAEs.  A TEAE is defined as an 
adverse event with onset after the start of study drug, or any worsening of a pre-existing medical 
condition/adverse event with onset after the start of study drug and until 7 days after the last 
dose.  The incidence of TEAEs will be summarized overall and by Medical Dictionary for 
Regulatory Activities (MedDRA) Version 18.1 or higher System Organ Class (SOC) and 
preferred term.  Incidences will be presented in order of decreasing frequency for the SAGE-217 
Oral Solution treatment group.  In addition, summaries will be provided by severity (mild, 
moderate, severe) and by causality (related, not related) to study drug (see Section 13.3).   
Treatment-emergent adverse events leading to discontinuation and serious adverse events (see 
Section 13.2.1.3 for definition) with onset after the start of randomized study drug will also be 
summarized.   
All adverse events and serious adverse events (including those with onset or worsening before 
the start of study drug) through the Day 28 follow-up visit will be listed.   
14.6.2. 
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 summarized.   
14.6.3. 
Physical Examinations 
Physical examinations in Parts A and B will be summarized at the Screening visit, Day 8, 
Day 15, Day 21, and Day 28 visits.  Any clinically significant change in physical examination 
compared to those observed at screening should be noted as an adverse event.   
14.6.4. 
Vital Signs 
Vital sign results will be listed by subject and timing of collection.  Mean changes from 
randomization in vital signs will be summarized by time point.   
14.6.5. 
12-Lead Electrocardiogram 
The following ECG parameters will be listed for each subject: heart rate, PR, QRS, QT, QTc, 
and QT interval calculated using the Fridericia method (QTcF).  Any clinically significant 
abnormalities or changes in ECGs should be listed as an adverse event.  Electrocardiogram 
findings will be listed by subject and visit.   
14.6.6. 
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.   
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 during the 30 days prior to 
informed consent.  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 
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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.   
14.6.7. 
Columbia Suicide Severity Rating Scale 
Suicidality data collected on the C-SSRS at baseline and by visit during the Treatment Period 
will be listed for all subjects.  Listings will include behavior type and/or category for Suicidal 
Ideation and Suicidal Behavior of the C-SSRS.   
14.6.8. 
Stanford Sleepiness Scale 
Sedation data collected on the SSS will be listed for all subjects.  Changes in score over time will 
be represented graphically, and change from Day 1 will be measured. 
14.7. 
Pharmacokinetic Analyses 
Pharmacokinetic parameters will be summarized using appropriate descriptive statistics.  Time at 
maximum (peak) plasma concentration (tmax) will be summarized using n, mean, SD, median, 
minimum, and maximum.  All other PK parameters will be summarized using n, geometric 
mean, coefficient of variation, median, minimum, and maximum and listed by subject.   
Plasma concentrations and PK parameters will be listed by subject.   
In addition to typical descriptive statistics, summaries should include geometric mean, 
coefficient of variation, and geometric coefficient of variation. 
14.8. 
Determination of Sample Size 
The sample size of ten subjects for Part A was selected based on clinical and not statistical 
considerations.   
For Part B, assuming a two-sided t-test at an alpha level of 0.10, a sample size of 23 subjects per 
group would provide 80% power to detect an effect size of 0.75 between the SAGE-217 Oral 
Solution and matching placebo groups with regard to the secondary efficacy outcome variable of 
change from baseline in HAM-D total score.  An effect size of 0.75 corresponds to a matching 
placebo-adjusted difference of 7.5 points in the change from baseline in HAM-D total score at 
15 days with an assumed SD of 10 points.  By including two treatment groups and using a 1:1 
randomization, a total of 46 subjects are required.  Assuming a non-evaluability rate of 10%, up 
to 52 subjects will be randomized.   
14.9. 
Changes From Protocol Specified Analyses 
Any changes from the analytical methods outlined in the protocol will be documented in the final 
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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
Study Monitoring 
Before an investigational site can enter a subject into the study, a representative of Sage 
Therapeutics or designee will visit the investigational study site to:   
• Determine the adequacy of the facilities; and 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of Sage Therapeutics or designee or its 
representatives.  This will be documented in a Clinical Study Agreement between 
Sage Therapeutics and the Investigator.   
During the study, a monitor from Sage Therapeutics or designee will have regular contacts with 
the investigational site for the following: 
• Provide information and support to the Investigator(s); 
• Confirm that facilities remain acceptable; 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the eCRFs, and that investigational product accountability 
checks are being performed; 
• Perform source data verification. This includes a comparison of the data in the eCRFs 
with the subject’s medical records at the hospital or practice, and other records 
relevant to the study. This will require direct access to all original records for each 
subject (eg, clinic charts); 
• Record and report any protocol deviations not previously sent to Sage Therapeutics or 
designee; and 
• Confirm adverse events and serious adverse events have been properly documented 
on eCRFs and confirm any serious adverse events have been forwarded to Sage 
Therapeutics or designee and those serious adverse events that met criteria for 
reporting have been forwarded to the IRB.   
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice.   
15.2. 
Audits and Inspections 
Authorized representatives of Sage Therapeutics, a regulatory authority, an Independent Ethics 
Committee (IEC) or an IRB may visit the site to perform audits or inspections, including source 
data verification.  The purpose of a Sage Therapeutics or designee 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 
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Harmonisation (ICH), and any applicable regulatory requirements.  The Investigator should 
contact Sage Therapeutics immediately if contacted by a regulatory agency about an inspection.   
15.3. 
Institutional Review Board (IRB) 
The Principal Investigator must obtain IRB approval for the investigation.  Initial IRB approval 
and all materials approved by the IRB for this study, including the subject consent form and 
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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Investigator and institution will permit study-related monitoring, audits, IRB review, and 
regulatory inspections as requested by the Food and Drug Administration, the Sponsor, or the 
Sponsor’s designee, including direct access to source data/documents (ie, original medical 
records, laboratory reports, hospital documents, progress reports, signed ICFs) in addition to 
eCRFs.   
Quality assurance and quality-control systems with written standard operating procedures will be 
followed to ensure this study will be conducted and data will be generated, documented 
(recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory 
requirements.   
The site’s dedicated study monitor will arrange to visit the Investigator at regular intervals during 
the study.  The monitoring visits must be conducted according to the applicable ICH and GCP 
guidelines to ensure protocol adherence, quality of data, drug accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities. 
During these visits, eCRFs and other data related to the study will be reviewed and any 
discrepancies or omissions will be identified and resolved. The study monitor will be given 
access to study-relevant source documents (including medical records) for purposes of source 
data verification. 
During and/or after completion of the study, quality-assurance officers named by Sage 
Therapeutics or the regulatory authorities may wish to perform on-site audits. The Investigator is 
expected to cooperate with any audit and provide assistance and documentation (including 
source data) as requested. 
Quality control will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. 
Agreements made by the Sponsor with the Investigator/institution and any other parties involved 
with the clinical study will be in writing in a separate agreement. 


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17. 
ETHICS 
17.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate.  The Investigator must submit 
written approval to Sage Therapeutics or designee before he or she can enroll any subject into the 
study.   
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB or IEC must approve all 
advertising used to recruit subjects for the study.  The protocol must be re-approved by the IRB 
or IEC 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 or designee will provide this information to the Principal 
Investigator.   
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines.   
17.2. 
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 its most recent amendment (2008) and are consistent with ICH/GCP 
and other applicable regulatory requirements.   
17.3. 
Written Informed Consent 
The Principal Investigator 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 
before signing the ICF.   
As additional assessments, the ICF will contain provisions for optional consent for the collection 
of blood samples for biochemistry during screening, Day 8, and Day 15 and biomarker testing 
during screening. The ICF, as specified by the clinical site’s IRB, must follow the Protection of 
Human Subjects regulations listed in the Code of Federal Regulations, Title 21, Part 50. 
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 ICF.  A copy of the signed ICF 
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18. 
DATA HANDLING AND RECORDKEEPING 
Procedures for data handling (including electronic data) used in this protocol will be documented 
in a Data Management Plan.   
Electronic CRFs will be completed for each study subject.  It is the Investigator’s responsibility 
to ensure the accuracy, completeness, and timeliness of the data reported in the subject’s eCRF.  
Source documentation supporting the eCRF data should indicate the subject’s participation in the 
study and should document the dates and details of study procedures, adverse events, and subject 
status.   
The Investigator will have access to the electronic data capture system and will receive a copy of 
the subject eCRF data at the end of the study.  For subjects who discontinue or terminate from 
the study, the eCRFs will be completed as much as possible, and the reason for the 
discontinuation or termination clearly and concisely specified on the appropriate eCRF. 
18.1. 
Inspection of Records 
Sage Therapeutics or designee will be allowed to conduct site visits to the investigational 
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 related to study conduct.   
18.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval or, if not approved, 2 years following the 
discontinuation 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.   
18.3. 
Confidentiality 
To maintain subject privacy, all eCRFs, study reports, and communications will identify the 
subject by the assigned subject number.  The Investigator will grant monitor(s) and auditor(s) 
from the Sponsor or its designee and regulatory authority(ies) access to the subject’s original 
medical records for verification of data gathered on the eCRFs and to audit the data collection 
process.  The subject’s confidentiality will be maintained and will not be made publicly available 
to the extent permitted by the applicable laws and regulations.   
Subjects will be notified that registration information, results, and other information about this 
study will be submitted to ClinicalTrials.gov, a publicly available trial registry database; 
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All information regarding the investigational product supplied by Sage Therapeutics to the 
Investigator is privileged and confidential information.  The Investigator agrees to use this 
information to accomplish the study and will not use it for other purposes without consent from 
the Sponsor.  It is understood that there is an obligation to provide the Sponsor with complete 
data obtained during the study.  The information obtained from the clinical study will be used 
towards the development of the investigational product and may be disclosed to regulatory 
authorities, other Investigators, corporate partners, or consultants, as required.   


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19. 
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 
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20. 
LIST OF REFERENCES 
Angst J, Angst F, Stassen HH. Suicide risk in patients with major depressive disorder. J Clin 
Psychiatry. 1999;60 Suppl 2:57-62; discussion 75-6, 113-6. 
Busner J, Targum S. CGI-S. (2007a), as adapted from Kay, Stanley R, Positive and Negative 
Symptoms in Schizophrenia:Assessment and Research.  Clinical and Experimental Psychiatry, 
Monograph No. 5.  Brunner/Mazel, 1991.  Modified from Guy W. Clinical Global Impressions: 
In ECDEU Assessment Manual for Psychopharmacology. 1976; 218-22. Revised DHEW Pub. 
(ADM) Rockville, MD: National Institute for Mental Health.   
Busner J, Targum S. CGI-I.  (2007b), as adapted from Spearing, et al.  Psychiatry Research, 
1997;73:159-71.  Modified from Guy W. Clinical Global Impressions: In ECDEU Assessment 
Manual for Psychopharmacology. 1976; 218-22. Revised DHEW Pub. (ADM) Rockville, MD: 
National Institute for Mental Health.   
Conradi HJ, Ormel J, de Jonge P. Presence of individual (residual) symptoms during depressive 
episodes and periods of remission: a 3-year prospective study. Psychol Med. 2011 
Jun;41(6):1165-74. 
Drugan RC, Morrow AL, Weizman R, et al. Stress-induced behavioral depression in the rat is 
associated with a decrease in GABA receptor-mediated chloride ion flux and brain 
benzodiazepine receptor occupancy. Brain Res. 1989;487: 45–51. 
DSM-5.  Diagnostic and statistical manual of mental disorders (5th ed.).  American Psychiatric 
Association 2013.  Arlington, VA: American Psychiatric Publishing. 
Fournier JC, DeRubeis RJ, Hollon SD, et al. Antidepressant drug effects and depression 
severity—a patient-level meta-analysis. JAMA. 2010;303:47-53.   
Gerner RH, Hare TA. GABA in normal subjects and patients with depression, schizophrenia, 
mania, and anorexia nervosa. Am J Psychiatry. 1981;138:1098–101. 
Greenberg PE, Fournier AA, Sisitsky T, Pike CT, Kessler RC. The economic burden of adults 
with major depressive disorder in the United States (2005 and 2010). J Clin Psychiatry. 2015 
Feb;76(2):155-62. 
Hoddes E, Zarcone V, Smythe H, Phillips R, Dement WC. Quantification of sleepiness: a new 
approach. Psychophysiology. 1973 Jul;10(4):431-6. 
Honig A, Bartlett JR, Bouras N, Bridges PK. Amino acid levels in depression: a preliminary 
investigation. J Psychiatr Res. 1988; 22:159–64. 
Kirsch I, Deacon BJ, Huedo-Medina TB, et al. Initial severity and antidepressant benefits: A 
meta-analysis of data submitted to the Food and Drug Administration. PLoS Med. 
2008;5(2):e45.   
Luscher B, Shen Q, Sahir N. The GABAergic deficit hypothesis of major depressive disorder. 
Mol Psychiatry. 2011;16(4):383-406. 
Maguire J, Mody I. GABA(A)R plasticity during pregnancy: Relevance to postpartum 
depression. Neuron. 2008;59(2);207-13.   


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Maguire J, Ferando I, Simonsen C, Mody I. Excitability changes related to GABAA receptor 
plasticity during pregnancy. J Neurosci. 2009;29(30):9592-601.   
Mann JJ, Oguendo MA, Watson KT, et al. Anxiety in major depression and cerebrospinal fluid 
free gamma-aminobutyric acid. Depress Anxiety. 2014;31(10):814-21. 
Matza LS, Murray LT, Phillips GA, et al. Qualitative Research on Fatigue Associated with 
Depression: Content Validity of the Fatigue Associated with Depression Questionnaire (FAsD-
V2). Patient. 2015 Oct;8(5):433-43.   
Posner K, Brent D, Lucas C, et al. C-SSRS BL/Scr: 2008a Research Foundation for Mental 
Hygiene, Inc.C-SSRS—Baseline/Screening (Version 1/14/09).   
Posner K, Brent D, Lucas C, et al. C-SSRS SLV: 2008b Research Foundation for Mental 
Hygiene, Inc.C-SSRS—Since Last Visit (Version 1/14/09).   
Romera I, Pérez V, Ciudad A, et al. Residual symptoms and functioning in depression, does the 
type of residual symptom matter? A post-hoc analysis. BMC Psychiatry. 2013 Feb 11;13:51. 
Schüle C, Nothdurfter C, Rupprecht R.  The role of allopregnanolone in depression and anxiety. 
Prog Neurobiol. 2014 Feb;113:79-87. 
Trivedi MH, Rush AJ, Wisniewski SR, et al. (STAR*D Study Team). Evaluation of outcomes 
with citalopram for depression using measurement-based care in STAR*D: implications for 
clinical practice. Am J Psychiatry. 2006 Jan;163(1):28-40. 
Ware JE Jr, Kosinski M, Bjorner JB, et al.  User's Manual for the SF-36v2 Health Survey.  2nd 
ed.  Lincoln, RI:  QualityMetric Incorporated; 2007. 
Williams JBW, Kobak KA. Development and reliability of a structured interview guide for the 
Montgomery-Asberg Depression Rating Scale (SIGMA). Br J Psychiatry. 2008;192:52-8. 
Williams JBW.  SIGH-D 24hr: V1.3 – 24 HR Version. 2013a. 
Williams JBW.  SIGH-D Past week: - Past Week Version. 2013b. 
Williams JBW.  SIGH-A 24hr: V1.3 – 24 HR Version. 2013c. 
Williams JBW.  SIGH-A Past week: - Past Week Version. 2013d. 
 


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21. 
APPENDICES 
 


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Appendix 1. 
HAMILTON RATING SCALE FOR DEPRESSION, 
17-ITEM (HAM-D) 
 


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Appendix 2. 
MONTGOMERY-ÅSBERG DEPRESSION RATING 
SCALE (MADRS) 


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APPENDIX 4. CLINICAL GLOBAL IMPRESSION–IMPROVEMENT 
SCALE (CGI-I) AND SEVERITY SCALE (CGI-S) 
 


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APPENDIX 5. SHORT-FORM 36 (SF-36) 
 


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APPENDIX 7. COLUMBIA - SUICIDE SEVERITY RATING SCALE 
(C-SSRS) 
 


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APPENDIX 8. STANFORD SLEEPINESS SCALE (SSS) 
 






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INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for SAGE-217.  I have read the Clinical 
Protocol 217-MDD-201 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 
 


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CONTACTS IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Clinical Research Organization 
 
 
 
 
 
 
 
 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Sage Therapeutics 
215 First Street  
Cambridge, MA  02142 
Name of Investigational Product: 
SAGE-217 Oral Solution 
Name of Active Ingredient: 
SAGE-217  
Title of Study: A Phase 2, Two-Part (Open-Label Followed by Double-Blind) Study Evaluating the 
Safety, Tolerability, Pharmacokinetics, and Efficacy of SAGE-217 in the Treatment of Adult Subjects 
With Moderate to Severe Major Depressive Disorder 
Study centers: Approximately 3 sites in Part A and approximately 15 sites in Part B 
Phase of development: 2a 
Methodology:  
This study will assess the safety, tolerability, pharmacokinetics (PK), and efficacy of SAGE-217 Oral 
Solution in adult subjects diagnosed with moderate to severe major depressive disorder (MDD).   
There are two parts to the study: 
Part A:  Open-label dosing with SAGE-217 Oral Solution (14 days) 
All subjects will receive a 30 mg SAGE-217 Oral Solution dose administered at 8:00 PM 
(±15 minutes) with food on Day 1 to Day 14 as tolerated.   
Part B:  Randomized, double-blind, parallel-group, placebo-controlled (14 days) 
Based on the results of Part A, eligible subjects will be stratified based on use of antidepressant 
treatment (current/stable or not treated/withdrawn ≥30 days) and randomized within each stratum in a 
1:1 fashion to receive SAGE-217 Oral Solution 30 mg or matching placebo for 14 days beginning on 
Day 1 as tolerated.  All doses of study drug will be administered at 8:00 PM (±15 minutes) with food.   
Dose adjustments based on tolerability are detailed in Section 9.3.   
Separate cohorts of subjects will be enrolled in Part A and Part B; subjects participating in Part A 
cannot enroll in Part B.  Part B may be initiated after termination or completion of Part A if there is a 
clear signal of activity based on the 17-item Hamilton Rating Scale for Depression (HAM-D) scores 
and/or other scales being assessed.   
Both parts of the study will consist of an up to 7-day Screening Period (Days -7 to -1), a 14-day 
Treatment Period, and a 2-week Follow-up Period.  During the study Treatment Period, subjects must 
remain inpatient for the first 7 days at minimum and per Investigator’s judgement thereafter.   
Screening Period: The Screening Period begins with the signing of the informed consent form (ICF) 
at the Screening Visit, which can occur on any one calendar day of the 7-day window (from Day -7 
through Day -1).  The diagnosis of MDD must be made according to Structured Clinical Interview for 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Axis I Disorders 
(SCID-I) performed by a qualified healthcare professional.  Subjects will undergo preliminary 
screening procedures at the Screening Visit to determine eligibility, including completion of the 
HAM-D, Hamilton Anxiety Rating Scale (HAM-A), Clinical Global Impression - Severity (CGI-S), 
and Montgomery-Åsberg Depression Rating Scale (MADRS).  The Screening Period assessments will 
be conducted on an outpatient basis.  Most eligibility criteria are the same for both parts of the study.   


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Treatment Period:  
Part A – Once subjects are confirmed as eligible, they will receive a 30 mg dose of study drug at 
8:00 PM (±15 minutes) with food for 14 days (Day 1 to Day 14) as tolerated.  Subjects who cannot 
tolerate 30 mg will receive 20 mg for the rest of the Treatment Period.  Subjects who cannot tolerate 
20 mg will be terminated from the study.  The following assessments will be performed: HAM-D, 
HAM-A, and MADRS total scores and Clinical Global Impression – Improvement (CGI-I).   
Part A may be terminated and Part B initiated if there is a clear signal of activity based on the HAM-D 
scores and/or other scales being assessed.  Alternatively, upon completion of Part A, Part B may begin.  
The study may be terminated if there is clear lack of activity based on HAM-D scores during Part A.  
Separate cohorts of subjects will be enrolled in Part A and Part B; subjects participating in Part A 
cannot enroll in Part B.   
Part B - Based on the results of Part A, eligible subjects will be stratified based on use of antidepressant 
treatment (current/stable or not treated/withdrawn ≥30 days) and randomized within each stratum to 
one of two treatment groups (SAGE-217 Oral Solution 30 mg or matching placebo) in a 1:1 ratio.  
Subjects will be administered study drug at 8:00 PM (±15 minutes) with food for 14 days.  Subjects 
who cannot tolerate 30 mg will receive 20 mg for the rest of the Treatment Period.  Subjects who 
cannot tolerate 20 mg will be terminated from the study.   
In both parts of the study, subjects may be discharged after a minimum 7-day inpatient stay, following 
completion of the Day 7 assessments.  If their clinical condition does not allow discharge, the 
Investigator may keep the subjects as inpatients for a longer period of time.   
In both parts of the study, subjects discharged from the inpatient unit may receive treatment with study 
drug for the remainder of the 14-day Treatment Periods as outpatients.  The outpatient phase treatment 
may be provided at the clinical site or, if suitable arrangements can be made, via home administration.  
Home administration of study drug will be performed according to a site-specific plan by a healthcare 
professional trained on the protocol and delivery of the study drug. 
With the exception of subjects permitted to use current stable antidepressant treatment, initiation of 
psychotropic medications and other medications that may potentially have an impact on efficacy or 
safety endpoints will not be allowed between screening and completion of the Day 15 assessments 
(Parts A and B).  Psychotropic medications, which must have been initiated at least 14 days prior to 
screening, must remain at a stable dose until completion of the Day 15 assessments (Parts A and B).   
Efficacy and safety assessments will be performed periodically during the study, and blood samples 
will be collected for analysis of SAGE-217 as outlined in the Schedule of Events (Table 2 and Table 3).  
Follow-up Period: Follow-up visits will be conducted on an outpatient basis.  Follow-up visits for 
Parts A and B will be conducted at 1 week (21±1 day) and 2 weeks (28±3 days) after the last dose of 
study drug.   
Objectives:  
Part A:  
Primary:  
The primary objective of the study is to evaluate the safety and tolerability of SAGE-217 Oral Solution 
30 mg.   
Secondary: 
The secondary objective of Part A is to determine if treatment with SAGE-217 Oral Solution 30 mg for 
14 days reduces depressive symptoms.   


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Part B:  
Primary:  
The primary objective of the study is to evaluate the safety and tolerability of SAGE-217 Oral Solution 
30 mg.   
Secondary: 
The secondary efficacy objective for Part B of the study is to determine if treatment with SAGE-217 
Oral Solution 30 mg reduces depressive symptoms in subjects with moderate to severe MDD compared 
to matching placebo.   
Endpoints: 
Part A:  
Primary:  
The primary endpoint is 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 
electrocardiograms (ECGs); Stanford Sleepiness Scale (SSS) score; physical examination; and suicidal 
ideation using the Columbia-Suicide Severity Rating Scale (C-SSRS).   
Secondary: 
Reduction in depressive symptoms as assessed by the following: 
• 
Change from baseline in HAM-D total score at all time points;  
• 
HAM-D response;  
• 
HAM-D remission;  
• 
Change from baseline in the MADRS total score at all time points; 
• 
Change from baseline in HAM-D subscale and individual item scores at all time points; and  
• 
CGI-I response. 
Part B:  
Primary:  
The primary endpoint is 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; SSS score; physical examination; and suicidal ideation using the C-SSRS.   
Secondary: 
Reduction in depressive symptoms, compared to placebo, as assessed by the following:   
• 
Change from baseline in the 17-item HAM-D total score at all time points;  
• 
HAM-D response;  
• 
HAM-D remission;  
• 
Change from baseline in the MADRS total score at all time points; 
• 
Change from baseline in HAM-D subscale and individual item scores at all time points;  
• 
CGI-I response; and 
• 
36-item short form survey (SF-36) and fatigue associated with depression (FAs-D) patient-reported 
outcome.   
Pharmacokinetic: 
The PK objective of Part A and Part B is:  
• 
To assess the PK profile of SAGE-217 Oral Solution in plasma samples.   


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Number of subjects (planned):  
Approximately ten subjects will be enrolled in Part A.  Up to 52 subjects may be randomized in Part B. 
Diagnosis and main criteria for inclusion:  
Inclusion criteria: 
1. Subject has signed an ICF prior to any study-specific procedures being performed. 
2. Subject is an ambulatory male or female between 18 and 65 years of age, inclusive. 
3. Subject is in good physical health and has no clinically significant findings, as determined by 
the Investigator, on physical examination, 12-lead ECG, or clinical laboratory tests. 
4. Subject agrees to adhere to the study requirements.   
5. Subject has a diagnosis of MDD that has been present for at least a 4-week period as diagnosed 
by SCID-I.   
6. Subject has a HAM-D total score of ≥22 at screening and Day 1 (prior to dosing).   
7. Subject has a HAM-A total score of ≥20 at screening and Day 1 (prior to dosing) (Part B only).   
8. Subject is willing to delay start of other antidepressant or antianxiety medications and any new 
pharmacotherapy regimens, including as-needed benzodiazepine anxiolytics, during the 
screening and treatment periods.   
9. Subject agrees to practice an acceptable method of highly effective birth control at screening 
and throughout study participation.  Highly effective methods of birth control include sexual 
abstinence (for males and females); vasectomy; or a condom with spermicide in combination 
with a highly effective female partner’s method (for males); and hormonal methods of 
contraception (ie, established use of oral, implantable, injectable, or transdermal hormones); 
placement of an intrauterine device; placement of an intrauterine system; and 
mechanical/barrier method of contraception (ie, condom or occlusive cap [diaphragm or 
cervical/vault cap] in conjunction with spermicide [foam, gel, film, cream, or suppository]) (for 
females). 
Exclusion criteria: 
1. Subject has a history of suicide attempt.   
2. Subject has a recent history or active clinically significant manifestations of metabolic, hepatic, 
renal, hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, 
dermatological, urogenital, neurological, or eyes, ears, nose, and throat disorders, or any other 
acute or chronic condition that, in the Investigator's opinion, would limit the subject's ability to 
complete or participate in this clinical study.   
3. Subject has a history of treatment-resistant depression, defined as persistent depressive 
symptoms despite treatment with adequate doses of antidepressants from two different classes 
for an adequate amount of time (ie, at least 4 weeks of treatment).   
4. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds.   
5. Subject has a positive pregnancy test at screening or on Day 1 prior to the start of study drug 
administration.   
6. Subject has detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV), or 
human immunodeficiency virus (HIV) antibody at screening.   
7. Subject has active psychosis per Investigator assessment.   
8. Subject has a medical history of seizures.   
9. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder.   


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10. Subject has a history of alcohol or drug dependence (including benzodiazepines) in the 
12 months prior to screening.   
11. Subject has had exposure to another investigational medication or device within 30 days prior 
to screening.   
12. Subject has been treated or randomized in this study (eg, Part A) or any other study employing 
SAGE-217 previously (ie, subject may not have received study drug and then re-enroll).   
13. Subject has had administration of psychotropics that have been initiated within 14 days prior to 
screening and/or are not being taken at a stable dose.   
14. Use of any known strong inhibitors and/or inducers of cytochrome P450 (CYP)3A4 within the 
14 days or five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, 
Seville oranges, or St. John's Wort or products containing these within 30 days prior to 
receiving the first dose of study drug.   
Investigational product, dosage and mode of administration:  
SAGE-217 Oral Solution is available as a 6 mg/mL stock aqueous solution of SAGE-217 Drug 
Substance containing 40% hydroxypropyl-β-cyclodextrin (HPβCD) and 0.0025% sucralose, which is 
further diluted with Sterile Water for Injection to achieve the selected dose.   
Duration of participation:   
Part A:  Up to 38 days (14 days of treatment) 
Part B:  Up to 38 days (14 days of treatment) 
Reference therapy, dosage and mode of administration:  
Reference therapy is taste-matched placebo.   
Randomization: 
Subjects participating in Part A of the study will be administered study drug (SAGE-217 Oral Solution) 
in an open-label manner.  Subjects in Part B will be randomized within each antidepressant treatment 
stratum to receive SAGE-217 Oral Solution or matching placebo oral solution in a 1:1 ratio.  Subjects, 
clinicians, and the study team will be blinded to treatment allocation.  The pharmacist and/or 
designated pharmacy staff, who will prepare the oral solutions according to the randomization 
schedule, will be unblinded.   
Dose Adjustment for Safety/Tolerability Reasons: 
During the Treatment Period, subjects will be able to receive study drug as long as there are no 
dose-limiting safety/tolerability concerns.  Subjects who experience moderate or severe adverse events 
that according to the clinical judgement of the Investigator are related to study drug while receiving the 
30 mg dose of study drug will receive 20 mg for the remaining of the Treatment Period.  Subjects who 
experience moderate or severe related adverse events while receiving the 20 mg dose of study drug 
may not be able to continue receiving study drug based on the evaluation and clinical judgment of the 
Investigator, and may be terminated from the study.  Dosing may also be modified based on tolerability 
as assessed with SSS scores.   
Part A may be terminated and Part B initiated if there is a clear signal of activity based on the HAM-D 
scores and/or other scales being assessed.  The study may be terminated if there is clear lack of activity 
based on HAM-D scores during Part A.  A Data Review Team will assess the HAM-D and other data 
on an ongoing basis during Part A.   


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Inpatient Length of Stay and Discharge Instructions 
The minimum length of inpatient stay in both parts of this study is 7 days.  It is the Investigator’s 
responsibility to assess whether the subject can safely be discharged home and continue taking study 
drug administered by a healthcare professional trained on the protocol and delivery of the study drug 
for the rest of the treatment days (Days 8 to 14 for Parts A and B) or by returning to the clinic daily.  
The Investigator may decide to extend the subject’s inpatient stay to maximize safety oversight.  In 
making this assessment, the Investigator may consider not only the drug tolerability but also clinical 
factors including, but not limited to, availability of social support, transportation, severity of symptoms, 
and suicidality.   
Discharge instructions must include warnings about avoiding activities for which sedative effects of the 
study drug may impair performance, such as driving a motor vehicle and operating machinery.   
Criteria for evaluation: 
Efficacy: 
Reduction of depressive symptoms will be assessed by the change from baseline at various time points 
in HAM-D total score; HAM-D response; HAM-D remission; change from baseline in the MADRS 
total score; CGI-I response; change from baseline in HAM-D subscale and individual item scores; 
change from baseline in HAM-A total score; change from baseline in SF-36; and change from baseline 
in FAs-D.   
Pharmacokinetics: 
Plasma samples will be collected to assay for concentrations of SAGE-217.  The following PK 
parameters will be derived from the plasma concentrations (where evaluable): area under the 
concentration-time curve (AUC), AUC from time zero to infinity (AUC∞), maximum (peak) plasma 
concentration (Cmax), time at maximum (peak) plasma concentration (tmax), steady-state drug 
concentration in the plasma during oral intake (Css), and in the plasma at steady state during a dosing 
interval. 
Safety: 
The safety and tolerability of SAGE-217 Oral Solution will be evaluated by frequency, type, and 
severity of adverse events; mean changes from baseline in clinical laboratory measures, vital signs, and 
ECGs; SSS score; physical examination; and suicidal ideation using the C-SSRS during both Part A 
and Part B.   
Statistical methods: 
General 
For the purpose of all safety and efficacy analyses where applicable, baseline is defined as the last 
measurement prior to the start of blinded 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.    


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Analysis Populations and Methods:  
The Safety Population (for both Part A and Part B), defined as all subjects administered study drug, 
will be used to provide descriptive summaries of safety data.  Adverse events will be classified by type, 
incidence, severity, and causality.  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, physical examinations, 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 at baseline and at each visit during the active Treatment 
Period will be listed for all subjects.  The C-SSRS listings will include behavior type and/or category 
for suicidal ideation and suicidal behavior of the C-SSRS.  Out-of-range safety endpoints may be 
categorized as low or high, where applicable.  Subjects will be summarized according to treatment 
received.    
The Efficacy Population (for both Part A and Part B), defined as all subjects in the Safety Population 
who complete at least 1 day of dosing of study drug and have at least one post-baseline efficacy 
evaluation, will be used to analyze efficacy data.  Efficacy data will be analyzed using appropriate 
descriptive statistics and pre-specified statistical methods, as well as other data presentation methods 
where applicable; subject listings will be provided for all efficacy data.  For (the open-label) Part A, 
efficacy data will be summarized descriptively.  For Part B, subjects will be analyzed according to 
randomized treatment.   
For 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, 
antidepressant use strata, assessment time point, and time point-by-treatment as explanatory variables.  
All post-baseline time points will be included in the model.  The primary comparison will be between 
SAGE-217 Oral Solution and matching placebo at the 15-day time point.  Model-based point estimates 
(ie, least squares [LS] means), 95% confidence intervals, and p-values will be reported.  An 
unstructured covariance structure will be used to model the within-subject errors.  Continuous variables 
will be analyzed using similar methods.   
Binary efficacy endpoints, including responder and remission endpoints, will be analyzed using logistic 
regression model.   
The PK Population will consist of all subjects in the Safety Population with sufficient plasma 
concentrations for PK evaluations, and will be used to summarize PK data.  PK parameters will be 
summarized using appropriate descriptive statistics and listed by subject.  The PK parameters to be 
summarized where possible will include AUC∞, Cmax, tmax, t½, and Css.   
Sample Size Calculation 
The sample size of ten subjects for Part A was selected based on clinical and not statistical 
considerations.   
For Part B, assuming a two-sided t-test at an alpha level of 0.10, a sample size of 23 subjects per group 
would provide 80% power to detect an effect size of 0.75 between the SAGE-217 Oral Solution and 
matching placebo groups with regard to the secondary efficacy outcome variable of change from 
baseline in HAM-D total score.  An effect size of 0.75 corresponds to a matching placebo-adjusted 
difference of 7.5 points in the change from baseline in HAM-D total score at 15 days with an assumed 
SD of 10 points.  By including two treatment groups and using a 1:1 randomization, a total of 
46 subjects are required.  Assuming a non-evaluability rate of 10%, up to 52 subjects will be 
randomized.   


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Table 2: 
Schedule of Events (Part A) 
 
Screening Period 
Open-Label Treatment Period 
Follow-up Period 
Visits 
OUTPATIENT 
INPATIENT 
INPATIENT or OUTPATIENT
a 
OUTPATIENT 
Visit Days 
D-7 to D-1 
D1* 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
D15/ 
ET 
D21 
(+1d) 
D28 
(±3d) 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Family History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCID-I 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confinement 
 
X 
(X) 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
Body Weight/Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X (wt 
only) 
X (wt 
only) 
X (wt 
only) 
Clinical Laboratory 
Assessments
b 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
Drug & Alcohol Screen
c 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test
d 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
e 
 
X 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Sample
f 
O 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genetic Sample
g 
O 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs
h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse Oximetry 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
12-Lead ECG
i 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
C-SSRS
j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-S
k 
X 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 


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Screening Period 
Open-Label Treatment Period 
Follow-up Period 
Visits 
OUTPATIENT 
INPATIENT 
INPATIENT or OUTPATIENT
a 
OUTPATIENT 
Visit Days 
D-7 to D-1 
D1* 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
D15/ 
ET 
D21 
(+1d) 
D28 
(±3d) 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CGI-Ik 
 
 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
HAM-Ak 
X 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
HAM-Dk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
MADRSk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
SSS
l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Plasma PK
m 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
X 
X 
 
 
Study Drug 
Administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse Events 
X 
Prior/Concomitant 
Medications
n 
X 
CGI-I = Clinical Global Impression - Improvement; CGI-S – Clinical Global Impression - Severity; C-SSRS = Columbia Suicide Severity Rating Scale; D = day; ET = early 
termination; ECG = electrocardiogram; HAM-A = Hamilton Anxiety Rating Scale; HAM-D = Hamilton Rating Scale for Depression, 17-item; HIV = human immunodeficiency 
virus; MADRS = Montgomery-Åsberg Depression Rating Scale; PK = pharmacokinetic; SCID-I = Structured Clinical Interview for Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition Axis I Disorders; SSS = Stanford Sleepiness Scale 
*D1 procedures are to be completed prior to dosing 
a Outpatient visits may take place at the subject’s residence or in the clinic. 
b Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis.  Laboratory assessments are to be completed in the morning on Days 8 and 15 and 
during the follow-up visits on Day 21 and Day 28.  
c Urine toxicology for selected drugs of abuse and serum or breath test for alcohol.   
d Serum pregnancy test at screening and urine pregnancy test at Day 1 and Day 28.   
e Female subjects who prematurely discontinue will have a pregnancy test performed at the ET visit. 
f An optional blood sample for hormone and exploratory biochemistry testing, where consent is given.   
g An optional genetic sample for biomarker testing, where consent is given. 
h Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing).  Vital signs will be obtained within ±5 minutes of the scheduled 
time point through 0.5 hours after dosing and ±30 minutes of the scheduled time point from 1 hour after dosing and greater, unless the subject is asleep between the hours of 
23:00 h and 06:00 h.  From Day 1 through Day 7, vital signs will be completed at the following time points: predose, 0.25, 0.5, 1, 2, and 12 hours after dosing.  During the 
outpatient treatment period, vital signs will be completed prior to dosing and 1 hour after dosing.  Vital signs may be repeated at the discretion of the Investigator or Visiting 
Home Healthcare Provider as clinically indicated.   
i Will be performed 1 hour ±15 minutes after dosing on Days 1, 2, 7, and 14, and during the follow-up visit on Day 21. 


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j 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.   
k To be completed to be completed at 8:00 AM (±30 minutes) at each scheduled time point during the Treatment Period, and in the morning on Day 15, Day 21, and Day 28.  
l To be completed within ±5 minutes of the scheduled time point through 0.5 hours after dosing and ±15 minutes of the scheduled time point from 1 hour after dosing and greater, 
unless the subject is asleep between 23:00 h and 06:00 h during the inpatient treatment period.  From Day 1 through Day 7, SSS will be completed at the following time points: 
predose, 0.25, 0.5, 1, and 2 hours after dosing.  During the outpatient treatment period, SSS will be completed prior to dosing and 1 hour after dosing. 
m Plasma samples for PK analysis in Part A and Part B will be collected predose and 0.25, 0.5, 1, 2, 10, and 12 hours postdose on Day 7 (within ±5 minutes of the scheduled time 
point through 0.5 hours after dosing and ±15 minutes of the scheduled time point from 1 hour after dosing and greater), prior to discharge on Day 8 for subjects being discharged 
or 16 hours postdose for subjects remaining as inpatients, predose on Day 14, and in the morning on Day 15.  The time of study drug administration is time zero and all post-
dosing sampling times are relative to this time.  In the event of a dose adjustment, an unscheduled PK sample should be collected just prior to the dose change.  Plasma samples 
for PK analysis will be collected per protocol and subjects may need to be awoken for sample collection.   
n To include those taken within 30 days prior to informed consent and throughout the study. 
 


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Table 3: 
Schedule of Events (Part B) 
 
Screening Period 
Double-Blind, Placebo-Controlled Treatment Period 
Follow-up Period 
Visits 
OUTPATIENT 
INPATIENT 
INPATIENT or OUTPATIENT
a 
OUTPATIENT 
Visit Days 
D-7 to D-1 
D1* 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
D15/ 
ET 
D21 
(+1d) 
D28 
(±3d) 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Family History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCID-I 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confinement 
 
X 
(X) 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
Body Weight/Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X (wt 
only) 
X (wt 
only) 
X (wt 
only) 
Clinical Laboratory 
Assessments
b 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
Drug & Alcohol Screen
c 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test
d 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
e 
 
X 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Sample
f 
O 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genetic Sample
g 
O 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs
h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse Oximetry 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
12-Lead ECG
i 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
C-SSRS
j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Screening Period 
Double-Blind, Placebo-Controlled Treatment Period 
Follow-up Period 
Visits 
OUTPATIENT 
INPATIENT 
INPATIENT or OUTPATIENT
a 
OUTPATIENT 
Visit Days 
D-7 to D-1 
D1* 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
D15/ 
ET 
D21 
(+1d) 
D28 
(±3d) 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CGI-S
k 
X 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
CGI-Ik 
 
 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
HAM-Ak 
X 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
HAM-Dk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
MADRSk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
SF-36k 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
FAs-Dk 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
SSS
l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Plasma PK
m 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
X 
X 
 
 
Study Drug 
Administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse Events 
X 
Prior/Concomitant 
Medications
n 
X 
CGI-I = Clinical Global Impression - Improvement; CGI-S – Clinical Global Impression - Severity; C-SSRS = Columbia Suicide Severity Rating Scale; D = day; ET = early 
termination; ECG = electrocardiogram; FAs-D = fatigue associated with depression; HAM-A = Hamilton Anxiety Rating Scale; HAM-D = Hamilton Rating Scale for Depression, 
17-item; HIV = human immunodeficiency virus; MADRS = Montgomery-Åsberg Depression Rating Scale; PK = pharmacokinetic; SCID-I = Structured Clinical Interview for 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition Axis I Disorders; SF-36 = 36-item short form survey; SSS = Stanford Sleepiness Scale 
*D1 procedures are to be completed prior to dosing 
a Outpatient visits may take place at the subject’s residence or in the clinic. 
b Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis.  Laboratory assessments are to be completed in the morning on Days 8 and 15 and 
during the follow-up visits on Day 21 and Day 28.  
c Urine toxicology for selected drugs of abuse and serum or breath test for alcohol.   
d Serum pregnancy test at screening and urine pregnancy test at Day 1 and Day 28.   
e Female subjects who prematurely discontinue will have a pregnancy test performed at the ET visit. 
f An optional blood sample for hormone and exploratory biochemistry testing, where consent is given.   
g An optional genetic sample for biomarker testing, where consent is given. 


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h Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing).  Vital signs will be obtained within ±5 minutes of the scheduled 
time point through 0.5 hours after dosing and ±30 minutes of the scheduled time point from 1 hour after dosing and greater, unless the subject is asleep between the hours of 
23:00 h and 06:00 h.  From Day 1 through Day 7, vital signs will be completed at the following time points: predose, 0.25, 0.5, 1, 2, and 12 hours after dosing.  During the 
outpatient treatment period, vital signs will be completed prior to dosing and 1 hour after dosing.  Vital signs may be repeated at the discretion of the Investigator or Visiting 
Home Healthcare Provider as clinically indicated.   
i Will be performed 1 hour ±15 minutes after dosing on Days 1, 2, 7, and 14, and during the follow-up visit on Day 21. 
j 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.   
k To be completed at 8:00 AM (±30 minutes) at each scheduled time point during the Treatment Period, and in the morning on Day 15, Day 21, and Day 28.  
l To be completed within ±5 minutes of the scheduled time point through 0.5 hours after dosing and ±15 minutes of the scheduled time point from 1 hour after dosing and greater, 
unless the subject is asleep between 23:00 h and 06:00 h during the inpatient treatment period.  From Day 1 through Day 7, SSS will be completed at the following time points: 
predose, 0.25, 0.5, 1, and 2 hours after dosing.  During the outpatient treatment period, SSS will be completed prior to dosing and 1 hour after dosing. 
m Plasma samples for PK analysis in Part A and Part B will be collected predose and 0.25, 0.5, 1, 2, 10, and 12 hours postdose on Day 7 (within ±5 minutes of the scheduled time 
point through 0.5 hours after dosing and ±15 minutes of the scheduled time point from 1 hour after dosing and greater), prior to discharge on Day 8 for subjects being discharged 
or 16 hours postdose for subjects remaining as inpatients, predose on Day 14, and in the morning on Day 15.  The time of study drug administration is time zero and all post-
dosing sampling times are relative to this time.  In the event of a dose adjustment, an unscheduled PK sample should be collected just prior to the dose change.  Plasma samples 
for PK analysis will be collected per protocol and subjects may need to be awoken for sample collection.   
n To include those taken within 30 days prior to informed consent and throughout the study. 
 
 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............18 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................23 
5. 
INTRODUCTION ......................................................................................................25 
5.1. 
Background of Major Depressive Disorders and Unmet Medical Need ....................25 
5.2. 
SAGE-217 Oral Solution ............................................................................................26 
5.3. 
Summary of Nonclinical and Clinical Experience with SAGE-217 ..........................26 
5.3.1. 
Nonclinical Studies with SAGE-217 ..........................................................................26 
 
26 
 
28 
5.5. 
Dose Justification ........................................................................................................28 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................29 
6.1. 
Part A ..........................................................................................................................29 
6.1.1. 
Primary Objective .......................................................................................................29 
6.1.2. 
Secondary Objective ...................................................................................................29 
6.2. 
Part B ..........................................................................................................................29 
6.2.1. 
Primary Objective .......................................................................................................29 
6.2.2. 
Secondary Objective ...................................................................................................29 
6.3. 
Pharmacokinetic Objective .........................................................................................29 
6.4. 
Endpoints ....................................................................................................................29 
6.4.1. 
Part A ..........................................................................................................................29 
6.4.1.1. 
Primary .......................................................................................................................29 
6.4.1.2. 
Secondary ...................................................................................................................29 
6.4.2. 
Part B ..........................................................................................................................30 
6.4.2.1. 
Primary .......................................................................................................................30 
6.4.2.2. 
Secondary ...................................................................................................................30 
7. 
INVESTIGATIONAL PLAN .....................................................................................31 
7.1. 
Overall Study Design ..................................................................................................31 


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7.2. 
Blinding and Randomization ......................................................................................32 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................34 
8.1. 
Subject Inclusion Criteria ...........................................................................................34 
8.2. 
Subject Exclusion Criteria ..........................................................................................34 
8.3. 
Subject Withdrawal Criteria .......................................................................................35 
8.3.1. 
Study Drug Withdrawal ..............................................................................................35 
8.3.2. 
Criteria for Study Termination ...................................................................................36 
9. 
TREATMENT OF SUBJECTS ..................................................................................37 
9.1. 
Number of Subjects ....................................................................................................37 
9.2. 
Treatment Assignment ................................................................................................37 
9.2.1. 
Part A ..........................................................................................................................37 
9.2.2. 
Part B ..........................................................................................................................37 
9.3. 
Dose Adjustment Criteria ...........................................................................................37 
9.4. 
Prior/Concomitant Medications ..................................................................................38 
9.4.1. 
Prior/Concomitant Medications ..................................................................................38 
9.4.2. 
Restricted Medications ...............................................................................................38 
9.5. 
Treatment Compliance ................................................................................................39 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................40 
10.1. 
Study Drug ..................................................................................................................40 
10.2. 
Batch Formula for Stock SAGE-217 Oral Solution 6 mg/mL ...................................40 
10.3. 
Study Drug Packaging and Labeling ..........................................................................40 
10.4. 
Study Drug Storage .....................................................................................................41 
10.5. 
Administration and Study Drug Accountability .........................................................41 
10.5.1. 
Study Drug Administration.........................................................................................42 
10.5.2. 
Study Drug Accountability .........................................................................................42 
10.6. 
Study Drug Handling and Disposal ............................................................................42 
11. 
ASSESSMENT OF EFFICACY ................................................................................43 
11.1. 
Hamilton Rating Scale for Depression (HAM-D) ......................................................43 
11.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) ........................................43 
11.3. 
Hamilton Anxiety Rating Scale (HAM-A) .................................................................44 
11.4. 
Clinical Global Impression (CGI) ..............................................................................44 
11.5. 
Short Form-36 (SF-36) ...............................................................................................45 


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11.6. 
The Fatigue Associated With Depression (FAs-D) Patient-Reported 
Outcome (PRO) ..........................................................................................................45 
12. 
PHARMACOKINETICS ...........................................................................................46 
12.1. 
Blood Sample Collection ............................................................................................46 
12.2. 
Storage and Shipment of Pharmacokinetic Samples ..................................................46 
12.3. 
Sample Analysis .........................................................................................................46 
13. 
ASSESSMENT OF SAFETY .....................................................................................47 
13.1. 
Safety Parameters .......................................................................................................47 
13.1.1. 
Demographic/Medical History ...................................................................................47 
13.1.2. 
Vital Signs ..................................................................................................................47 
13.1.3. 
Weight and Height ......................................................................................................47 
13.1.4. 
Physical Examination .................................................................................................47 
13.1.5. 
Electrocardiogram (ECG) ...........................................................................................47 
13.1.6. 
Laboratory Assessments .............................................................................................47 
13.1.6.1. 
Hematology .................................................................................................................48 
13.1.6.2. 
Blood Chemistry .........................................................................................................48 
13.1.6.3. 
Urinalysis ....................................................................................................................48 
13.1.6.4. 
Hormones and Exploratory Biochemistry ..................................................................48 
13.1.6.5. 
Virus Serology ............................................................................................................48 
13.1.6.6. 
Pregnancy Test ............................................................................................................48 
13.1.6.7. 
Genetic Testing ...........................................................................................................49 
13.1.6.8. 
Drugs of Abuse and Alcohol ......................................................................................49 
13.1.7. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................49 
13.1.8. 
Stanford Sleepiness Scale (SSS) .................................................................................50 
13.2. 
Adverse and Serious Adverse Events .........................................................................50 
13.2.1. 
Definition of Adverse Events .....................................................................................50 
13.2.1.1. 
Adverse Event .............................................................................................................50 
13.2.1.2. 
Suspected Adverse Reaction .......................................................................................50 
13.2.1.3. 
Serious Adverse Event ................................................................................................50 
13.3. 
Relationship to Study Drug ........................................................................................51 
13.4. 
Recording Adverse Events .........................................................................................51 
13.5. 
Reporting Adverse Events ..........................................................................................52 
13.6. 
Emergency Identification of Study Drug ....................................................................52 


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14. 
STATISTICS ..............................................................................................................54 
14.1. 
Data Analysis Sets ......................................................................................................54 
14.1.1. 
Analysis Populations and Methods .............................................................................54 
14.2. 
Handling of Missing Data ...........................................................................................54 
14.3. 
General Considerations ...............................................................................................54 
14.4. 
Demographics and Baseline Characteristics ...............................................................54 
14.5. 
Efficacy Analyses .......................................................................................................54 
14.6. 
Safety Analyses ..........................................................................................................55 
14.6.1. 
Adverse Events ...........................................................................................................56 
14.6.2. 
Clinical Laboratory Evaluations .................................................................................56 
14.6.3. 
Physical Examinations ................................................................................................56 
14.6.4. 
Vital Signs ..................................................................................................................56 
14.6.5. 
12-Lead Electrocardiogram ........................................................................................56 
14.6.6. 
Prior and Concomitant Medications ...........................................................................56 
14.6.7. 
Columbia Suicide Severity Rating Scale ....................................................................57 
14.6.8. 
Stanford Sleepiness Scale ...........................................................................................57 
14.7. 
Pharmacokinetic Analyses ..........................................................................................57 
14.8. 
Determination of Sample Size ....................................................................................57 
14.9. 
Changes From Protocol Specified Analyses ...............................................................57 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................58 
15.1. 
Study Monitoring ........................................................................................................58 
15.2. 
Audits and Inspections ................................................................................................58 
15.3. 
Institutional Review Board (IRB) ...............................................................................59 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................60 
17. 
ETHICS ......................................................................................................................61 
17.1. 
Ethics Review .............................................................................................................61 
17.2. 
Ethical Conduct of the Study ......................................................................................61 
17.3. 
Written Informed Consent ..........................................................................................61 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................62 
18.1. 
Inspection of Records .................................................................................................62 
18.2. 
Retention of Records ..................................................................................................62 
18.3. 
Confidentiality ............................................................................................................62 
19. 
PUBLICATION POLICY ..........................................................................................64 


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20. 
LIST OF REFERENCES ............................................................................................65 
21. 
APPENDICES ............................................................................................................67 
APPENDIX 1. HAMILTON RATING SCALE FOR DEPRESSION, 17-ITEM 
(HAM-D) ....................................................................................................................68 
APPENDIX 2. MONTGOMERY-ÅSBERG DEPRESSION RATING SCALE 
(MADRS) ...................................................................................................................69 
APPENDIX 3. HAMILTON ANXIETY RATING SCALE (HAM-A) .....................................71 
APPENDIX 4. CLINICAL GLOBAL IMPRESSION–IMPROVEMENT SCALE 
(CGI-I) AND SEVERITY SCALE (CGI-S) ..............................................................72 
APPENDIX 5. SHORT-FORM 36 (SF-36) ................................................................................73 
APPENDIX 6. THE FATIGUE ASSOCIATED WITH DEPRESSION (FAS-D) 
PATIENT-REPORTED OUTCOME (PRO) .............................................................78 
APPENDIX 7. COLUMBIA - SUICIDE SEVERITY RATING SCALE (C-SSRS).................80 
APPENDIX 8. STANFORD SLEEPINESS SCALE (SSS) .......................................................86 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Schedule of Events (Part A) .......................................................................................12 
Table 3: 
Schedule of Events (Part B) ........................................................................................15 
Table 4: 
Abbreviations and Specialist Terms ...........................................................................23 
Table 5: 
Batch Formula for 125 mL of Stock SAGE-217 Oral Solution 6 mg/mL..................40 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 4: 
Abbreviations and Specialist Terms 
Abbreviation or Specialist Term Explanation 
AUC 
area under the concentration-time curve 
AUC∞ 
area under the concentration-time curve from time zero to infinity 
BMI 
body mass index 
CGI-I 
Clinical Global Impression - Improvement 
CGI-S 
Clinical Global Impression - Severity 
Cmax 
maximum (peak) plasma concentration 
CS 
clinically significant  
Css 
steady-state drug concentration in the plasma during oral intake 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP450 
cytochrome P450 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EP 
European Pharmacopeia 
FAs-D  
fatigue associated with depression 
GABA 
γ-aminobutyric acid 
GABAA 
γ-aminobutyric acid-ligand gated chloride channel 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HAM-A 
Hamilton Anxiety Rating Scale 
HAM-D 
17-item Hamilton Rating Scale for Depression 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HPβCD 
hydroxypropyl-β-cyclodextrin 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 


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Abbreviation or Specialist Term Explanation 
IRB 
Institutional Review Board 
MAD 
multiple-ascending dose 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDD 
major depressive disorders 
MMRM 
mixed effects model for reported measures 
MTD 
maximum tolerated dose 
n 
number 
NCS 
not clinically significant  
NF 
National Formulary 
PK 
pharmacokinetic(s) 
PPD 
postpartum depression 
SAD 
single-ascending dose 
SCID-I 
Structured Clinical Interview for DSM-5 Axis I Disorders 
SD 
standard deviation 
SF-36 
36-item short form survey 
SOC 
system organ class 
SRC 
Safety Review Committee 
SSS 
Stanford Sleepiness Scale 
TEAE 
treatment-emergent adverse event  
tmax 
time at maximum (peak) plasma concentration 
USP 
United States Pharmacopeia 
WHO 
World Health Organization 
WHO-DD 
World Health Organization-Drug Dictionary 
 


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25 
5.
INTRODUCTION
5.1.
Background of Major Depressive Disorders and Unmet Medical
Need
World Health Organization (WHO) has identified depression as the leading cause of disability 
worldwide, and a major contributor to the overall global burden of disease 
(http://www.who.int/mediacentre/factsheets/fs369/en/).  Globally, depression has been estimated 
to affect 350 million people.  
In DSM-5, depression refers to an overarching set of diagnoses, including disruptive mood 
dysregulation disorder, major depressive disorder, persistent depressive disorder (dysthymia), 
premenstrual dysphoric disorder, substance/medication-induced depressive disorder, depressive 
disorder due to another medical condition, other specified depressive disorder, and unspecified 
depressive disorder.   
In the US, the economic burden of depression, including workplace costs, direct costs and 
suicide-related costs, was estimated to be $210.5 billion in 2010 (Greenberg 2015).  As per 
WHO statistics, over 800,000 people die due to suicide every year, and suicide is the second 
leading cause of death in 15- to 29-year-olds.  In the US, an estimated 10% to 15% of individuals 
with depression commit suicide (Angst 1999).   
Antidepressants are mainstay of pharmacological treatment for depressive disorders.  Selective 
serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic 
antidepressants, monoamine oxidase inhibitors, and other compounds that affect monoaminergic 
neurotransmission, such as mirtrazapine and bupropion, represent the major classes of 
antidepressants.  While antidepressants are widely used, large scale studies have demonstrated 
their limited efficacy.  For example, in the STAR*D trial where over 2800 patients were treated 
in “real world” settings, the HAM-D remission rate was 28% following 14 weeks of treatment 
with citalopram, a typical selective serotonin reuptake inhibitor (Trivedi 2006).  Recent studies 
have shown a number of symptoms that remain untreated, such as cognitive impairment, sleep 
disturbances and anxiety, even in patients that are in remission over a long period of time after 
treatment (Conradi 2011; Romera 2013).  A close examination of randomized placebo-controlled 
trials of antidepressants approved by the Food and Drug Administration in the treatment of both 
major or minor depressive disorders demonstrated Cohen’s d effect sizes below 0.2 and high 
placebo response rates (Kirsch 2008; Fournier 2010), emphasizing the challenges in assessing 
antidepressant drug efficacy and the unmet need in the treatment of depression.   
Converging preclinical and clinical evidence (Gerner 1981; Honig 1988; Drugan 1989; 
Luscher 2011; Mann 2014) implicates deficits in GABAergic neurotransmission in the 
pathophysiology of depressive disorders including MDD and PPD.  Furthermore, several pieces 
of experimental data implicate deficiencies in the normal regulation of endogenous neuroactive 
steroids in depressive disorders (Maguire 2008; Maguire 2009).  The neuroactive steroid class of 
compounds includes the endogenous neuroactive steroid, allopregnanolone.  Allopregnanolone is 
a positive allosteric modulator of both synaptic and extrasynaptic GABAA receptors – the 
prominent inhibitory transmitter system in the brain.  Depressed patients show low levels of 
GABA in the brain and of neurosteroids in the CSF and plasma, and antidepressant therapy 








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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Part A 
6.1.1. 
Primary Objective 
The primary objective of the study is to evaluate the safety and tolerability of SAGE-217 Oral 
Solution 30 mg.   
6.1.2. 
Secondary Objective 
The secondary objective of Part A is to determine if treatment with SAGE-217 Oral Solution 
30 mg for 14 days reduces depressive symptoms.   
6.2. 
Part B 
6.2.1. 
Primary Objective 
The primary objective of the study is to evaluate the safety and tolerability of SAGE-217 Oral 
Solution 30 mg.   
6.2.2. 
Secondary Objective 
The secondary efficacy objective for Part B of the study is to determine if treatment with 
SAGE-217 Oral Solution 30 mg reduces depressive symptoms in subjects with moderate to 
severe MDD compared to matching placebo.   
6.3. 
Pharmacokinetic Objective 
The PK objective of Part A and Part B is to assess the PK profile of SAGE-217 Oral Solution in 
plasma samples.   
6.4. 
Endpoints 
6.4.1. 
Part A 
6.4.1.1. 
Primary 
The primary endpoint is 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 electrocardiograms (ECGs); Stanford Sleepiness Scale (SSS) score; physical examination; 
and suicidal ideation using the Columbia-Suicide Severity Rating Scale (C-SSRS).   
6.4.1.2. 
Secondary 
Reduction in depressive symptoms as assessed by the following: 
• Change from baseline in HAM-D total score at all time points;  


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• HAM-D response (defined as having a 50% or greater reduction from baseline in 
HAM-D total score);  
• HAM-D remission (defined as having a HAM-D total score of ≤7);  
• Change from baseline in the Montgomery-Åsberg Depression Rating Scale 
(MADRS) total score at all time points; 
• Change from baseline in HAM-D subscale and individual item scores at all time 
points;  
• Change from baseline in Hamilton Anxiety Rating Scale (HAM-A) total score at all 
time points; and  
• Clinical Global Impression – Improvement (CGI-I) response (defined as a CGI-I 
score of “very much improved” or “much improved”).   
6.4.2. 
Part B 
6.4.2.1. 
Primary 
The primary endpoint is 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; SSS score; physical examination; and suicidal ideation using the C-SSRS.   
6.4.2.2. 
Secondary 
Reduction in depressive symptoms, compared to placebo, as assessed by the following: 
• Change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D) 
total score at all time points;  
• HAM-D response;  
• HAM-D remission;  
• Change from baseline in the MADRS total score at all time points; 
• Change from baseline in HAM-D subscale and individual item scores at all time 
points;  
• Change from baseline in HAM-A total score at all time points;  
• CGI-I response; and 
• 36-item short form survey (SF-36) and fatigue associated with depression (FAs-D) 
patient-reported outcome.   


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This study is a two-part, multicenter, Phase 2a study to evaluate the safety, tolerability, PK, and 
efficacy of SAGE-217 Oral Solution in approximately 62 adult subjects with MDD.  Part A of 
the study is an open-label design with SAGE-217 Oral Solution dosing for 14 days.  Part B of the 
study is a randomized, double-blind, parallel-group, placebo-controlled design with SAGE-217 
Oral Solution or matching placebo dosing for 14 days.  Separate cohorts of subjects will be 
enrolled in Part A and Part B; subjects participating in Part A cannot enroll in Part B.   
Parts A and B of the study will consist of an up to 7-day Screening Period (Days -7 to -1), a 
14-day Treatment Period, and a 2-week Follow-up Period (through Day 28).   
During the Screening Period (Day -7 to Day -1), after signing the informed consent form (ICF), 
subjects will be assessed for study eligibility, and the severity of each subject’s MDD will be 
evaluated using HAM-D.  The Screening Period assessments will be conducted on an outpatient 
basis.   
If applicable, standard of care data collected prior to obtaining informed consent may also be 
included as screening data, if appropriate, such as laboratory tests, ECG, physical examination, 
and vital signs conducted within the preceding 48 hours, as long as the requirement for the 
screening assessment to be collected retrospectively is met in full.  If applicable, to ensure 
protocol compliance, any standard of care data eligible for inclusion as screening data must 
include the precise nature and timing of data collection.   
During the 14-day study Treatment Period of Parts A and B, subjects must remain inpatient for 
the first 7 days at minimum and per Investigator’s judgement thereafter.  The Follow-up Period 
assessments will be conducted on an outpatient basis.   
The study will be conducted in two parts: 
• Part A:  Beginning on Day 1, subjects will receive open-label SAGE-217 Oral 
Solution at 8:00 PM (±15 minutes) with food (as outlined in Section 9.2.1).  Subjects 
will receive SAGE-217 Oral Solution 30 mg from Day 1 to Day 14 as tolerated.   
• Part B:  Based on the results of Part A, eligible subjects will be stratified based on use 
of antidepressant treatment (current/stable or not treated/withdrawn ≥30 days) and 
randomized within each stratum in a 1:1 fashion to receive SAGE-217 Oral Solution 
or matching placebo for 14 days beginning on Day 1 as tolerated.  All doses of study 
drug will be administered at 8:00 PM (±15 minutes) with food as outlined in 
Section 9.2.2.   
Part A may be terminated and Part B initiated if there is a clear signal of activity based on the 
HAM-D scores and/or other scales being assessed.  Alternatively, upon completion of Part A, 
Part B may begin.  The study may be terminated if there is clear lack of activity based on 
HAM-D scores during Part A.   
In Part A and Part B, study drug (SAGE-217 Oral Solution or matching placebo) will be 
administered at the study center for at least the first 7 days of the Treatment Period, which 


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includes Day 1 of study drug administration through completion of study drug administration on 
Day 14.  Subjects may be discharged after a minimum 7-day inpatient stay, following completion 
of the Day 7 assessments.  If their clinical condition does not allow discharge, the Investigator 
may keep the subjects as inpatients for a longer period of time.  Subjects discharged from the 
inpatient unit may receive treatment with study drug for the remainder of the 14-day Treatment 
Period as outpatients.  For the outpatient phase, dosing will be done at the clinical site or, if 
suitable arrangements can be made, via home administration where local regulations allow.  
Home administration of study drug will be performed according to a site-specific plan by a 
healthcare professional trained on the protocol and delivery of the study drug.   
Subjects will be monitored for safety during the Treatment and Follow-up Periods including 
monitoring for adverse events/serious adverse events, routine clinical laboratory assessments, 
physical examination, vital signs, and ECG. 
During the Treatment Period, subjects will be able to receive study drug as long as there are no 
dose-limiting safety/tolerability concerns.  Subjects who experience moderate or severe adverse 
events that according to the clinical judgement of the Investigator are related to study drug while 
receiving the 30 mg dose of study drug will receive 20 mg for the remaining of the Treatment 
Period.  Subjects who experience moderate or severe related adverse events while receiving the 
20 mg dose of study drug may not be able to continue receiving study drug based on the 
evaluation and clinical judgment of the Investigator, and may be terminated from the study.   
Dosing may also be modified based on tolerability as assessed with SSS scores.  Any SSS score 
of ≥6 will be reassessed within 10 minutes.  If a subject is receiving the 30 mg dose of study 
drug and has an SSS score of ≥6 that is confirmed on repeat assessment during normal waking 
hours, the dose will be decreased to 20 mg for the rest of the Treatment Period.  If a subject is 
receiving the 20 mg dose of study drug and has an SSS score of ≥6 that is confirmed on repeat 
assessment during normal waking hours, then study drug will be discontinued and the subject 
will be terminated from the study.   
7.2. 
Blinding and Randomization 
Part A is open-label with no control group; therefore, there will be no randomization or blinding.   
Part B is a double-blind, placebo-controlled study.  Subjects who meet the entrance criteria will 
be stratified based on use of antidepressant treatment (current/stable or not treated/withdrawn 
≥30 days) and randomly assigned within each stratum in a 1:1 ratio to receive SAGE-217 Oral 
Solution or taste-matched placebo according to a computer-generated randomization schedule.  
Once it has been determined that a subject meets eligibility criteria, the subject will be 
sequentially assigned a subject number from the randomization schedule provided to the 
unblinded pharmacist.  Subject identification numbers will consist of the site number (eg, “01”) 
followed by numbering starting with double zero (eg, 01-001, 01-002, 01-003 through 01-062).   
The randomization schedule will be generated using SAS V9.2 or later.  Only the clinic 
pharmacist or designated pharmacy staff, who is responsible for preparing the solutions, will be 
given a copy of the randomization schedule.  In the event of a medical emergency, the 
pharmacist may reveal actual solution contents to the Investigator, who should also alert Sage of 
the emergency (see Section 13.6 for more details related to unblinding).  In all cases where the 
study drug allocation for a subject is unblinded, pertinent information (including the reason for 


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unblinding) must be documented in the subject’s records and on the electronic case report form 
(eCRF).  If the subject or study center personnel (other than pharmacist) have been unblinded, 
the subject will be terminated from the study.  In addition, an unblinded Monitor will perform 
drug accountability during the study.   


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
The following inclusion criteria must be met for individuals to be eligible for the study.   
1. Subject has signed an ICF prior to any study-specific procedures being performed. 
2. Subject is an ambulatory male or female between 18 and 65 years of age, inclusive. 
3. Subject is in good physical health and has no clinically significant findings, as 
determined by the Investigator, on physical examination, 12-lead ECG, or clinical 
laboratory tests. 
4. Subject agrees to adhere to the study requirements.   
5. Subject has a diagnosis of MDD that has been present for at least a 4-week period as 
diagnosed by Structured Clinical Interview for Diagnostic and Statistical Manual of 
Mental Disorders, Fifth Edition (DSM-5) Axis I Disorders (SCID-I).   
6. Subject has a HAM-D total score of ≥22 at screening and Day 1 (prior to dosing).   
7. Subject has a HAM-A total score of ≥20 at screening and Day 1 (prior to dosing) (Part B 
only).   
8. Subject is willing to delay start of other antidepressant or antianxiety medications and 
any new pharmacotherapy regimens, including as-needed benzodiazepine anxiolytics, 
during the screening and treatment periods.   
9. Subject agrees to practice an acceptable method of highly effective birth control at 
screening and throughout study participation.  Highly effective methods of birth control 
include sexual abstinence (for males and females); vasectomy; or a condom with 
spermicide in combination with a highly effective female partner’s method (for males); 
and hormonal methods of contraception (ie, established use of oral, implantable, 
injectable, or transdermal hormones); placement of an intrauterine device; placement of 
an intrauterine system; and mechanical/barrier method of contraception (ie, condom or 
occlusive cap [diaphragm or cervical/vault cap] in conjunction with spermicide [foam, 
gel, film, cream, or suppository]) (for females).   
8.2. 
Subject Exclusion Criteria 
Subjects will be excluded if they meet any of the following exclusion criteria.   
1. Subject has a history of suicide attempt.   
2. Subject has a recent history or active clinically significant manifestations of metabolic, 
hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, 
musculoskeletal, dermatological, urogenital, neurological, or eyes, ears, nose, and throat 
disorders, or any other acute or chronic condition that, in the Investigator's opinion, 
would limit the subject's ability to complete or participate in this clinical study.   


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3. Subject has a history of treatment-resistant depression, defined as persistent depressive 
symptoms despite treatment with adequate doses of antidepressants from two different 
classes for an adequate amount of time (ie, at least 4 weeks of treatment).   
4. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds.   
5. Subject has a positive pregnancy test at screening or on Day 1 prior to the start of study 
drug administration.   
6. Subject has detectable hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (HCV), 
or human immunodeficiency virus (HIV) antibody at screening. 
7. Subject has active psychosis per Investigator assessment.   
8. Subject has a medical history of seizures.   
9. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder.   
10. Subject has a history of alcohol or drug dependence (including benzodiazepines) in the 
12 months prior to screening.   
11. Subject has had exposure to another investigational medication or device within 30 days 
prior to screening.   
12. Subject has been treated or randomized in this study (eg, Part A) or any other study 
employing SAGE-217 previously (ie, subject may not have received study drug and then 
re-enroll).   
13. Subject has had administration of psychotropics that have been initiated within 14 days 
prior to screening and/or are not being taken at a stable dose.   
14. Use of any known strong inhibitors and/or inducers of CYP3A4 within the 14 days or 
five half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, Seville 
oranges, or St. John's Wort or products containing these within 30 days prior to receiving 
the first dose of study drug.   
8.3. 
Subject Withdrawal Criteria 
If there is an adverse event or medical reason for the withdrawal, the subject should be followed 
medically until the condition has either resolved or is stable.  Details of the reason for 
withdrawal should be recorded in the subject’s eCRF.   
Subjects who withdraw should, if possible, have a follow-up examination, including a physical 
examination, the appropriate investigations, vital signs, and clinical laboratory tests (including 
pregnancy tests), as outlined for the Day 15 visit (Table 2 and Table 3).  All details of this 
follow-up examination should be recorded in the subject’s medical source documents.   
8.3.1. 
Study Drug Withdrawal 
Participation in the study is strictly voluntary.  Subjects are free to discontinue the study at any 
time without giving their reason(s).   
A subject must be withdrawn from the study treatment in the event of any of the following: 


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• Withdrawal of the subject’s consent; 
• New onset of a condition that would have met exclusion criterion, is clinically 
relevant and affects the subject’s safety, and discontinuation is considered necessary 
by the Investigators and/Sponsor; 
• Occurrence of intolerable adverse events;  
• Occurrence of pregnancy;  
• Intake of nonpermitted concomitant medication; 
• Subject noncompliance;  
• Significant protocol deviation determined in consultation with the Medical Monitor. 
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.   
Subjects may be withdrawn from the study if there is concern for the subject’s safety or it is 
determined that the subject is no longer a qualified participant.  Subjects who withdraw should, if 
possible, have a follow-up examination, including a physical examination, the appropriate 
investigations, vital signs, and clinical laboratory tests (including pregnancy tests), as outlined 
for the Day 15 visit (Table 2 and Table 3).  All details of this follow-up examination should be 
recorded in the subject’s medical source documents.   
Subjects who withdraw or are withdrawn from the study will be replaced only if they withdraw 
prior to dosing.  Subjects who are withdrawn from the study, fail to return or are no longer 
qualified will not be replaced.   
8.3.2. 
Criteria for Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons, including the occurrence of adverse events or other findings suggesting unacceptable 
risk to subjects, or for administrative reasons.  In the event of study termination, Sage 
Therapeutics will provide written notification to the Investigator.  Investigational sites must 
promptly notify their Institutional Review Board (IRB) and initiate withdrawal procedures for 
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9. 
TREATMENT OF SUBJECTS 
9.1. 
Number of Subjects 
Approximately ten subjects with MDD will be enrolled into Part A of the study.  Up to 
52 subjects may be randomized in Part B to ensure at least 46 evaluable subjects for Part B.  
Evaluable subjects are defined as those subjects receiving study drug with at least one post-
baseline HAM-D assessment.   
9.2. 
Treatment Assignment 
Study drug will be administered with food in both the inpatient and outpatient treatment periods.  
Food intake will be standardized as specified by the Sponsor.   
9.2.1. 
Part A 
Subjects participating in Part A of the study will take study drug (SAGE-217) in an open-label 
manner.  Subjects will be administered a 30 mg dose of study drug at 8:00 PM (±15 minutes) 
with food for 14 days (Day 1 to Day 14) as tolerated.   
9.2.2. 
Part B 
Subjects participating in the randomized, double-blind, placebo-controlled portion of the study 
(Part B) will be randomly assigned to receive SAGE-217 Oral Solution 30 mg or matching 
placebo solution on a 1:1 basis according to a computer-generated randomization schedule; the 
randomization schedule will be stratified to allow for treatment balance within each use of 
antidepressant stratum.   
Subjects, clinicians, and study team will be blinded to treatment allocation.  The pharmacist, who 
will prepare the oral solutions according to the randomization schedule, and an unblinded 
Monitor, who will perform drug accountability during the study, will be unblinded.  
9.3. 
Dose Adjustment Criteria 
During the Treatment Period, subjects will be able to receive study drug as long as there are no 
dose-limiting safety/tolerability concerns.   
In both Part A and Part B, subjects who experience moderate or severe adverse events that 
according to the clinical judgement of the Investigator are related to study drug while receiving 
the 30 mg dose of study drug will receive 20 mg for the remaining of the Treatment Period.  
Subjects who experience moderate or severe related adverse events while receiving the 20 mg 
dose of study drug may not be able to continue receiving study drug based on the evaluation and 
clinical judgment of the Investigator, and may be terminated from the study.   
Dosing may also be modified based on tolerability as assessed with SSS scores.  Any SSS score 
of ≥6 will be reassessed within 10 minutes.  If a subject is receiving the 30 mg dose of study 
drug and has an SSS score of ≥6 that is confirmed on repeat assessment during normal waking 
hours, the dose will be decreased to 20 mg for the rest of the Treatment Period.  If a subject is 
receiving the 20 mg dose of study drug and has an SSS score of ≥6 that is confirmed on repeat 


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assessment during normal waking hours, then study drug will be discontinued and the subject 
will be terminated from the study.   
Part A may be terminated and Part B initiated if there is a clear signal of activity based on the 
HAM-D scores and/or other scales being assessed.  The study may be terminated if there is clear 
lack of activity based on HAM-D scores during Part A.  A Data Review Team will assess the 
HAM-D and other data on an ongoing basis during Part A.   
9.4. 
Prior/Concomitant Medications 
9.4.1. 
Prior/Concomitant Medications 
Subjects will receive standard of care for adult patients diagnosed with moderate to severe MDD.  
Psychotropic medications, which must have been initiated at least 14 days prior to screening, 
must remain at a stable dose until completion of the Day 15 assessments (Parts A and B).   
Eligible subjects will be stratified based on use of antidepressant treatment (current/stable or not 
treated/withdrawn ≥30 days) and randomly assigned within each stratum in a 1:1 ratio to receive 
SAGE-217 Oral Solution or taste-matched placebo.   
In this study, psychotropic medications refer to central nervous system active medications taken 
to help depressive symptoms, and include antidepressants, benzodiazepines, and hypnotic agents.  
Subjects presenting to the study on antidepressants may be eligible to participate if they have 
been on a stable dose for at least 14 days.  Those subjects on benzodiazepines and hypnotic 
agents may be considered for eligibility based on specific discussions between the Investigator 
and the Sponsor to ensure safety.  Subjects on other psychotropic medications, including 
stimulants, antipsychotics, and mood stabilizers, are not eligible to participate in this study.   
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 
Section 9.4.2.  In both Part A and Part B, all medications should be documented throughout the 
study from 30 days prior to signing the ICF through Day 28 (±3 days) and recorded on the eCRF.  
Prior medications (ie, those taken prior to signing of ICF) that required washout for study entry 
will also be documented.   
9.4.2. 
Restricted Medications 
Restrictions on specific classes of medications include the following: 
• Initiation of new antidepressant therapy is prohibited upon admission to the study 
center for those eligible subjects who desire study participation.  Those subjects 
already taking an antidepressant at the time of study entry (and meeting all study 
inclusion criteria) will be permitted to remain on the pre-existing antidepressant at 
their current dose if they were on this medication for at least 14 days prior to study 
enrollment.   
• Benzodiazepines are to be avoided as much as possible.  Eligible subjects taking a 
stable dose of benzodiazepine for at least 14 days prior to the study will be discussed 
on a case-by-case basis with the Sponsor to determine eligibility.  Subjects may be 
permitted to continue to take their current dose of the benzodiazepine (to prevent 


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acute withdrawal), but no new benzodiazepine use will be permitted during the course 
of the study.   
• The use of hypnotics for sleep/insomnia such as Ambien® and trazodone is to be 
avoided; use of hypnotics will be discussed on a case-by-case basis with the Sponsor.   
• Anticonvulsants and atypical antipsychotics are prohibited.   
9.5. 
Treatment Compliance 
Investigational product will be prepared by the site pharmacist.  The Investigator(s) or designee 
will record the time and dose of study drug administration in the source documents.  Any reasons 
for noncompliance will also be documented, including: 
• Missed visits;  
• Interruptions in the schedule of administration; and 
• Nonpermitted medications. 
The time at which study procedures are conducted should follow the protocol timelines as 
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10.
STUDY DRUG MATERIALS AND MANAGEMENT
10.1. 
Study Drug 
SAGE-217 Oral Solution is available as a 6 mg/mL stock aqueous solution of SAGE-217 Drug 
Substance containing 40% HPβCD and 0.0025% sucralose, which is further diluted with Sterile 
Water for Injection to achieve the selected dose.  The 6 mg/mL stock SAGE-217 Oral Solution 
will be compounded from SAGE-217 Drug Substance Powder in the Bottle and Excipient (s) in 
the Bottle (manufactured under current Good Manufacturing Practice [GMP] conditions  
) and further admixed at the clinical site in preparation for dosing.   
A matching placebo oral solution will be prepared for administration without the active 
ingredient, but including the HPβCD and sucralose, as well as three taste-masking components to 
preserve the blinding.  Detailed instructions for study drug (SAGE-217 Oral Solution 30 mg and 
matching placebo) preparation will be provided in the Pharmacy Manual.   
10.2. 
Batch Formula for Stock SAGE-217 Oral Solution 6 mg/mL 
Each bottle of SAGE-217 Oral Solution 6 mg/mL will be compounded at the clinical pharmacy 
from components manufactured 
 and supplied by the Sponsor per the directions 
provided in the Pharmacy Manual.  The batch formula for a 125 mL solution of the 6 mg/mL 
stock solution is shown in Table 5.   
Table 5: 
Batch Formula for 125 mL of Stock SAGE-217 Oral Solution 6 mg/mL 
Ingredient 
Compendia Specification Concentration (mg/mL) 
Amount (mg/Bottle) 
SAGE-217 
not applicable 
6 
750 
HPβCD
USP/EP 
457 
57,100 
Sucralose 
USP/NF 
0.025 
3.124 
Water for Injection 
USP 
not applicable 
85,650 
Abbreviations:  EP = European Pharmacopeia; HPβCD = hydroxypropyl-β-cyclodextrin; NF = National Formulary; 
USP = United States Pharmacopeia 
Additional excipients will be utilized in matching placebo to match the taste of SAGE-217 Oral 
Solution.  They include sucrose octaacetate, tannic acid, and ammonium glycyrrhizate.  The 
quantities of these excipients will vary depending on the dose of SAGE-217 to match the taste of 
each individual dose.   
10.3. 
Study Drug Packaging and Labeling 
The composition and pharmaceutical quality of the investigational product will be maintained 
according to the current GMP and Good Clinical Practice (GCP) guidelines and available for 
review in the study medication documentation.  Study drug will be provided to the site as powder 
in the bottle and excipient(s) in the bottle units to be compounded in the pharmacy at a volume of 
125 mL of a 6 mg/mL stock solution and then further diluted to approximately 40 mL at the 
identified doses.  The taste-matching excipients will be provided to the clinical pharmacies via 
suitable suppliers or can be ordered directly by the clinical pharmacies.  Study drug labels with 


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all required information and conforming to all applicable Code of Federal Regulations and 
GMP/GCP guidelines will be prepared by the clinical research organization.   
10.4. 
Study Drug Storage 
Upon receipt of study drug, the Investigator or designee will inspect the materials and complete 
and return the acknowledgment of receipt form enclosed with the parcel.  A copy of the signed 
receipt will be kept in the study files.  
The study drug materials must be carefully stored at the temperature specified in the Pharmacy 
Manual (eg, clinical dosing solutions stored at approximately 2 to 8°C for 11 days with room 
temperature excursions allowed for up to 24 hours after preparation), safely and separately from 
other drugs.  The study drug may not be used for any purpose other than the present study.  After 
the study is completed, all unused study drug must be retained, returned as directed, or destroyed 
on site per the Sponsor’s instructions.   
The Investigator or designee will be responsible for ensuring appropriate storage, compounding, 
dispensing, inventory, and accountability of all clinical supplies.  An accurate, timely record of 
the disposition of all clinical supplies must be maintained.  The supplies and inventory must be 
available for inspection by the designated representatives of the Sponsor or the Sponsor’s 
representatives on request, and must include the information below: 
• The identification of the subject to whom the drug was dispensed; 
• The date(s) and quantity of the drug dispensed to the subject; and 
• The product lot/batch number. 
The preparation of the study drugs must be documented on a ‘Drug Preparation and Dispensing 
Log Form’ or similar form. 
The drug inventory and any clinical supplies that have been destroyed must be documented.  
This documentation must include at least the information below or as agreed with the Sponsor: 
• The number of prepared units; 
• The number of administered units; 
• The number of unused units; 
• The number of units destroyed at the end of the study; 
• The date, method, and location of destruction. 
10.5. 
Administration and Study Drug Accountability 
Doses will be prepared as an approximate 40 mL oral solution to be swallowed all at once, 
followed by approximately 200 mL of water that has been used to rinse the dosing bottle.  The 
start time of swallowing the approximately 40 mL oral solution is time zero for all assessments.  
Subjects may have assistance from the clinic staff when taking the study drug.   


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10.5.1. 
Study Drug Administration 
While confined in the clinical unit (at least Day 1 through Day 7 of Part A and Part B), subjects 
will receive study drug at 8:00 PM (±15 minutes) with food.   
Food intake will be standardized as specified by the Sponsor.  Subjects who experience moderate 
or severe related adverse events while receiving study drug may not be able to continue receiving 
study drug based on the evaluation and clinical judgment of the Investigator, and may be 
terminated from the study.   
Subjects may be discharged after a minimum 7-day inpatient stay, following completion of the 
Day 7 assessments.  If their clinical condition does not allow discharge, the Investigator may 
keep the subjects as inpatients for a longer period of time.   
For non-confinement days (Days 8 through 14 of Parts A and B), dosing will be done at the 
clinical site or, if suitable arrangements can be made, via home administration where local 
regulations allow.  Home administration of study drug will be performed according to a site-
specific plan by a healthcare professional trained on the protocol and delivery of the study drug.   
10.5.2. 
Study Drug Accountability 
The study drug provided is for use only as directed in this protocol.   
The Investigator or designee must maintain a record of all study drug received, used, and 
discarded.  It must be clear from the records which subject received which dose of active or 
matching placebo treatment.   
The Sponsor 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.  Only unblinded personnel will be able to access the study drug and 
accountability documentation from first dosing through database hard lock.   
10.6. 
Study Drug Handling and Disposal 
The pharmacist or designee for drug accountability is to document the date and time of initial 
compounding, subsequent admixture of dosing solutions, administration of test article, and for 
which subject the study drug was intended (ie, record subject initials and birth date or other 
unique identifier).   
At the end of the study, any unused study drug will be retained or returned to the Sponsor for 
destruction or destroyed locally per the Sponsor’s directions.  The disposition of study drug will 
be documented.   


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11. 
ASSESSMENT OF EFFICACY 
11.1. 
Hamilton Rating Scale for Depression (HAM-D) 
The primary outcome measure in Part B will be the change from baseline in 17-item HAM-D 
total score at the end of the Treatment Period (Day 15).  The HAM-D will be administered 
before, during, and after the administration of open-label (Part A) and blinded (Part B) study 
drug.   
The 17-item HAM-D will be used to rate the severity of depression in subjects who are already 
diagnosed as depressed (Hamilton 1960).  The 17-item HAM-D comprises individual ratings 
related to the following symptoms: depressed mood (sadness, hopeless, helpless, worthless), 
feelings of guilt, suicide, insomnia (early, middle, late), work and activities, retardation 
(slowness of thought and speech; impaired ability to concentrate; decreased motor activity), 
agitation, anxiety (psychic and somatic), somatic symptoms (gastrointestinal and general), 
genital symptoms, hypochondriasis, loss of weight, and insight.  The HAM-D assessments are to 
be completed at 8:00 AM (±30 minutes) at each scheduled time point during the Treatment 
Period, and in the morning on Day 15, Day 21, and Day 28.  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.  Item 16 
can be rated according to history (item 16A) or actual weight change (item 16B).  The item 16 
score is calculated as the item 16 response that is not equal to 3 (ie, “Not assessed”).   
In addition to the primary efficacy endpoint of change from baseline in HAM-D total score 
(Part B), 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.  A copy of the HAM-D is 
provided in Appendix 1.   
11.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item diagnostic questionnaire that psychiatrists use to measure the severity 
of depressive episodes in subjects with mood disorders.  It was designed as an adjunct to the 
HAM-D that would be more sensitive to the changes brought on by antidepressants and other 
forms of treatment than the Hamilton Scale.   
The MADRS assessments are to be completed at 8:00 AM (±30 minutes) at each scheduled time 
point during the Treatment Period, and in the morning on Day 15, Day 21, and Day 28.   
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 (McDowell 2006; Müller-Thomsen 2005). 
The questionnaire includes questions on the following symptoms:   
1. Apparent sadness  
2. Reported sadness  


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3. Inner tension  
4. Reduced sleep  
5. Reduced appetite  
6. Concentration difficulties  
7. Lassitude  
8. Inability to feel  
9. Pessimistic thoughts  
10. Suicidal thoughts 
The MADRS total score will be calculated as the sum of the 10 individual item scores.  A copy 
of the MADRS is provided in Appendix 2.   
11.3. 
Hamilton Anxiety Rating Scale (HAM-A) 
The 14-item HAM-A will be used to rate the severity of symptoms of anxiety (Hamilton 1959).  
Each of the 14 items is defined by a series of symptoms, and measures both psychic anxiety 
(mental agitation and psychological distress) and somatic anxiety (physical complaints related to 
anxiety).  Scoring for HAM-A is calculated by assigning scores of 0 (not present) to 4 (very 
severe), with a total score range of 0 to 56, where <17 indicates mild severity, 18 to 24 mild to 
moderate severity, and 25 to 30 moderate to severe severity.   
The HAM-A assessments are to be completed at 8:00 AM (±30 minutes) at each scheduled time 
point during the Treatment Period, and in the morning on Day 15, Day 21, and Day 28.  Every 
effort should be made for the same rater to perform all HAM-A assessments for an individual 
subject.   
The HAM-A total score will be calculated as the sum of the 14 individual item scores.  A copy of 
the HAM-A is provided in Appendix 3.   
11.4. 
Clinical Global Impression (CGI) 
The CGI is a validated measure often utilized in clinical trials to allow clinicians to integrate 
several sources of information into a single rating of the subject’s condition.  The CGI scale 
consists of 3 items.  Only the first 2 items are being used in this study.   
The 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.  The CGI-S assessments are to be completed at 8:00 AM (±30 minutes) at each 
scheduled time point during the Treatment Period, and in the morning on Day 15, Day 21, and 
Day 28.   
The CGI-I employs a 7-point Likert scale to measure the overall improvement in the subject’s 
condition posttreatment.  The Investigator will rate the subject’s total improvement whether or 
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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 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.”  The 
CGI-I assessments are to be completed at 8:00 AM (±30 minutes) at each scheduled time point 
during the Treatment Period, and in the morning on Day 15, Day 21, and Day 28.  A copy of the 
CGI is provided in Appendix 4.   
11.5. 
Short Form-36 (SF-36) 
The SF-36® Health Survey is a subject-reported 36-item instrument for measuring functional 
health and well-being in eight dimensions (physical functioning, role physical, bodily pain, 
general health, vitality, social functioning, role emotional, and mental health) (Ware 2007).  
Scores are provided for each of the eight dimensions and are totaled into a Physical Component 
Summary and a Mental Component Summary.  Higher SF-36 scores indicate a better state of 
health.  The SF-36 requires approximately 10 minutes to complete, and can be self-administered 
or completed by interview in person or by telephone.  In Part B, the SF-36 assessments are to be 
completed at 8:00 AM (±30 minutes) at each scheduled time point during the Treatment Period, 
and in the morning on Day 15, Day 21, and Day 28.   
A copy of the SF-36 is provided in Appendix 5.   
11.6. 
The Fatigue Associated With Depression (FAs-D) Patient-Reported 
Outcome (PRO) 
Fatigue is one of the most common symptoms of MDD.  The Fatigue Associated with 
Depression Questionnaire (FAs-D) was developed to assess fatigue and its impact in patients 
with MDD.  The 13-item patient-reported questionnaire was designed to assess fatigue 
associated with depression in the past week.  Three scores are computed: a six-item fatigue 
experience subscale (fatigued, tired, exhausted, lack of energy, physically weak, and feeling like 
everything requires too much effort), a seven-item fatigue impact subscale (impact on household 
chores; family relationships; enjoyable activities; social activities with friends; self-care; intimate 
relationships; and productivity at work or school), and a total score (all 13 items).  Items 12 
(impact on intimate relationships) and 13 (impact on productivity at work or school) are not 
applicable to all subjects, so these items are not answered in some cases.  The fatigue experience 
items are rated on a five-point scale with response options of “never,” “rarely,” “sometimes,” 
“often,” and “always.”  The impact items are rated on a five-point scale with response options of 
“not at all,” “a little,” “somewhat,” “quite a bit,” and “very much.”  The two subscales and the 
total score are computed as the mean of all answered items within each scale, and each scale 
score has a possible range of 1 to 5, with higher scores representing greater fatigue.  In Part B, 
the FAs-D assessments are to be completed at 8:00 AM (±30 minutes) at each scheduled time 
point during the Treatment Period, and in the morning on Day 15, Day 21, and Day 28.   
A copy of the FAs-D is provided in Appendix 6.   


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12. 
PHARMACOKINETICS 
12.1. 
Blood Sample Collection 
Plasma samples for PK analysis in Part A and Part B will be collected predose and 0.25, 0.5, 1, 
2, 10, and 12 hours postdose on Day 7 (within ±5 minutes of the scheduled time point through 
0.5 hours after dosing and ±15 minutes of the scheduled time point from 1 hour after dosing and 
greater), prior to discharge on Day 8 for subjects being discharged or 16 hours postdose for 
subjects remaining as inpatients, predose on Day 14, and in the morning on Day 15.  The time of 
study drug administration is time zero and all post-dosing sampling times are relative to this 
time.  The Investigator or designee will arrange to have the plasma samples processed, stored, 
and transported as directed for bioanalysis.   
In the event of a dose adjustment, an unscheduled PK sample should be collected just prior to the 
dose change.  An additional PK sample may be collected at any time if clinically indicated and at 
the discretion of the Investigator (eg, for unusual or severe adverse events).   
Each sample will be marked with unique identifiers such as the study number, subject number, 
and the nominal sample time.  The date and actual time that the blood sample was taken will be 
recorded on the CRF or electronically with a bar code or other method.   
12.2. 
Storage and Shipment of Pharmacokinetic Samples 
The plasma samples should be kept frozen at approximately -70 to -80°C until analyzed.  They 
should be packed as directed to avoid breakage during transit and with sufficient dry ice to 
prevent thawing for at least 72 hours.  A specimen-identification form must be completed and 
sent to the laboratory with each set of samples.  The clinical site will arrange to have the plasma 
samples transported as directed for bioanalysis as detailed in the PK instructions.   
12.3. 
Sample Analysis 
Bioanalysis of plasma samples for the determination of SAGE-217 will be performed utilizing a 
validated liquid chromatography-tandem mass spectrometry method at a qualified laboratory.   
 


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13. 
ASSESSMENT OF SAFETY 
13.1. 
Safety Parameters 
Safety and tolerability of study drug will be evaluated in Parts A and B by vital signs 
measurements, clinical laboratory measures, physical examination, ECGs, concomitant 
medication usage, C-SSRS, SSS, and adverse event reporting.   
13.1.1. 
Demographic/Medical History 
Age, race, and ethnic origin will be recorded at the Screening visit.  The diagnosis of MDD will 
be determined using the SCID-I.   
13.1.2. 
Vital Signs 
Vital signs include respiratory rate, oral temperature, and supine (for at least 5 minutes prior to 
the measurement) and standing systolic and diastolic blood pressure and heart rate.  Vital signs 
will be obtained within ±5 minutes of the scheduled time point through 0.5 hours after dosing 
and ±30 minutes of the scheduled time point from 1 hour after dosing and greater, unless the 
subject is asleep between the hours of 23:00 h and 06:00 h.   
From Day 1 through Day 7, vital signs and pulse oximetry will be performed at screening (vital 
signs only) and at the following time points: predose, 0.25, 0.5, 1, 2, and 12 hours after dosing.  
During the outpatient treatment period, vital signs will be completed prior to dosing and 1 hour 
after dosing.  Vital signs may be repeated at the discretion of the Investigator or Visiting Home 
Healthcare Provider as clinically indicated.   
13.1.3. 
Weight and Height 
Body weight and height will be measured at the Screening visit; weight will also be measured on 
in the morning on Day 15, and during the follow-up visits on Days 21 and 28.   
13.1.4. 
Physical Examination 
A physical examination of all major body systems will be undertaken and recorded at the 
Screening visit, Day 8, Day 15, and Day 21, with a brief physical examination on Day 28.   
13.1.5. 
Electrocardiogram (ECG) 
A 12-lead ECG will be assessed at the Screening visit and 1 hour ±15 minutes after dosing on 
Days 1, 2, 7, and 14 and during the follow-up visit on Day 21.  All time points are relative to the 
time of dosing.  The standard intervals as well as any abnormalities will be recorded.   
13.1.6. 
Laboratory Assessments 
Blood and urine samples will be collected for hematology, serum chemistry, coagulation, select 
hormone parameters, and urinalysis at the Screening visit, and in the morning on Days 8 and 15 
and during the follow-up visits on Days 21 and 28.  Where consent is given, an optional blood 
sample for hormone and exploratory biochemistry testing and optional genetic sample for 
biomarker testing will be collected at the Screening visit.   


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Serum and urine samples for pregnancy tests will also be collected.  These assessments should be 
performed as outlined below.   
All samples will be analyzed at the central laboratory.  Subjects may be considered eligible for 
the study based on local laboratory results; however, screening samples must also be sent to the 
central laboratory.   
All clinical laboratory test results outside the reference range will be interpreted by the 
Investigator as abnormal, not clinically significant (NCS) or abnormal, clinically significant 
(CS).  Screening results considered abnormal, CS recorded at the Screening visit may make the 
subject ineligible for the study pending review by the Medical Monitor.  Clinical laboratory 
results that are abnormal, CS during the study but within normal range at baseline and/or indicate 
a worsening from baseline will be considered adverse events, assessed according to 
Section 13.2.1, and recorded in the eCRF.   
13.1.6.1. Hematology 
Hematology tests will include complete blood count, including red blood cells, white blood cells 
with differentiation, hemoglobin, hematocrit, reticulocytes, and platelets.  The coagulation panel 
will include activated partial thromboplastin time, prothrombin time, and international 
normalized ratio.   
13.1.6.2. Blood Chemistry 
Serum chemistry tests will include serum electrolytes; renal function tests, including creatinine, 
blood urea nitrogen, bicarbonate or total carbon dioxide; liver function tests, including total 
bilirubin, aspartate aminotransferase, and alanine aminotransferase; total protein; and albumin.   
13.1.6.3. Urinalysis 
Urinalysis will include assessment of protein, blood, glucose, ketones, bile, urobilinogen, 
hemoglobin, leukocyte esterase, nitrites, color, turbidity, pH, and specific gravity.   
13.1.6.4. Hormones and Exploratory Biochemistry 
Optional blood samples will be collected and may be analyzed for stress hormone levels, 
kynurenine biochemistry, and markers of inflammation.  Future research may suggest other 
biochemical pathways as candidates for influencing not only response to SAGE-217 but also 
susceptibility to disorders for which SAGE-217 may be evaluated.  Thus, the exploratory 
biochemistry may involve study of additional unnamed molecular pathways, but only as related 
to disease susceptibility and drug action.   
13.1.6.5. Virus Serology 
Subjects will be screened for hepatitis (HBsAg and anti-HCV) and HIV prior to being enrolled in 
the study.   
13.1.6.6. Pregnancy Test 
Females of childbearing potential will be tested for pregnancy by serum pregnancy test at the 
Screening visit and by urine pregnancy test on Day 1 (predose) and at the follow-up visit on 


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Day 28.  In addition, female subjects who prematurely discontinue before Day 28 will have a 
pregnancy test performed at the early termination visit. 
13.1.6.7. Genetic Testing 
Where consent is given, an optional genetic sample for biomarker testing will be collected at the 
Screening visit.   
The objective of this research is to collect and store blood samples for possible DNA extraction 
and exploratory research into how genes or specific genetic variation may influence response (ie, 
distribution, safety, tolerability, and efficacy) to SAGE-217.  Specific genetic variations of 
interest include but are not limited to: classes of metabolizing enzymes (eg, cytochrome P450 
supra-family genes), genes encoding enzymes involved in the production and metabolism of 
SAGE-217 (eg, AKR1C4 [3α-hydroxysteroid dehydrogenase]), genes associated with the 
γ-aminobutyric acid (GABA) receptor (eg, GABRA1-A6, GABRB1-B3, GABRD, GABRE, 
GABRG1-3), and genes associated with the production and degradation of GABA.   
Future research may suggest other genes or gene categories as candidates for influencing not 
only response to SAGE-217 but also susceptibility to disorders for which SAGE-217 may be 
evaluated.  Thus, the genetic research may involve study of additional unnamed genes or gene 
categories, but only as related to disease susceptibility and drug action.   
13.1.6.8. Drugs of Abuse and Alcohol 
A urine sample for assessment of selected drugs of abuse (including amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, opiates, phencyclidine, and propoxyphene) and a serum 
or breath sample for alcohol screen will be collected at screening and predose on Day 1.  Use of 
benzodiazepines at screening is not necessarily exclusionary, as subjects will be allowed to take 
psychotropics that have been initiated at least 14 days prior to admission to the study center at a 
stable dose following discussion with the Sponsor (see Section 9.3).   
13.1.7. 
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).   
If, in the opinion of the Investigator, the subject is showing clinically meaningful changes in 
suicidality, no further study drug will be administered and the subject will be referred to a 
psychologist or psychiatrist for further evaluation.  This information will be tracked.   
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 any time of day at all 
subsequent time points, as outlined in Table 2 and Table 3 .  The C-SSRS is provided in 
Appendix 5.   


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13.1.8. 
Stanford Sleepiness Scale (SSS) 
The SSS is subject-rated scale designed to quickly assess how alert a subject is feeling.  Degrees 
of sleepiness and alertness are rated on a scale of 1 to 7, where the lowest score of ‘1’ indicates 
the subject is ‘feeling active, vital, alert, or wide awake’ and the highest score of ‘7’ indicates the 
subject is ‘no longer fighting sleep, sleep onset soon; having dream-like thoughts’.   
In both Part A and Part B, from Day 1 through Day 7, SSS will be completed at the following 
time points: predose, 0.25, 0.5, 1, and 2 after dosing.  The scale is to be completed within 
±5 minutes of the scheduled time point through 0.5 hours after dosing and ±15 minutes of the 
scheduled time point from 1 hour after dosing and greater, unless the subject is asleep between 
23:00 h and 06:00 h during the inpatient treatment period.  During the outpatient treatment 
period, SSS will be completed prior to dosing and 1 hour after dosing.  All time points are 
relative to the time of dosing.  The SSS is provided in Appendix 8.   
13.2. 
Adverse and Serious Adverse Events 
13.2.1. 
Definition of Adverse Events 
13.2.1.1. Adverse Event 
An adverse event is the development of an undesirable medical condition or the deterioration of 
a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  In clinical studies, an adverse event 
can include an undesirable medical condition occurring at any time, including baseline or 
washout periods, even if no study treatment has been administered.   
13.2.1.2. Suspected Adverse Reaction 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event.  For the purposes of Investigational New Drug safety 
reporting, “reasonable possibility” means there is evidence to suggest a causal relationship 
between the drug and the adverse event.  Suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a drug.   
13.2.1.3. Serious Adverse Event 
A serious adverse event is an adverse event occurring during any study phase and at any dose of 
the investigational product, comparator or placebo, that fulfils one or more of the following: 
• It results in death 
• It is immediately life-threatening 
• It requires inpatient hospitalization or prolongation of existing hospitalization 
• It results in persistent or significant disability or incapacity 
• It results in a congenital abnormality or birth defect 
• It is an important medical event that may jeopardize the subject or may require 
medical intervention to prevent one of the outcomes listed above. 


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All serious adverse events that occur after any subject has been enrolled, whether or not they are 
related to the study, must be recorded for the duration of the study on forms provided by Sage 
Therapeutics or designee.   
13.3. 
Relationship to Study Drug 
An Investigator who is qualified in medicine must make the determination of relationship to the 
investigational product for each adverse event (unrelated, 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 “unrelated.”  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 “related.”   
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 to be related 
to the investigational product for the purposes of expedited regulatory reporting.   
13.4. 
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.  Clinically significant changes in laboratory values, blood pressure, and 
pulse need not be reported as adverse events unless they prompt corrective medical action by the 
Investigator, constitute a serious adverse event, or lead to discontinuation of administration of 
study drug.   
Information about adverse events will be collected from the signing of the ICF until the final 
visit of the study for that subject.  Adverse events that occur after the first administration of study 
drug will be denoted TEAEs.   
All adverse events will be followed until they are resolved or have reached a clinical plateau with 
no expectation of future change.   
The adverse event term should be reported in standard medical terminology when possible.  For 
each adverse event, the Investigator will evaluate and report the onset (date and time), resolution 
or clinical plateau (date and time), severity, causality, action taken, outcome, and whether or not 
it caused the subject to discontinue the study.   
Severity 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) 
13.5. 
Reporting Adverse Events 
All serious adverse events (regardless of causality) will be recorded from the signing of the ICF 
until the Day 28 follow-up visit.  Any serious adverse events considered possibly or probably 
related to the investigational product and discovered by the Investigator at any time after the 
study should be reported.  All serious adverse events must be reported to the Sponsor or 
Sponsor’s designee immediately by phone and in writing within 24 hours of the first awareness 
of the event.  The Investigator must complete, sign and date the serious adverse event pages, 
verify the accuracy of the information recorded on the serious adverse event pages with the 
corresponding source documents, and send a copy to Sage Therapeutics or designee.   
Additional follow-up information, if required or available, should be sent to Sage Therapeutics 
or designee within 24 hours of receipt; a follow-up serious adverse event form should be 
completed and placed with the original serious adverse event information and kept with the 
appropriate section of the study file.   
Sage Therapeutics or designee is responsible for notifying the relevant regulatory authorities of 
certain events.  It is the Principal Investigator’s responsibility to notify the IRB of all serious 
adverse events that occur at his or her site if applicable per the IRB’s requirements.  Investigators 
will also be notified of all unexpected, serious, drug-related events (7-/15-Day Safety Reports) 
that occur during the clinical study.  Each site is responsible for notifying its IRB of these 
additional serious adverse events.   
13.6. 
Emergency Identification of Study Drug 
Part B of the study is double-blind.  The pharmacist responsible for preparing the solutions will 
be unblinded and will retain an official paper copy of the randomization schedule.  In addition, 
an unblinded Monitor will perform drug accountability during the study.   
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 the Sponsor 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 the Sponsor.  If the unblinding occurs 
without the Sponsor’s knowledge, the Investigator must notify the Sponsor 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 the Sponsor 
and approved by the appropriate Sponsor 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 matching 
placebo.   


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In all cases where the study drug allocation for a subject is unblinded, pertinent information must 
be documented in the subject’s records and on the eCRF.  If the subject or study center personnel 
(other than pharmacist) have been unblinded, the subject will be terminated from the study.   


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14. 
STATISTICS 
14.1. 
Data Analysis Sets 
14.1.1. 
Analysis Populations and Methods 
The Safety Population (for both Part A and Part B), defined as all subjects administered study 
drug, will be used to provide descriptive summaries of safety data.   
The Efficacy Population (for both Part A and Part B), defined as all subjects in the Safety 
Population who complete at least 1 day of dosing of study drug and have at least one post-
baseline efficacy evaluation, will be used to analyze efficacy data.   
The PK Population will consist of all subjects in the Safety Population with sufficient plasma 
concentrations for PK evaluations, and will be used to summarize PK data.   
14.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data.  All subjects will be used in the analyses, as 
per the analysis populations, using all non-missing data available.  No imputation process will be 
used to estimate missing data.  A sensitivity analysis will be used to investigate the impact of 
missing data if ≥5% of subjects have missing data.   
14.3. 
General Considerations 
For the purpose of all safety and efficacy analyses where applicable, baseline is defined as the 
last measurement prior to the start of study drug administration.   
Continuous endpoints will be summarized with 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.   
14.4. 
Demographics and Baseline Characteristics 
Demographic data, such as age, race, and ethnicity, and baseline characteristics, such as height, 
weight, and body mass index (BMI), will be summarized using the Safety Population.   
Hepatitis, HIV, drug and alcohol, and pregnancy screening results will be listed, but not 
summarized as they are considered part of the inclusion/exclusion criteria.   
Medical/family history will be listed by subject.   
14.5. 
Efficacy Analyses 
Efficacy data will be summarized using appropriate descriptive statistics and other data 
presentation methods where applicable; subject listings will be provided for all efficacy data.  
For (the open-label) Part A, efficacy data will be summarized descriptively.  For Part B, subjects 
will be analyzed according to randomized treatment.   
An analysis of ten subjects completing Part A is planned to inform Part B study conduct. 


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For Part B of the study, change from baseline to each assessment in HAM-D total score will be 
analyzed using a mixed effects model for repeated measures (MMRM); the model will include 
center, treatment, baseline HAM-D total score, antidepressant use strata, assessment time point, 
and time point-by-treatment as explanatory variables.  Center will be treated as a random effect 
while all other explanatory variables will be treated as fixed effects.  All post-baseline time 
points will be included in the model.  The main comparison will be between SAGE-217 Oral 
Solution and matching placebo at the 15-day time point.  Model-based point estimates (ie, least 
squares [LS] means), 95% confidence intervals, and p-values) will be reported where applicable.  
An unstructured covariance structure will be used to model the within-subject errors.  Compound 
symmetry covariance structure will be used if there is a convergence issue with the unstructured 
covariance model.   
Descriptive statistics for HAM-D total score and change from baseline values will be presented 
by assessment time point for Part A.  Summaries will include n, mean, SD, median, minimum, 
and maximum.   
Similar to those methods described above for Part B, an MMRM will be used for the analysis of 
the following variables: changes from baseline in MADRS total score and HAM-A total score, 
and select individual item and subscale scores.  For each model, the comparison of interest will 
be between SAGE-217 Oral Solution and matching placebo at the 15-day time point.  
Model-based point estimates (ie, LS means), 95% confidence intervals, and p-values will be 
reported.   
Logistic regression methods will be used for the analysis of the following binary variables: 
HAM-D response (defined as ≥50% reduction from baseline in HAM-D total score), HAM-D 
remission (defined as HAM-D total score of ≤7.0), and CGI-I response.  Logistic regression 
models will include terms for center, treatment, antidepressant use strata, and baseline score.  
The comparison of interest will be the difference between SAGE-217 Oral Solution and 
matching placebo at the 15-day time point in Part B.  Model-based point estimates (ie, odds 
ratios), 95% confidence intervals, and p-values will be reported.  For the CGI-I response 
analysis, baseline CGI-S score will be included in the model.   
For all scores, descriptive statistics, change from baseline values, and response variables will be 
presented by treatment and assessment time point.  Summaries will include n, mean, SD, median, 
minimum, and maximum.   
Similar to the main comparison of HAM-D total score in Part B, descriptive summary statistics 
will be provided and an MMRM model will be used to analyze the change from baseline in 
SF-36 and FAs-D.   
14.6. 
Safety Analyses 
Safety and tolerability of study drug will be evaluated by adverse events, concomitant 
medication usage, changes from baseline in physical examination, vital signs, clinical laboratory 
evaluations, and 12-lead ECG.  Suicidality will be monitored by the C-SSRS.  Sedation will be 
assessed using the SSS.  Safety data will be listed by subject and summarized by treatment 
group.  All safety summaries will be performed on the Safety Population.   


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14.6.1. 
Adverse Events 
The analysis of adverse events will be based on the concept of TEAEs.  A TEAE is defined as an 
adverse event with onset after the start of study drug, or any worsening of a pre-existing medical 
condition/adverse event with onset after the start of study drug and until 7 days after the last 
dose.  The incidence of TEAEs will be summarized overall and by Medical Dictionary for 
Regulatory Activities (MedDRA) Version 18.1 or higher System Organ Class (SOC) and 
preferred term.  Incidences will be presented in order of decreasing frequency for the SAGE-217 
Oral Solution treatment group.  In addition, summaries will be provided by severity (mild, 
moderate, severe) and by causality (related, not related) to study drug (see Section 13.3).   
Treatment-emergent adverse events leading to discontinuation and serious adverse events (see 
Section 13.2.1.3 for definition) with onset after the start of randomized study drug will also be 
summarized.   
All adverse events and serious adverse events (including those with onset or worsening before 
the start of study drug) through the Day 28 follow-up visit will be listed.   
14.6.2. 
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 summarized.   
14.6.3. 
Physical Examinations 
Physical examinations in Parts A and B will be summarized at the Screening visit, Day 8, 
Day 15, Day 21, and Day 28 visits.  Any clinically significant change in physical examination 
compared to those observed at screening should be noted as an adverse event.   
14.6.4. 
Vital Signs 
Vital sign results will be listed by subject and timing of collection.  Mean changes from 
randomization in vital signs will be summarized by time point.   
14.6.5. 
12-Lead Electrocardiogram 
The following ECG parameters will be listed for each subject: heart rate, PR, QRS, QT, QTc, 
and QT interval calculated using the Fridericia method (QTcF).  Any clinically significant 
abnormalities or changes in ECGs should be listed as an adverse event.  Electrocardiogram 
findings will be listed by subject and visit.   
14.6.6. 
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.   
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 during the 30 days prior to 
informed consent.  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 


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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.   
14.6.7. 
Columbia Suicide Severity Rating Scale 
Suicidality data collected on the C-SSRS at baseline and by visit during the Treatment Period 
will be listed for all subjects.  Listings will include behavior type and/or category for Suicidal 
Ideation and Suicidal Behavior of the C-SSRS.   
14.6.8. 
Stanford Sleepiness Scale 
Sedation data collected on the SSS will be listed for all subjects.  Changes in score over time will 
be represented graphically, and change from Day 1 will be measured. 
14.7. 
Pharmacokinetic Analyses 
Pharmacokinetic parameters will be summarized using appropriate descriptive statistics.  Time at 
maximum (peak) plasma concentration (tmax) will be summarized using n, mean, SD, median, 
minimum, and maximum.  All other PK parameters will be summarized using n, geometric 
mean, coefficient of variation, median, minimum, and maximum and listed by subject.   
Plasma concentrations and PK parameters will be listed by subject.   
In addition to typical descriptive statistics, summaries should include geometric mean, 
coefficient of variation, and geometric coefficient of variation. 
14.8. 
Determination of Sample Size 
The sample size of ten subjects for Part A was selected based on clinical and not statistical 
considerations.   
For Part B, assuming a two-sided t-test at an alpha level of 0.10, a sample size of 23 subjects per 
group would provide 80% power to detect an effect size of 0.75 between the SAGE-217 Oral 
Solution and matching placebo groups with regard to the secondary efficacy outcome variable of 
change from baseline in HAM-D total score.  An effect size of 0.75 corresponds to a matching 
placebo-adjusted difference of 7.5 points in the change from baseline in HAM-D total score at 
15 days with an assumed SD of 10 points.  By including two treatment groups and using a 1:1 
randomization, a total of 46 subjects are required.  Assuming a non-evaluability rate of 10%, up 
to 52 subjects will be randomized.   
14.9. 
Changes From Protocol Specified Analyses 
Any changes from the analytical methods outlined in the protocol will be documented in the final 
statistical analysis plan.  
 


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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
Study Monitoring 
Before an investigational site can enter a subject into the study, a representative of Sage 
Therapeutics or designee will visit the investigational study site to:   
• Determine the adequacy of the facilities; and 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of Sage Therapeutics or designee or its 
representatives.  This will be documented in a Clinical Study Agreement between 
Sage Therapeutics and the Investigator.   
During the study, a monitor from Sage Therapeutics or designee will have regular contacts with 
the investigational site for the following: 
• Provide information and support to the Investigator(s); 
• Confirm that facilities remain acceptable; 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the eCRFs, and that investigational product accountability 
checks are being performed; 
• Perform source data verification. This includes a comparison of the data in the eCRFs 
with the subject’s medical records at the hospital or practice, and other records 
relevant to the study. This will require direct access to all original records for each 
subject (eg, clinic charts); 
• Record and report any protocol deviations not previously sent to Sage Therapeutics or 
designee; and 
• Confirm adverse events and serious adverse events have been properly documented 
on eCRFs and confirm any serious adverse events have been forwarded to Sage 
Therapeutics or designee and those serious adverse events that met criteria for 
reporting have been forwarded to the IRB.   
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice.   
15.2. 
Audits and Inspections 
Authorized representatives of Sage Therapeutics, a regulatory authority, an Independent Ethics 
Committee (IEC) or an IRB may visit the site to perform audits or inspections, including source 
data verification.  The purpose of a Sage Therapeutics or designee 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, GCP guidelines of the International Council for 
Harmonisation (ICH), and any applicable regulatory requirements.  The Investigator should 
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15.3. 
Institutional Review Board (IRB) 
The Principal Investigator must obtain IRB approval for the investigation.  Initial IRB approval 
and all materials approved by the IRB for this study, including the subject consent form and 
recruitment materials, must be maintained by the Investigator and made available for inspection.   


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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Investigator and institution will permit study-related monitoring, audits, IRB review, and 
regulatory inspections as requested by the Food and Drug Administration, the Sponsor, or the 
Sponsor’s designee, including direct access to source data/documents (ie, original medical 
records, laboratory reports, hospital documents, progress reports, signed ICFs) in addition to 
eCRFs.   
Quality assurance and quality-control systems with written standard operating procedures will be 
followed to ensure this study will be conducted and data will be generated, documented 
(recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory 
requirements.   
The site’s dedicated study monitor will arrange to visit the Investigator at regular intervals during 
the study.  The monitoring visits must be conducted according to the applicable ICH and GCP 
guidelines to ensure protocol adherence, quality of data, drug accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities. 
During these visits, eCRFs and other data related to the study will be reviewed and any 
discrepancies or omissions will be identified and resolved. The study monitor will be given 
access to study-relevant source documents (including medical records) for purposes of source 
data verification. 
During and/or after completion of the study, quality-assurance officers named by Sage 
Therapeutics or the regulatory authorities may wish to perform on-site audits. The Investigator is 
expected to cooperate with any audit and provide assistance and documentation (including 
source data) as requested. 
Quality control will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. 
Agreements made by the Sponsor with the Investigator/institution and any other parties involved 
with the clinical study will be in writing in a separate agreement. 


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17. 
ETHICS 
17.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate.  The Investigator must submit 
written approval to Sage Therapeutics or designee before he or she can enroll any subject into the 
study.   
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB or IEC must approve all 
advertising used to recruit subjects for the study.  The protocol must be re-approved by the IRB 
or IEC 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 or designee will provide this information to the Principal 
Investigator.   
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines.   
17.2. 
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 its most recent amendment (2008) and are consistent with ICH/GCP 
and other applicable regulatory requirements.   
17.3. 
Written Informed Consent 
The Principal Investigator 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 
before signing the ICF.   
As additional assessments, the ICF will contain provisions for optional consent for the collection 
of blood samples for hormone and biomarker testing during screening and the collection of 
breast milk for biobanking and PK analysis purposes.  The ICF, as specified by the clinical site’s 
IRB, must follow the Protection of Human Subjects regulations listed in the Code of Federal 
Regulations, Title 21, Part 50. 
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 ICF.  A copy of the signed ICF 
must be given to the subject.   
 


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18. 
DATA HANDLING AND RECORDKEEPING 
Procedures for data handling (including electronic data) used in this protocol will be documented 
in a Data Management Plan.   
Electronic CRFs will be completed for each study subject.  It is the Investigator’s responsibility 
to ensure the accuracy, completeness, and timeliness of the data reported in the subject’s eCRF.  
Source documentation supporting the eCRF data should indicate the subject’s participation in the 
study and should document the dates and details of study procedures, adverse events, and subject 
status.   
The Investigator will have access to the electronic data capture system and will receive a copy of 
the subject eCRF data at the end of the study.  For subjects who discontinue or terminate from 
the study, the eCRFs will be completed as much as possible, and the reason for the 
discontinuation or termination clearly and concisely specified on the appropriate eCRF. 
18.1. 
Inspection of Records 
Sage Therapeutics or designee will be allowed to conduct site visits to the investigational 
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 related to study conduct.   
18.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval or, if not approved, 2 years following the 
discontinuation 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.   
18.3. 
Confidentiality 
To maintain subject privacy, all eCRFs, study reports, and communications will identify the 
subject by the assigned subject number.  The Investigator will grant monitor(s) and auditor(s) 
from the Sponsor or its designee and regulatory authority(ies) access to the subject’s original 
medical records for verification of data gathered on the eCRFs and to audit the data collection 
process.  The subject’s confidentiality will be maintained and will not be made publicly available 
to the extent permitted by the applicable laws and regulations.   
Subjects will be notified that registration information, results, and other information about this 
study will be submitted to ClinicalTrials.gov, a publicly available trial registry database; 
however, protected health information of individual subjects will not be used.   


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All information regarding the investigational product supplied by Sage Therapeutics to the 
Investigator is privileged and confidential information.  The Investigator agrees to use this 
information to accomplish the study and will not use it for other purposes without consent from 
the Sponsor.  It is understood that there is an obligation to provide the Sponsor with complete 
data obtained during the study.  The information obtained from the clinical study will be used 
towards the development of the investigational product and may be disclosed to regulatory 
authorities, other Investigators, corporate partners, or consultants, as required.   


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19. 
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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20. 
LIST OF REFERENCES 
Angst J, Angst F, Stassen HH. Suicide risk in patients with major depressive disorder. J Clin 
Psychiatry. 1999;60 Suppl 2:57-62; discussion 75-6, 113-6. 
Conradi HJ, Ormel J, de Jonge P. Presence of individual (residual) symptoms during depressive 
episodes and periods of remission: a 3-year prospective study. Psychol Med. 2011 
Jun;41(6):1165-74. 
Drugan RC, Morrow AL, Weizman R, et al. Stress-induced behavioral depression in the rat is 
associated with a decrease in GABA receptor-mediated chloride ion flux and brain 
benzodiazepine receptor occupancy. Brain Res. 1989;487: 45–51. 
DSM-5.  Diagnostic and statistical manual of mental disorders (5th ed.).  American Psychiatric 
Association 2013.  Arlington, VA: American Psychiatric Publishing. 
Fournier JC, DeRubeis RJ, Hollon SD, et al. Antidepressant drug effects and depression 
severity—a patient-level meta-analysis. JAMA. 2010;303:47-53.   
Gerner RH, Hare TA. GABA in normal subjects and patients with depression, schizophrenia, 
mania, and anorexia nervosa. Am J Psychiatry. 1981;138:1098–101. 
Greenberg PE, Fournier AA, Sisitsky T, Pike CT, Kessler RC. The economic burden of adults 
with major depressive disorder in the United States (2005 and 2010). J Clin Psychiatry. 2015 
Feb;76(2):155-62. 
Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32:50-5.   
Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56-62.   
Honig A, Bartlett JR, Bouras N, Bridges PK. Amino acid levels in depression: a preliminary 
investigation. J Psychiatr Res. 1988; 22:159–64. 
Kirsch I, Deacon BJ, Huedo-Medina TB, et al. Initial severity and antidepressant benefits: A 
meta-analysis of data submitted to the Food and Drug Administration. PLoS Med. 
2008;5(2):e45.   
Luscher B, Shen Q, Sahir N. The GABAergic deficit hypothesis of major depressive disorder. 
Mol Psychiatry. 2011;16(4):383-406. 
Maguire J, Mody I. GABA(A)R plasticity during pregnancy: Relevance to postpartum 
depression. Neuron. 2008;59(2);207-13.   
Maguire J, Ferando I, Simonsen C, Mody I. Excitability changes related to GABAA receptor 
plasticity during pregnancy. J Neurosci. 2009;29(30):9592-601.   
Mann JJ, Oguendo MA, Watson KT, et al. Anxiety in major depression and cerebrospinal fluid 
free gamma-aminobutyric acid. Depress Anxiety. 2014;31(10):814-21. 
McDowell, I.  Measuring Health: A guide to rating scales and questionnaires.  2006: 3rd Ed.  
New York: Oxford University Press.   
Müller-Thomsen T, Arlt S, Mann U, Mass R, Ganzer S.  Detecting depression in Alzheimer’s 
disease: evaluation of four different scales.  Arch Clin Neuropsychol. 2005;20:271-6.   


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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. 
Romera I, Pérez V, Ciudad A, et al. Residual symptoms and functioning in depression, does the 
type of residual symptom matter? A post-hoc analysis. BMC Psychiatry. 2013 Feb 11;13:51. 
Schüle C, Nothdurfter C, Rupprecht R.  The role of allopregnanolone in depression and anxiety. 
Prog Neurobiol. 2014 Feb;113:79-87. 
Trivedi MH, Rush AJ, Wisniewski SR, et al. (STAR*D Study Team). Evaluation of outcomes 
with citalopram for depression using measurement-based care in STAR*D: implications for 
clinical practice. Am J Psychiatry. 2006 Jan;163(1):28-40. 
Ware JE Jr, Kosinski M, Bjorner JB, et al.  User's Manual for the SF-36v2 Health Survey.  2nd 
ed.  Lincoln, RI:  QualityMetric Incorporated; 2007. 
 


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21. 
APPENDICES 
 


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APPENDIX 1. HAMILTON RATING SCALE FOR DEPRESSION, 
17-ITEM (HAM-D) 
 


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APPENDIX 2. MONTGOMERY-ÅSBERG DEPRESSION RATING 
SCALE (MADRS) 
 


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APPENDIX 3. HAMILTON ANXIETY RATING SCALE (HAM-A) 
 


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APPENDIX 4. CLINICAL GLOBAL IMPRESSION–IMPROVEMENT 
SCALE (CGI-I) AND SEVERITY SCALE (CGI-S) 
 
 
 


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APPENDIX 5. SHORT-FORM 36 (SF-36) 
 


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APPENDIX 7. COLUMBIA - SUICIDE SEVERITY RATING SCALE 
(C-SSRS) 
 


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APPENDIX 8. STANFORD SLEEPINESS SCALE (SSS) 
 
 

SAP_001.pdf: 
Sage Therapeutics, Inc. 
Confidential Information 
Statistical Analysis Plan 
Methods 
Protocol Number 217-MDD-201 / NCT03000530
A Phase 2, Two-Part (Open-Label Followed by Double-Blind) Study 
Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of 
SAGE-217 in the Treatment of Adult Subjects with Moderate to Severe Major 
Depressive Disorder 
Author of SAP: 
 
Version: Version 3.0 
Version Date of SAP: 16 NOV 2017 
Sponsor: Sage Therapeutics, Inc. 
215 First Street 
Cambridge, Massachusetts 02142 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Sage Therapeutics,Inc. is strictly prohibited except to the extent required under applicable laws or 
regulations.  Persons to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them. 




 
 
Sage Therapeutics Inc. 
Confidential Information 
 
1 
TABLE OF CONTENTS 
1 
Table of Contents ............................................................................................................. 3 
2 
List of Abbreviations ....................................................................................................... 6 
3 
Introduction...................................................................................................................... 8 
4 
Study Objectives .............................................................................................................. 8 
4.1 
Part A .......................................................................................................................... 8 
4.1.1 
Primary Objective ............................................................................................... 8 
4.1.2 
Secondary Objective ........................................................................................... 8 
4.1.3 
Pharmacokinetic Objective ................................................................................. 8 
4.2 
Part B .......................................................................................................................... 8 
4.2.1 
Primary Objective ............................................................................................... 8 
4.2.2 
Secondary Objective ........................................................................................... 8 
4.2.3 
Exploratory Objective ......................................................................................... 8 
4.2.4 
Pharmacokinetic Objective ................................................................................. 8 
5 
Study Endpoints ............................................................................................................... 9 
5.1 
Part A .......................................................................................................................... 9 
5.1.1 
Primary ............................................................................................................... 9 
5.1.2 
Secondary ........................................................................................................... 9 
5.1.3 
Pharmacokinetic ................................................................................................. 9 
5.2 
Part B ........................................................................................................................ 10 
5.2.1 
Primary ............................................................................................................. 10 
5.2.2 
Secondary ......................................................................................................... 10 
5.2.3 
Exploratory ....................................................................................................... 10 
5.2.4 
Pharmacokinetic ............................................................................................... 10 
6 
Study Design ................................................................................................................... 10 
6.1 
Overall Design .......................................................................................................... 10 
6.2 
Sample Size and Power ............................................................................................ 12 
6.3 
Randomization .......................................................................................................... 12 
6.4 
Blinding and Unblinding .......................................................................................... 13 
7 
Modifications .................................................................................................................. 14 
7.1 
Modifications to the Approved Clinical Study Protocol .......................................... 14 
7.2 
Modifications to the Approved Statistical Analysis Plan ......................................... 14 
7.3 
Modifications to the Approved DMC Charter .......................................................... 16 
8 
Analysis Sets ................................................................................................................... 16 
8.1 
Efficacy Set .............................................................................................................. 16 
8.2 
Safety Set .................................................................................................................. 16 
8.3 
Pharmacokinetic (PK) Set ........................................................................................ 16 
9 
Statistical Analysis ......................................................................................................... 16 
9.1 
General Considerations ............................................................................................ 16 
9.1.1 
Study Day Definition ........................................................................................ 17 
9.1.2 
Missing Data ..................................................................................................... 17 
9.2 
Background Characteristics ...................................................................................... 17 
9.2.1 
Subject Disposition ........................................................................................... 17 


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9.2.2 
Demographics and Baseline Characteristics ..................................................... 18 
9.2.3 
Prior and Concomitant Medications ................................................................. 18 
9.2.4 
Study Drug Exposure........................................................................................ 19 
9.2.5 
Protocol Deviations .......................................................................................... 19 
9.3 
Efficacy Analysis ...................................................................................................... 19 
9.3.1 
Definition of Efficacy Variable(s) .................................................................... 19 
9.3.1.1 
Hamilton Rating Scale for Depression (HAM-D) ..................................... 19 
9.3.1.2 
Montgomery-Åsberg Depression Rating Scale (MADRS) ........................ 20 
9.3.1.3 
Hamilton Anxiety Rating Scale (HAM-A) ................................................ 21 
9.3.1.4 
Clinical Global Impression – Severity (CGI-S) ......................................... 21 
9.3.1.5 
Clinical Global Impression – Improvement (CGI-I) .................................. 21 
9.3.1.6 
Short Form-36 (SF-36) ............................................................................... 21 
9.3.1.7 
The Fatigue Associated with Depression (FAs-D) Patient-Reported 
Outcome (PRO) .......................................................................................... 21 
9.3.1.8 
Remission in Depression Questionnaire (RDQ) ........................................ 22 
9.3.1.9 
Health-Related Productivity Questionnaire (HRPQ) ................................. 22 
9.3.2 
Visit Windows .................................................................................................. 22 
9.3.3 
Analysis of Efficacy Variable(s) ...................................................................... 24 
9.3.3.1 
Mixed Effects Model for Repeated Measures ............................................ 25 
9.3.3.2 
HAM-D Response and HAM-D Remission Analyses ............................... 26 
9.3.4 
Supportive Analysis .......................................................................................... 26 
9.3.5 
Sensitivity Analysis .......................................................................................... 27 
9.4 
Safety Analysis ......................................................................................................... 27 
9.4.1 
Adverse Events ................................................................................................. 29 
9.4.2 
Clinical Laboratory ........................................................................................... 30 
9.4.3 
Electrocardiogram ............................................................................................ 32 
9.4.4 
Vital Signs ........................................................................................................ 33 
9.4.5 
Physical Examination ....................................................................................... 34 
9.4.6 
Columbia Suicide Severity Rating Scale (C-SSRS) ......................................... 34 
9.4.7 
Stanford Sleepiness Scale (SSS)....................................................................... 34 
9.5 
Pharmacokinetic Analysis ........................................................................................ 35 
9.5.1 
Collection schedule........................................................................................... 35 
9.5.2 
Derived PK parameters ..................................................................................... 35 
9.5.3 
Handling of dropouts or missing data............................................................... 35 
9.5.4 
Summary statistics ............................................................................................ 36 
9.5.5 
Data presentation .............................................................................................. 36 
10 Summary of Interim and DMC Analyses .................................................................... 36 
11 Index of Tables ............................................................................................................... 37 
11.1 Part A ........................................................................................................................ 37 
11.2 Part B ........................................................................................................................ 39 
12 Index of Figures ............................................................................................................. 44 
12.1 Part A ........................................................................................................................ 44 
12.2 Part B ........................................................................................................................ 45 
13 Index of Listings ............................................................................................................. 46 
13.1 Part A ........................................................................................................................ 46 


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13.2 Part B ........................................................................................................................ 48 
14 References ....................................................................................................................... 50 
15 List of Appendices.......................................................................................................... 51 
15.1 Appendix A: Schedule of Assessments .................................................................... 51 
15.2 Appendix B: Details of Statistical Methodology ...................................................... 58 
 
 


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2 
LIST OF ABBREVIATIONS 
Abbreviation or 
Specialist Term 
Explanation 
ATC 
anatomical therapeutic chemical 
AUC  
area under the concentration-time curve  
AUC∞  
area under the concentration-time curve from time zero to infinity  
BMI  
body mass index  
bpm 
beats per minute 
CGI-I  
Clinical Global Impression - Improvement  
CGI-S  
Clinical Global Impression - Severity  
Cmax  
maximum (peak) plasma concentration  
CS  
clinically significant  
Css  
steady-state drug concentration in the plasma during oral/capsule intake  
Cavg,ss 
steady-state drug concentration in the plasma 
C-SSRS  
Columbia-Suicide Severity Rating Scale  
DSM-5  
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition  
ECG  
electrocardiogram  
eCRF  
electronic case report form  
FAs-D  
fatigue associated with depression  
GEE 
Generalized Estimating Equation 
HAM-A  
Hamilton Anxiety Rating Scale  
HAM-D  
17-item Hamilton Rating Scale for Depression  
HIV  
human immunodeficiency virus  
HRPQ 
Health-Related Productivity Questionnaire 
ICF  
informed consent form  
Kg 
kilogram 
LOCF 
Last Observation Carried Forward 
m 
meter 
MADRS  
Montgomery-Åsberg Depression Rating Scale  
Max 
maximum 
MDD  
major depressive disorder  
MedDRA  
Medical Dictionary for Regulatory Activities  
MI 
Multiple Imputation 
Min 
minimum 
mmHg 
millimeter of mercury 
MMRM  
mixed effects model for reported measures  
msec 
millisecond 
n  
number  
PCS 
potentially clinically significant 
PCSC 
potentially clinically significant change 
PK  
pharmacokinetic(s)  
PRO 
patient reported outcome 
PT 
preferred term 
RDQ 
Remission in Depression Questionnaire 
SAP 
statistical analysis plan 


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SCID-I  
Structured Clinical Interview for DSM-5 Axis I Disorders  
SD  
standard deviation  
SF-36  
36-item short form survey  
SI 
International System of Units 
SOC  
system organ class  
ss 
steady state 
SSS  
Stanford Sleepiness Scale  
TEAE  
treatment-emergent adverse event  
t1/2 
Elimination half-life 
tmax  
time at maximum (peak) plasma concentration  
WHO  
World Health Organization  
WHO-DD  
World Health Organization-Drug Dictionary 


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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, dated 12 Jul 2017, version 5.0.  There are two parts to the study. Part 
A of the study has been completed and Part B was initiated upon completion of Part A.  
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.  The SAP will be approved and 
finalized before Part B database lock.  
All analyses and summary outputs will be generated using SAS® version 9.3 or higher. 
4 
STUDY OBJECTIVES  
4.1 Part A 
4.1.1 Primary Objective 
The primary objective of Part A is to evaluate the safety and tolerability of SAGE-217 Oral 
Solution 30 mg.  
4.1.2 Secondary Objective 
The secondary objective of Part A is to determine if treatment with SAGE-217 Oral Solution 
30 mg for 14 days reduces depressive symptoms.  
4.1.3 Pharmacokinetic Objective 
The Pharmacokinetic (PK) objective of Part A is to assess the PK profile of SAGE-217 Oral 
Solution in plasma samples. 
4.2 Part B 
4.2.1 Primary Objective 
The primary objective for Part B of the study is to determine if treatment with SAGE-217 
Capsules (30 mg) reduces depressive symptoms in subjects with moderate to severe major 
depressive disorder (MDD) compared to matching placebo. 
4.2.2 Secondary Objective 
The secondary objective of Part B is to evaluate the safety, tolerability and efficacy of 
SAGE-217 Capsule (30 mg). 
4.2.3 Exploratory Objective 
The exploratory objective for Part B of the study is to assess the patient-reported outcome 
(PRO) measures as they relate to quality of life, work function, productivity, and depressive 
symptoms. 
4.2.4 Pharmacokinetic Objective 
The PK objective of Part B is to assess the PK profile of SAGE-217 Capsules in plasma 
samples. 


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5 
STUDY ENDPOINTS 
5.1 Part A  
5.1.1 Primary  
The primary endpoint for Part A is the safety and tolerability of SAGE-217 Oral Solution as 
assessed by the frequency and severity of adverse events; changes from baseline in clinical 
laboratory measures, vital signs, and electrocardiograms (ECGs); Stanford Sleepiness Scale 
(SSS) score; physical examination; and suicidal ideation using the Columbia-Suicide 
Severity Rating Scale (C-SSRS).  
5.1.2 Secondary 
Reduction in depressive symptoms as assessed by the following: 
• 
 Change from baseline in Hamilton Rating Scale for Depression (HAM-D) total score 
at Day 15 (ET) and all other time points; 
• 
 HAM-D response (defined as having a 50% or greater reduction from baseline in 
HAM-D total score); 
• 
 HAM-D remission (defined as having a HAM-D total score of ≤7);  
• 
Change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) 
total score at Day 15 (ET) and all other time points;  
• 
 Change from baseline in HAM-D subscale and individual item scores at Day 15 (ET) 
and all other time points;  
• 
 Change from baseline in Hamilton Anxiety Rating Scale (HAM-A) total score at all 
time points; and  
• 
 Clinical Global Impression - Improvement (CGII) response (defined as a CGI-I score 
of “very much improved” or “much improved”).  
5.1.3 Pharmacokinetic 
• 
 Maximum (peak) plasma concentration (Cmax), time at maximum (peak) plasma 
concentration (tmax), plasma elimination half-life (t½), area under the curve from zero 
to infinity (AUC∞), and steady-state drug concentration in the plasma during oral 
intake (Css). 


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5.2 Part B  
5.2.1 Primary 
The primary endpoint for Part B is the reduction in depressive symptoms, compared to 
placebo, as assessed by the change in the 17-item HAM-D total score from baseline to      
Day 15.  
5.2.2 Secondary 
• Reduction in depressive symptoms, compared to placebo, as assessed by the 
following: 
o 
 Change in the 17-item HAM-D total score from baseline at all time points; 
o 
 HAM-D response; 
o 
 HAM-D remission; 
o 
 Change from baseline in the MADRS total score at Day 15 (ET ) and all other 
time points; 
o 
 Change from baseline in HAM-D subscale and individual item scores at all time 
points; 
o 
 Change from baseline in HAM-A total score at Day 15 (ET) and all other time 
points; and 
o 
 CGII response. 
• The safety and tolerability of SAGE-217 Capsules as assessed by the frequency and 
severity of adverse events; changes from baseline in clinical laboratory measures, 
vital signs, and ECGs; SSS score; physical examination; and suicidal ideation using 
the C-SSRS. 
5.2.3 Exploratory 
Responses to the  36-item short form survey (SF-36), fatigue associated with depression 
(FAs-D), Remission in Depression Questionnaire (RDQ), and the Health-Related 
Productivity Questionnaire (HRPQ) will be summarized as exploratory endpoints for Part B. 
5.2.4 Pharmacokinetic 
• 
 Cmax, tmax, t½, AUC∞ and Css. 
 
6 
STUDY DESIGN  
6.1 Overall Design  
This study is a two-part, multicenter, Phase 2a study to evaluate the safety, tolerability, PK, 
and efficacy of SAGE-217 Oral Solution (Part A) and SAGE-217 Capsules (Part B) in 
approximately 98 adult subjects (approximately 10 subjects in Part A and up to 88 
randomized adult subjects in Part B) with MDD.  Part A of the study is an open-label design 
with SAGE-217 Oral Solution dosing for 14 days.  Part B of the study is a randomized, 
double-blind, parallel-group, placebo-controlled design with SAGE-217 Capsule or matching 
placebo dosing for 14 days.  Part B will consist of an up to 14-day Screening Period (Days    


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-14 to -1), a 14-day Treatment Period, and a 4-week Follow-up Period.  Separate cohorts of 
subjects will be enrolled in Part A and Part B; subjects participating in Part A cannot enroll 
in Part B.  
During the Screening Period, after signing the informed consent form (ICF), subjects will be 
assessed for study eligibility, and the severity of each subject’s MDD will be evaluated using 
HAM-D.  The Screening Period assessments will be conducted on an outpatient basis.  
If applicable, standard of care data collected prior to obtaining informed consent may also be 
included as screening data, if appropriate, such as laboratory tests, ECG, physical 
examination, and vital signs conducted within the preceding 48 hours, as long as the 
requirement for the screening assessment to be collected retrospectively is met in full.  If 
applicable, to ensure protocol compliance, any standard of care data eligible for inclusion as 
screening data must include the precise nature and timing of data collection. 
During the 14-day study Treatment Period of Part A and B, subjects must remain inpatient 
for the first 7 days at minimum and per Investigator’s judgement thereafter.  The Follow-up 
Period assessments will be conducted on an outpatient basis. 
The study will be conducted in two parts:  
•  Part A: Beginning on Day 1, subjects will receive open-label SAGE-217 Oral 
Solution at 8:00 PM (±15 minutes) with food (as outlined in protocol Section 9.2.1).  
Subjects will receive SAGE-217 Oral Solution 30 mg from Day 1 to Day 14 as 
tolerated.  
•  Part B: Based on the results of Part A, eligible subjects will be stratified based on use 
of antidepressant treatment (current/stable or not treated/withdrawn ≥30 days) and 
randomized within each stratum in a 1:1 ratio to receive SAGE-217 Capsules (30 mg) 
or matching placebo for 14 days beginning on Day 1, as tolerated.  All doses of study 
drug will be administered at 8:00 PM (±15 minutes) with food as outlined in protocol 
Section 9.2.2. 
Enrollment into Part A may be stopped and Part B initiated if there is a clear signal of 
activity based on the HAM-D scores and/or other scales being assessed.  Alternatively, upon 
completion of Part A, Part B may begin.  The study may be terminated if there is clear lack 
of activity based on HAM-D scores during Part A. 
In Part A and Part B, study drug (SAGE-217 Oral Solution in Part A; SAGE-217 Capsule or 
matching placebo in Part B) will be administered at the study center for at least the first 7 
days of the Treatment Period, which includes Day 1 of study drug administration through 
completion of study drug administration on Day 14.  Subjects may be discharged after a 
minimum 7-day inpatient stay, following completion of the Day 7 assessments.  If their 
clinical condition does not allow discharge, the Investigator may keep the subjects as 
inpatients for a longer period of time.  Subjects discharged from the inpatient unit may 
receive treatment with study drug for the remainder of the 14-day Treatment Period as 
outpatients.  For the outpatient phase, dosing will be done at the clinical site or, if suitable 
arrangements can be made, via home administration where local regulations allow.  All 
dosing will be observed, either in the clinical unit or by a healthcare professional at home.  


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Home administration of study drug will be performed according to a site-specific plan by a 
healthcare professional trained on the protocol and delivery of the study drug.  
Subjects will be monitored for safety during the Treatment and Follow-up Periods including 
monitoring for adverse events/serious adverse events, routine clinical laboratory assessments, 
physical examination, vital signs, and ECG (only Day 15 during Follow-up).  
During the Treatment Period, subjects will be able to receive study drug as long as there are 
no dose limiting safety/tolerability concerns.  Subjects cannot tolerate 30 mg will receive 20 
mg for the remaining of the Treatment Period.  Subjects who experience intolerable AEs at 
the 20-mg dose level may be terminated from the study at the discretion of the Investigator.  
Dosing may also be modified based on tolerability as assessed with SSS scores.  Any SSS 
score of ≥6 will be reassessed within 10 minutes.  If a subject is receiving the 30-mg dose of 
study drug and has an SSS score of ≥6 that is confirmed on repeat assessment during normal 
waking hours, the dose will be decreased to 20 mg for the rest of the Treatment Period.  If a 
subject is receiving the 20-mg dose of study drug and has an SSS score of ≥6 that is 
confirmed on repeat assessment during normal waking hours, then study drug will be 
discontinued and the subject will be terminated from the study.  
Follow-up visits will be conducted on an outpatient basis.  Follow-up visits will be conducted 
weekly for 2 weeks after completion of the Treatment Period in Part A (Day 28 ±1 day) and 
weekly for 4 weeks after completion of the Treatment Period in Part B (Day 42 ±3 days). 
See section 15.1 for schedule of events in Part A and Part B. 
6.2 Sample Size and Power 
The sample size of ten subjects for Part A was selected based on clinical and not statistical 
considerations.  
For Part B, assuming a two-sided t-test at an alpha level of 0.05, a sample size of 40 subjects 
per group would provide 90% power to detect an effect size of 0.75 between the SAGE-217 
Capsules and matching placebo groups with regard to the efficacy outcome variable of 
change from baseline in HAM-D total score.  An effect size of 0.75 corresponds to a 
matching placebo-adjusted difference of 7.5 points in the change from baseline in HAM-D 
total score at 15 days with an assumed SD of 10 points.  By including two treatment groups 
and using a 1:1 randomization, a total of 80 subjects are required.  Assuming a non-
evaluability rate of 10%, up to 88 subjects will be randomized.  Additional subjects may be 
enrolled if the drop-out rate is higher than 10%. 
 
6.3 Randomization 
Part A is open-label with no control group; therefore, there will be no randomization or 
blinding. 
Part B is a double-blind, placebo-controlled study.  Subjects who meet the entrance criteria 
will be stratified based on use of antidepressant treatment (current/stable or not 
treated/withdrawn ≥30 days) and randomly assigned within each stratum in a 1:1 ratio to 
receive SAGE-217 Capsules or matched placebo according to a computer-generated 


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randomization schedule.  Once it has been determined that a subject meets eligibility criteria, 
the subject will be sequentially assigned a subject number from the randomization schedule 
provided to the unblinded pharmacist and/or designated pharmacy staff.  Subject 
identification numbers will consist of the site number (e.g., “01”) followed by numbering 
starting with double zero (e.g., 01-001, 01-002, 01-003 through 01-0xx), for Part A of the 
study.  Moreover, to avoid duplicate patient numbers between Part A and Part B the 
sequential counter will begin at 201 for all sites in Part B. 
The randomization schedule will be computer-generated. 
6.4 Blinding and Unblinding 
Part A is open-label with no control group; therefore, procedures for blinding and unblinding 
are not applicable. 
Part B is a double-blind, placebo-controlled study.  Only the clinic pharmacist and/or 
designated pharmacy staff, who is responsible for preparing the study drug, will be given a 
copy of the randomization schedule.  In the event of a medical emergency, the pharmacist 
may reveal actual capsules content to the Investigator, who should also alert Sage of the 
emergency.  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 electronic case report form (eCRF).  If the subject or study center 
personnel (other than pharmacist) have been unblinded, the subject will be terminated from 
the study.  In addition, an unblinded Monitor will perform drug accountability during the 
study. 
 
 


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7 
MODIFICATIONS  
7.1 Modifications to the Approved Clinical Study Protocol 
 
Protocol Text 
SAP Text 
1. Physical examinations in Parts A 
and B will be summarized at the 
Screening visit, Day 8, Day 15, Day 
21, and Day 28 visits. 
2. Center will be treated as random 
effect 
3. The HAM-D total score will be 
calculated as the sum of the 17 
individual item scores.  Item 16 can 
be rated according to history (item 
16A) or actual weight change (item 
16B).  The item 16 score is 
calculated as the item 16 response 
that is not equal to 3 (i.e., “Not 
assessed”). 
4. The PK Set will consist of all subjects 
in the Safety Set with sufficient plasma 
concentrations for PK evaluations, and 
will be used to summarize PK data  
 
 
1. All physical examinations data in 
Parts A and B will be listed. 
 
2. Center will be treated as a fixed 
effect in the primary efficacy 
analysis.  
As a supportive analysis, the 
MMRM models will be used to 
study the heterogeneity of study 
drug effect by considering center 
and treatment-by-center effects to 
be random   
 
3. Item 16 mentioned in Section 11 of 
the protocol corresponds to item 8 
(loss of weight) in the structured 
interview guide and is scored in a 
range of 0 to 2. 
4. The PK Set will consist of all 
subjects in the Safety Set with at 
least 1 post-dose PK assessment in 
the study, and will be used to 
summarize PK data 
 
7.2 Modifications to the Approved Statistical Analysis Plan 
This SAP has been modified to incorporate protocol version 4.0. Per protocol version 4.0, 
center should be treated as a random effect.  
Summary of changes from SAP V1.0: 
• Incorporation of changes due to protocol amendment 2, version 3.0 and protocol 
amendment 3, version 4.0 
• Minor editorial changes 
• Prior and concomitant medications: changes in definitions 
• HAM-D:  
o Added details on the subscales (Core, Anxiety, Bech-6, and Meier) 
o Separated summary tables for subscale and individual item scores 
o Modified total score categorization 


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• Additional details for Part B 
o Study drug exposure: added a different categorization for number of days the 
study drug was received 
o Protocol deviations: added summary table 
o Demographics and Baseline Characteristics: added antidepressant use 
o Rules for determining if missing scores will be replaced and approach to 
replacement 
o Binary variable analysis (HAM-D response and remission, CGI-I response): 
removed logistic regression  
o Sensitivity analyses 
o Supportive analyses 
o Statistical methodology (sample SAS code) 
o Safety:  
 Labs, ECGs, and vital signs: added potentially clinically significant 
criterion and summaries/listings  
 AEs:  
• Added summary table for TEAEs resulting in dose adjustment 
• Changed types of TEAEs summarized for the overall summary 
table 
 Labs:  
• Listed lab tests 
• added shift tables 
 Stanford sleepiness scale: changed figure display to spaghetti plots for 
Day 1 through 7 
o PK:  
 Added mean and SD as summary statistics for all parameters 
 Re-numbered the concentration and parameter listings 
Summary of changes from SAP V2.0: 
• Incorporation of changes due to protocol amendment 4, version 5.0  
• HAM-D 
o Modified total score categorization for Part A and Part B 
o Subset analysis 
• Added summary table for TEAEs by preferred term 
• Changed PK Set definition 
• For Part B, modified text on subject data to be displayed in listings 
• For Part B, changed sort order for adverse event SOC 
• Added note regarding modifications to GEE model for HAM-D Remission. 


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7.3 Modifications to the Approved DMC Charter 
Not applicable.  
8 
ANALYSIS SETS 
8.1 Efficacy Set 
The Efficacy Set for Part A is defined as all subjects who received at least one dose of the 
study drug and have a baseline and at least one post-baseline efficacy evaluation.  The 
Efficacy Set will be used to analyze efficacy data.  
The Efficacy Set for Part B is defined as all subjects who are randomized and who received 
at least one dose of the double-blind study drug and have a baseline and at least one post-
baseline efficacy evaluation.  The Efficacy Set will be used to analyze efficacy data.  
8.2 Safety Set 
The Safety Set for Part A is defined as all subjects who received at least one dose of the 
study drug.  The Safety Set will be used to provide descriptive summaries of safety data. 
The Safety Set for Part B is defined as all subjects who received at least one dose of the 
double-blind study drug.  The Safety Set will be used to provide descriptive summaries of 
safety data. 
8.3 Pharmacokinetic (PK) Set 
The PK Set (for Part A and Part B) will consist of all subjects in the Safety Set with at least 1 
post-dose PK assessment in the study, and will be used to summarize PK data. 
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 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.  
All analyses and summary outputs will be generated using SAS® version 9.3 (or higher). 
All subject data, including those derived, will be presented in the subject data listings; 
listings will display subjects in analysis sets for Part A and all subjects for Part B, regardless 
of whether or not they received study drug.  In general, the subject data listings will be sorted 
by randomized treatment group (Part B), subject number and assessment visit and date (and 


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time, if applicable).  The summary tables will be presented descriptively overall for Part A 
and by treatment group for Part B.  
For the purpose of all safety and efficacy analyses where applicable, baseline is defined as 
the last non-missing measurement prior to the start of study drug administration. 
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. 
•  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.  For Part A, no imputation 
process will be used to estimate missing data.  
For Part B, SF-36 subscales will be calculated and missing responses will be handled using 
the built-in scoring software.  For all the other efficacy and exploratory endpoints, the pro-
rating approach will be considered when calculating the total scores.  If no more than 20% of 
item responses are missing for a given subject on the scale, the missing scores will be 
replaced with the mean score on all other non-missing scores, or the maximum possible 
values for the missing responses, whichever is smaller.  Otherwise, if more than 20% of item 
scores are missing for a given subject on the scale, the total score will not be calculated and 
will be left as missing.  See section 9.3.1 for the details of this approach on each endpoint.  
A sensitivity analysis will be used to investigate the impact of missing data if ≥5% of 
subjects have missing data in primary efficacy endpoint assessment (i.e., HAM-D total score) 
or key secondary endpoint assessment (i.e., MADRS total score).  Two techniques will be 
considered for the sensitivity analysis: 1) Multiple Imputation (MI) technique, i.e. by 
replacing each missing value with a set of plausible values that represent the uncertainty 
about the right value to impute; 2) Last Observation Carried Forward (LOCF) Imputation 
technique, i.e. the last observed non-missing value is used to fill in missing values at a later 
point in the study.  See section 9.3.5 for details. 
Safety data will not be subject to any imputation and will be summarized on an observed case 
basis. 
9.2 Background Characteristics  
9.2.1 Subject Disposition 
For Part A, the summaries of subject disposition will include the number of subjects who 
were enrolled, who were dosed, who completed Part A of the study, who discontinued from 
study drug in Part A, and reasons for discontinuation from study drug.  Enrolled subject is 
defined as any screened subject who met the study requirements (inclusion/exclusion 
criterion) during screening. 


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For Part B, the summaries of subject disposition will include the number of subjects who 
were randomized, who were dosed, who completed Part B of the study, who prematurely 
discontinued, and reasons for premature discontinuation by treatment group. The summary 
will also be provided by site. 
For both Part A and Part B, the number and percentage of subjects in each analysis set will 
be summarized. 
For screen failure subjects, reasons for screen failure will be summarized separately along 
with the number of subjects who were screened.  A screened subject is defined as any subject 
who signed the study specific informed consent.  A screen failure subject is defined as any 
subject who is screened but failed to meet study requirements (inclusion/exclusion criterion) 
during screening. 
A listing of subject randomization will also be presented. 
9.2.2 Demographics and Baseline Characteristics 
Demographic data, such as age, gender, race and ethnicity, and baseline characteristics, such 
as antidepressant use, height, weight, and body mass index (BMI, calculated as weight (kg)/ 
[height (m) 2]), will be summarized using the Safety Set.   
Hepatitis, human immunodeficiency virus (HIV), drug and alcohol, and pregnancy screening 
results will be listed, but not summarized as they are considered part of the 
inclusion/exclusion criteria.  
Medical history collected at screening will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA), Version 19.1 or higher. 
Medical/family history data will be summarized by system organ class (SOC) and preferred 
term (PT) and listed by subject for the Safety Set.  
9.2.3 Prior and Concomitant Medications  
Concomitant Medications will be recorded throughout the study and will be coded using 
World Health Organization-Drug dictionary (WHO-DD) September 1, 2016, 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 first 
dose 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. 
Details of prior and concomitant medications will be listed by subject, start date, and 
verbatim term. 
Medication summaries will be performed by anatomical therapeutic chemical (ATC) level 2 
term and PT based on the Safety Set.   


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9.2.4 Study Drug Exposure  
Exposure to study drug is defined as total number of days treated with study drug during the 
study, with total days calculated as last dose date of study drug - first dose date of study drug 
+ 1.  The number and percentage of subjects exposed to 20 mg and 30 mg of study drug and 
discontinued study drug will be presented.  Subjects exposed to 30 mg of study drug will be 
further summarized by the number of days the study drug was received (Part A: <3, 3-7, >7; 
Part B: 1-14 by day).  Study drug exposure will be summarized using the Safety Set. 
 
For Part B, summary of study drug exposure will also be performed based on the subgroup 
by current antidepressant use status for the Safety Set.  
9.2.5 Protocol Deviations 
Protocol deviations identified during site monitoring in consultation with Medical Monitor 
will be captured in a protocol deviation log and categorized.  These deviations data for all 
subjects that violated the clinical study protocol at any time during the study will be listed. 
 
Protocol deviation data for Part B will be summarized by site and treatment group for All 
Randomized Subjects. Number and percentage of subjects with each protocol deviation type 
will be presented.  
9.3 Efficacy Analysis  
The secondary objective of Part A of the study is to determine if SAGE-217 Oral Solution 30 
mg given for 14 days reduces the depressive symptoms measured by change from baseline at 
various time points in HAM-D total score, HAM-D subscale and individual item scores, 
HAM-A total score, MADRS total score.  In addition, HAM-D response; HAM-D remission; 
and CGI-I response will be assessed.   
 
The secondary objective for Part B of the study is to determine if treatment with SAGE-217 
Capsules 30 mg reduces depressive symptoms in subjects with moderate to severe MDD 
compared to matching placebo measured by change from baseline at various time points in 
HAM-D total score, HAM-D subscale and individual item scores, HAM-A total score, 
MADRS total score.  In addition, HAM-D response; HAM-D remission; and CGI-I response 
will be assessed.  
 
9.3.1 Definition of Efficacy Variable(s) 
The efficacy variables are defined as follows:   
9.3.1.1 Hamilton Rating Scale for Depression (HAM-D) 
HAM-D consists of 17 items that will be used to rate the severity of depression in subjects 
who are already diagnosed as depressed using the Diagnostic and Statistical Manual of 
Mental Disorders, Fifth Edition (DSM-5) Axis I Disorders (SCID-I). 
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; 


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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.  Item 16 mentioned in Section 
11 of the protocol corresponds to item 8 (loss of weight) in the structured interview guide and 
is scored in a range of 0 to 2.  The score for each item will be summed to compute a total 
score, which ranges from 0 to 52.  For Part B, if more than 3.4 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 3.4 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. 
The HAM-D subscales are Core, Anxiety, Bech-6, and Meier.  The Core subscale comprises 
individual ratings related to the following symptoms: depressed mood, feelings of guilt, 
suicide, work and activities, and retardation.  The Anxiety subscale comprises individual 
ratings related to the following symptoms: anxiety (psychic and somatic), somatic symptoms 
(gastrointestinal and general), hypochondriasis, and loss of weight.  The Bech-6 subscale 
comprises individual ratings related to the following symptoms: depressed mood, feelings of 
guilt, work and activities, retardation, anxiety psychic, and somatic symptoms general.  The 
Meier subscale comprises individual ratings related to the following symptoms: depressed 
mood, feelings of guilt, work and activities, retardation, agitation, and anxiety psychic.  The 
subscale scores will be calculated as the sum of the individual rating scores related to each 
subscale, divided by the total possible score within the subscale, multiplied by 100, and 
rounded to a whole number. 
 
Hamilton Rating Scale for Depression response will be defined as having a 50% or greater 
reduction from baseline in HAM-D total score.  Any subject who met this criterion will be 
defined as a HAM-D Responder.  
Hamilton Rating Scale for Depression remission will be defined as having a HAM-D total 
score of ≤7.  Any subject who met this criterion will be defined as a subject in HAM-D 
remission. 
As a measure of the severity of depression, HAM-D total score will be categorized as: 0-
7=Normal, 8-16=Mild Depression, 17-23=Moderate Depression, >=24=Severe Depression. 
9.3.1.2 Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item diagnostic questionnaire that psychiatrists use to measure the 
severity of depressive episodes in subjects with mood disorders.  It was designed as an 
adjunct to the HAM-D that would be more sensitive to the changes brought on by 
antidepressants and other forms of treatment than the Hamilton Scale. 
Higher MADRS scores indicate more severe depression, and each item yields a score of 0 to 
6.  The 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 


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available item scores, or the maximum possible values for the missing responses, whichever 
is smaller, to calculate the MADRS total score. 
9.3.1.3 Hamilton Anxiety Rating Scale (HAM-A) 
The 14-item HAM-A will be used to rate the severity of symptoms of anxiety.  Scoring for 
HAM-A is calculated by assigning scores of 0 (not present) to 4 (very severe).  The HAM-A 
total score will be calculated as the sum of the 14 individual item scores.  If more than 2.8 
individual items are missing, the HAM-A total score will not be calculated and will be left as 
missing.  If less than or equal to 2.8 individual item scores are missing, the missing item 
scores will be imputed by the mean of all other available item scores, or the maximum 
possible values for the missing responses, whichever is smaller, to calculate the HAM-A total 
score. 
As a measure of the severity of anxiety, HAM-A total score will be categorized as follows in 
the shift table: 0-13=Normal, 14-17 Mild Anxiety, 18-24 Moderate Anxiety, >=25 Severe 
Anxiety, per the Psych Congress Network. 
9.3.1.4 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. 
9.3.1.5 Clinical Global Impression – Improvement (CGI-I)  
The CGI-I employs a 7-point Likert scale to measure the overall improvement in the 
subject’s condition posttreatment.  The Investigator will rate the subject’s total improvement 
whether or not it is due entirely to drug treatment.  Response choices include: 0=not assessed, 
1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 
5=minimally worse, 6=much worse, and 7=very much worse.  
CGI-I response will be defined as having a CGI-I score of “very much improved” or “much 
improved.”  
9.3.1.6 Short Form-36 (SF-36) 
The SF-36 Health Survey is a subject-reported 36-item instrument for measuring functional 
health and well-being.  The scores are totaled and higher score will indicate a better state of 
health.  
9.3.1.7 The Fatigue Associated with Depression (FAs-D) Patient-Reported 
Outcome (PRO) 
Fatigue is one of the most common symptoms of MDD.  The 13-item patient-reported 
questionnaire was designed to assess fatigue associated with depression in the past week.  
Three scores are computed: 
•  A six-item fatigue experience subscale 


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•  A seven-item fatigue impact subscale 
•  A total score (all 13 items). 
The two subscales and the total score are computed as the mean of all answered items within 
each scale, and each scale score has a possible range of 1 to 5, with higher scores 
representing greater fatigue. 
9.3.1.8 Remission in Depression Questionnaire (RDQ) 
The Remission from Depression Questionnaire (RDQ) was developed to capture the broader 
array of domains considered by subjects to be relevant to the construct of remission 
symptoms of depression, non-depressive symptoms, features of positive mental health, 
coping ability, functioning, life satisfaction, and a general sense of well-being.  The RDQ is a 
reliable and valid measure that evaluates the multiple domains that depressed patients 
consider important in determining remission.  
Each item ranges from 0 (not at all or rarely true) to 2 (often or almost always true).  Each of 
the seven subscales is scored separately by taking the sum of scores that are within the same 
subscale.  The score for each item will be summed to compute a total score, which ranges 
from 0 to 82, where ≤27 indicates remission, per the Psych Congress Network.  The total 
score is calculated as the sum of the 41 items.  
9.3.1.9 Health-Related Productivity Questionnaire (HRPQ) 
The Health-Related Productivity Questionnaire (HRPQ) is a generic measure developed to 
measure health-related work productivity in patients with a particular disease and/or being 
treated for the disease.  The instrument collects productivity data in terms of absenteeism, 
presenteeism, and combined lost productivity for three work venues: work outside home, 
housework, and classes/homework.  
 
9.3.2 Visit Windows 
The unscheduled or early termination (ET) visit will be mapped to a scheduled visit for 
analysis using the date of collection/assessment as a basis to determine study day and then 
study day will be mapped to the intended visit.  The table below contains the visit windows 
for efficacy analysis. 
Once analysis visit windows get assigned, all visits, including scheduled visits, unscheduled 
visits, and 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.  


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• 
 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 data not flagged as the “analyzed record” will also be listed in subject listings.  
 
 


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Table 1: Visit Windows for Efficacy Analysis, for Both Part A and Part B 
Scheduled Visit 
Study Day of Expected Visit 
Study Day Window for Visit 
Screening 
Day -1 
Days (-14) to (-1) 
Baseline  
Day 1 
Day 1 
Day 2 
Day 2 
Day 2 
Day 3 
Day 3 
Day 3 
Day 4 
Day 4 
Day 4 
Day 5 
Day 5 
Day 5 
Day 6 
Day 6 
Day 6 
Day 7 
Day 7 
Day 7 
Day 8  
Day 8 
Day 8 
Day 15  
Day 15 
Day 15 
Day 21 (±1 day)  
Day 21 
Day 20 - 22 
Day 28 (±3 days) 
Day 28 
Day 25 - 31 
Day 35 (±3 days) 
Day 35 
Day 32 - 38 
Day 42 (±3 days) 
Day 42 
Day 39 - 45 
 
9.3.3 Analysis of Efficacy Variable(s) 
Efficacy data will be summarized using appropriate descriptive statistics and other data 
presentation methods where applicable; subject listings will be provided for all efficacy data.  
For (the open-label) Part A, efficacy data will be summarized descriptively.  For Part B, 
subjects will be analyzed according to randomized treatment group.  The Efficacy Set will be 
used for all efficacy summary tables.  
Descriptive statistics including n, mean, SD, median, minimum, and maximum of actual, 
change from baseline, and percentage change from baseline values will be presented by 
assessment time point for the following continuous efficacy variables:  
•  HAM-D total score; 
• MADRS total score; 
•  HAM-D subscale and individual item scores (Note: percentage change from baseline 
values will not be presented for HAM-D individual item scores); 
•  HAM-A total score; 
• RDQ subscale and total score; 
Summaries using descriptive statistics described above will also be performed based on the 
subgroup by current antidepressant use status for HAM-D total score, MADRS total score 
and HAM-A total score for Part B.  


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Descriptive statistics including n, mean, SD, median, minimum, and maximum of actual 
values and change from baseline will be presented by assessment time point for the following 
continuous efficacy variables: 
• CGI-I (actual value only) and CGI-S scale scores; 
• SF-36 subscale scores (Part B only); 
•  FAs-D subscales and total score (Part B only); 
Descriptive statistics including counts and percentages will be summarized by assessment 
time point for the following categorical efficacy variables:  
•  HAM-D response; 
•  HAM-D remission; 
• CGI-I response; 
• HRPQ response.  
Shift analysis pre- and post-treatment will be presented for the following depression 
categories (0-7 normal, 8-16 mild depression, 17-23 moderate depression, >=24 severe 
depression ) based on sum scores from the first 17 items of the HAM-D rating scale.  Shift 
analysis for the following anxiety categories (0-13=Normal, 14-17 Mild Anxiety, 18-24 
Moderate Anxiety, >=25 Severe Anxiety) will also be presented based on the 14-item HAM-
A rating scale total score.  
Change from baseline and percentage change from baseline in HAM-D, HAM-A, and 
MADRS total score over time will be presented graphically overall for Part A and by study 
treatments for Part B. Plots of change from baseline in HAM-D, MADRS and HAM-A total 
score over time will also be performed based on the subgroup by current antidepressant use 
status for Part B.  
9.3.3.1 Mixed Effects Model for Repeated Measures 
For Part B of the study, the change from baseline for HAM-D total score will be analyzed 
using a mixed effects model for repeated measures (MMRM).   
The model will include the change from baseline at each visit as the dependent variable. 
Treatment, baseline HAM-D total score, center, antidepressant use strata, assessment time 
point, and time point-by-treatment interaction will be included as explanatory variables in the 
model. All explanatory variables including center will be treated as a fixed effect.  The main 
comparison will be (difference in least mean square [LSMEAN]) between SAGE-217 
Capsules and placebo at the 15-day timepoint.  
Model-based point estimates (i.e, LSMEAN, 95% confidence intervals, and p-values) will be 
reported where applicable. An unstructured covariance structure will be used to model the 
within-subject errors. Compound symmetry covariance structure will be used if there is a 
convergence issue with the unstructured covariance model. 
See sample SAS code for MMRM in section 15.2.  
 


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Similarly, an MMRM will be used for the analysis of the following variables: changes from 
baseline in MADRS total score and HAM-A total score, and select individual item and 
subscale scores. For each model, the comparison of interest will be between SAGE 217 
Capsules and matching placebo at the 15-day time point. However, model-based point 
estimates (i.e, LS means), 95% confidence intervals, and p-values will be reported for all 
time points. 
 
9.3.3.2 HAM-D Response and HAM-D Remission Analyses 
At each visit during the treatment period (Day 2 - Day 8) and at the first follow-up visit 
(Day15/ET), a subject will be classified as a responder to the study drug if the subject is 
having a 50% or greater reduction from baseline in HAM-D total score. These binary 
outcome variables are expected to be correlated rather than independent. The correlated 
binary outcome variables will be analyzed using the SAS GENMOD procedure that 
implemented the generalized estimating equations (GEE) approach.  
The models will include the response at each of the 8 visits as the dependent variable.  The 
center, treatment, antidepressant use strata, baseline HAM-D total score, assessment time 
point, and time point-by-treatment will be included as explanatory variables.  
The GEE marginal model approach allows to estimate the odds ratio of a response for the 
subjects who receive SAGE-217 versus the placebo.  Odds ratios, 95% confidence intervals, 
and p-values will be reported.  For the model parameters estimation, the following working 
correlation structures for the binary outcome variables will be assumed: Independence, 
exchangeable, and unstructured.  
At each visit during the treatment period (Day 2 - Day 8) and at Day 15/ET, a subject will be 
classified as a HAM-D remitter to the study drug if the subject is having a HAM-D total 
score of ≤7.  This correlated binary outcome variable will be analyzed using the SAS 
GENMOD procedure that implemented the GEE approach as described above.  
At Day 2, Day 3, Day 8 and at Day 15/ET, a subject will be classified as a CGI-I responder 
to the study drug if the subject is having a CGI-I score of “very much improved” or “much 
improved.” The correlated binary outcome variable will be analyzed similarly as HAM-D 
responder and HAM-D remitter. For the CGI-I response analysis, baseline CGI-S score will 
be included in the model. 
See sample SAS code for GEE model in section 15.2.  
9.3.4 Supportive Analysis  
A MMRM methods similar to those described in section 9.3.3.1 will be used to study the 
heterogeneity of study drug effect by considering center and treatment-by- center effects to 
be random. This supportive analysis applies to HAM-D total score and MADRS total score.  
A subset analysis based on subjects that had negative serum drug screening results will be 
performed for HAM-D total score, HAM-D response and HAM-D remission. The subset 
analysis will include: 


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• Descriptive statistics including n, mean, SD, median, minimum, and maximum of 
actual, change from baseline, and percentage change from baseline values for HAM-
D total score; 
• MMRM methods similar to those described in section 9.3.3.1 for HAM-D total score; 
•  Descriptive statistics including counts and percentages for HAM-D response and 
HAM-D remission.  
9.3.5 Sensitivity Analysis 
A sensitivity analysis will be used to investigate the impact of missing data if ≥5% of 
subjects have missing data in primary efficacy endpoint assessment (i.e, HAM-D total score) 
or key secondary endpoint assessment (i.e., MADRS total score).  Two techniques will be 
considered for the sensitivity analysis:  
1) Multiple Imputation (MI) technique, i.e. by replacing each missing dependent value with a 
set of plausible values that represent the uncertainty about the right value to impute, will be 
considered for the sensitivity analyses.  In our case, since we assume arbitrary missing 
pattern and the variables to be imputed are continuous, a fully conditional specification 
(FCS) regression method that is available in SAS will be used.  
The imputed datasets generated with the approach described above do contain only non-
missing value and are used as input in the model for the sensitivity analysis.  MMRM similar 
as described in section 9.3.3.1 will thus be run on each of the generated imputed datasets and 
the treatment difference between SAGE-217 Capsules and matching placebo at the end of the 
treatment period (Day 15/ET) will be estimated.  Finally, the results will be combined from 
these several imputed datasets to derive overall estimates.  In addition to the estimates, 
corresponding 95% confidence intervals and p-values will be calculated.  
2) Last Observation Carried Forward (LOCF) Imputation technique, i.e., the last observed 
non-missing value will be used to fill in missing values at a later point in the study, 
regardless of when the missing value occurred.  
The imputed dataset generated with the LOCF technique will be used as input data in the 
MMRM similarly as described in section 9.3.3.1.  The treatment difference between SAGE-
217 Capsules and matching placebo at the end of the treatment period (Day 15/ET) will be 
estimated.  Model-based point estimates (i.e., LS means), 95% confidence intervals, and p-
values will be reported.  
The Efficacy Set will be used for the sensitivity analyses.  See sample SAS code for MI in 
section 15.2. 
 
9.4 Safety Analysis 
The primary endpoint is the safety and tolerability of SAGE-217, as evaluated by adverse 
events, concomitant medication usage, changes from baseline in physical examination, vital 
signs, clinical laboratory evaluations, and 12-lead ECG.  Suicidality will be monitored by the 
C-SSRS.  Sedation will be assessed using the SSS.  Safety data will be listed by subject and 


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summarized descriptively in Part A and by study drug in Part B.  All safety summaries will 
be performed on the Safety Set.  All safety data will be presented in subject data listings. 
 
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 
Actual 
Value 
Change 
from 
Baseline 
Abnormality/Clinical 
Significance (CS) 
Potentially Clinical 
Significance (PCS) 
AEs 
X 
 
 
 
 
Con Meds 
X 
* 
 
 
 
Labs 
 
X 
X  
* 
X 
ECG 
 
X 
X 
* 
X 
Vital Signs 
 
X 
X  
 
X 
PE 
 
* 
 
 
 
C-SSRS 
X 
* 
 
 
 
SSS 
 
X 
X 
 
 
Note: PCS criteria are outlined in sections 9.4.2-9.4.4 
X = Safety Assessment will be summarized in tables 
* = Safety Assessment will be presented in individual subject data listings 
 
9.4.1 Adverse Events  
A treatment-emergent adverse event (TEAE) is defined as an adverse event with onset after 
the start of study drug, or any worsening of a pre-existing medical condition/adverse event 
with onset after the start of study drug and until 7 days after the last dose.  
All adverse events will be coded using MedDRA version 19.1 or higher and summarized by 
SOC and PT.  Multiple occurrences of an AE are counted only once per subject per SOC and 
PT for summary tables.  
Summary tables of TEAEs will be presented and will summarize the number and percentage 
of subjects for the following:   
• Any TEAE 
• TEAEs by relationship to study drug (not related, related) 
• TEAEs by severity 
• Serious AEs (SAEs) 
• TEAEs that resulted in discontinuation of study drug 
• TEAEs that resulted in discontinuation of study drug based on the subgroup by 
current antidepressant use status (Part B only) 
• TEAEs that resulted in dose adjustment (Part B only) 
• TEAEs that resulted in dose adjustment based on the subgroup by current 
antidepressant use status (Part B only) 


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•  Overall summary of the number and percentage of subjects reporting TEAEs,  drug-
related TEAEs, severe TEAEs,  serious AEs, TEAEs leading to study drug 
discontinuation, and TEAEs leading to death  
• Summary of the number and percentage of subjects reporting one event, moderate or 
severe events, severe events, related events, serious events, drug-related serious 
events, events leading to dose adjustments, and events leading to study drug 
discontinuation (Part B only). 
Subjects will be counted only once within each SOC and PT at the maximum severity in the 
following order: severe, moderate, and mild.  An AE with missing severity will be 
considered as a severe AE.  Subjects will be counted only once within each SOC and PT at 
the strongest relationship to study drug in the following order: related, not related to study 
drug.  If the relationship between the adverse event and the study drug is determined to be 
“possible” or “probable”, the event will be considered to be related to the study drug.  An 
AE with missing relationship to study drug will be considered as related to study drug.  For 
Part A, the incidences will be presented by overall descending frequency of SOC and then, 
within a SOC, by overall descending frequency of PT based on the subject count in the 
SAGE-217 column.  For Part B, the incidences will be presented in alphabetical order of 
SOC and then, within a SOC, by overall descending frequency of PT based on the subject 
count for the SAGE-217 Capsules study drug column.  Incidences will also be presented in 
order of decreasing frequency of the SAGE-217 Capsules group by PT only. 
All adverse events and serious adverse events (including those with onset or worsening 
before the start of study drug) through the Day 28 follow-up visit (Part A) or Day 42 follow-
up visit (Part B) will be listed. 
9.4.2 Clinical Laboratory 
Clinical laboratory results will be listed by subject and timing of collection.  
 
Hematology tests will include complete blood count, including red blood cells, white blood 
cells with differentiation, hemoglobin, hematocrit, reticulocytes, and platelets. The 
coagulation panel will include activated partial thromboplastin time, prothrombin time, and 
international normalized ratio.  Serum chemistry tests will include serum electrolytes; renal 
function tests, including creatinine, blood urea nitrogen, bicarbonate or total carbon dioxide; 
liver function tests, including alkaline phosphatase, total bilirubin, aspartate aminotransferase, 
and alanine aminotransferase; total protein; albumin; and thyroid stimulating hormone.  
Urinalysis will include assessment of protein, blood, glucose, ketones, bilirubin, urobilinogen, 
hemoglobin, leukocyte esterase, nitrites, color, turbidity, pH, and specific gravity. 
 
Summary tables will include descriptive statistics for the actual values and changes from 
baseline by study visit (Day) in hematology, serum chemistry, coagulation and quantitative 
urinalysis test results and overall in Part A and by study treatments in Part B.  Out-of-range 
values will be flagged as low, high, or abnormal, where applicable, in the subject data 
listings.  
 


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For qualitative urinalysis parameters, test results will be categorized as normal and abnormal. 
Frequency counts and percentages will be presented over time for these categorical data in 
Part A and by treatment group in Part B.  
 
The number and percentage of subjects with PCS values in hematology, serum chemistry and 
quantitative urinalysis tests will be summarized by treatment and visit and listed in Part B. 
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 (Actual values) 
 
 
 
High  
Low  
Hemoglobin                  Male 
g/L  
>185  
<125 
 
Female 
g/L  
>165 
<110 
Hematocrit    
Male 
Fraction of 1 
>0.504  
<0.415  
 
Female 
Fraction of 1 
>0.446 
<0.359 
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 
Bilirubin  
 
μ/L  
>2xULN  
NA  
Albumin  
 
g/L  
>70  
<28  
Aspartate 
Aminotransferase  
 
U/L  
>3xULN  
NA  
Alanine 
Aminotransferase  
 
U/L  
>3xULN  
NA  
Alkaline Phosphatase   
U/L  
>1.5xULN  
NA  
Creatinine (μmol/L) 
 
μmol/L  
>141.4 
NA  
Sodium  
 
mmol/L  
>145  
<132  
Potassium  
 
mmol/L  
>5.2  
<3.5  
Carbon dioxide  
 
mmol/L  
>30  
<18  
Chloride  
 
mmol/L  
>120  
<90  
Occult Blood 
 
 
>=2+ 
NA 
Urine Glucose 
 
 
>=1+ 
NA 
Urine Protein 
 
 
>=1+ 
NA 
 
Shift analysis pre- and post-treatment will be presented for the following laboratory 
categories: low, normal and high. 
 
All parameters will be converted to consistent units according to the International System of 
Units (SI) before summarization. 


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9.4.3 Electrocardiogram 
The following ECG parameters will be listed for each subject: heart rate (bpm), PR (msec), 
QRS (msec), QT (msec), QTc (msec) interval calculated using the Fridericia method (QTcF).  
Any clinically significant abnormalities or changes in ECGs should be listed as an adverse 
event.  Electrocardiogram findings will be listed by subject and visit. 
QTcF (msec) is calculated as: QT (msec)/ RR1/3, where RR (msec) = 60000 / heart rate 
(bpm). 
The actual value at each time point and change from baseline at each post-baseline time point 
will be summarized overall in Part A and by study drug  in Part B.  The number and 
percentage of subjects with ‘normal’, ‘abnormal, not clinically significant’ and ‘abnormal, 
clinically significant’ ECG results will be summarized at baseline and each post-baseline 
time point. 
QT and QTcF will be categorized into the following groups: 
 
• Maximum value > 450 msec  
• Maximum value > 480 msec  
• Maximum value > 500 msec  
The maximum positive change from baseline in QTcF and QT will be categorized into 
following groups:  
 
• >30 msec increase 
• >60 msec increase 
 
The number and percent of subjects who meet the above threshold criteria will be tabulated. 
Additionally, the number and percentage of subjects with PCS and potentially clinically 
significant change (PCSC) values will be summarized by treatment and visit and listed in 
Part B. Potentially clinically significant values will be identified for ECG parameters as 
outlined in the following table. 
 
ECG 
Units 
Criteria for PCS 
Values (Actual 
values) 
Criteria for PCSC values 
(Change from Baseline) 
 
 
High  
Low  
Increase  
Decrease  
QT Interval  
msec  
>450 
>480 
>500  
NA  
>30  
>60  
NA  
QTcF Interval 
msec  
>450 
>480 
>500 
NA  
>30 
>60 
 
NA  
 


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Note: If the assessment is ‘Abnormal, clinically significant’, the event is reported as adverse 
event if identified after the date of informed consent; and any clinically significant 
abnormality at screening as judged by the investigator should be recorded in the medical 
history. 
 
9.4.4 Vital Signs 
Descriptive summaries of actual values and changes from baseline will be calculated for vital 
signs (respiratory rate (breaths/minute), oral temperature (degrees C), supine systolic blood 
pressure (mmHg), supine diastolic blood pressure (mmHg), standing systolic blood pressure 
(mmHg), and standing diastolic blood pressure (mmHg) by time point.  Vital sign results will 
be listed by subject and timing of collection.  The actual value at each time point and change 
from baseline at each post-baseline time point will be summarized overall in Part A and by 
study drug  in Part B. 
Blood pressure and heart rate will be categorized into the following groups: 
 
• Systolic blood pressure:  
o Minimum value < 90 mmHg 
• Diastolic blood pressure: 
o Minimum value < 50 mmHg 
• Heart rate: 
o Minimum value < 40 bpm 
o Maximum value >120 bpm 
o  
Change from baseline in blood pressure and heart rate will be categorized into following 
groups:  
• Systolic blood pressure:  
o Maximum increase from Baseline  >=30  mmHg 
o Maximum decrease from Baseline  >=30  mmHg 
 
• Diastolic blood pressure: 
o Maximum increase from Baseline  >=20  mmHg 
o Maximum decrease from Baseline  >=20  mmHg 
 
The number and percent of subjects who meet the above threshold criteria will be tabulated. 
Additionally, the number and percentage of subjects with PCS and PCSC values will be 
summarized by treatment and visit and listed in Part B. Potentially clinically significant 
values will be identified for vital sign parameters as outlined in the following table. 
 
 


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Vital Sign 
Units 
Criteria for PCS Values 
(Actual values) 
Criteria for PCSC values 
(Change from Baseline 
values) 
 
 
High  
Low  
Increase  
Decrease  
Heart rate 
Beats/m
in  
>120  
<40  
NA 
NA 
Systolic Blood 
Pressure (supine 
and standing)  
mmHg  
NA  
<90  
≥30 
≥30 
Diastolic Blood 
pressure (supine 
and standing)  
mmHg  
NA 
<50  
≥20 
≥20  
 
9.4.5 Physical Examination  
All physical examinations data in Parts A and B will be listed.  
Note: Any clinically significant abnormalities that are new or worsened are recorded as an 
adverse event. 
 
9.4.6 Columbia Suicide Severity Rating Scale (C-SSRS) 
Suicidality data collected on the C-SSRS at baseline and by visit during the Treatment Period 
will be listed for all subjects.  Listings will include all data collected on the C-SSRS.  In 
addition, the number and percentage of subjects with a response of ‘Yes’ to any C-SSRS 
Suicidal Ideation or Suicidal Behavior item will be presented in a table. 
 
9.4.7 Stanford Sleepiness Scale (SSS) 
The SSS is subject-rated scale designed to quickly assess how alert a subject is feeling.  
Degrees of sleepiness and alertness are rated on a scale of 1 to 7, where the lowest score of 
‘1’ indicates the subject is ‘feeling active, vital, alert, or wide awake’ and the highest score of 
‘7’ indicates the subject is ‘no longer fighting sleep, sleep onset soon; having dream-like 
thoughts’. 
Sedation data collected on the SSS will be listed for all subjects.  Spaghetti plots of actual 
value over time during inpatient days (Day 1 through Day 7) will be represented graphically.  
The actual value at each time point and change from baseline at each post-baseline time point 
will be summarized overall in Part A and by treatment group  in Part B.  In addition, the 
number and percentage of subjects at each SSS scale rating will be presented.  Spaghetti plots 
and summary table will also be performed based on the subgroup by current antidepressant 
use status for Part B.  
 


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9.5 Pharmacokinetic Analysis 
PK analyses will be performed for the PK Set. 
9.5.1 Collection schedule 
Plasma samples for PK analysis in Part A and Part B will be collected predose on Days 2, 3, 
4, 5, and 6, predose and 0.25, 0.5, 1, 2, 10, and 12 hours postdose on Day 7 (within ±5 
minutes of the scheduled time point through 0.5 hours after dosing and ±15 minutes of the 
scheduled time point from 1 hour after dosing and greater), prior to discharge on Day 8 for 
subjects being discharged or 16 hours postdose for subjects remaining as inpatients, predose 
on Day 14, and in the morning on Day 15.  
The time of study drug administration is time zero and all post-dosing sampling times are 
relative to this time.  In the event of a dose adjustment, an unscheduled PK sample should be 
collected just prior to the dose change.  Plasma samples for PK analysis will be collected per 
protocol. 
9.5.2 Derived PK parameters 
Non-compartmental PK parameters for SAGE-217 will be calculated using Phoenix 
WinNonlin 6.4 or higher version.  Actual sampling times will be used in the determination of 
the individual PK parameters.  Linear up log down method will be used for derivation of 
AUC. 
The following PK parameters will be derived (where possible): 
Table 3: PK parameters and definitions 
AUC0-t (or 
AUC) 
Area under the plasma concentration time curve up to time t 
AUC∞ 
AUC from time 0 to infinity 
Cmax 
Maximum (peak) plasma concentration 
Tmax 
Time at maximum (peak) plasma concentration 
t1/2 
Elimination half-life (where possible) 
Css (or Cavg,ss) 
Steady-state drug concentration in the plasma during oral intake , the dosing interval 
will be considered as 24 hours 
 
9.5.3 Handling of dropouts or missing data 
Missing concentration data for all subjects who are administered scheduled study treatment 
will be considered as non-informative missing and will not be imputed. 
The following rules will apply for the derivation of all kinds of AUCs: 
• Pre-dose concentration values below the assay’s limit of quantification (BLQ) will be 
treated as zero. 
• The sampling time relative to dosing for pre-dose samples will also be treated as zero. 


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• Post-dose BLQ values will be set to missing. 
If the actual time of sampling is missing, the planned time may be used. 
9.5.4 Summary statistics 
The plasma concentrations along with time point deviation from scheduled time will be listed 
by subject. 
Pharmacokinetic parameters will be summarized using appropriate descriptive statistics 
separately for Part A and B.  Time at maximum (peak) plasma concentration (tmax) will be 
summarized using n, mean, SD, median, minimum, and maximum.  All other PK parameters 
will be summarized using n, mean, SD, geometric mean, geometric coefficient of variation, 
coefficient of variation, median, minimum, and maximum and listed by subject.  For Part B, 
summary analysis using descriptive statistics will also be performed based on the subgroup 
by current antidepressant use status. 
9.5.5 Data presentation 
The descriptive statistics will be generated as discussed above in Section 9.5.4. 
The following figures will be produced: 
• Mean ± SD plasma concentration-time profiles for Day 7 will be plotted on linear and 
semi-log scales separately for Part A and B 
• Individual subject concentration-time profiles on linear and semi-logarithmic 
concentration scales separately for Part A and B  
• Individual subject concentration-time profiles on linear scale based on the subgroup 
by current antidepressant use status for Part B 
• Spaghetti plots for each study drug  on Day 7 separately for Part A and B (linear and 
semi-logarithmic scale) 
• Spaghetti plots for each study drug on Day 7 on linear scale based on the subgroup by 
current antidepressant use status for Part B 
10 SUMMARY OF INTERIM AND DMC ANALYSES 
Not applicable 
 
 




























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14 REFERENCES 
Clinical Study Protocol: Version 4.0 (06 June, 2017), Company: Sage Therapeutics Inc. 
 
Psych Congress Network site: http://www.psychcongress.com/saundras-corner/scales-
screeners/anxiety-disorders/hamilton-anxiety-rating-scale-ham-d. 
 
Psych Congress Network site: http://www.psychcongress.com/saundras-corner/scales-
screeners/depression/remission-depression-questionnaire-rdq. 
 
 


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15 LIST OF APPENDICES 
15.1 Appendix A: Schedule of Assessments 
 


 
 
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Confidential Information 
 
Table 3:  Schedule of Events (Part A) 
 
Screening Period 
Open-Label Treatment Period 
Follow-up Period 
Visits 
OUTPATIENT 
INPATIENT 
INPATIENT or OUTPATIENTa 
OUTPATIENT 
Visit Days 
D -7 to -1 
D1* 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
D15/ 
ET 
D21 
(+1d) 
D28 
(±3d) 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Family History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCID-I 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confinement 
 
X 
(X) 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
Body Weight/Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X (wt 
only) 
X (wt 
only) 
X (wt 
only) 
Clinical Laboratory 
Assessmentsb 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
Drug & Alcohol Screenc 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testd 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xe 
 
X 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Samplef 
O 
 
 
 
 
 
 
 
O 
 
 
 
 
 
 
O 
 
 
Genetic Sampleg 
O 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse Oximetry 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
12-Lead ECGi 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
C-SSRSj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-Sk 
X 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 


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Screening Period 
Open-Label Treatment Period 
Follow-up Period 
Visits 
OUTPATIENT 
INPATIENT 
INPATIENT or OUTPATIENTa 
OUTPATIENT 
Visit Days 
D -7 to -1 
D1* 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
D15/ 
ET 
D21 
(+1d) 
D28 
(±3d) 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CGI-Ik 
 
 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
HAM-Ak 
X 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
HAM-Dk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
MADRSk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
SSSl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Plasma PKm 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
 
 
Study Drug Administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse Events 
X 
Prior/Concomitant 
Medicationsn 
X 
CGI-I = Clinical Global Impression - Improvement; CGI-S – Clinical Global Impression - Severity; C-SSRS = Columbia Suicide Severity Rating Scale; D = day; ET = early 
termination; ECG = electrocardiogram; HAM-A = Hamilton Anxiety Rating Scale; HAM-D = Hamilton Rating Scale for Depression, 17-item; HIV = human 
immunodeficiency virus; MADRS = Montgomery-Åsberg Depression Rating Scale; PK = pharmacokinetic; SCID-I = Structured Clinical Interview for Diagnostic and 
Statistical Manual of Mental Disorders, Fifth Edition Axis I Disorders; SSS = Stanford Sleepiness Scale; wt = weight 
*D1 procedures are to be completed prior to dosing 
a Outpatient visits may take place at the subject’s residence or in the clinic. 
b Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis.  Laboratory assessments are to be completed in the morning on Days 8 and 15 
and during the follow-up visits on Day 21 and Day 28. 
c  Urine toxicology for selected drugs of abuse and serum or breath test for alcohol.   
d  Serum pregnancy test at screening and urine pregnancy test at Day 1 and Day 28.   
e  Female subjects who prematurely discontinue will have a pregnancy test performed at the ET visit. 
f  An optional blood sample for hormone and exploratory biochemistry testing, where consent is given. 
g An optional genetic sample for biomarker testing, where consent is given. 
h Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing). Vital signs will be obtained within ±5 minutes of the 
scheduled time point through 0.5 hours after dosing and ±30 minutes of the scheduled time point from 1 hour after dosing and greater, unless the subject is asleep between 
the hours of 23:00 h and 06:00 h. From Day 1 through Day 7, vital signs will be completed at the following time points: predose, 0.25, 0.5, 1, 2, and 12 hours after dosing. 
During the outpatient treatment period, vital signs will be completed prior to dosing and 1 hour after dosing. Vital signs may be repeated at the discretion of the Investigator 
or Visiting Home Healthcare Provider as clinically indicated. 
i Will be performed 1 hour ±15 minutes after dosing on Days 1, 2, 7, and 14, and during the follow-up visit on Day 21.  


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j 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. 
k To be completed to be completed at 8:00 AM (±30 minutes) at each scheduled time point during the Treatment Period, and in the morning on Day 15, Day 21, and Day 28. 
The assessment timeframe for HAM-D and HAM-A scales will refer to the past 7 days (1 week) on Screening, Day 1, Day 15/ET, Day 21, and Day 28 visits, and the past 
24 hours on visits occurring on Days 2 through 8.  
l To be completed within ±5 minutes of the scheduled time point through 0.5 hours after dosing and ±15 minutes of the scheduled time point from 1 hour after dosing and 
greater, unless the subject is asleep between 23:00 h and 06:00 h during the inpatient treatment period. From Day 1 through Day 7, SSS will be completed at the following 
time points: predose, 0.25, 0.5, 1, and 2 hours after dosing. During the outpatient treatment period, SSS will be completed prior to dosing and 1 hour after dosing.  
m Plasma samples for PK analysis in Part A and Part B will be collected predose on Days 2, 3, 4, 5, and 6, predose and 0.25, 0.5, 1, 2, 10, and 12 hours postdose on Day 7 
(within ±5 minutes of the scheduled time point through 0.5 hours after dosing and ±15 minutes of the scheduled time point from 1 hour after dosing and greater), prior to 
discharge on Day 8 for subjects being discharged or 16 hours postdose for subjects remaining as inpatients, predose on Day 14, and in the morning on Day 15. The time of 
study drug administration is time zero and all post-dosing sampling times are relative to this time. In the event of a dose adjustment, an unscheduled PK sample should be 
collected just prior to the dose change. Plasma samples for PK analysis will be collected per protocol and subjects may need to be awoken for sample collection. 
n To include those taken within 30 days prior to informed consent and throughout the study. 
 
 


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Table 4:  Schedule of Events (Part B) 
 
Screening 
Period 
Double-Blind, Placebo-Controlled Treatment Period 
Follow-up Period 
Visits 
OUTPATIENT 
INPATIENT 
INPATIENT or OUTPATIENTa 
OUTPATIENT 
Visit Days 
D -14 to -1 
D1* 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 D10 D11 D12 D13 D14 
D15/ 
ET 
D21 
(+1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d) 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Family History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCID-I 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confinement 
 
X 
(X) 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
Body Weight/Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X (wt 
only) 
X (wt 
only) 
X (wt 
only) 
X (wt 
only) 
X (wt 
only) 
Clinical Laboratory 
Assessmentsb 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Drug & Alcohol Screenc 
X 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testd 
X 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xe 
 
 
 
X 
Hepatitis & HIV Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Samplef 
O 
 
 
 
 
 
 
 
O 
 
 
 
 
 
 
O 
 
 
 
 
Genetic Sampleg 
O 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsh 
X 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse Oximetry 
 
X* 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECGi 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 


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Screening 
Period 
Double-Blind, Placebo-Controlled Treatment Period 
Follow-up Period 
Visits 
OUTPATIENT 
INPATIENT 
INPATIENT or OUTPATIENTa 
OUTPATIENT 
Visit Days 
D -14 to -1 
D1* 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 D10 D11 D12 D13 D14 
D15/ 
ET 
D21 
(+1d) 
D28 
(±3d) 
D35 
(±3d) 
D42 
(±3d) 
Study Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRSj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-Sk 
X 
X* 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
CGI-Ik 
 
 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
HAM-Ak 
X 
X* 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
HAM-Dk 
X 
X* 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
MADRSk 
X 
X* 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
SF-36k 
 
X* 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
FAs-D k 
 
X* 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
RDQ k 
 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
HRPQ k 
 
X* 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
SSSl 
X 
X* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Plasma PKm 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
 
 
 
 
Study Drug 
Administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Adverse Events 
X 
Prior/Concomitant 
Medicationsn 
X 
CGI-I = Clinical Global Impression - Improvement; CGI-S – Clinical Global Impression - Severity; C-SSRS = Columbia Suicide Severity Rating Scale; D = day; ET = early 
termination; ECG = electrocardiogram; FAs-D = fatigue associated with depression; HAM-A = Hamilton Anxiety Rating Scale; HAM-D = Hamilton Rating Scale for 
Depression, 17-item; HIV = human immunodeficiency virus; HRPQ = Health-Related Productivity Questionnaire; MADRS = Montgomery-Asberg Depression Rating Scale; 
PK = pharmacokinetic; RDQ = Remission in Depression Questionnaire; SCID-I = Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition Axis I Disorders; SF-36 = 36-item short form survey; SSS = Stanford Sleepiness Scale; wt = weight 
*D1 procedures are to be completed prior to dosing 
a Outpatient visits may take place at the subject’s residence or in the clinic. 


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b Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. Laboratory assessments are to be completed in the morning on Days 8 and 15 
and during the follow-up visits on Day 21,Day 28, Day 35, and Day 42.  
c Urine toxicology for selected drugs of abuse and serum or breath test for alcohol.   
d Serum pregnancy test at screening and urine pregnancy test at Day 1 and Day 42. 
e Female subjects who prematurely discontinue will have a pregnancy test performed at the ET visit. 
f An optional blood sample for hormone and exploratory biochemistry testing, where consent is given. 
g An optional genetic sample for biomarker testing, where consent is given. 
h Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing). Vital signs will be obtained within ±5 minutes of the 
scheduled time point through 0.5 hours after dosing and ±30 minutes of the scheduled time point from 1 hour after dosing and greater, unless the subject is asleep between 
the hours of 23:00 h and 06:00 h. From Day 1 through Day 7, vital signs will be completed at the following time points: predose, 0.25, 0.5, 1, 2, and 12 hours after dosing. 
During the outpatient treatment period, vital signs will be completed prior to dosing and 1 hour after dosing. Vital signs may be repeated at the discretion of the Investigator 
or Visiting Home Healthcare Provider as clinically indicated. 
i Will be performed 1 hour ±15 minutes after dosing on Days 1, 2, 7, and 14, and during the follow-up visit on Day 21.  
j 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.  
k To be completed at 8:00 AM (±30 minutes) at each scheduled time point during the Treatment Period, and in the morning on Day 15, Day 21, and Day 28. The assessment 
timeframe for HAM-D and HAM-A scales will refer to the past 7 days (1 week) on Screening, Day 1, Day 15/ET, Day 21, Day 28, Day 35 and Day 42 visits, and the past 
24 hours on visits occurring on Days 2 through 8. 
l To be completed within ±5 minutes of the scheduled time point through 0.5 hours after dosing and ±15 minutes of the scheduled time point from 1 hour after dosing and 
greater, unless the subject is asleep between 23:00 h and 06:00 h during the inpatient treatment period. From Day 1 through Day 7, SSS will be completed at the following 
time points: predose, 0.25, 0.5, 1, and 2 hours after dosing. During the outpatient treatment period, SSS will be completed prior to dosing and 1 hour after dosing. 
m Plasma samples for PK analysis in Part A and Part B will be collected predose on Days 2, 3, 4, 5, and 6, predose and 0.25, 0.5, 1, 2, 10, and 12 hours postdose on Day 7 
(within ±5 minutes of the scheduled time point through 0.5 hours after dosing and ±15 minutes of the scheduled time point from 1 hour after dosing and greater), prior to 
discharge on Day 8 for subjects being discharged or 16 hours postdose for subjects remaining as inpatients, predose on Day 14, and in the morning on Day 15. The time of 
study drug administration is time zero and all post-dosing sampling times are relative to this time. In the event of a dose adjustment, an unscheduled PK sample should be 
collected just prior to the dose change. Plasma samples for PK analysis will be collected per protocol and subjects may need to be awoken for sample collection. 
n To include those taken within 30 days prior to informed consent and throughout the study. 
 
 


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15.2  Appendix B: Details of Statistical Methodology 
Sample SAS code for Mixed Effects Model for Repeated Measures (MMRM): 
proc mixed data=&data; 
by param; 
class trtan avisitn siteid usubjid strata; 
model chg=base siteid trtan strata avisitn trtan*avisitn / ddfm=kr s; 
repeated avisitn / subject=usubjid type=un;  
lsmeans trtan*avisitn /cl pdiff e; 
estimate 'SAGE-217 vs PLACEBO at day 15' trtan 1 -1 trtan*avisitn 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 -1 0 0 0 0/ cl;  
run;  
Note: if convergence not met, use type=cs instead 
 
Sample SAS code for Generalized Estimating Equation (GEE): 
proc genmod data=&data; 
by param; 
class usubjid trtan siteid strata avisitn; 
model aval=base siteid trtan strata avisitn trtan*avisitn/dist=bin link=logit; 
repeated subject=usubjid / type=un; * if convergence not met, use type=exch; 
lsmeans trtan*avisitn / diff exp cl; 
estimate 'SAGE-217 vs PLACEBO at day 15' trtan 1 -1 trtan*avisitn 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 -1 0 0 0 0/ exp cl; 
run;  
Note: for HAM-D Remission, the Day 2 visit and siteid will be excluded from the model due to too few subjects for model convergence. 
 
Sample SAS code for Multiple Imputation (MI): 


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proc mi data=&data seed=xxxx nimpute=4 round=. . . . 1 1 1 1 1 1 1 1 1 1 1 1 1 out=fcs_reg; 
class trtan strata; 
fcs discrim (trtan strata /details classeffects=include); 
fcs nbiter=20 reg (base day2 day3 day4 day5 day6 day7 day8 day15 day21 day28 day35 day42/details); 
var trtan strata base day2 day3 day4 day5 day6 day7 day8 day15 day21 day28 day35 day42; 
run;