Clinical trial NCT03864614
Conditions: Major Depressive Disorder
Sponsor: Biogen
Start date: 2019-02-27; Completion date: 2023-06-22
Enrollment: 1515 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 3, open-label, 1-year study of the safety, tolerability, and need for re-treatment with SAGE-217 in adult participants with MDD.

Detailed description:
This study was previously posted by Sage Therapeutics. In July 2024, sponsorship of the trial was transferred to Biogen.

Arms: arm 1: None
Interventions: intervention 1: SAGE-217
Intervention descriptions: intervention 1: SAGE-217

Protocol documents:
SAP_002.pdf: 
COVER PAGE 
Official Title: 
A Phase 3, Open-Label, 1-Year Study of the Safety, Tolerability, and Need 
for Re-Treatment with SAGE-217 in Adult Subjects with Major Depressive 
Disorder 
NCT Number: 
 NCT03864614 
Document Date: Part B SAP Version 1.0: 23 January 2023


Clinical Study Report 
217-MDD-303B
16.1 Study Information 
1 
9.
DOCUMENTATION OF STATISTICAL METHODS
The following statistical analysis plan is provided: 
217-MDD-303B Statistical Analysis Plan v1.0_signed 20 January 2023


Statistical Analysis Plan Methods  
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Statistical Analysis Plan 
Methods 
Protocol Number 217-MDD-303 
[SAP for Part B – Rollover Participants Only] 
 
 STUDY TITLE: A PHASE 3, OPEN-LABEL, 1-YEAR STUDY OF THE SAFETY, 
TOLERABILITY, AND NEED FOR RE-TREATMENT WITH SAGE-217 IN 
ADULT SUBJECTS WITH MAJOR DEPRESSIVE DISORDER 
Author of SAP:  
 
Version: Version 1.0 
Version Date of SAP: 20 January 2023 
Sponsor: Sage Therapeutics, Inc. 
   215 First Street 
  Cambridge, Massachusetts 02142 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written consent of 
Sage Therapeutics Incorporated is strictly prohibited except to the extent required under applicable laws or regulations.  
Persons to whom the information is disclosed must be informed that the information is confidential and may not be further 
disclosed by them. 
 
 
 
 
 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................. 3 
LIST OF TABLES ....................................................................................................... 5 
LIST OF FIGURES ..................................................................................................... 5 
LIST OF ABBREVIATIONS ...................................................................................... 6 
1. 
INTRODUCTION .................................................................................... 8 
2. 
STUDY OBJECTIVES (PART B ONLY) ............................................... 9 
2.1. 
Primary Objective ..................................................................................... 9 
2.2. 
Secondary Objective ................................................................................. 9 
9 
3. 
STUDY ENDPOINTS (PART B ONLY) .............................................. 10 
3.1. 
Primary Endpoints .................................................................................. 10 
3.2. 
Secondary Endpoints .............................................................................. 10 
10 
4. 
STUDY DESIGN ................................................................................... 12 
4.1. 
Overall Design ........................................................................................ 12 
4.2. 
Sample Size and Power .......................................................................... 15 
4.3. 
Randomization ........................................................................................ 15 
4.4. 
Blinding and Unblinding ........................................................................ 15 
5. 
MODIFICATIONS ................................................................................. 16 
5.1. 
Modifications to the Approved Clinical Study Protocol ........................ 16 
5.2. 
Modifications to the Approved Statistical Analysis Plan ....................... 16 
5.3. 
Modifications to the Approved DMC Charter ........................................ 16 
6. 
ANALYSIS SETS .................................................................................. 17 
6.1. 
Enrolled Set ............................................................................................ 17 
6.2. 
Safety Set ................................................................................................ 17 
6.3. 
Study-specific Safety Set ........................................................................ 17 
6.4. 
Period-specific Safety Set ....................................................................... 17 
6.5. 
Full Analysis Set ..................................................................................... 17 
7. 
STATISTICAL ANALYSIS .................................................................. 18 
7.1. 
General Considerations ........................................................................... 18 
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7.1.1. 
Study Day Definition .............................................................................. 19 
7.1.2. 
Study Period Definition .......................................................................... 19 
7.1.3. 
Participant Completion Status ................................................................ 21 
7.1.3.1. 
Eligible/Qualified for Treatment/Re-treatment for Safety Set ............... 22 
7.1.4. 
Missing Data ........................................................................................... 23 
7.2. 
Background Characteristics .................................................................... 23 
7.2.1. 
Participant Disposition ............................................................................ 23 
7.2.2. 
Protocol Deviations ................................................................................ 26 
7.2.3. 
Demographics and Baseline Characteristics ........................................... 26 
7.2.4. 
Medical/Surgical History ........................................................................ 27 
7.2.5. 
Prior and Concomitant Medications / Concomitant Procedures ............. 28 
7.2.6. 
Investigational Product Exposure ........................................................... 30 
7.2.7. 
Investigational Product Adherence ......................................................... 31 
7.3. 
Efficacy Analysis .................................................................................... 31 
7.3.1. 
Definition of Response Variables ........................................................... 33 
7.3.1.1. 
Hamilton Rating Scale for Depression (HAM-D) .................................. 33 
7.3.1.2. 
Clinical Global Impression – Improvement (CGI-I) .............................. 35 
7.3.1.3. 
Clinical Global Impression – Severity (CGI-S) ...................................... 35 
7.3.1.4. 
Patient Health Questionnaire (PHQ-9) ................................................... 35 
36 
36 
7.3.1.7. 
Montgomery-Åsberg Depression Rating Scale (MADRS) .................... 36 
7.3.2. 
Visit Windows ........................................................................................ 37 
7.3.3. 
Analysis of Response Variable(s) ........................................................... 38 
7.3.4. 
Durability of Response ........................................................................... 40 
7.3.5. 
Time to Relapse ...................................................................................... 40 
7.4. 
Safety Analysis ....................................................................................... 41 
7.4.1. 
Adverse Events ....................................................................................... 42 
7.4.2. 
Clinical Laboratory ................................................................................. 47 
7.4.3. 
Vital Signs .............................................................................................. 50 
7.4.4. 
Electrocardiogram ................................................................................... 51 
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7.4.5. 
Physical Examination ............................................................................. 52 
7.4.6. 
Columbia Suicide Severity Rating Scale (C-SSRS) ............................... 52 
8. 
SUMMARY OF INTERIM AND DMC ANALYSES .......................... 54 
9. 
REFERENCES ....................................................................................... 55 
10. 
APPENDICES ........................................................................................ 56 
10.1. 
Appendix A: Schedule of Events (Screening and Observational 
Period) ..................................................................................................... 56 
10.2. 
Appendix B: Schedule of Events (Treatment and Follow-Up Periods) . 58 
10.3. 
Appendix C: Handling of Missing Dates ................................................ 60 
10.4. 
Appendix D: Algorithms ........................................................................ 62 
Appendix E: List of Displays ..................................................................................... 66 
 
LIST OF TABLES 
Table 1: 
 HAM-D Subscale Score Calculations ................................................... 34 
Table 2: 
Visit Windows for Efficacy Analysis (with respect to each treatment 
cycle) ....................................................................................................... 37 
Table 3: 
 Safety endpoints and variables in the summary tables .......................... 41 
Table 4: 
Clinical Laboratory Tests ....................................................................... 47 
Table 5: 
Laboratory Parameters – Criteria for PCS Values .................................. 48 
Table 6: 
Vital Signs – Criteria for PCS Values .................................................... 51 
Table 7: 
ECG Parameters – Criteria for PCS and PCSC Values .......................... 52 
 
LIST OF FIGURES 
Figure 1: 
Part B Study Design Schematic .............................................................. 13 
 
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LIST OF ABBREVIATIONS 
Abbreviation or specialist term 
Explanation 
ADT 
antidepressant therapy 
AE 
adverse event 
ATC 
anatomical therapeutic chemical 
BLQ 
below the limit of quantitation 
BMI 
body mass index 
CGI-I 
Clinical Global Impression scale for improvement 
CGI-S 
Clinical Global Impression scale for severity 
CS 
Clinically significant 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DSM-5  
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition  
ECG 
electrocardiogram 
eCRF  
electronic case report form  
EDC 
electronic data capture 
EOT 
end of treatment 
ET 
early termination 
FSH  
follicle stimulating hormone  
GABA 
γ-aminobutyric acid 
HAM-D 
Hamilton Depression Rating Scale 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
 
 
LFT 
liver function tests 
LLOQ 
lower limit of quantification 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MDD 
major depressive disorder 
MDE 
major depressive episode 
MedDRA 
Medical Dictionary for Regulatory Activities 
PCS 
 
Potentially clinically significant  
PCSC 
potentially clinically significant change 
PHQ-9 
Patient health Questionnaire 
 
 
PT 
preferred term 
QTcF 
QT corrected according to Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCID-5-CT 
Structured Clinical Interview for Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition for clinical trials 
SD 
standard deviation 
 
 
SE 
standard error 
SI 
International System of Units 
SNRI 
serotonin-norepinephrine reuptake inhibitor 
SOC 
system organ class 
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Abbreviation or specialist term 
Explanation 
SpO2 
pulse oximetry 
SSRI 
selective serotonin reuptake inhibitor 
TEAE 
treatment-emergent adverse event 
WHO 
World Health Organization  
 
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1. 
INTRODUCTION 
This statistical analysis plan (SAP) is for the final analysis of 217-MDD-303 study, Part B 
(hereafter referred to as 217-MDD-303B), and is based on the clinical study protocol, version 
7.0, dated 10 May 2021. Study 217-MDD-303 has two parts – Part A for de novo 
participants, and Part B for participants rolling over from Study 217-MDD-305 (parent 
study).  Study 217-MDD-305 is a completed Sage-sponsored randomized, double-blind, 
placebo-controlled study in which participants co-initiated an FDA-approved antidepressant 
therapy along with investigational product (SAGE-217 or placebo).  This SAP is meant for 
217-MDD-303 Part B participants only and describes the analyses to be summarized in the 
217-MDD-303B CSR. It will be approved and finalized before database lock. The SAP for 
Part A will be provided separately, along with its own CSR. 
 
 
 
 
 
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2. 
STUDY OBJECTIVES (PART B ONLY) 
2.1. 
Primary Objective 
The primary objective of this study is to determine the safety and tolerability of initial 
treatment and/or re-treatment(s) with SAGE-217 in adults with MDD experiencing a major 
depressive episode (MDE) at entry in the parent study for rollover participants over a 1-year 
period. 
2.2. 
Secondary Objective 
The secondary objectives of this study are: 
 To assess the need for re-treatment with SAGE-217 following initial treatment in 
adults with MDD experiencing an MDE at entry in the parent study for rollover 
participants over a 1-year period 
 To assess the response of initial treatment and/or re-treatment(s) with SAGE-217 
following an initial 2-week treatment period in adults with MDD experiencing an 
MDE at entry in the parent study for rollover participants over a 1-year period  
 
 
 
 
 
 
 
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3. 
STUDY ENDPOINTS (PART B ONLY) 
3.1. 
Primary Endpoints 
The primary endpoint of this study is the safety and tolerability of the initial treatment with 
SAGE-217 and re-treatment with SAGE-217, as assessed by measures including the 
incidence and severity of  adverse events (AEs)/ serious adverse events (SAEs); changes 
from baseline in clinical laboratory measures, vital signs, and electrocardiograms (ECGs); 
and suicidal ideation and behavior using the Columbia Suicide Severity Rating Scale (C-
SSRS). 
3.2. 
Secondary Endpoints 
Secondary endpoints of this study are: 
  The need for re-treatment with SAGE-217 as assessed by:  
  Time to first re-treatment (Kaplan-Meier curves) 
  Number of participants achieving the requirements for re-treatment 
 Number of re-treatment cycles for each participant 
   The response of initial treatment and/or re-treatment as assessed by:  
  Change from baseline in the 17-item Hamilton Rating Scale for Depression 
(HAM-D) total score at the end of each 14-day treatment (initial and/or re-
treatment) period 
  HAM-D response at the end of each 14-day treatment (initial and/or re-
treatment) period, defined as a ≥50% reduction in HAM-D score from 
baseline 
  HAM-D remission at the end of each 14-day treatment (initial and/or re-
treatment) period, defined as HAM-D total score ≤7 
  Clinical Global Impression - Improvement (CGI-I) response, defined as 
“much improved” or “very much improved”, at the end of each 14-day 
treatment (initial and/or re-treatment) period 
  Change from baseline in Clinical Global Impression - Severity (CGI-S) score 
at the end of each 14-day treatment (initial and/or re-treatment) period 
 
 
 
 
 
 
 
 
 
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 
 
 
 
 
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4. 
STUDY DESIGN  
4.1. 
Overall Design  
Adults with MDD who have completed Study 217-MDD-305 (the sole "parent study" and 
source of participants for the current study, 217-MDD-303B) will sign the ICF and be 
screened to determine eligibility to enter the study at the Day 42 visit of the parent study.  
Study 217-MDD-305 (parent study) utilized a double-blind treatment period of 14 days, 
wherein SAGE-217 or placebo was co-initiated with an investigator-selected and 
prespecified open-label ADT. Study 217-MDD-305 included a safety follow-up period of 28-
days where the participants continued to receive open-label ADT (but not SAGE-
217/placebo) with an end of study visit at Day 42. 
The screening visit for 217-MDD-303B may occur on the same calendar day as the end-of-
study visit in the parent study; in that case, no assessments conducted for the final, end-of-
study visit in the parent study will need to be repeated. If participants do not enroll in the 
current study at the final, end-of-study visit in the parent study, but complete the screening 
visit for the current study within 5 calendar days, the drug and alcohol screen and pregnancy 
test (female participants only) should be repeated. Additional assessments may be conducted 
at the screening visit if necessary.  
Participants are eligible to receive the first SAGE-217 treatment within this study only after 4 
weeks into the study – 56 days since last blinded Investigational Product (IP) dose in the 
parent study.  They could receive up to 4 treatment courses within this study separated by at 
least 56 days.  This study is 46 weeks long, making the total follow up of a participant as 
long as 52 weeks from the first dose of blinded IP in 217-MDD-305. Participants are 
followed with remote assessment of PHQ-9 every two weeks and a score of >=10 would 
prompt them to return to the site within a week for HAM-D assessment.  If HAM-D total 
score is >=20 and 56 days has elapsed since the last dose of study drug, the participant is 
qualified to receive SAGE-217 treatment course.  Without any trigger by PHQ-9 score 
described above, a participant would return to the site every 8 weeks for clinical assessments. 
A Part B study schematic is shown in Figure 1. 
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Figure 1: 
Part B Study Design Schematic 
 
ADT = antidepressant therapy; D = day; EOS = end of study; HAM-D = Hamilton Rating Scale for Depression; PHQ-9 = 9-item Patient Health 
Questionnaire; Q2W = once every 2 weeks; Q8W = once every 8 weeks 
Note: Study Days are based on Day 1 dosing in the parent study. 
Note: Assigned ADT from parent study may continue into Study 217-MDD-303B. 
 
 
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SAGE-217 treatment cycles 
Each 14-day treatment period of SAGE-217 and corresponding 14-day follow-up period is 
considered a cycle (28 days). The observation period is defined as the end of treatment cycle 
until the beginning of next treatment cycle. The database reflects that first treatment and 
follow-up period (28 days) as Cycle 2, rather than Cycle 1 (i.e., these participants completed 
an initial double-blind treatment cycle in the parent study). For analyses purposes, the cycles 
are numbered differently based on the treatment the participants received in the parent study. 
Further information about the numbering of cycles is noted in Section 7.1. Unless otherwise 
specified, the data from the parent study were reported in the corresponding CSR and are out-
of-scope for the analysis of data from this protocol. 
The dose of SAGE-217 administered during each new treatment cycle is 50 mg or reduced 
dose of 40 mg, according to the criteria provided in the protocol. Each cycle begins with Day 
1 (i.e., the first day of the first treatment period in this study is Day 1 of Cycle 2). A 
maximum of 4 treatment cycles within this study is permitted, so 5 overall (i.e., 4 cycles in 
the current study plus the initial double-blinded cycle in the parent study). A new re-
treatment cycle cannot start after Week 48; participants starting a new SAGE-217 treatment 
cycle between Weeks 45 and 48 will be followed through the end of the treatment cycle (Day 
28, end of Follow-up period of treatment cycle). If a participant does not tolerate the 50 mg 
dose, and has been reduced to 40 mg, the participant may initiate subsequent cycles at the 
reduced dose of 40 mg, as determined by the investigator.  
The need for re-treatment will be assessed every 14 days via remote assessments during the 
48 week period from the first dose of parent study (i.e., 42 weeks from the ICF within this 
study) based on the results of the participant-reported PHQ-9; if the PHQ-9 score is ≥10, the 
participant will return to the site in approximately one week to be assessed by the clinician-
administered HAM-D. New SAGE-217 cycles may be initiated for participants with a HAM-
D score ≥20 as long as 56 days since last dose in last cycle have elapsed. In all participants, 
the End of Study/Week 52 Visit from the first dose of parent study (i.e., 46 weeks from the 
ICF within this study) is mandatory if another scheduled on site visit does not fall in the 
Week 52 window. 
A minimum period of 8 weeks (56 days) is required between SAGE-217 treatment periods. 
This is based on a span of 8 weeks establishing ‘full remission’ of a depressive episode. 
Rollover participants, therefore, will not be eligible to begin their first SAGE-217 treatment 
period within this study until 56 days have elapsed from the date of last dose of blinded IP - 
SAGE-217 + ADT or Placebo + ADT - administered in the parent study.   
If a participant exhibits suicidality at any time, they will return to the site as soon as possible 
for assessment by the Investigator. 
The assessments for the Screening Period and Observational Period are summarized in 
Section 10.1, Appendix A; the assessments for the Treatment and Follow-up Periods  are 
summarized in Section 10.2, Appendix B.  
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4.2. 
Sample Size and Power 
The sample size depends on the number of participants rolling over from the parent study 
(217-MDD-305).  Approximately 350 participants are expected to roll-over to this study 
from the parent study. No formal power calculations were performed. In total, 277 
participants from the parent study had rolled over to this protocol - 133 from SAGE-217 + 
ADT and 144 from Placebo + ADT. 
4.3. 
Randomization 
Study 217-MDD-303B is an open-label rollover design, with participants who were 
previously randomized in the parent study 217-MDD-305 to Placebo + ADT or SAGE-217 + 
ADT, stratified by class of co-initiated ADT– selective serotonin reuptake inhibitor (SSRI) or  
serotonin-norepinephrine reuptake inhibitor (SNRI). All participants in 217-MDD-303B will 
have the opportunity to receive open-label SAGE-217 if protocol-specified criteria are met.  
4.4. 
Blinding and Unblinding 
All participants in this study will receive SAGE-217 in an open-label manner as needed; 
hence blinding/unblinding does not apply.  However, the blinding of the randomized 
treatment group in the parent study was maintained until the parent study was completed and 
treatment assignment unblinded. 
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5. 
MODIFICATIONS  
5.1. 
Modifications to the Approved Clinical Study Protocol 
The word “subject” has been updated to “participant” and the words “study drug” have been 
updated to “investigational product (IP)” according to the new convention. 
Following FDA comments on the statistical section of the protocol, 
 
, anxiolytic, anti-insomnia medications 
 
. 
Additional efficacy analyses have been incorporated – durability of response and time to 
relapse (Section 7.3.4 and 7.3.5, respectively). 
The study conduct in the protocol calculated the study day based on the first dose of blinded 
IP in 217-MDD-305. In this analysis plan, sometimes we deviated from this by calculating 
the study day based on ICF date in this protocol. These are specified clearly in the respective 
section.  
In the protocol, Safety Set was defined as all participants administered IP. In this analysis 
plan, the Safety Set definition has been updated to the subset of the Enrolled Set (i.e., all 
participants who signed the 217-MDD-303B ICF for rolling over to this study from the 
parent study) who were administered SAGE-217 – either in the parent study (i.e. 217-MDD-
305) or within this protocol (217-MDD-303B).   The Study-specific Safety Set is defined as 
all participants who are administered SAGE-217 within the protocol, 217-MDD-303B.   
5.2. 
Modifications to the Approved Statistical Analysis Plan 
This is the first version of the SAP for the final analysis. 
5.3. 
Modifications to the Approved DMC Charter 
Not applicable. 
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6. 
ANALYSIS SETS 
6.1. 
Enrolled Set 
The Enrolled Set is defined as all participants who signed the 217-MDD-303B ICF for 
rolling over to this study from the parent study.  
6.2. 
Safety Set 
The Safety Set is defined as the subset of the Enrolled Set who were administered SAGE-217 
– either in the parent study (i.e., 217-MDD-305) or within this protocol (217-MDD-303B). 
6.3. 
Study-specific Safety Set 
The Study-specific Safety Set is defined as all participants who are administered SAGE-217 
within the protocol 217-MDD-303B.   
6.4. 
Period-specific Safety Set 
The Period-specific Safety Set includes participants in the Safety Set who are administered 
SAGE-217 in the corresponding analysis period.  
6.5. 
Full Analysis Set 
The Full Analysis Set (FAS) is defined as all participants in the Study-specific Safety Set 
who have at least one HAM-D total score available after the first dose of SAGE-217 within 
this protocol.  Period-specific efficacy analysis will be done on the subset of FAS who have 
been administered SAGE-217 in the corresponding analysis period. 
Programming algorithms for Period-specific Safety Set and FAS derivations are discussed in 
Section 10.4, Appendix D. 
 
 
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7. 
STATISTICAL ANALYSIS 
7.1. 
General Considerations 
Unless otherwise specified, continuous endpoints will be summarized with n, mean standard 
deviation (SD), median, minimum (min) and maximum (max).  The minimum and maximum 
will be reported with the same degree of precision (i.e., the same number of decimal places) 
as the observed data.  Measures of location (mean and median) will be reported to 1 degree 
of precision more than the observed data and measures of spread (standard deviation) will be 
reported to 2 degrees of precision more than the observed data.  
For categorical endpoints, descriptive summaries will include counts and percentages.  
Percentages will be presented to 1 decimal place unless otherwise specified; the denominator 
of percentages will be the number of participants in the analysis set used unless specified 
otherwise.  
All analyses and summary outputs will be generated using SAS® 9.4 or higher. 
The first cycle of treatment in the rollover participants is collected as Cycle 2. Cycle 1 refers 
to the treatment cycle experienced in the parent study which could be either SAGE-217 + 
ADT or Placebo + ADT. It is to be noted that for participants who received only Placebo + 
ADT in the parent study, Cycle 2, the first treatment cycle in this protocol, will be the first 
exposure to SAGE-217 for such participants.  In order to present data from Placebo + ADT 
participants and SAGE-217 + ADT participants from parent study pooled together (referred 
to as All Participants in table outputs), yet to be able to interpret data based on the number of 
treatment cycles received, the treatment cycle and study periods need to be redefined for 
analysis purposes.  The definitions of analysis treatment cycles and analysis study periods are 
described in Section 7.1.2.  A graphical presentation of redefining cycles (Cx) is presented 
below, with arrows presenting how the SAGE-217 + ADT cycles align with Placebo + ADT 
cycles in analysis:     
SAGE-217  +ADT (as collected/analyzed)   Pre-Dose           C2            C3            C4           C5 
Placebo + ADT (as collected)                               Pre-Dose          C2            C3            C4           C5 
Placebo + ADT (as analyzed)                      Pre-Dose           C1            C2            C3           C4         
Relationship between analysis treatment cycles and analysis study periods is presented 
below:  
 
ICF 
Dosed 
in C1 
Obs 
period 1 
Dosed 
in C2 
Obs 
period 2 
…..Periods 3, 4 
Dosed in 
C5 
Obs 
Period 5 
EOS 
Placebo + 
ADT 
Obs 
Period 0 
Analysis Study 
Period 1 
Analysis Study 
Period 2 
Similar to 
Analysis Study 
Period 2 
Not Applicable 
X 
SAGE-
217 + 
ADT 
Obs Period 0  
(Analysis Study Period 1 Not 
Applicable) 
Analysis Study  
Period 2 
Analysis Study 
Period 5 
X 
Note: Cycle refers to analysis cycle; pre-dose periods present events in Observation Period 0; 
for SAGE-217 + ADT group, Analysis Study Period 1 is not applicable; for Placebo + ADT 
group, Analysis Study Period 5 is not applicable.  
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All reference to cycle/period in this SAP hereafter refers to analysis cycles/periods.   
All participant data, including those derived to support tables and figures will be presented in 
the participant data listings. Listings will contain data from participants who signed ICF for 
this protocol, unless specified otherwise.  Events will be identified by study period.  In 
general, the participant data listings will be sorted by participant number and assessment visit 
and date (and time, if applicable).  The summary tables will be presented descriptively for the 
analysis population – for the entire study and/or by treatment cycle/study period.   
For baseline subgroup definitions (refer to Section 7.2.3), baseline is defined as the last non-
missing measurement prior to the first dose of blinded IP in the parent study.  
Unless specified otherwise, period-specific baseline is defined as the last non-missing 
measurement before the first dose of SAGE-217 in each treatment cycle within this protocol.  
If the time of an assessment is collected, baseline will be the latest assessment prior to first 
dose administration time in this period; if the time of an assessment is not collected or 
missing, the assessment on Day 1 is assumed to be prior to dosing if the protocol or study 
manual mentions that this assessment needs to be before dosing or it is collected as “pre-
dose”.  For determination of period-specific baseline for the first treatment cycle within this 
protocol, only the values collected within this study will be used; if it does not exist, the 
record will not be used for comparison with period-specific baseline (change or response). 
For the pooled analysis across the treatment groups (Placebo + ADT and SAGE-217 + ADT 
as designated in the parent study), displays for cycles/periods 2, 3, and 4 will be presented by 
analysis cycle/period with pooled data from both groups. Cycle/Period 1 results of Placebo + 
ADT group and Cycle/Period 5 of SAGE-217 + ADT group will be presented separately. 
All assessments, including unscheduled assessments or un-windowed assessments, are 
included in the derivation for last value on treatment, last value in the study period, and 
potentially clinically significant (PCS) values.  
7.1.1. 
Study Day Definition 
SAGE-217 is administered in the evening with food.  The assessments at the clinic on Day 1 
are hence before the first dose of SAGE-217 for a particular treatment period. 
Study day from ICF of this study will be defined as follows, unless specified otherwise:  
  The day of participant signing the ICF in this study is designated as Day 1. 
  For visit days on or after Day 1, study day = visit date – Day 1 date + 1. 
 For visits before ICF date, study day =  visit date - Day 1 date 
Study day from the first dose of SAGE-217 within specific study period will be calculated as: 
visit date – first dose date in the specific period +1. 
7.1.2. 
Study Period Definition 
Analysis study periods within this protocol are defined for participants who received Placebo 
+ ADT and SAGE-217 + ADT as follows: 
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 For Placebo + ADT participants, the pre-dose Observation Period 0 starts from the 
signing of the ICF for this study protocol and ends either prior to first dose of SAGE-
217 in this protocol, if any, or goes until the last day in the study (whichever occurs 
first).  For study period X, where X =1, 2, 3, 4, the study period starts with the first 
dose in Cycle X and ends prior to the first dose in Cycle X+1 if it exists, or until the 
last day in the study (whichever occurs first). Note that Study Period 5 does not reside 
within this protocol for these participants. 
 For SAGE-217 + ADT participants, the pre-dose Observation Period 0 starts from the 
signing of the ICF for this study protocol and ends either prior to first dose of SAGE-
217 in this protocol, if any, or goes until the last day in the study (whichever occurs 
first).  For study period X, where X = 2, 3, 4, 5, the study period starts with the first 
dose in Cycle X and ends prior to the first dose in Cycle X+1 if it exists, or until the 
last day in the study (whichever occurs first). Note that Study Period 1 does not reside 
within this protocol for these participants. 
Each analysis study period (except pre-dose Observation Period 0) is divided into three 
exclusive analysis periods - treatment period, follow up period, and observation period; in 
addition, treatment period and follow up period together constitute of treatment cycle period. 
The definition for different analysis periods (study periods 1, 2, 3, 4 for placebo+ADT 
participants and study periods 2, 3, 4, 5 for SAGE-217+ADT participants) are as follows: 
 Treatment Period X starts with first dose of SAGE-217 date/time in Study Period X 
and ends with last dose of SAGE-217 in Study Period X (both with >0 capsules 
consumed) + 1 day.  
 Follow-up Period X starts after the end of Treatment Period X, and ends on Day 28 
visit date/time from vitals; or if vital signs are not assessed, HAM-D date/time is to be 
used. If none of these have a recorded time available, Day 28 vitals date will be used; 
if no vitals date, Day 28 HAM-D date will be used.  If Day 28 does not exist in either 
HAM-D or vitals, then the earlier of (treatment period X start date/time + 28 days, 
study completion/discontinuation date) is to be used. 
 Treatment Cycle Period X starts with start of Treatment Period X and ends with end 
of Follow-up Period X. 
 Observation Period X (OBS <x>) starts right after the end of Treatment Cycle X and 
ends right before the first dose of SAGE-217 in Treatment Cycle X+1.   Observation 
Period X end date/time: Right before the first dose of SAGE-217 in the Treatment 
Cycle X+1 if such treatment cycle exists, or study completion/discontinuation date if 
no Treatment Cycle X+1 exists. 
The definitions for periods may be slightly different for different endpoints.  For details of 
the algorithm used for defining the periods for concomitant medication, please refer to 
Section 7.2.5 and Section 10.4, Appendix D. 
Except for AEs, which has been described separately in Section 7.4.1, if the evaluation date 
is the same as treatment start date but time for either the evaluation or the treatment start is 
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missing, this evaluation is considered according to the nominal visit designation (e.g. Cycle 1 
or OBS1 will be assigned Study period 1); if the nominal visit designation is ambiguous, then 
assign in Study Period X-1, not in Study Period X. 
7.1.3. 
Participant Completion Status 
Participants completion status for the Enrolled Set are classified in the following manner: 
Prematurely withdrew from the study in pre-dose period:  
 Study Conclusion CRF Page: indicates premature withdrawal from the study AND 
 Participant dosing status: must not have been dosed with SAGE-217 within this 
protocol 
Completed study in pre-dose period: 
 Study Conclusion CRF Page: indicates completion of the study AND 
 Participant dosing status: must not have been dosed with SAGE-217 within this 
protocol 
Completer for the study:   
 Study Conclusion CRF Page: indicates completion of the study AND 
 Participant dosing status: must have been dosed with SAGE-217 within this protocol 
Prematurely withdrawn from the study:  
 Study Conclusion CRF Page: indicates premature withdrawal from the study AND 
 Participant dosing status: must have been dosed with SAGE-217 within this protocol 
Prematurely withdrew from study period X, X=1,2,3,4 for participants who received Placebo 
+ ADT in the parent study, X=2,3,4,5 for participants who received SAGE-217 + ADT in the 
parent study:  
 
Study Conclusion CRF Page: indicates premature withdrawal from the study AND 
 Participant dosing status: Participant is dosed in study period X and not dosed in 
study period X+1 if X+1 is viable in the study, and the study discontinuation date is 
on or after the first dose of study period X 
For details of study discontinuation date derivation, refer to Section 10.4, Appendix D. 
Completed study period X, X=1,2,3,4 for participants who received Placebo + ADT in the 
parent study, X=2,3,4,5 for participants who received SAGE-217 + ADT in the parent study:   
 If the participant is dosed in Study period X+1 when X+1 is viable OR 
 Study period X is the last period the participant is dosed and the participant did not 
prematurely withdraw in study period X per the previous definition  
Discontinued treatment cycle X, X=1, 2, 3, 4 for participants who received Placebo + ADT 
in the parent study, X = 2, 3, 4, 5 for participants who received SAGE-217 + ADT in the 
parent study:  
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 Study Conclusion CRF Page: indicates premature withdrawal from the study AND 
 Participant dosing status:  Participant is dosed in cycle X and not dosed in cycle X+1 
if X+1 is viable in the study, and the study discontinuation date is on or before the 
treatment cycle X end date 
 
For details of study discontinuation date derivation, refer to Section 10.4, Appendix D. 
Completed treatment cycle X, X=1, 2, 3, 4 for participants who received Placebo + ADT in 
the parent study, X = 2, 3, 4, 5 for participants who received SAGE-217 + ADT in the parent 
study:  
 If the participant is dosed in cycle X+1 when X+1 is viable OR 
 Cycle X is the last cycle the participant is dosed and the participant did not 
prematurely withdraw in treatment cycle X per the previous definition  
7.1.3.1. 
Eligible/Qualified for Treatment/Re-treatment for Safety Set 
Participants eligible/qualified for treatment/re-treatment for Safety Set are defined as 
follows: 
A participant is eligible for treatment in treatment cycle X if (discontinuation/completion 
date – last dose date in cycle X-1 ≥56). For being eligible in the first cycle within this 
protocol, this means that at least 56 days have elapsed from the last dose of blinded IP in the 
parent study.  
A participant is qualified for treatment in treatment cycle X if the participant is eligible for 
treatment in treatment cycle X AND there exists at least one HAM-D within this protocol 
where HAM-D total score ≥20 between end of treatment cycle X-1 and  
    - first dose in treatment cycle X when treatment cycle X start date/time is non-missing 
      OR 
   - last day in the study 
Participants reached threshold of treatment based on HAM-D and PHQ-9 seperately: 
A participant reached threshold of treatment based on HAM-D in treatment cycle X if the 
participant is eligible for treatment in treatment cycle X AND there exists at least one HAM-
D total score ≥20 on or after 56 days from the treatment end date in cycle X-1 (for reaching 
the threshold in the first cycle of this protocol, the treatment end date is the last dose of 
blinded IP in the parent study) and this HAM-D evaluation must be before treatment cycle X 
start date/time if the treatment cycle X start date/time is non-missing.  If the Treatment Cycle 
X start date/time is missing, then the date of study discontinuation/completion will be used.  
A participant reached threshold of treatment based on PHQ-9 in treatment cycle X if the 
participant is eligible for treatment in treatment cycle X AND there exists at least one PHQ-9 
score ≥10 on or after 56 days from the treatment end date in cycle X-1 (for reaching the 
threshold in the first cycle of this protocol, the treatment end date is the last dose of blinded 
IP in the parent study) and this PHQ-9 evaluation must be before treatment cycle X start 
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date/time if the treatment cycle X start date/time is non-missing.  If the Treatment Cycle X 
start date/time is missing, then the date of study discontinuation/completion will be used. 
Relationship between treatment in this study and re-treatment of SAGE-217 
 for Placebo + ADT participants from the parent study, first re-treatment of SAGE-217 
is the second treatment within this study 
 for SAGE-217 + ADT participants from the parent study, first re-treatment of SAGE-
217 is the first treatment within this protocol 
For SAGE-217 + ADT participants from the parent study: re-treatment of SAGE-217 is 
consistent with the treatment within this protocol. Relationship between treatment in this 
study and re-treatment of SAGE-217 is presented below:  
 
Study Period 2 
Study Period 3 
Study Period 4 
Study Period 5 
Treatment in this study 
First Treatment 
Second Treatment 
Third Treatment 
Fourth Treatment 
Re-treatment of SAGE-
217 
First Re-treatment 
Second Re-treatment 
Third Re-treatment 
Fourth  Re-
treatment 
 
For Placebo + ADT participants from the parent study: relationship between treatment in this 
study and re-treatment of SAGE-217 is presented below:   
 
 
Study Period 1 
Study Period 2 
Study Period 3 
Study Period 4 
Treatment in this study 
First Treatment 
Second Treatment 
Third Treatment 
Fourth Treatment 
Re-treatment of SAGE-217 
 
First Re-treatment 
Second Re-
treatment 
Third Re-treatment 
7.1.4. 
Missing Data 
All participants will be used in the analyses, as per the analysis populations, using all non-
missing data available; this may include windowing of unscheduled visits when scheduled 
visit data is missing.  For windowing algorithm, please see Section 7.3.2. Imputation of 
missing data in scoring of questionnaires is discussed in respective sections below.  Handling 
of missing or incomplete dates is discussed in Section 10.3, Appendix C. 
7.2. 
Background Characteristics  
Data will be presented using Placebo + ADT, SAGE-217 + ADT and All Participants column 
with Placebo + ADT and SAGE-217 + ADT referring to the treatment received in the parent 
study. In the parent study, all participants received the treatment (SAGE-217/Placebo) as 
planned. Data may be pooled across the Placebo + ADT and SAGE-217 + ADT groups in 
some summaries; this plan explicitly states how the summaries will be produced. 
7.2.1. 
Participant Disposition 
The analyses of participant disposition will use Enrolled set and will be presented by actual 
treatment group in the parent study in addition to the pooled group. The summary of 
participant disposition will include: 
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 the number of participants who signed ICF for this protocol (Enrolled Set), 
 the number and percentage of participants who were dosed with SAGE-217 in 
either the parent study or this study (Safety Set), 
 the number and percentage of participants who were never dosed with SAGE-217 
in either the parent study or this study, 
 the number and percentage of participants who were or were not dosed with 
SAGE-217 in this study (Study-specific Safety Set),  
 the number and percentage of participants who completed this study,  
 the number and percentage of participants who prematurely withdrew from this 
study and primary reasons for not completing the study, and  
 the number and percentage of participants who discontinued investigational 
product in any treatment cycle in this study    
A summary of participant disposition will be presented by study period using the period-
specific Safety Set.  This summary will include the number and percentage of participants 
dosed in the treatment cycle, who discontinued treatment during the 14-day treatment period, 
primary reason for discontinuing the treatment, who completed the treatment cycle, who 
completed the treatment period, who discontinued the study during the study period, and 
primary reason for study discontinuation. The denominator for percentages will be the 
period-specific Safety Set. 
A separate data listing will be provided for all participants who prematurely discontinued 
treatment or prematurely withdrew from the study with reasons, number of days on SAGE-
217, etc. Separate data listings will be provided for participant involvement by study period, 
and by treatment cycle. 
The number and percentage of participants in each analysis set will be provided, using 
Enrolled Set as the denominator. 
The number and percentage of participants by the length of study participation (through 
study completion/discontinuation date) since the time of ICF will be provided in category of 
months: < 3 months , ≥3 months but less than 6 months, ≥6 months but less than 9 months, 
≥9 months. 
Below is the definition of the cut off for the category, where start date varies based on the 
analysis: 
 
End of 3 month period: start date + 90 days 
 
End of 6 month period: start date + 181 days 
 
End of 9 month period: start date + 272 days 
Refer to Section 10.4, Appendix D for the details of calculation of month. 
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In addition, the number and percentage of participants by the length of study participation 
since the time of first dose of SAGE-217 will be provided. For SAGE-217 + ADT 
participants from the parent study, the first dose of SAGE-217 is the first dose in the parent 
study; for Placebo + ADT participants from the parent study, the first dose of SAGE-217 is 
the first dose within this protocol. The number and percentage of participants completing 6 
months follow up of SAGE-217, completing 6 months follow up of SAGE-217 without 
retreatment, complete 1 year follow up of SAGE-217, and complete 1 year follow up of 
SAGE-217 without retreatment since the first dose of SAGE-217 will be provided. The 
number and percentage of participants completing the latest re-treatment cycle X will be 
provided, along with the number and percentage of participants who have not needed any 
retreatment.  This will use Safety Set. 
The number and percentage of participants by the length of study participation (through 
study completion/discontinuation date) since the first dose in the parent study will also be 
provided in catgory of months: <3 months, ≥3 months but less than 6 months, ≥6 months but 
less than 9 months, ≥9 months.  This will use the Safety Set, and will use blinded IP 
treatment group from the parent study.  Study discontinuation reasons will be provided for 
each category.  The number and percentage of participants completing the latest re-treatment 
cycle X will be provided, along with the number and percentage of participants who have not 
needed any retreatment. 
The severity of depression, as measured by HAM-D, PHQ-9 and CGI-S, at the latest 
measurement within this protocol will be summarized, for the Enrolled Set and Full Analysis 
Set separately and by the completion status in the study.  The level of severity will be 
categorized as follows: 
 HAM-D Total Score categories:  
<=7-None, 8-13 – Mild, 14-19 – Moderate, 20-25 – Severe, ≥26 – Very Severe 
 PHQ-9 Total Score categories:  
0-4 – Minimal, 5-9 – Mild, 10-14 – Moderate, 15-19 – Moderately severe, 20-27 – 
Severe 
 CGI-S Total Score categories:  
1-2 = Normal/Borderline, 3 = Mild, 4 = Moderate, 5 = Severe, 6-7=Very severe  
In addition, the following duration will be included: 
 Days since start of most recent treatment cycle in this protocol to last day on study 
within this protocol (for participants enrolled and not received treatment in this 
protocol, this is missing) 
 Days since start of treatment in parent study to last day on study within this protocol 
 Days since start of most recent treatment cycle in parent study or this protocol to last 
day on study within this protocol (for participants enrolled and not dosed in this 
protocol, this is days since start of treatment in parent study to last day on study 
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within this protocol; for participants dosed in this protocol, this is days since start of 
most recent treatment cycle in this protocol to last day on study within this protocol) 
A summary of participant progression will be prepared for the Enrolled Set, with summary 
statistics presented by actual treatment received in the parent study and overall.  The number 
of participants enrolled, eligible for treatment, qualified for treatment, and dosed in this 
protocol will be provided; for participants treated with Placebo + ADT in the parent study, 
the count of participants not dosed in this study in total and by completion status will be 
provided along with the associated mean and median days since ICF in this study; for 
participants treated with SAGE-217 + ADT in the parent study, the count of participants with 
at least one dose of SAGE-217 in the parent or current study, at least one dose of SAGE-217 
in the parent study (also subset to those eligible for retreatment in this protocol, qualified for 
retreatment in this protocol, and qualified and retreated in the next cycle in this protocol), and 
not dosed in the current study (also subset to those who withdrew, completed, completed 
before being eligible for retreatment, eligible and qualified for retreatment, qualified and 
were not retreated) will be provided, along with the associated mean and median days since 
first SAGE-217 dose in the parent study.  For each treatment cycle in this study, the count of 
participants who discontinued the treatment cycle, completed the treatment cycle and entered 
observation, discontinued before eligibility for retreatment, eligible for retreatment, and 
qualified for retreatment (overall, not retreated, and retreated) will be provided. 
The number and percentage of participants reaching the threshold of retreatment for a 
particular cycle of treatment based on HAM-D total score ≥20 or PHQ-9 total score ≥10 will 
be summarized for the FAS by actual treatment in the parent study and overall.  For a given 
treatment cycle, participants who discontinued/completed the study at least 56 days since last 
dose of SAGE-217 in immediately prior treatment cycle are used as the denominator for 
percentages. For participants receiving placebo + ADT in the parent study, possible 
retreatment cycles include Treatment Cycles 2, 3, and 4; for participants receiving SAGE-
217 + ADT in the parent study, possible retreatment cycles include Treatment Cycles 2, 3, 4, 
and 5.  
7.2.2. 
Protocol Deviations 
Protocol deviations identified during site monitoring will be captured on eCRF and 
categorized by the study team as major (efficacy, safety and GCP, separately) and minor 
deviations. The major deviations will be summarized by type, for the FAS and Enrolled Set 
separately. 
7.2.3. 
Demographics and Baseline Characteristics 
The following analyses will be done for the Safety Set, FAS, and Enrolled Set, separately.  
This data comes from the parent study database and will be presented by the actual treatment 
group from the parent study in addition to the pooled group. 
The below demographic data and baseline characteristics will be summarized: 
 age, race, sex, ethnicity 
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 baseline HAM-D total score in parent study 
 latest HAM-D total score in parent study 
 baseline HAM-A total score in parent study 
 latest HAM-A total score in parent study 
 Day 15 HAM-D responder in parent study (Yes, No) 
 baseline height, weight and body mass index (BMI) in parent study  
Subgroups of interest at baseline will be summarized for the following categories: 
  Sex (Male, Female) 
  Race (Black or African American, White, Other) 
  Age (18-24, 25-50, 51-64 years) 
  BMI in parent study (≤18.4, 18.5-24.9, 25-29.9, ≥30 kg/m2) 
 Latest value of HAM-D total score in parent study (<20, ≥20) 
 Assigned ADT in parent study (SSRI, SNRI) – if the participant received a 
different ADT in the parent study than that which was assigned in the parent 
study, then the ADT actually used in the parent study is used for summarization. 
 Still using same ADT at the time of ICF in this protocol 
  Depression with Elevated Anxiety (Yes/No) 
 Defined as HAM-D Anxiety subscale standardized score ≥39 (same as HAM-
D Anxiety subscale raw score ≥7) at baseline of the parent study 
 Defined as HAM-A total score ≥20 at baseline of the parent study 
7.2.4. 
Medical/Surgical History 
The following analyses will use the Safety Set and the actual treatment group in the parent 
study, in addition to the pooled group.  
The history related to MDD (date of initial diagnosis of MDD, information of depressive 
episodes, etc.) are collected within the parent study database.  Years since initial diagnosis of 
MDD and information of depressive episodes will be summarized. Years since initial 
diagnosis of MDD, days since start of current episode and days since start of first episode 
will be calculated using:   First dose date of the blinded IP in the parent study – Date of 
interest. For imputation of incomplete dates in medical history, please see Section 10.3, 
Appendix C. 
All medical/surgical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA), Version 24.0. Medical/surgical history data will be summarized by 
system organ class (SOC) and preferred term (PT) – separately for what is collected at 
Screening in the parent study as well as what is collected for this protocol as interim medical 
history.    
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Participant history of psychiatric disorders and family psychiatric history from the parent 
study database will be summarized.   
A listing of drug and alcohol screening from this protocol will be provided. 
7.2.5. 
Prior and Concomitant Medications / Concomitant Procedures 
The following analyses will use the Study-specific Safety Set. 
All medications taken and procedures undergone during the study will be recorded; in 
addition, medications that are being taken at the time of entering this study (ICF) will be 
collected.  All medications will be coded using World Health Organization-Drug dictionary 
(WHO-DD) March 2021. 
Those medications that started prior to the first dose of SAGE-217 within this protocol are 
denoted as “prior”.  Those medications that started on or after the first dose of SAGE-217 
within this protocol or are started before the first dose of SAGE-217 within this protocol yet 
continuing beyond the first dose of SAGE-217 will be denoted “Concomitant” (i.e., those 
with a start date on or after the first dose of SAGE-217, or those with a start date before the 
first dose of SAGE-217 that are ongoing or with a stop date on or after the first dose of 
SAGE-217).   Note that a drug could be marked as both “prior” as well as “concomitant”. 
Medications will be presented according to whether they are “Prior” or “Concomitant” as 
defined above. If medication dates are incomplete and it is not clear whether the medication 
was concomitant, it will be assumed to be concomitant.  
Details of prior and concomitant medications will be listed by participant, start date, and 
verbatim term.  
For study period = 1,2,3,4 for participants who received Placebo + ADT and study period = 
2,3,4,5 for participants who received SAGE-217 + ADT in the parent study, concomitant 
medications will also be defined by study period as follows: all medications with a start date 
on or after the first dose of SAGE-217 in the study period X but before the first dose of 
SAGE-217 in the study period X+1, or those with a start date before the first dose of SAGE-
217 that were ongoing at the time of first dose of SAGE-217 in the study period X or with a 
stop date on or after the first dose of SAGE-217 in the study period X.  These will be further 
divided by study period as follows (if time is missing, the date will be used for this 
algorithm):  
 On-treatment concomitant medications in study period X are all medications with 
a start date on or after the first dose of SAGE-217 in the study period X AND the 
start date on or before the last dose of SAGE-217 in the study period X or those 
with a start date before the first dose of SAGE-217 that were ongoing at the time 
of first dose of SAGE-217 in the study period X,  
 Post-treatment concomitant medications in study period X are all medications 
with a start date after the last dose of SAGE-217 in the study period X but before 
the first dose of SAGE-217 in the study period X+1. 
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For further details on the programming algorithm of concomitant medication periods, please 
refer to Section 10.4, Appendix D. 
Prior and concomitant non-psychotropic medication use will be summarized for Study-
specific Safety Set for all participants in a pooled group by anatomical therapeutic chemical 
(ATC) level 1 and Standard Medication Name. Similar summary tables will be provided for 
psychotropic medications. The differentiation of non-psychotropic versus psychotropic 
medications are based on the answer to the prior or current psychotropic medication question 
on CRF page.   
Concomitant medications overall, and on-treatment and post-treatment concomitant 
medications separately will be summarized for all participants in a pooled group by study 
period – psychotropic and non-psychotropic medications separately – using Period-specific 
Safety Set. 
Antidepressant (ADT) medications are identified by ATC3 level code of N06A.  
Antidepressants other than the assigned ones in the parent study are not permitted within the 
parent study, but modification of ADT during this protocol is permitted within limits defined 
in the protocol.  A summary of Antidepressant concomitant medication use at period-specific 
baseline and any change in these medications post-baseline (including the observation 
period) will be provided by study period, using Period-specific Safety Set and pooled group. 
New ADT use is determined by a coded ADT term record that has a start date after the ICF 
date and is different from the ADT record that has been ongoing at the time of ICF.  This 
analysis will use the Enrolled Set. 
Anxiolytic medications are identified by ATC3 level code of N05B. A summary of anxiolytic 
concomitant medication use at period-specific baseline and any change in these medications 
post-baseline (including the observational period) will be provided by study period, using 
Period-specific Safety Set and pooled group.  Time to first new anxiolytic use compared to 
the anxiolytic use at the time of ICF in this protocol will be analyzed with Kaplan-Meier plot 
by Pplacebo + ADT versus SAGE-217 + ADT group in the parent study, provided there is at 
least 20 participants in the pooled group.  New anxiolytic use is determined by the similar 
algorithm as done for ADT, except ADT is replaced anxiolytic.  This analysis will use the 
Enrolled Set. 
Anti-insomnia medications are identified by ATC3 level code of N05C except when ATC 
level 4 = N05CF or standard medication name is in (TRAZODONE , MIRTAZAPINE) ] or 
ATC Level 4 = R06AA. A summary of anti-insomnia concomitant medication use at period-
specific baseline and any change in these medications post-baseline (including the 
observation period) will be provided by study period, using Period-specific Safety Set and 
pooled group. Time to first new anti-insomnia medication use compared to the anti-insomia 
use at the time of ICF in this protocol will be analyzed with Kaplan-Meier plot by Placebo + 
ADT versus SAGE-217 + ADT group in the parent study, provided there is at least 20 
participants in the pooled group.  New anti-insomnia drug use is determined by the similar 
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algorithm as done for ADT, except ADT is replaced with anti-insomnia drug. This analysis 
will use the Enrolled Set. 
Concomitant procedures are recorded on a separate eCRF page; this will be presented in a 
listing by participant and will not be summarized. The study day for the end date of the 
procedure will be provided, when a complete end date is available. 
7.2.6. 
Investigational Product Exposure 
The following analyses will use the Period-specific Safety Set. 
Total SAGE-217 exposure (in mg) is defined as the total SAGE-217 in mg that was taken 
during the study period.  If the patient skips the dose on any of the days, the dose taken is 
0 mg. Total SAGE-217 exposure for the entire study is the sum of period-specific total drug 
exposure.  
The daily dose is 2 capsules – 30+20 for 50mg, 20+20 for 40mg.  The capsules cannot be 
distinguished for the strength.  If one capsule is taken within 50mg dosing in a day, 30mg 
exposure will be assumed for that day. If one capsule is taken within 40mg dosing in a day, 
20mg exposure is unambiguous for that day. If more than 2 capsules are taken in a day, 
within 50mg dosing, additional capsules are assumed to be on strength 30mg; within 40mg 
dosing, additional capsules are assumed to be on strength 20mg.   
Total SAGE-217 exposure duration (in days) for each study period is defined as:  Date of last 
dose in the specific period – date of first dose in the specific period + 1. Note that this does 
not exclude days when the dose has been missed.  Total SAGE-217 exposure duration for the 
entire study is the sum of SAGE-217 exposure duration over all study periods. 
Percent of the planned SAGE-217 exposure received is defined as the total SAGE-217 
exposure, divided by planned SAGE-217 exposure, times 100.  Planned SAGE-217 exposure 
will be based on actual duration of treatment within the specific study period for the 
participant, further based on whether there was a dose reduction in the dosing days:   
1.  If the participant discontinues treatment within Day 2 and Day 14 (both inclusive) 
without a dose reduction, the planned exposure is: last dose day of SAGE-217 x 
initial dose in the cycle (50mg or 40mg) 
2.  If the participant discontinues treatment within Day 2 and Day 14 (both inclusive), 
but the participant has undergone a dose reduction on Day X, the planned exposure is: 
(X-1) x 50mg + (last dose day of SAGE-217 – X + 1) x 40mg. 
3.  If the participant does not discontinue treatment and does not have a dose reduction, 
the planned exposure is: 14 x initial dose in the cycle (50mg or 40mg) 
4. If the participant does not discontinue treatment but has undergone a dose reduction 
on Day X, the planned exposure is: (X-1) x 50mg + (14 – X + 1) x 40mg. 
Planned SAGE-217 exposure for the entire study is the sum of period-specific planned 
exposure and will be used as the denominator for the percent calculation for the entire study. 
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Total SAGE-217 exposure, total SAGE-217 exposure duration and percent of the planned 
SAGE-217 exposure received for the entire study will be summarized descriptively. 
SAGE-217 exposure will also be summarized descriptively by study period. 
7.2.7. 
Investigational Product Adherence 
The following analyses will use the Full Analysis Set. 
IP adherence (%) is defined as the number of capsules taken, divided by the number of 
capsules planned to be taken, times 100.   
The schedule of SAGE-217 intake is 2 capsules per day.   
1. If the participant discontinues treatment within Day 2 and Day 14 (both inclusive), 
the planned number of capsules is the last dose day of SAGE-217, times 2.  
2. If the participant does not discontinue treatment, the planned number of capsules 
within a treatment cycle/study period is 28. 
The planned number of capsules to be taken for the entire study is the sum of period-specific 
planned number of capsules to be taken and will be used as the denominator for the 
calculation of adherence for the entire study. 
SAGE-217 adherence will be summarized descriptively by study period as well as for the 
entire study. Number and percentage of participants with IP adherence in categories - <75%, 
75-100%, >100% - will be provided. [Since the dispensation of SAGE-217 had more 
capsules than required between consecutive visits, it is possible to have adherence to be more 
than 100%.] 
7.3. 
Efficacy Analysis  
Data will be presented by study period whenever appropriate.  Unless otherwise specified, all 
efficacy analyses will use Full Analysis Set for the entire study and a subset to FAS for study 
period X who have been dosed in study period X. 
For Placebo + ADT participants from the parent study: first treatment of SAGE-217 in this 
protocol is the treatment received on Analysis Cycle 1 Day 1 and the first re-treatment of 
SAGE-217 in this protocol is the treatment received on Analysis Cycle 2 Day 1. 
For SAGE-217 + ADT participants from the parent study: first treatment/re-treatment of 
SAGE-217 in this protocol is the treatment received on Analysis Cycle 2 Day 1. 
Summary of Retreatment of SAGE-217 
Refer to Section 7.1.3 for the definition of eligible/qualified for re-treatment. 
The number and percentage of participants eligible for at least 1 SAGE-217 re-treatment, 
qualified for at least 1 SAGE-217 re-treatment, dosing in at least 1 SAGE-217 re-treatment, 
and dosing in exactly X re-treatments, and the number of re-treatment cycles per participant 
and time between treatment cycles will be summarized for the FAS by blinded IP in the 
parent study. 
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Kaplan-Meier (KM) survival curves will be provided for time to first SAGE-217 re-
treatment. Median and interquartile ranges will be provided from KM estimates which uses 
censored observations and will be presented in the figure.  Time to first re-treatment in days 
is calculated as below: 
 For Placebo + ADT participants from the parent study: time to first re-treatment 
in days = first dose date in Cycle 2 Day 1 - last dose of in Cycle 1 Day 1 + 1 
 For SAGE-217 + ADT participants from the parent study: time to first re-
treatment in days = first dose date in Cycle 2 Day 1 - last dose of blinded IP in 
parent study +1 
The analysis will be provided separately for each group based on blinded IP received in the 
parent study.  A participant will be censored at the last day in the study if the participant did 
not get any re-treatment. This analysis will be provided for the Study-specific Safety Set and 
the Safety Set.  Algorithms for censoring are discussed in Section 10.4, Appendix D. 
The number of participants not having a re-treatment, number of participants having at least 
one re-treatment, and summary statistics (mean, standard deviation, median, minimum, 
maximum) for time to first re-treatment for those having at least one re-treatment will be 
presented by blinded IP from the parent study for the Study-specific Safety Set.  
Summary of Treatment 
The number and percentage of participants needing at least one SAGE-217 treatment (i.e., 
meeting the criteria for treatment, but not necessarily treated) and exactly X treatments 
within this protocol will be provided. The number of treatment cycles per participant and 
time between treatment cycles will be summarized for the FAS by blinded IP in the parent 
study. 
A listing of PHQ-9 and HAM-D scores leading to SAGE-217 treatment will be provided. A 
listing of treatment cycles, including treatment cycle number, dates of each treatment start 
and end (including first treatment), duration of treatment, date of 28-day follow-up visit, and 
last day on study (only populated on last retreatment) will be provided. 
Kaplan-Meier (KM) survival curves will be provided for time to first SAGE-217 treatment 
within this protocol since ICF date by blinded IP in the parent study. Median and 
interquartile ranges will be provided from KM estimates which uses censored observations 
and will be presented in the figure. Time to first treatment in days is counted as below: 
 For Placebo + ADT participants from the parent study: time to first treatment in 
days = first dose date in Cycle 1 Day 1 – ICF date + 1 
 For SAGE-217 + ADT participants from parent study: time to first treatment in 
days = first dose date in Cycle 2 Day 1 – ICF date + 1 
The analysis will be provided for the Enrolled Set by blinded IP received in the parent study.  
A participant will be censored at the last day in the study if the participant did not get any 
treatment.  Algorithms for censoring are discussed in Section 10.4, Appendix D. 
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The number of participants not having a treatment, number of participants having at least one 
treatment, and summary statistics (mean, standard deviation, median, minimum, maximum) 
for time to first treatment for those having at least one treatment will be presented by blinded 
IP from the parent study for the Enrolled Set.  
For exploratory purposes the time to first treatment within this protocol since the last dose of 
blinded IP in parent study will be analyzed to compare Placebo + ADT versus SAGE-217 + 
ADT group from the parent study.  This analysis will use Enrolled Set and KM survival 
curve will be provided. Time to first treatment in days is counted as below: 
 For Placebo + ADT participants from the parent study: time to first treatment in 
days = first dose date in Cycle 1 Day 1 – last dose of blinded IP in parent study + 
1 
 For SAGE-217 + ADT participants from parent study: time to first treatment in 
days = first dose date in Cycle 2 Day 1 – last dose of blinded IP in parent study + 
1 
 If a participant does not have any treatment within this protocol, the participant will be 
censored at the last day in the study. Algorithms for censoring are discussed in Section 10.4, 
Appendix D. 
The number of participants not having a treatment, number of participants having at least one 
treatment, and summary statistics (mean, standard deviation, median, minimum, maximum) 
for time to first treatment calculated using last dose of parent study for those having at least 
one treatment will be presented by blinded IP from the parent study for the Safety Set. 
Kaplan-Meier (KM) survival curve will be provided for time to first SAGE-217 treatment 
within this protocol by assigned ADT class (SSRI or SNRI) at the baseline of parent study – 
separately for SAGE-217 + ADT and Placebo + ADT group from the parent study.  The days 
are counted from the last dose of blinded IP in the parent study to the first dose of SAGE-217 
in this protocol.  A participant will be censored at the last day in the study if the participant 
did not get any treatment in this protocol. Algorithms for censoring are discussed in Section 
10.4, Appendix D. This analysis will be done on the Enrolled Set. 
7.3.1. 
Definition of Response Variables 
The efficacy variables are defined below. 
7.3.1.1. 
 Hamilton Rating Scale for Depression (HAM-D) 
The 17-item HAM-D will be used to rate the severity of depression in participants already 
diagnosed as depressed.  HAM-D is collected during the clinic visit on Days 1, 8, 15, 28 
during each treatment cycle, and then once every 8 weeks (Q8W) during the observation 
periods. 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, 
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hypochondriasis, loss of weight, and insight.  Each item is scored in a range of 0 to 2 or 0 to 
4, with higher scores indicating a greater degree of depression.  The score for each item will 
be summed to compute a total score, which ranges from 0 to 52.  If more than 3 individual 
items are missing a response, the HAM-D total score will not be calculated and will be left as 
missing.  If less than or equal to 3 individual item scores are missing, the missing item scores 
will be imputed by the mean of all other available item scores, or the maximum possible 
values for the missing responses, whichever is smaller, to calculate the HAM-D total score.   
Four HAM-D subscale scores will be calculated as the sum of the individual rating scores 
related to each subscale, divided by the total possible score within the subscale, multiplied by 
100, and rounded to a whole number.  If more than one item is missing or HAM-D total score 
is missing, the subscale score is left as missing; if one item on a particular subscale is 
missing, but has been imputed for the calculation of total score, the imputed value from total 
score calculation will be used in subscale score calculation for that item.  The following table 
describes the subscale score calculation: 
Table 1: 
 HAM-D Subscale Score Calculations 
HAM-D Subscales 
Items 
Calculation 
Core 
Depressed mood 
Feeling of guilt 
Suicide 
Work and activities 
Retardation 
Sum of the 5-item responses/20 x 100.   
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale.  
Anxiety 
Anxiety psychic 
Anxiety somatic 
Somatic symptoms gastrointestinal 
Somatic symptoms general 
Hypochondriasis 
Insight 
Sum of the 6-item responses/18 x 100.   
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale.  
Bech-6 
Depressed mood 
Feeling of guilt 
Work and activities 
Retardation 
Anxiety psychic 
Somatic symptoms general 
Sum of the 6-item responses/22 x 100.   
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale.  
Maier 
Depressed mood 
Feeling of guilt 
Work and activities 
Retardation 
Sum of the 6-item responses/24 x 100.   
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
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HAM-D Subscales 
Items 
Calculation 
Agitation 
Anxiety psychic 
calculate HAM-D total score to 
calculate the subscale.  
HAM-D response will be defined as having a 50% or greater reduction from period-specific 
baseline in HAM-D total score; only participants who have non-missing total score of HAM-
D at period-specific baseline as well as the visit will be considered in HAM-D response 
evaluation.  HAM-D remission will be defined as having a HAM-D total score of ≤7; if 
HAM-D total score is missing at the visit, remission will not be defined. For a sensitivity 
analysis the worst-case scenario imputation will be used, i.e. missing values for HAM-D 
response (remission) will be considered as “No response” (“No remission”). 
7.3.1.2. 
 Clinical Global Impression – Improvement (CGI-I) 
The Clinical Global Impression Improvement (CGI-I) employs a 7-point Likert scale to 
measure the overall improvement in the participant’s condition post-treatment. The 
Investigator will rate the participant’s total improvement. Response choices include: 0=not 
assessed, 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 
5=minimally worse, 6=much worse, and 7=very much worse. The CGI-I is rated at post-
treatment assessments on Days 8, 15, 28 during each treatment cycle, and Q8W visit during 
the observation periods. By definition, all CGI-I assessments are evaluated against baseline 
conditions. CGI-I response will be defined as having a CGI-I score of “very much improved” 
or “much improved.” Missing CGI-I at the visit will not be evaluated for response. For a 
sensitivity analysis the worst-case scenario imputation will be used, i.e. missing values for 
CGI-I response will be considered as “No response”.  
7.3.1.3. 
 Clinical Global Impression – Severity (CGI-S) 
The Clinical Global Impression Severity (CGI-S) uses a 7-point Likert scale to rate the 
severity of the participant’s illness at the time of assessment, relative to the clinician’s past 
experience with participants who have the same diagnosis. Considering total clinical 
experience, a participant is assessed on severity of mental illness at the time of rating as 
1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly 
ill; 6=severely ill; and 7=extremely ill.  CGI-S is collected on Days 1, 8, 15, 28 during each 
treatment cycle, and at Q8W visit during the observation periods. 
7.3.1.4. 
Patient Health Questionnaire (PHQ-9)  
The PHQ-9 is a 9-item participant-rated depressive symptom severity scale. It is collected 
during the clinic visit on Days 1, 8, 15, 28 during each treatment cycle, at Q2W (remote), and 
at Q8W visit during the observation periods. Scoring is based on responses to specific 
questions, as follows: 0=not at all; 1=several days; 2=more than half the days; and 3=nearly 
every day.  
The PHQ-9 total score will be calculated as the sum of the 9 individual item scores. If more 
than 1 individual item is missing, the PHQ-9 total score will not be calculated and will be left 
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as missing.  If 1 individual item score is missing, the missing item score will be imputed by 
the mean of all other available item scores to calculate the PHQ-9 total score. The PHQ-9 
total score will be categorized as follows: 0 to 4=minimal depression, 5 to 9=mild 
depression, 10 to 14=moderate depression, 15 to 19=moderately severe depression; and 20 to 
27=severe depression. 
 
 
 
 
7.3.1.7. 
Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive 
episodes in participants with mood disorders.  MADRS is collected at Screening in the parent 
study and during the clinic visit on Day 1 of each study period. 
Each MADRS item ranges from 0 to 6; higher MADRS scores indicate more severe 
depression.  The MADRS total score will be calculated as the sum of the 10 individual item 
scores, which ranges from 0 to 60.  If more than two individual items are missing, the 
MADRS total score will not be calculated and will be left as missing.  If less than or equal to 
two individual item scores are missing, the missing item scores will be imputed by the mean 
of all other available item scores, or the maximum possible values for the missing responses, 
whichever is smaller, to calculate the MADRS total score. 
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7.3.2. 
Visit Windows 
The scheduled visits within a treatment cycle will not be windowed and will be used at 
nominal visit value for analysis purposes. Visits are scheduled in the observation period 
every eight weeks, but they are collected in the database without reference to the exact day; 
therefore the data from these visits need to be mapped to the observational visit scheduled, 
Days 70, 126, 182, 238, 294, 350 for each observational period. In addition, the unscheduled, 
end-of-treatment (EOT) and early termination (ET) visit will be mapped to a scheduled visit 
for analysis.  The visits before the first dose of SAGE-217 within this protocol do not need to 
be windowed but will be used for determination of period-specific baseline or end-of-study 
values.  Note that according to the protocol, the schedule of visits starts fresh once the 
participant is dosed in a cycle, and no longer follows the schedule of every 8 weeks from the 
previous period. 
In order to accommodate as much data as possible into analysis, these windows have been 
widened compared to protocol-specified operational window; these windows are used for 
analysis purposes only.  Once analysis visit windows are assigned, all visits, including 
scheduled visits, unscheduled visits, and EOT/ET visits will be eligible for being flagged as 
the “analyzed record” within the analysis window; a participant’s individual analysis visit 
window could potentially contain more than 1 visit.  In the event of multiple visits falling 
within an analysis window or in case of a tie, the following rules will be used in sequence to 
determine the “analyzed record” for the analysis visit window: 
 If the data from the scheduled visit is available, except for observational visits, 
then the scheduled visit data will be used.  
 If there is no data from the scheduled visit available, the data closest to the 
scheduled study day for that window will be used.  
 If there is a tie between the data in the number of days before and after the 
scheduled day, the later data will be used.  
 If there is a tie on the target day, the record with later time will be used. 
The summary by visit will use the “analyzed records” only – at most one per participant.  The 
data not flagged as the “analyzed record” will be included in listings. An unscheduled visit 
that does not fall under any analysis window (e.g. in case one is available after Week 52) will 
remain in the database and will be included in the listings.   
Table 2 displays windows for response analysis.  
Table 2: 
Visit Windows for Efficacy Analysis (with respect to each treatment 
cycle) 
Scheduled Visit 
Target Study Day  
Study Day Window for Visit  
Period-specific Baseline 
(Periods 2,3,4,5 for SAGE-217, 
Periods 1,2,3,4 for Placebo) 
Day 1  
Latest available before the first dose in 
Treatment Cycle X but data collected 
within this protocol 
Day 8 (1 day) 
Day 8 
Day 2 – Day 11 
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Scheduled Visit 
Target Study Day  
Study Day Window for Visit  
Day 15 (1 day) 
Day 15 
Day 12 – Day 18 
Day 28 (3 day) 
Day 28 (last dose date 
+ 14 days) 
Day 19 – Day 37 (last dose date + 5 days, 
+23 days) 
Q8W (±3 days)* 
Day 70  
Day 126  
Day 182 
Day 238 
Day 294 
Day 350 
Day 63 – Day 77 
Day 119 – Day 133 
Day 175 – Day 189 
Day 231 – Day 245 
Day 287 – Day 301 
Day 343 – Day 357 
*To be used for all observational period visit – scheduled or unscheduled.   
Note: Parenthesized study day and study day window are for unscheduled visits, EOT, and ET for participants 
who have discontinued treatment prematurely and such visit date is more than 4 days from the last dose of 
SAGE-217 intake (visit date – last dose date +1 >4) within the cycle 
End-of-Study (EOS) visit is a scheduled visit which is to be done for participants who 
completed the study (target date from the first dose date in parent study = Day 364).  If the 
data from the EOS visit is available, then scheduled visit data will be used.  If EOS scheduled 
visit is not available, and there are visits (observational period visit, unscheduled visit, EOT, 
or ET) that cannot be windowed to a cycle-specific day, they will then be evaluated for EOS 
window for the completers (per study conclusion CRF page) (≥Day 358 counting from the 
first dose in the parent study) and in case of multiple visits the one closest to the target date 
of Day 364 (from first dose date in parent study) will be used in analysis. In summaries by 
study period, EOS visit will be presented within the last study period the participant had been 
treated with SAGE-217.   
7.3.3. 
Analysis of Response Variable(s) 
The following endpoints will be summarized descriptively by scheduled assessment time 
point – by each study period separately: 
 HAM-D total score – observed, change from period-specific baseline, percent 
change from period-specific baseline  
 HAM-D subscale scores – observed, change from period-specific baseline, 
percent change from period-specific baseline 
 HAM-D individual item score – observed, change from period-specific baseline, 
percent change from period-specific baseline  
 HAM-D response – missing response not accounted (bar chart will also be 
provided) 
 HAM-D response – missing response counted as No response (bar chart will also 
be provided) 
 HAM-D remission – missing remission not accounted (bar chart will also be 
provided) 
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 HAM-D remission – missing remission counted as No remission (bar chart will 
also be provided) 
 CGI-I score -observed  
 CGI-I response – missing response not accounted (bar chart will also be provided) 
 CGI-I response ¬ missing response counted as No response (bar chart will also be 
provided) 
 CGI-S scores – observed and change from period-specific baseline 
Line plot of mean and standard deviation (SD) over time will be prepared for change and 
percent change from baseline in HAM-D total score and HAM-D subscale scores, separately 
for each study period. For line plots of these efficacy endpoints and bar charts of HAM-D 
response and remission by study period, for each time point on X axis, the number of 
participants withdrawing from the study between last time point and this time point will be 
provided in a row below the X-axis.  For time points beyond Day 70, another row of numbers 
indicating how many participants got retreated (and thus are no longer continuing within this 
study period) between the last time point and this time point will be provided; this number 
should be ‘not applicable’ (NA) at time points before Day 70 within each period. In line 
plots, a vertical line at Day 70 will be provided to indicate in footnote that this is when a 
participant becomes eligible for re-treatment; for bar charts, Day 70 will be starred and 
footnoted in a similar way. 
Forest plot for change from period-specific baseline in HAM-D scores at Day 15 –means, 
95% confidence interval – will be provided for total score by subgroup and by study period. 
Similar plot will be provided for change from period-specific baseline in subscale scores of 
HAM-D by study period. 
Following subgroup summaries by study period will be provided for HAM-D total score: 
 Sex (Male, Female) 
  Race (Black or African American, White, Other) 
  Age (18-24, 25-50, 51-64 years) 
 Depression with Elevated Anxiety, measured by HAM-D Anxiety Subscale Score 
(Yes, No) 
 Depression with Elevated Anxiety, measured by HAM-A Total Score (Yes, No) 
 BMI in parent study (≤18.4, 18.5-24.9, 25-29.9, ≥30 kg/m2) 
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A listing of MADRS collected at baseline of each study period including the screening value 
from the parent study will be provided. 
7.3.4. 
Durability of Response 
Durability measured by HAM-D is defined as follows: Take only the HAM-D responders in 
study period X on D15.  Durability of response by HAM-D criterion is defined as the number 
of days between Day 15 HAM-D assessment in study period X to the first period-specific 
study day when the reduction in the HAM-D total score from the period-specific baseline 
within the study period X is less than 50%.  A participant who does not have any HAM-D 
showing less than 50% reduction in HAM-D total score from the period-specific baseline 
after Day 15 in the study period X will be censored at the latest HAM-D evaluation date 
before the first dose date in study period X+1 if it exists or the last HAM-D evaluation in the 
study if there is no further treatment cycle for the participant. Durability measured by HAM-
D will be calculated only for the subset of D15 HAM-D responders in Study Period X who 
have at least one HAM-D after Day 15 HAM-D date. 
Durability measured by PHQ-9: Take only the HAM-D responders in study period X on 
D15.  Durability of response by PHQ-9 criterion is defined as the number of days from Day 
15 PHQ-9 assessment in study period X to the first PHQ-9 after Day 15 when PHQ-9 score 
≥10 within the study period X.  A participant who does not have any PHQ-9 showing score 
≥10 within the study period X will be censored at the latest PHQ-9 evaluation date before the 
first dose date in study period X+1 if it exists or the last PHQ-9 evaluation in the study if 
there is no further treatment cycle for the participant. 
 
 
 
 
 
. 
For each study period, number of HAM-D evaluations post Day 15 per participant, percent of 
HAM-D evaluations post Day 15 per participant ≥50% reduction from period-specific 
baseline, number of PHQ-9 evaluations post Day 15 per participant and percent of PHQ-9 
evaluations post Day 15 per participant with score <10 will be summarized. 
7.3.5. 
Time to Relapse 
A relapse is defined within each study period separately and is restricted to HAM-D 
responders at Day 15 in the specific period.  Time to relapse is the number of days between 
Day 15 HAM-D and the first time after Day 15 in the specific period when the participant 
has HAM-D total score ≥20 preceded by PHQ-9 score ≥10 within 10 days.  If the participant 
does not have a relapse within Study Period X, the participant will be censored at the latest 
HAM-D evaluation date before the first dose date of next study period if it exists, or the latest 
HAM-D evaluation date in the study if there is no further treatment cycle for the participant. 
Time to relapse will be calculated only for the subset of D15 HAM-D responders in Cycle X 
who have at least one HAM-D after Day 15 HAM-D date. KM survival curve will be 
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provided by study period, using Safety Set for each period (restricted to Day 15 HAM-D 
responders only). The number of participants not having a relapse within the study period 
(i.e. censored), number of participants having a relapse within the study period, and summary 
statistics (mean, standard deviation, median, minimum, maximum) for time to relapse for 
those having relapse within the study period will be summarized. 
7.4. 
Safety Analysis 
The primary objective of this study is to evaluate the safety and tolerability of SAGE-217 as 
assessed by the incidence and severity of adverse events; changes from baseline in clinical 
laboratory measures, vital signs, and ECGs; and suicidal ideation and behavior using the C-
SSRS. Safety analyses will use the Safety Set and/or Study-specific Safety Set for overall 
safety.  Safety analyses will be provided based on the Period-Specific Safety Set for each 
study period when appropriate.   
The safety endpoints evaluated at scheduled visits are taken as done in nominal visit, without 
any windowing.  If a value is available for a nominal scheduled visit, that value will be used 
in summary by visit.  Unscheduled visits, EOT and ET visits will be windowed using the 
same window days outlined in Table 2 for efficacy endpoints.  If scheduled visit value is not 
available, a value from the specific visit window will be included in summary, the choice of 
the record following the same rule as described in Section 7.3.2. 
Last value on treatment and Last value in the study period will be included in the summaries 
whenever indicated in the relevant sections below.  Last value on treatment is defined as the 
last value between the first dose of SAGE-217 (exclusive) and up to last dose of SAGE-217 
+ 1 day (inclusive) within the specific study period. Last value on study is defined as the last 
value after the first dose of SAGE-217 within the entire study.  
Potentially clinically significant (PCS) values for parameters in lab, vital signs and ECG have 
been identified by the medical personnel in the team ahead of the analysis.  These are listed 
in the respective sections below.  
The safety endpoints and variables considered in the summary tables for this study are 
summarized in Table 3. 
Table 3: 
 Safety endpoints and variables in the summary tables 
Safety 
Evaluation 
Incidence 
Observed 
Value 
Change/ 
Period-
specific 
change from 
Baseline 
Abnormality/Clinical 
Significance (CS) 
Potentially Clinical 
Significance (PCS) 
AEs 
X 
 
 
 
 
Labs 
 
X 
X  
Z 
X 
ECGs 
 
X 
X 
Z 
X 
Vital Signs 
 
X 
X  
 
X 
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Safety 
Evaluation 
Incidence 
Observed 
Value 
Change/ 
Period-
specific 
change from 
Baseline 
Abnormality/Clinical 
Significance (CS) 
Potentially Clinical 
Significance (PCS) 
C-SSRS 
X 
X 
X 
 
 
Note: PCS criteria are outlined in Sections 7.4.2-7.4.4 
X = to be summarized in tables 
Z = to be presented in listings only 
7.4.1. 
Adverse Events 
Adverse events (AEs) are collected starting at the time of informed consent and throughout 
the duration of the participant’s participation in the study.  All AEs will be coded using 
MedDRA version 24.0. AEs collected in parent study are not included in AE summary in this 
study.  
A treatment-emergent adverse event (TEAE) is defined as an adverse event with onset on or 
after the first dose of SAGE-217 – either in the parent study or within this protocol and on or 
after the ICF sign off date. For more clarification, a TEAE is defined as below:  
 For Placebo + ADT participants from parent study: TEAE is defined as an AE with 
onset on or after the first dose of SAGE-217 in this protocol. 
 For SAGE-217 + ADT participants from the parent study: TEAE is defined as an AE 
with onset on or after the ICF sign off in this protocol.  
Adverse events recorded in the database of this protocol with onset on or after the ICF sign 
date in this protocol and before the first dose of SAGE-217 within this protocol if it exists or 
before the last day of study within this protocol if the participant was never treated with 
SAGE-217 within this protocol are considered as Observation Period 0 AE. Obervation 
Period 0 AE are divided into 2 groups:  
 for SAGE-217 + ADT participants from the parent study - these are part of 
TEAEs for this study  
 for Placebo + ADT participants from the parent study - these are not part of 
TEAEs for this study, but are flagged as pre-treatment adverse events for listing 
purposes.   
The TEAEs will be further categorized by study period of occurrence as follows (X=1 
through 5 defined within this protocol): 
A TEAE for study period X is defined as an AE with onset on or after the first dose of 
SAGE-217 in the treatment cycle X until prior to the first dose of SAGE-217 in the 
subsequent study period X+1. Each analysis study period is divided into three exclusive 
analysis periods - treatment period, follow up period, and observation period; in addition, 
treatment period and follow up period together constitute of treatment cycle period. For 
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details of the algorithm used for defining the periods for AEs, please refer to Section 10.4, 
Appendix D. 
If the date of an AE is incomplete and an unambiguous determination could not be made with 
respect to its onset time versus the first dose of SAGE-217 and/or last dose of SAGE-217, the 
AE will be assumed to be a TEAE and a treatment period TEAE in the cycle it started (or 
assigned to Cycle 1 for Placebo + ADT or Cycle 2 for SAGE-217 + ADT if cycle of AE start 
could not be determined).  For imputation of missing AE dates, please refer Section 10.3, 
Appendix C. For further details on the programming algorithm of AE periods, please refer to 
Section 10.4, Appendix D. 
An overview summary table of TEAEs will present the number and percentage of 
participants as well as the number of events using Safety Set as well as Study-specific Safety 
Set for the following: 
 TEAE 
 TEAEs by maximum severity (severe>moderate>mild) 
 TEAE leading to discontinuation of SAGE-217 
 TEAE leading to dose reduction 
 TEAE leading to withdrawal from the study 
 Death 
 Serious Adverse Event (SAE) 
An overview summary table of TEAE by study period (including Observation Period 0 
TEAEs) will present the number and percentage of participants as well as the number of 
events using Safety Set for the following: 
 TEAE  
 Treatment Cycle Period TEAE 
 Treatment Period TEAE 
 Follow-up Period TEAE 
  Observation Period TEAE 
 TEAEs by maximum severity (severe>moderate>mild) 
 Treatment Cycle Period TEAE 
 Treatment Period TEAE 
 Follow-up Period TEAE 
 Observation Period TEAE 
 TEAE leading to discontinuation of SAGE-217 
 TEAE leading to Dose Reduction  
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 TEAE leading to withdrawal from the study 
 Treatment Cycle Period TEAE 
 Treatment Period TEAE 
 Follow-up Period TEAE 
 Observation Period TEAE 
 Death 
 Treatment Cycle Period  
 
Treatment Period  
 
Follow-up Period 
 Observation Period  
 Serious Adverse Event (SAE) 
 Treatment Cycle Period Serious TEAE 
 Treatment Period Serious TEAE 
 Follow-up Period Serious TEAE 
 Observation Period Serious TEAE 
Incidence of TEAEs in following categories will be provided by SOC and PT.  A participant 
is counted only once under each SOC and PT in case of multiple occurrences of the same 
AE. All AE summaries described below will use the analysis data set mentioned with 
respective display.  The study level summaries will be sorted by decreasing frequency of 
SOC first, then by PT within the SOC, then alphabetical within the PT.  The by-period 
summaries will be sorted by decreasing frequency (percent) of Study Period 1 column, by 
Study Period 2, 3, 4, 5 respectively, then alphabetically – for SOC first, then by PT within 
SOC, then alphabetical within PT. For subperiod (treatment period/follow up 
period/treatment cycle period/observation period) TEAE summaries, participants in Period-
specific Safety Set in the study period X will be used as the denominator in calculating the 
percentage. 
 TEAE (Safety as well as Study-specific Safety Set at study level, Period-specific 
Safety Set for by-period (including Observation Period 0 TEAEs)) 
 Treatment Cycle Period TEAE (Study-specific Safety set at Study level, Period-
specific Safety Set for by-period summaries) 
 Treatment Period TEAE (Study-specific Safety set at Study level, Period-specific 
Safety Set for by-period summaries) 
 Follow-up Period TEAE (Study-specific Safety set at Study level, Period-specific 
Safety Set for by-period summaries) 
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 Observation Period TEAE (Study-specific Safety set at Study level, Period-
specific Safety Set for by-period summaries) 
 TEAEs by maximum severity (Safety and Study-specific Safety set at Study level) 
 Treatment Period TEAEs by maximum severity (“by study period” only – 
Period-specific Safety Set) 
 Follow-up Period TEAEs by maximum severity (“by study period” only – 
Period-specific Safety Set) 
 Treatment Cycle Period TEAEs by maximum severity (“by study period” only 
– Period-specific Safety Set) 
 Observation Period TEAEs by maximum severity (“by study period” only – 
Period-specific Safety Set) 
 TEAEs by relationship to SAGE-217 (Study-specific Safety Set at study level) 
 Treatment Period TEAEs by relationship to SAGE-217 (“by study period” 
only – Period-specific Safety Set) 
 Follow-up Period TEAEs by relationship to SAGE-217 (“by study period” 
only – Period-specific Safety Set) 
 Treatment Cycle Period TEAEs by relationship to SAGE-217 (“by study 
period” only – Period-specific Safety Set) 
 Observation Period TEAEs by relationship to SAGE-217 (“by study period” 
only – Period-specific Safety Set) 
 Serious TEAEs (Safety as well as Study-specific Safety Set at study level, Safety 
Set for by-period (including Observation Period 0 TEAEs)) 
 Treatment Cycle Period Serious TEAEs (Study-specific Safety set at Study level, 
Period-specific Safety Set for by-period summaries) 
 Treatment Period Serious TEAE (Study-specific Safety set at Study level, Period-
specific Safety Set for by-period summaries) 
 Follow-up Period Serious TEAE (Study-specific Safety set at Study level, Period-
specific Safety Set for by-period summaries) 
 Observation Period Serious TEAE (Study-specific Safety set at Study level, 
Period-specific Safety Set for by-period summaries) 
 Serious TEAEs by relationship to SAGE-217 (Study-specific Safety Set at study 
level, Period-specific Safety Set for by-period summaries) 
 Treatment Period TEAEs leading to discontinuation of SAGE-217 (Study-specific 
Safety set at Study level, Period-specific Safety Set for by-period summaries) 
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 Treatment Period TEAEs leading to dose reduction in SAGE-217 (Study-specific 
Safety set at Study level, Period-specific Safety Set for by-period summaries), 
(including a row for number of participants who completed treatment in the study 
period with dose reduction) 
 TEAEs leading to withdrawal from the study (Study-specific Safety set at Study 
level, Safety Set for by-period summaries) 
 Treatment Cycle Period TEAEs leading to withdrawal from the study (“by 
study period” only – Period-specific Safety Set) 
 Treatment Period TEAEs leading to withdrawal from the study (“by study 
period” only – Period-specific Safety Set) 
 Follow-up Period TEAEs leading to withdrawal from the study (“by study 
period” only – Period-specific Safety Set) 
Listing of Observation Period 0 AEs with onset prior to first dose of SAGE-217 but after the 
ICF sign off date in this protocol will be provided from participants who received Placebo + 
ADT in the parent study.  All listings on TEAEs will provide the study period of AE onset 
and AE period designation for each AE.   
A summary of most common TEAE (defined as incidence more than 2%) by preferred term 
will be provided, sorted by decreasing frequency using Safety as well as Study-specific 
Safety Set. A separate summary of most common treatment cycle period TEAE by preferred 
term will also be provided using Study-specific Safety Set.  Further, these summaries will be 
provided by the study period using the Safety Set and Period-specific Safety Set, 
respectively. 
For maximum severity, participants will be counted only once within each SOC and PT at the 
maximum severity in the following order: severe> moderate> mild; an AE with missing 
severity will be omitted from severity presentation.  For relationship to SAGE-217, ‘related’ 
is defined as relationship being “possible” or “probable” or missing. A participant will be 
counted only once within each SOC and PT at the strongest relationship to SAGE-217 in the 
following order: related, not related.  
Separate data listing for deaths and non-fatal SAEs will be provided. 
In addition, Treatment Cycle Period TEAE summary by SOC/PT by study period will also be 
presented by the following subgroups using Period-specific Safety Set: 
 Age group:18-24, 25-50, 51-64 years 
 Sex: Male, Female  
 Race: White, Black or African American, Other 
 Depression with Elevated Anxiety, measured by HAM-D Anxiety Subscale Score 
(Yes, No) 
 Depression with Elevated Anxiety, measured by HAM-A Total Score (Yes, No) 
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 BMI in parent study (≤18.4, 18.5-24.9, 25-29.9, ≥30 kg/m2) 
7.4.2. 
Clinical Laboratory 
The clinical laboratory tests to be performed for monitoring of safety are listed in Table 4.  
They are collected at Days 1, 8, 15, and Q8W. 
Table 4: 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Coagulation 
Red blood cell count 
Hemoglobin  
Hematocrit  
White blood cell count  
   with differential  
Platelet count 
Red blood cell  
    morphology 
Alanine aminotransferase  
Albumin  
Alkaline phosphatase  
Aspartate aminotransferase  
Total bilirubin  
Direct bilirubin  
Indirect bilirubin  
Total protein  
Creatinine  
Blood urea nitrogen  
Creatine kinase  
Gamma-glutamyl transferase  
Potassium  
Sodium  
Lactate dehydrogenase  
Glucose  
Chloride  
Bicarbonate  
Calcium  
Phosphorus  
Triglycerides  
Thyroid stimulating hormone  
pH  
Specific gravity  
Protein  
Glucose  
Red blood cell  
Nitrite  
Leukocyte 
esterase  
Ketones  
Bilirubin  
Urobilinogen  
Activated partial 
 Thromboplastin 
  time  
Prothrombin time  
International 
  normalized ratio  
All parameters will be converted to consistent units according to the International System of 
Units (SI) before presentation. 
For the laboratory results that are “< or = x”, where x is a number as collected in the data, the 
numeric part of the result will be used in calculation in the summary tables.  Same is true if 
the result is presented as BLQ and a LLOQ value is provided – LLOQ value will be used for 
calculation in the summary tables.  The actual results as collected will be displayed in the 
listings. 
Summary tables on lab parameters will be done by study period using Period-specific Safety 
Set, and will include descriptive statistics for the observed values and changes from period-
specific baseline by scheduled assessment timepoint in hematology, serum chemistry, 
coagulation and quantitative urinalysis test results.  It will also include the summary of last 
post-baseline values on treatment and on study within each study period.  The parameter 
values which are produced only if another parameter is abnormal will be included in data 
listings, but not summarized.   
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A listing of clinical lab data for all enrolled participants will be included in the data listing, 
identifying participants in Placebo + ADT and SAGE-217 + ADT group from the parent 
study.  The data listing will include study period number and visit for records.  Any 
assessments with start date on or after the ICF sign date in this protocol and before the first 
dose of SAGE-217 within this protocol if it exists or before the last day of study within this 
protocol if the participant was never treated with SAGE-217 within this protocol will be 
assigned Observation Period 0.  
If a normal range is provided for the parameter, out-of-range values will be flagged as low or 
high, where applicable, in the participant data listings.  A shift table for these parameters will 
include the out-of-range values for the period-specific baseline, then the shift from normal at 
period-specific baseline to high or low at any time during treatment (on or after first dose and 
on or before last dose + 1 day) and any time post-baseline during the study period (on or after 
first dose in the respective period but before the first dose of next study period). This will be 
provided using Period-specific Safety Set.  Qualitative urinalysis parameters will be 
summarized descriptively using number and percentage of participants. 
The number and percentage of participants with PCS values will be provided in separate 
displays in hematology, serum chemistry, and liver function tests for such occurrence any 
time post-baseline (i.e. after first dose of SAGE-217, irrespective of whether it happens in 
scheduled or unscheduled assessments) during the entire study. Potentially clinically 
significant values will be identified for specific laboratory parameters as outlined in Table 5.  
For each study period, an occurrence of PCS values any time in the treatment period, the last 
value during the treatment period, any time in the treatment cycle, the last value during the 
treatment cycle and any time during the study period will be summarized, using Period-
specific Safety Set. 
Table 5: 
Laboratory Parameters – Criteria for PCS Values 
Laboratory  
Parameter 
Sex 
Units 
Criteria for PCS Values (Observed 
values) 
High  
Low  
Hematology 
Hemoglobin              Male 
g/L  
>185  
<115 
 
Female 
g/L  
>170 
<100 
Hematocrit    
Male 
Fraction of 1 
>0.55  
<0.385  
 
Female 
Fraction of 1 
>0.49 
<0.345 
Platelet count  
 
10^9/L  
>600 
<125 
White blood cell 
 
10^9/L  
>15  
<2.5  
Basophils  
 
10^9/L  
>0.5 
NA 
Eosinophils 
 
10^9/L  
>1.5 
NA 
Neutrophils  
 
10^9/L  
NA  
<1.5  
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Lymphocytes  
 
10^9/L  
>6.0  
<0.5  
Monocytes  
 
10^9/L  
>1.4 
NA 
 
 
 
 
 
Serum Chemistry 
Albumin  
 
g/L  
>70  
<28  
Blood urea 
nitrogen  
 
mmol/L 
>10.71 
NA 
Calcium 
 
mmol/L 
>2.75 
<2.0 
Chloride 
 
mmol/L 
>120 
<90 
Creatinine 
 
mmol/L 
>3xULN or >3x 
Baseline 
 
Gamma Glutamyl 
Transferase  
 
 
>3xULN 
 
Glucose 
 
mmol/L 
>13.9 
<2.8 
Sodium  
 
mmol/L  
>150  
<132  
Potassium  
 
mmol/L  
>5.4  
<3.3  
Protein  
 
g/L 
 
<45 
Bicarbonate  
 
mmol/L  
>34  
<18  
Chloride  
 
mmol/L  
>120  
<90  
Phosphorus  
 
mmol/L 
>1.94 
<0.61 
Liver Function Tests (LFT) 
Total Bilirubin  
 
μmol/L  
>2xULN  
NA  
Aspartate 
Aminotransferase  
 
U/L  
>3xULN  
NA  
Alanine 
Aminotransferase  
 
U/L  
>3xULN  
NA  
Alkaline 
Phosphatase  
 
U/L  
>1.5xULN  
NA 
Liver function tests will be monitored more closely than above for potentially clinically 
significant values, and will be summarized by each study period for an occurrence of PCS 
values any time in the treatment period, the last value during the treatment period, any time 
in the treatment cycle, the last value during the treatment cycle and any time during the study 
period,  for the following parameters for these PCS threshold: 
 Alanine Aminotransferase: >3xULN, >5xULN, >10xULN 
Aspartate Aminotransferase: >3xULN, >5xULN, >10xULN 
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Alanine Aminotransferase or Aspartate Aminotransferase: >3xULN, >5xULN, 
>10xULN 
Alkaline Phosphatase: >1.5xULN, >2xULN 
Total Bilirubin: >1.5xULN, >2xULN 
Total Bilirubin > 2xULN AND (Alanine Aminotransferase or Aspartate 
Aminotransferase >3xULN) [any time post-baseline, does not need to be measured 
at the same time point of assessment] 
 [(Total Bilirubin >2xULN) AND Alkaline Phosphatase <2xULN (any time post-
baseline, measured at the same time point of assessment)] AND [(ALT or AST 
>3xULN) AND Alkaline Phosphatase <2xULN, any time post-baseline, measured at 
the same time point of assessment], refer to algorithm in Section 10.4, Appendix D. 
Any lab results considered clinically significant by the investigator will be captured as 
adverse events, hence will show up in AE displays. 
Pregnancy test results will be listed but not summarized.  
7.4.3. 
Vital Signs 
Vital signs for the following parameters – respiratory rate (breaths/minute), oral temperature 
(degrees C), supine heart rate (beats/minute), supine systolic blood pressure (mmHg), supine 
diastolic blood pressure (mmHg), standing heart rate (beats/minute), standing systolic blood 
pressure (mmHg), standing diastolic blood pressure (mmHg),– are collected at Days 1, 8, 15, 
28, and Q8W. Descriptive summaries of observed values and changes from period-specific 
baseline will be provided for vital sign parameters – by scheduled assessment time point 
within each study period, using Period-specific Safety Set.  It will also include the last values 
on treatment and on study within study period assessments. The orthostatic vital sign – the 
change from supine to standing (Supine – Standing) – heart rate, systolic and diastolic blood 
pressure – will also be summarized by study period and scheduled assessment timepoint. 
A listing of vital signs data collected will be included in the data listing, identifying 
participants in Placebo + ADT and SAGE-217 + ADT group from the parent study.  The data 
listing will include study period number and visit for records.  Any assessments with start 
date on or after the ICF sign date in this protocol and before the first dose of SAGE-217 
within this protocol if it exists or before the last day of study within this protocol if the 
participant was never treated with SAGE-217 within this protocol will be assigned 
Observation Period 0. 
Potentially clinically significant values will be identified for vital sign parameters as outlined 
in the Table 6.  For each study period, an occurrence of PCS values any time in the treatment 
period, the last value during the treatment period, any time in the treatment cycle, the last 
value during the treatment cycle and any time during the study period will be summarized, 
using Period-specific Safety Set. 
 
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Table 6: 
Vital Signs – Criteria for PCS Values 
 
 
Criteria for PCS Values 
Vital Sign 
Units 
 Observed values 
Change from Baseline values 
 
 
High  
Low  
Increase  
Decrease  
Heart rate (supine and 
standing) 
Beats/min  
>120  
<40  
NA 
NA 
Systolic Blood Pressure 
(supine and standing)  
mmHg  
>180 
<90  
≥30 
≥30 
Diastolic Blood pressure 
(supine and standing)  
mmHg  
>110 
<50  
≥20 
≥20  
Supine – Standing 
Systolic Blood Pressure 
mmHg 
≥20 
 
 
 
Supine – Standing 
Diastolic Blood Pressure 
mmHg 
≥10 
 
 
 
Possible Orthostatic 
hypotension: supine – 
standing SBP and DBP 
mmHg 
SBP ≥ 20 
and DBP ≥ 
10 
 
 
 
 
mmHg 
SBP ≥ 20 
or DBP ≥ 
10 
 
 
 
Any vital signs results considered clinically significant by the investigator will be captured as 
adverse events, hence will show up in AE displays. 
7.4.4. 
Electrocardiogram 
Supine 12-lead ECGs will be performed in triplicate, and are collected at Days 1, 15 and 
Q8W. The following ECG parameters will be collected for each participant: heart rate (beats 
per minute), PR (msec), QRS (msec), QT (msec), and QTcF (msec).     
The average of the triplicate values will be used in the summary, including period-specific 
baseline ECG values.  The observed value at each time point and change from period-
specific baseline at each post-baseline scheduled time point will be summarized for the 
Period-specific Safety Set.  This summary will also include the last values on treatment and 
on study within study period. Each ECG is evaluated as ‘normal’, ‘abnormal, not clinically 
significant’ and ‘abnormal, clinically significant’; the number and percentage of participants 
with at least one of the triplicate values in the categories of ‘abnormal, clinically significant’ 
and ‘abnormal, not clinically significant’ will be provided by period-specific baseline and 
each post-baseline scheduled assessment time point (plus the end of treatment and EOS 
assessments, if any) for the Period-specific Safety Set. 
Potentially clinically significant values will be identified for ECG parameters as outlined in 
Table 7.  This analysis includes triplicate values individually and is not based on the average 
value (note: for the PCS values derived from change from Baseline: Baseline is the average 
of the triplicate values).  For each study period, an occurrence of PCS values any time in the 
treatment period, the last value during the treatment period, any time in the treatment cycle, 
the last value during the treatment cycle and any time during the study period will be 
summarized, using Period-specific Safety Set. 
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The maximum value of QTcF if within any of the PCS criteria will also be summarized by 
study period. 
Table 7: 
ECG Parameters – Criteria for PCS and PCSC Values 
 
 
Criteria for PCS Values 
ECG 
Units 
 Observed values 
 Change from Baseline 
 
 
High  
Low  
Increase  
Decrease  
QTcF 
Interval 
msec  
>450 but <=480, >480 but <=500,  
>500 
NA  
≥30 to 60 
>60 
 
NA  
A listing of ECG data collected this study will be included in the data listing, identifying 
participants in Placebo + ADT and SAGE-217 + ADT group from the parent study.  The data 
listing will include study period number and visit for records. Any assessments with start 
date on or after the ICF sign date in this protocol and before the first dose of SAGE-217 
within this protocol if it exists or before the last day of study within this protocol if the 
participant was never treated with SAGE-217 within this protocol will be assigned 
Observation Period 0. 
7.4.5. 
Physical Examination  
Physical examination is scheduled at Day 1 and Q8W. Only clinically significant 
abnormalities are captured in the database – for post-baseline observations, these will be 
reported as adverse events, hence these will be included in AE displays; for pre-baseline 
observations, these will be reported as medical history, hence these will be included in 
Medical History displays.  The dates of physical examination will be listed to confirm that 
the examination was done. 
7.4.6. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
Suicidality data collected on the C-SSRS “Since Last Visit” form is collected during the 
clinical visits at Days 1, 8, 15, 28, and Q8W. The C-SSRS includes ‘yes’ or ‘no’ responses 
for assessment of suicidal ideation and behavior as well as numeric ratings for severity of 
ideation, if present (from 1 to 5, with 5 being the most severe).  
The participant’s non-suicidal self-injurious behavior is also assessed separately as part of C-
SSRS.  
The assessments for suicidal ideation are ranked as follows with 5 being the worst: 
1. Wish to be dead 
2. Non-specific active suicidal thoughts 
3. Active suicidal ideation with any methods 
4. Active suicidal ideation with some intent 
5. Active suicidal ideation with specific plan 
The assessments for suicidal behavior are ranked as follows with 5 being the worst: 
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1. Preparatory acts or behavior 
2. Aborted attempt 
3. Interrupted attempt 
4. Actual attempt (non-fatal) 
5. Completed suicide 
Suicidal behavior is considered worse than suicidal ideation.   
Period-specific baseline for each question is defined as the response in the latest assessment 
before the first dose of SAGE-217 in the specific period.   
The number and percentage of participants with at least one response of ‘Yes’ to any C-
SSRS suicidal ideation or suicidal behavior item, as well as for participant’s non-suicidal 
self-injurious behavior, will be summarized for period-specific baseline and any time post-
baseline (period-specific) separately within each study period, using Period-specific Safety 
Set. 
Summary of shift from period-specific baseline in C-SSRS suicidal ideation and suicidal 
behavior will be presented for the following categories (no suicidal ideation/behavior, 
suicidal ideation, suicidal behavior) for each scheduled assessment time point within each 
study period, using Period-specific Safety Set. If the answer to all available assessments in 
suicidal ideation and all available assessments in suicidal behavior is ‘No’ then the category 
for the table is considered as ‘No suicidal ideation/behavior’.  If any of the assessments in 
suicidal behavior is Yes, the category is considered as ‘Suicidal behavior’.  If any of the 
assessments in suicidal ideation is Yes but all available assessments in suicidal behavior is 
No, the category is considered as ‘Suicidal ideation’.  
In addition, a summary of shift in suicidal ideation from period-specific baseline to the 
maximum rank score for any time post- period-specific baseline will be presented by study 
period, using Period-specific Safety Set. Maximum score 0 refers to No for all assessments in 
the desired period for all 5 questions on suicidal ideation. 
  
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8. 
SUMMARY OF INTERIM AND DMC ANALYSES 
This is an open-label study. An interim data cut with data cleaned to a pre-specified level (in 
data management documentation, as agreed by the study team) up to data entered at the pre-
specified date has been undertaken at the time of NDA submission.  Analyses from this 
snapshot of data have been included in the original NDA submission in separate section of 
Integrtaed Summary of Safety.  
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9. 
REFERENCES 
Clinical study protocol, version 7.0, 10 May 2021, Company: Sage Therapeutics Inc. 
American Psychiatric Association. Diagnostic and statistical manual of mental disorders (5th 
edition, DSM-5). Arlington, VA: American Psychiatric Publishing. 2013. 
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10. 
APPENDICES 
10.1. 
Appendix A: Schedule of Events (Screening and Observational 
Period) 
 
 
Screeninga (within 5 days 
of completing the final, 
end-of-study visit in the 
parent study) 
Observational Periodb 
(Day 56 through Week 52) 
EOS/Week
 52 (±7 d) 
 
 
Remote 
Assessment 
Q2W (±1 
d) 
Visit 
Q8W/ ET 
(±3 d) 
Unschedule
d Visit 
(as needed)c 
Study Procedure 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
Interim Medical History d 
X 
 
 
 
 
PHQ-9 e 
 
Xf 
X 
X 
X 
Inclusion/Exclusion 
X 
 
 
 
 
Abbreviated Physical 
Examination 
 
 
X 
 
X 
Body Weight 
 
 
X  
 
X  
Clinical Laboratory 
Assessments 
 
 
X 
  
X 
Drug & Alcohol Screen 
X g 
 
X 
 
X 
Pregnancy Test (urine) 
X g 
 
X 
 
X 
Vital Signs 
 
 
X 
 
X 
12-Lead ECG 
 
 
X 
 
X 
C-SSRS 
 
 
X 
 
X 
HAM-D h 
 
 
X 
X 
X 
CGI-S 
 
 
X 
 
X 
CGI-I 
 
 
X 
 
X 
Prior/Concomitant 
Medicationsi  
X 
 
X 
X 
X 
Adverse Events/SAEsj 
X 
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ECG = electrocardiogram; ET = early termination; d = days; EOS = end of study; HAM-D = Hamilton Rating 
Scale for Depression, 17-item; 
 O = optional; PHQ-9 = 9-item Patient Health 
Questionnaire; Q2W = once every 2 weeks; Q8W = once every 8 weeks; 
 
SAE = serious adverse event 
a  Rollover participants will enter the study for screening at the Day 42 visit during the Observational Period. 
This visit may occur on the same day as the final, end-of-study visit in the parent study. If conducted on the 
same day, the assessments listed at this visit do not need to be repeated; in this case, the informed consent and 
inclusion/exclusion criteria only will be documented. If the Screening Visit is not conducted on the same day 
as the final, end-of-study visit in the parent study, the pregnancy test and drug and alcohol screen are to be 
conducted. Additional assessments may be conducted if necessary. 
b  Within an Observational Period, the Q2W remote assessments will begin on Day 56 (±1 day) and occur every 
2 weeks (14 days) thereafter. The Q8W visits will begin on Day 70 (±3 days) and occur every 8 weeks (56 
days) thereafter. 
c A participant will return to the site outside of the Q8W visit schedule if the PHQ-9 score is ≥10 and/or upon 
any suicidal thoughts or behaviors.  
d Any new medical conditions or procedures with onset/start date after completion of the parent study and prior 
to signing informed consent in the current study will be recorded as interim medical history. 
e  All PHQ-9 assessments will be performed 
. 
f The participant will take the PHQ-9 every 14 days; if the PHQ-9 score is ≥10, then the participant will return 
to the site to be assessed by the clinician-administered HAM-D in approximately one week. If the HAM-D 
score is <20, the participant will take the PHQ-9 on a weekly basis: the participant will return to the site to be 
assessed by the HAM-D each week that the PHQ-9 score remains ≥10; if the PHQ-9 score is <10, the 
participant will take the PHQ-9 every 2 weeks thereafter.  
g  To be assessed if the visit is not conducted on the same calendar day as the final (end-of-study) visit in the 
parent study. 
h  If the HAM-D score is ≥20 (assessed approximately one week from having a PHQ-9 score ≥10) and it has 
been at least 8 weeks since the last dose of double-blind treatment in the parent study (ie, Day 70 or later), the 
participant will begin a 14-day SAGE-217 treatment period with a 14-day follow-up visit. If the HAM-D 
score is ≥20 but it has been less than 8 weeks since the last dose of double-blind treatment in the parent study 
(ie, Day 69 or earlier), see Section 9.2.1 of the protocol for guidance on allowable interventions; the 
participant will take the PHQ-9 on a weekly basis until the 8-week period has lapsed, at which time the 
participant may begin a treatment period with SAGE-217, or until the PHQ-9 score is <10. 
i Concomitant medications ongoing at Screening and at subsequent visits will be collected. 
j   Adverse events will be collected starting at the time of informed consent and throughout the duration of the 
participant’s participation in the study. Ongoing adverse events from the parent study will be recorded at the 
Screening Visit. 
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10.2. 
Appendix B: Schedule of Events (Treatment and Follow-Up 
Periods) 
 
 
Cyclea 
Open-label Treatment Period 
(Re-treatments) 
Follow-up 
Days 
D1 
D8 
(+1d) 
D15 
(±1d)/ 
EOTb 
D28 
(±1d)  
 
Study Procedure 
 
 
 
 
Abbreviated Physical Examination 
X 
 
 
 
Body Weight 
 
 
X 
 
Clinical Laboratory Assessmentsc 
X 
X 
X 
 
Drug & Alcohol Screend 
X 
X 
X 
 
Pregnancy Teste 
X 
 
X 
 
Vital Signsg 
X 
X 
X 
X 
12-Lead ECGh 
X 
 
X 
 
C-SSRSi 
X 
X 
X 
X 
MADRS 
X 
 
 
 
HAM-D j,k 
X 
X 
X 
X 
CGI-S 
X 
X 
X 
X 
CGI-I 
 
X 
X 
X 
PHQ-9 
X 
X 
X 
X 
Investigational Product 
Dispensation 
X 
X 
 
 
Investigational Product 
Administration 
X (Day 1 through Day 14) 
 
Investigational Product 
Accountability/Return 
 
X 
X 
 
Adverse Events/SAEsl 
X 
Prior/Concomitant Medicationsm 
X 
CGI-I = Clinical Global Impression – Improvement; CGI-S – Clinical Global Impression – Severity; C-SSRS = 
Columbia Suicide Severity Rating Scale; D = day; ET = early termination; ECG = electrocardiogram; EOT = 
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end of treatment; FSH = follicle stimulating hormone; HAM-D = Hamilton Rating Scale for Depression, 17-
item; HIV = human immunodeficiency virus; MADRS = Montgomery-Åsberg Depression Rating Scale; O = 
Optional; PHQ-9 = 9-item Patient Health Questionnaire; 
 SAE = serious 
adverse event; 
 wt = weight 
a Each cycle is 28 days (±1 day) and is comprised of a 14-day treatment period and a 14-day follow-up period. 
Rollover participants may be eligible for re-treatment beginning on Day 1 of Cycle 2; any subsequent re-
treatments will be numbered sequentially. 
b Participants who discontinue treatment early should return to the site for an end of treatment (EOT) visit as 
soon as possible, preferably the day after treatment is discontinued. The follow-up visit should occur 14 days 
after the last dose of treatment. Participants who discontinue treatment due to tolerability should be followed 
without any further administration of study drug in any subsequent cycle. If at any time after the EOT visit, a 
participant decides to terminate the study, the participant should return for an early termination (ET) visit. The 
EOT and ET visits can be on the same day if a participant discontinues study drug and terminates the study on 
the same day during a clinic visit; in this case, all events scheduled for the EOT visit will be conducted. 
c Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. 
d Urine toxicology for selected drugs of abuse (as per the laboratory manual) and breath test for alcohol. 
e Urine pregnancy test.  
g Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and 
standing). Heart rate and blood pressure to be collected in supine position at all scheduled time points after the 
participant has been resting for 5 minutes and then after approximately 3 minutes in the standing position. 
Vital signs may be repeated at the discretion of the Investigator as clinically indicated. When vital signs are 
scheduled at the same time as blood draws, vital signs should be obtained first.  
h Triplicate ECGs will be collected. When ECG and blood draws are scheduled at the same time, ECG should 
be performed before blood draws.  
i The “Since Last Visit” C-SSRS form will be completed at any time of day. 
j The HAM-D is to be completed as early during the visit as possible. 
k The assessment timeframe for the HAM-D scale will refer to the past 7 days (1 week). 
l Adverse events will be collected starting at the time of informed consent and throughout the duration of the 
participant’s participation in the study. 
m  Concomitant medications will be collected during in-clinic visits. 
 
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10.3. 
Appendix C: Handling of Missing Dates 
Dates missing the day or both the day and month of the year will adhere to the following 
conventions in order to classify TEAEs and to classify prior and concomitant medications.  
In general, listings will present the actual partial or missing values rather than the imputed 
values that may be used in derivation. In instances where imputed values will be presented, 
imputed values will be flagged.  
Adverse Events 
If the AE start date is completely missing, do not impute a date but consider it as TEAE, 
unless the AE end date is before the initiation of treatment, in which case the AE will be 
considered prior. 
For partial AE start dates: 
 When the year is known, but the month and day is unknown, then: 
 If the year matches the year of first dose date and the end date (if present) is 
after first dose date, or AE is ongoing, then impute the month as the month of 
the first dose date, and day as the day of the first dose date + 1 day. 
 If the year of AE onset < year of the first dose of treatment within this 
protocol, then the month and day will be set to December 31st.  
 If the year of AE onset > the year of initiation of treatment, then the month 
and day will be set to January 1st. 
 If the year and month are known, but the day is unknown, then: 
 If the year of AE onset = the year of initiation of the treatment and: 
 
the month of AE onset = the month of initiation of the treatment, then the day 
will be set to the day of first dose day + 1 day. 
 
the month of AE onset < the month of initiation of the treatment, then the day 
will be set to the last day of month. 
 
if the month of AE onset > the month of initiation of the treatment, then the 
day will be set to the 1st day of month. 
 If the year of AE onset < the year of initiation of the treatment, then the day 
will be set to the last day of month. 
 If the year of AE onset > the year of initiation of the treatment, then the day 
will be set to the 1st day of month. 
 
If the imputed AE onset date is after the AE stop date, then the onset date 
will be set to the stop date. 
 When the year and day are present and the month is missing, treat it as if the day 
is missing, and only year is present.  Follow the imputation rules for “year is 
known, but the month and day is unknown”. 
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 When the year is missing, but the month and/or day is known, treat this date as 
missing; do not impute. 
Prior and Concomitant Medications 
If the medication start date is completely missing, do not impute a date but consider it as a 
concomitant medication, unless the conmed end date is before the initiation of treatment, in 
which case the conmed will be considered prior. 
For the partial start date of medication: 
 If the year is present and the month and day are missing, then the month and 
day will be set to January 1. 
 If the year and day are present and the month is missing, then treat it as if the 
day is also missing.  Set the month and day to be January 1. 
 If the year and month are present and the day is missing, then the day will be 
set to the 1st day of month. 
 If the imputed start date of medication is after the non-imputed end date of 
medication, then the start date will be set to the end date of medication. 
For the partial end date of medication: 
 If the year is present and the month and day are missing, then the month and 
day will be set to December 31. 
 If the year and day are present and the month is missing, then treat it as if the 
day is also missing.  Set the month and day to be December 31. 
 If the year and month are present and the day is missing, then the day will be 
set to the last day of the month. 
Dates in Disease History (Dates of diagnosis, current episode, first episode) 
 If the year is present and the month and day are missing, then the month and 
day will be set to January 1. 
 If the year and day are present and the month is missing, then treat it as if the 
day is also missing.  Set the month and day to be January 1. 
 If the year and month are present and the day is missing, then the day will be 
set to the 1st day of month. 
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10.4. 
Appendix D: Algorithms 
Defining Analysis Datasets 
Period-specific Safety Set: Participants who had Treatment Period X start date non-missing 
Full Analysis Set for Period X: Participants who are in the Safety Set for period X and have 
at least one post-baseline HAM-D total score available for study period X 
Adverse Event Periods 
Refer to Section 7.4.1 for the definition of TEAE and observation Period 0 AE derivation. 
Treatment Period AE in Study Period X: AE onset date/time on or after Treatment Cycle X 
start date/time and on or before last dose date + 1 day in Treatment Cycle X (Note that time 
does not matter for the end of this period.) 
Follow-up Period AE in Study Period X: AE onset date after last dose date +1 day and on or 
before last dose date + 14 days in Treatment Cycle X (Typically, Day 16 through Day 28 – 
time does not matter) 
Observation Period AE in Study Period X: AE onset date after last dose date + 14 days in 
Study Period X and before Study Period X+1 start date/time 
Treatment Cycle period AE in Study Period X: All AEs that are flagged as either Treatment 
Period or Follow-up Period AE in Study Period X 
If an AE start date is the same as start of Treatment Cycle X, but time is missing in AE start 
or treatment start, then AE is considered in Cycle X.   
Concomitant Medication Periods 
Prior: Medications with start date before first treatment cycle start date/time within this 
protocol 
On-treatment in Study Period X: Medication start date on or after Treatment Cycle X start 
date and on or before the last dose date in Treatment Cycle X, OR Conmed start date before 
Treatment Cycle X start date and conmed end date either missing or on or after the Treatment 
Cycle X start date 
Post-treatment in Study Period X: Conmed start date after last dose date in Treatment Cycle 
X and before the Treatment Cycle X+1 start date 
Concomitant in Study Period X: All Conmeds that are flagged as either on-treatment or post-
treatment in Study Period X 
[Note this is determined for period-specific baseline Antidepressant, Anxiolytic and Anti-
insomnia medications for each period.] 
If the end date of a period is the same as the start date of the next period, and 
a.
the medication start date falls on this date, then consider the medication as
occurring in the next period.
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b.  the medication end date falls on this date, then consider the medication 
concomitant in the next period in addition to being concomitant in the current 
period. 
Censoring for Time-To-Event Analysis 
For any time-to-event analysis, define time to event and include a flag (1/0) to identify 
censored observations 
For any time-to-event analysis with any snap shot of database – interim or final, each 
participant must have a non-missing time to event and a non-missing censor value.  Time is 
calculated in days with no respect to time component.  Censoring rules are provided below 
for each specific time-to-event analysis. 
If a participant has no assessment after the date of last dose in Treatment Cycle 1, the 
participant will be included and censored at Day 1.  
These general rules will apply in all cases, except for time to relapse and durability of 
investigational product effect in each study period.  Time to relapse and durability of 
investigational product effect for Study Period X will be computed and summarized only for 
those participants who are HAM-D responders at Day 15 in Study Period X and who have at 
least one HAM-D (for time to relapse and durability of investigational product effect by 
HAM-D) or at least one PHQ-9 (
) 
after the Day 15 date. 
Time to first retreatment: Ref Date – Date of last dose date in Treatment Cycle 1 +1, where  
Ref Date = Date of first dose in Treatment Cycle 2 (CENSOR = 0), OR 
= Date of Study Discontinuation or Completion if the participant has Study Conclusion page 
filled in and Treatment Cycle 2 dosing did not occur (CENSOR=1)  
Note:  For SAGE-217 + ADT participants from the parent study, Date of last dose date in 
Treatment Cycle 1 is the last dose of in parent study.  
Time to first treatment within this protocol: Ref Date – Date of last dose of blinded IP in 
the parent study (or Date of ICF – see Section 7.3 for relevant analysis) + 1, where  
Ref Date = Date of first dose within this protocol (CENSOR = 0), OR 
= Date of Study Discontinuation or Completion if the participant has Study Conclusion page 
filled in and SAGE-217 dosing within this protocol did not occur (CENSOR=1)  
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Time to first new anxiolytic use within this protocol: Ref Date – Date of ICF in this 
protocol + 1, where  
Ref Date = Date of first new anxiolytic start within this protocol (CENSOR = 0) [new is 
determined by a different code of anxiolytic with start date after the ICF date which was not 
being used at the date of ICF], OR 
= Date of Study Discontinuation or Completion if the participant has Study Conclusion page 
filled in and new ADT has not been started after ICF date (CENSOR=1)  
Time to first new anti-insomnia use within this protocol: Ref Date – Date of ICF in this 
protocol + 1, where  
Ref Date = Date of first new anti-insomnia start within this protocol (CENSOR = 0) [new is 
determined by a different code of anti-insomnia with start date after the ICF date which was 
not being used at the date of ICF], OR 
= Date of Study Discontinuation or Completion if the participant has Study Conclusion page 
filled in and new ADT has not been started after ICF date (CENSOR=1)  
Time to relapse in Study Period X: (Ref Date – Date of Day 15 visit in Study Period X) + 
1, where Ref Date  
= Date of first relapse in Study Period X where relapse is defined as a participant having a 
HAM-D total score after Day 15 where HAM-D total score ≥20 and there exists a PHQ-9 
≥10 within 10 days prior to this HAM-D (CENSOR = 0) 
= Date of the latest HAM-D evaluation before the first dose in Study Period X+1 if it exists 
(CENSOR = 1) 
= Date of the last HAM-D evaluation in the study if there is no further treatment cycle for the 
participant (CENSOR = 1) 
Durability of investigational product effect by HAM-D in Study Period X: (Ref Date – 
Date of Day 15 visit in Study Period X) + 1, where Ref Date  
= First date after Day 15 within Study Period X when the reduction in HAM-D total score 
from the period-specific baseline is less than 50% (CENSOR = 0) 
or, for participants without any HAM-D showing less than 50% reduction in HAM-D total 
score from the period-specific baseline after Day 15 in the Study Period X 
= Date of the latest HAM-D evaluation after Day 15 within Study Period X and before the 
first dose in Study Period X+1 if it exists (CENSOR = 1)  
= Date of the last HAM-D evaluation after Day 15 within Study Period X and in the study if 
there is no further treatment cycle for the participant (CENSOR = 1) 
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Study discontinuation/completion date: 
Study discontinuation/completion date is defined from the study conclusion page from the 
same variable, except when the participant is discontinued for the reason of Lost-to-follow-
up, in which case the date of discontinuation is defined as the date of last contact from the 
study conclusion page. 
Calcultion of Month: 
 a year is counted as 365.2425 days 
 a month is counted as 365.2425/12 = 30.436875 days 
“<3 months” = “Study Day 91 or less” 
“>=3 months and <6 months” = “Study Day >=92 and , <=182” 
“>=6 months and <9 months” = “Study Day >=183, <=273” 
“>= 9 months” = “Study Day >=274” 
where Start Day is calculated as: End Date-Start Date +1 
Derivation of PCS for liver function test based on combination results of Total 
Bilirubin, Alkaline Phosphatase, Alanine Aminotransferase or Aspartate 
Aminotransferase:  
 [(Total Bilirubin >2xULN) AND Alkaline Phosphatase <2xULN (any time post-
baseline, measured at the same time point of assessment)] AND [(ALT or AST 
>3xULN) AND Alkaline Phosphatase <2xULN, any time post-baseline, measured at 
the same time point of assessment] 
In order to derive the records which met the above criteria, the participants should meet both 
of the following 2 criteria: 
1. Total Bilirubin >2xULN AND Alkaline Phosphatase <2xULN (any time post-
baseline, measured at the same time point of assessment) 
2. (ALT or AST >3xULN) AND Alkaline Phosphatase <2xULN (any time post-
baseline, measured at the same time point of assessment) 
Time point of assessments in Criterion 1 and Criterion 2 do not have to be the same. 
However, in order to summarize by the time frame (for example, any time in the treatment 
period, the last value during the treatment period, etc.), the time point in both criteria should 
fall into the same time frame.  Note that the above PCS criterion cannot be evaluated for last 
value on treatment unless both condition happens to be satisfied on the last assessment.  
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Appendix E: List of Displays 
Index of Tables 
Table Number 
Title 
Analysis Set 
Table 14.1.1.1  
Summary of Participant Disposition 
Enrolled Set 
Table 14.1.1.2 
Summary of Analysis Sets 
Enrolled Set 
Table 14.1.1.3 
Summary of Participant Disposition by Study 
Period 
Period-Specific Safety Set 
Table 14.1.1.4 
Summary of Study Participation 
Safety Set 
Table 14.1.1.5 
Summary of Participant Progression by Interval 
of Time since the First Dose in Parent study 
Safety Set  
Table 14.1.1.6 
Summary of the Latest Severity of Depression by 
Study Completion Status 
Full Analysis Set  
Table 14.1.1.6.1 
Summary of the Latest Severity of Depression by 
Study Completion Status 
Enrolled Set 
Table 14.1.1.7 
Summary of Participant Progression 
Enrolled Set  
Table 14.1.1.8 
Reaching Threshold of Retreatment 
Full Analysis Set 
Table 14.1.2.1 
Summary of Major Protocol Deviations 
Full Analysis Set 
Table 14.1.2.2 
Summary of Major Protocol Deviations 
Enrolled Set 
Table 14.1.3.1 
Summary of Demographics and Baseline 
Characteristics 
Safety Set  
Table 14.1.3.2 
Summary of Demographics and Baseline 
Characteristics 
Full Analysis Set  
Table 14.1.3.3 
Summary of Demographics and Baseline 
Characteristics 
Enrolled Set 
Table 14.1.3.4 
Summary of Baseline Subgroups 
Safety Set  
Table 14.1.3.5 
Summary of Baseline Subgroups 
Full Analysis Set  
Table 14.1.3.6 
Summary of Baseline Subgroups 
Enrolled Set 
Table 14.1.4.1 
Summary of Interim Medical and Surgical 
History 
Safety Set  
Table 14.1.4.1.1 
Summary of Medical and Surgical History at 
Screening in Parent Study 
Safety Set   
Table 14.1.4.1.2 
Summary of Disease History at Screening in 
Parent Study 
Safety Set 
Table 14.1.4.2 
Summary of Participant History of Psychiatric 
Disorder 
Safety Set 
Table 14.1.4.3 
Summary of Family History of Psychiatric 
Disorder 
Safety Set 
Table 14.1.5.1 
Summary of Prior Non-Psychotropic Medications  Study-specific Safety Set 
Table 14.1.5.2 
Summary of Concomitant Non-Psychotropic 
Medications  
Study-specific Safety Set 
Table 14.1.5.3 
Summary of Concomitant Non-Psychotropic 
Medications by Study Period 
Period-Specific Safety Set 
Table 14.1.5.4 
Summary of On-treatment Non-Psychotropic 
Medications by Study Period  
Period-specific Safety Set 
Table 14.1.5.5 
Summary of Post-treatment Non-Psychotropic 
Medications by Study Period  
Period-specific Safety Set 
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Table 14.1.5.6 
Summary of Prior Psychotropic Medications  
Study-specific Safety Set 
Table 14.1.5.7 
Summary of Concomitant Psychotropic 
Medications  
Study-specific Safety Set 
Table 14.1.5.8 
Summary of Concomitant Psychotropic 
Medications by Study Period 
Period-specific Safety Set 
Table 14.1.5.9 
Summary of On-treatment Psychotropic 
Medications by Study Period 
Period-specific Safety Set 
Table 14.1.5.10 
Summary of Post-treatment Psychotropic 
Medications by Study Period 
Period-specific Safety Set 
Table 14.1.6.1 
Summary of Concomitant Antidepressant 
Medication Use by Study Period  
Period-specific Safety Set  
Table 14.1.6.2 
Summary of Concomitant Anti-Insomnia 
Medication Use by Study Period  
Period-specific Safety Set  
Table 14.1.6.3 
Summary of Concomitant Anxiolytic Medication 
Use by Study Period  
Period-specific Safety Set  
Table 14.1.7.1 
Summary of SAGE-217 Exposure by Study 
Period  
Period-specific Safety Set 
Table 14.1.7.2 
Summary of SAGE-217 Adherence by Study 
Period 
Full Analysis Set 
Table 14.2.1.1 
Summary of Treatment Within This Protocol 
Full Analysis Set  
Table 14.2.1.2.1 
Summary of Time to First Treatment within the 
Protocol since ICF, by Treatment Group in Parent 
Study 
Enrolled Set 
Table 14.2.1.2.2 
Summary of Time to First Treatment within the 
Protocol since Last Dose of Blinded IP in Parent 
Study, by Treatment Group in Parent Study 
Safety Set 
Table 14.2.1.3 
Summary of Retreatment of SAGE-217 Within 
This Protocol 
Full Analysis Set  
Table 14.2.1.4 
Summary of Time to First Retreatment within the 
Protocol, by Treatment Group in Parent Study 
Study-specific Safety Set 
Table 14.2.2.1 
Summary of Hamilton Rating Scale for 
Depression (HAM-D) Total Score by Study 
Period 
Full Analysis Set 
Table 14.2.2.2 
Summary of Hamilton Rating Scale for 
Depression (HAM-D) Subscale Scores by Study 
Period 
Full Analysis Set 
Table 14.2.2.3 
Summary of Hamilton Rating Scale for 
Depression (HAM-D) Individual Item Scores by 
Study Period 
Full Analysis Set 
Table 14.2.3.1 
Summary of Hamilton Rating Scale for 
Depression (HAM-D) Response by Study Period  
Full Analysis Set 
Table 14.2.3.2 
Sensitivity Analysis: Summary of Hamilton 
Rating Scale for Depression (HAM-D) Response 
by Study Period  
Full Analysis Set 
Table 14.2.4.1 
Summary of Hamilton Rating Scale for 
Depression (HAM-D) Remission by Study Period  
Full Analysis Set 
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Table 14.2.4.2 
Sensitivity Analysis: Summary of Hamilton 
Rating Scale for Depression (HAM-D) Remission 
by Study Period  
Full Analysis Set 
Table 14.2.5.1 
Summary of Hamilton Rating Scale for 
Depression (HAM-D) Total Score by Study 
Period and Sex 
Full Analysis Set 
Table 14.2.5.2 
Summary of Hamilton Rating Scale for 
Depression (HAM-D) Total Score by Study 
Period and Race 
Full Analysis Set 
Table 14.2.5.3 
Summary of Hamilton Rating Scale for 
Depression (HAM-D) Total Score by Study 
Period and Age 
Full Analysis Set 
Table 14.2.5.4 
Summary of Hamilton Rating Scale for 
Depression (HAM-D) Total Score by Study 
Period and Depression with Elevated Anxiety, as 
Measured by HAM-D Anxiety Subscale Score at 
Baseline in Parent Study  
Full Analysis Set 
Table 14.2.5.5 
Summary of Hamilton Rating Scale for 
Depression (HAM-D) Total Score by Study 
Period and Depression with Elevated Anxiety, as 
Measured by HAM-A Total Score at Baseline in 
Parent Study 
Full Analysis Set 
Table 14.2.5.6 
Summary of Hamilton Rating Scale for 
Depression (HAM-D) Total Score by Study 
Period and BMI at Baseline in Parent Study 
Full Analysis Set 
Table 14.2.6.1 
Summary of Durability of SAGE-217 Effect, 
Measured by HAM-D, by Study Period 
Full Analysis Set – HAM-
D Responders at Day 15 in 
Cycle X 
Table 14.2.6.3 
Summary of Time to Relapse, by Study Period 
Full Analysis Set – 
Responders Only 
Table 14.2.7.1 
Summary of Clinical Global Impression – 
Improvement (CGI-I) by Study Period  
Full Analysis Set 
Table 14.2.7.2 
Summary of Clinical Global Impression – 
Improvement (CGI-I) Response by Study Period  
Full Analysis Set 
Table 14.2.7.3 
Sensitivity Analysis: Summary of Clinical Global 
Impression - Improvement (CGI-I) Response by 
Study Period 
Full Analysis Set 
Table 14.2.8.1 
Summary of Clinical Global Impression – 
Severity (CGI-S) by Study Period  
Full Analysis Set 
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Table 14.3.1.1.1 
Overview of Treatment-Emergent Adverse 
Events 
Safety Set  
Table 14.3.1.1.2 
Overview of Treatment-Emergent Adverse 
Events 
Study-specific Safety Set 
Table 14.3.1.2 
Overview of Treatment-Emergent Adverse 
Events by Study Period 
Safety Set 
Table 14.3.2.1.1 
Summary of Treatment Emergent Adverse Events 
by System Organ Class and Preferred Term 
Safety Set  
Table 14.3.2.1.2 
Summary of Treatment-Emergent Adverse 
Events by System Organ Class and Preferred 
Term 
Study-specific Safety Set 
Table 14.3.2.1.3 
Summary of Treatment Cycle Period Treatment-
Emergent Adverse Events by System Organ 
Class and Preferred Term 
Study-specific Safety Set 
Table 14.3.2.1.4 
Summary of Treatment Period Treatment-
Emergent Adverse Events by System Organ 
Class and Preferred Term 
Study-specific Safety Set 
Table 14.3.2.1.5 
Summary of Follow-up Period Treatment-
Emergent Adverse Events by System Organ 
Class and Preferred Term 
Study-specific Safety Set 
Table 14.3.2.1.6 
Summary of Observation Period Treatment-
Emergent Adverse Events by System Organ 
Class and Preferred Term 
Study-specific Safety Set 
Table 14.3.2.2 
Summary of Treatment Emergent Adverse Events 
by System Organ Class and Preferred Term by 
Study Period 
Safety Set  
Table 14.3.2.3 
Summary of Treatment Cycle Period Treatment 
Emergent Adverse Events by System Organ 
Class and Preferred Term by Study Period 
Period-specific Safety Set 
Table 14.3.2.4 
Summary of Treatment Period Treatment 
Emergent Adverse Events by System Organ 
Class and Preferred Term by Study Period 
Period-specific Safety Set 
Table 14.3.2.5 
Summary of Follow Up Period Treatment-
Emergent Adverse Events by System Organ 
Class and Preferred Term by Study Period 
Period-specific Safety Set  
Table 14.3.2.6 
Summary of Observation Period Treatment-
Emergent Adverse Events by System Organ 
Class and Preferred Term by Study Period 
Period-specific Safety Set  
Table 14.3.3.1.1 
Summary of Treatment Emergent Adverse Events 
by System Organ Class, Preferred Term, and 
Maximum Severity 
Safety Set 
Table 14.3.3.1.2 
Summary of Treatment-Emergent Adverse 
Events by System Organ Class, Preferred Term, 
and Maximum Severity 
Study-specific Safety Set 
Table 14.3.3.2 
Summary of Treatment Cycle Period Treatment 
Emergent Adverse Events by System Organ 
Class, Preferred Term and Maximum Severity by 
Study Period 
Period-specific Safety Set  
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Table 14.3.3.3 
Summary of Treatment Period Treatment 
Emergent Adverse Events by System Organ 
Class, Preferred Term and Maximum Severity by 
Study Period 
Period-specific Safety Set 
Table 14.3.3.4 
Summary of Follow-up Period Treatment 
Emergent Adverse Events by System Organ 
Class, Preferred Term and Maximum Severity by 
Study Period 
Period-specific Safety Set 
Table 14.3.3.5 
Summary of Observation Period Treatment 
Emergent Adverse Events by System Organ 
Class, Preferred Term and Maximum Severity by 
Study Period 
Period-specific Safety Set 
Table 14.3.4.1 
Summary of Treatment Emergent Adverse Events 
by System Organ Class, Preferred Term, and 
Relationship to SAGE-217 
Study-specific Safety Set 
Table 14.3.4.2 
Summary of Treatment Cycle Period Treatment 
Emergent Adverse Events by System Organ 
Class, Preferred Term and Relationship to SAGE-
217 by Study Period  
Period-specific Safety Set  
Table 14.3.4.3 
Summary of Treatment Period Treatment 
Emergent Adverse Events by System Organ 
Class, Preferred Term and Relationship to SAGE-
217 by Study Period 
Period-specific Safety Set  
Table 14.3.4.4 
Summary of Follow-up Period Treatment 
Emergent Adverse Events by System Organ 
Class, Preferred Term and Relationship to SAGE-
217 by Study Period 
Period-specific Safety Set  
Table 14.3.4.5 
Summary of Observation Period Treatment 
Emergent Adverse Events by System Organ 
Class, Preferred Term and Relationship to SAGE-
217 by Study Period 
Period-specific Safety Set  
Table 14.3.5.1 
Summary of Treatment Emergent Adverse Events 
Leading to Discontinuation of SAGE-217 by 
System Organ Class and Preferred Term 
Study-specific Safety Set 
Table 14.3.5.2 
Summary of Treatment Period Treatment 
Emergent Adverse Events Leading to 
Discontinuation of SAGE-217 by System Organ 
Class and Preferred Term by Study Period 
Period-specific Safety Set 
Table 14.3.6.1 
Summary of Treatment Period Treatment 
Emergent Adverse Events Leading to Dose 
Reduction of SAGE-217 by System Organ Class 
and Preferred Term  
Study Specific Safety Set  
Table 14.3.6.2 
Summary of Treatment Period Treatment 
Emergent Adverse Events Leading to Dose 
Reduction of SAGE-217 by System Organ Class 
and Preferred Term by Study Period 
Period-specific Safety Set  
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Table 14.3.7.1 
Summary of Treatment Emergent Adverse Events 
Leading to Study Withdrawal by System Organ 
Class and Preferred Term 
Study-specific Safety Set  
Table 14.3.7.2 
Summary of Treatment Emergent Adverse Events 
Leading to Study Withdrawal by System Organ 
Class and Preferred Term by Study Period 
Safety Set 
Table 14.3.7.3 
Summary of Treatment Cycle Period Treatment 
Emergent Adverse Events Leading to Study 
Withdrawal by System Organ Class and Preferred 
Term by Study Period 
Period-specific Safety Set  
Table 14.3.7.4 
Summary of Treatment Period Treatment 
Emergent Adverse Events Leading to Study 
Withdrawal by System Organ Class and Preferred 
Term by Study Period 
Period-specific Safety Set  
Table 14.3.7.5 
Summary of Follow-up Period Treatment 
Emergent Adverse Events Leading to Study 
Withdrawal by System Organ Class and Preferred 
Term by Study Period 
Period-specific Safety Set  
Table 14.3.8.1.1 
Summary of Treatment Emergent Serious 
Adverse Events by System Organ Class and 
Preferred Term 
Safety Set  
Table 14.3.8.1.2 
Summary of Treatment-Emergent Serious 
Adverse Events by System Organ Class and 
Preferred Term 
Study-specific Safety Set 
Table 14.3.8.1.3 
Summary of Treatment Cycle Period Treatment 
Emergent Serious Adverse Events by System 
Organ Class and Preferred Term 
Study-specific Safety Set  
Table 14.3.8.1.4 
Summary of Treatment Period Treatment 
Emergent Serious Adverse Events by System 
Organ Class and Preferred Term 
Study-specific Safety Set  
Table 14.3.8.1.5 
Summary of Follow-up Period Treatment 
Emergent Serious Adverse Events by System 
Organ Class and Preferred Term 
Study-specific Safety Set  
Table 14.3.8.1.6 
Summary of Observation Period Treatment 
Emergent Serious Adverse Events by System 
Organ Class and Preferred Term 
Study-specific Safety Set  
Table 14.3.8.2 
Summary of Treatment Emergent Serious 
Adverse Events by System Organ Class and 
Preferred Term by Study Period 
Safety Set  
Table 14.3.8.3 
Summary of Treatment Cycle Period Treatment 
Emergent Serious Adverse Events by System 
Organ Class and Preferred Term by Study Period 
Period-specific Safety Set  
Table 14.3.8.4 
Summary of Treatment Period Treatment 
Emergent Serious Adverse Events by System 
Organ Class and Preferred Term by Study Period 
Period-specific Safety Set  
Table 14.3.8.5 
Summary of Follow-up Period Treatment 
Emergent Serious Adverse Events by System 
Organ Class and Preferred Term by Study Period 
Period-specific Safety Set  
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Table 14.3.8.6 
Summary of Observation Period Treatment 
Emergent Serious Adverse Events by System 
Organ Class and Preferred Term by Study Period 
Period-specific Safety Set  
Table 14.3.8.7 
Summary of Treatment Emergent Serious 
Adverse Events by System Organ Class, 
Preferred Term, and Relationship to SAGE-217  
Study-specific Safety Set 
Table 14.3.8.8 
Summary of Treatment Emergent Serious 
Adverse Events by System Organ Class, 
Preferred Term, and Relationship to SAGE-217 
by Study Period 
Period-specific Safety Set 
Table 14.3.9.1.1 
Summary of Most Common (>2%) Treatment 
Emergent Adverse Events by Preferred Term 
Safety Set  
Table 14.3.9.1.2 
Summary of Most Common (>2%) Treatment-
Emergent Adverse Events by Preferred Term 
Study-specific Safety Set 
Table 14.3.9.2 
Summary of Most Common (>2%) Treatment 
Emergent Adverse Events by Preferred Term by 
Study Period 
Safety Set  
Table 14.3.9.3 
Summary of Treatment Cycle Period Most 
Common (>2%) Treatment Emergent Adverse 
Events by Preferred Term 
Study-specific Safety Set  
Table 14.3.9.4 
Summary of Most Common (>2%) Treatment 
Cycle Period Treatment Emergent Adverse 
Events by Preferred Term by Study Period 
Period-specific Safety Set 
Table 14.3.10.1 
Summary of Treatment Cycle Period Treatment 
Emergent Adverse Events by System Organ 
Class, Preferred Term and Age Group by Study 
Period  
Period-specific Safety Set  
Table 14.3.10.2 
Summary of Treatment Cycle Period Treatment 
Emergent Adverse Events by System Organ 
Class, Preferred Term and Sex by Study Period  
Period-specific Safety Set  
Table 14.3.10.3 
Summary of Treatment Cycle Period Treatment 
Emergent Adverse Events by System Organ 
Class, Preferred Term and Race Group by Study 
Period  
Period-specific Safety Set  
Table 14.3.10.4 
Summary of Treatment Cycle Period Treatment 
Emergent Adverse Events by System Organ 
Class, Preferred Term and Depression with 
Elevated Anxiety, as Measured by HAM-D 
Anxiety Subscale Score at Baseline in Parent 
Study, by Study Period 
Period-specific Safety Set 
Table 14.3.10.5 
Summary of Treatment Cycle Period Treatment 
Emergent Adverse Events by System Organ 
Class, Preferred Term and Depression with 
Elevated Anxiety, as Measured by HAM-A Total 
Score at Baseline in Parent Study, by Study 
Period 
 
Period-specific Safety Set  
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Table 14.3.10.6 
Summary of Treatment Cycle Period Treatment 
Emergent Adverse Events by System Organ 
Class, Preferred Term and BMI Group at 
Baseline in Parent Study, by Study Period 
Period-specific Safety Set  
Table 14.3.11.1 
Summary of Serum Chemistry Results by Study 
Period and Study Visit 
Period-specific Safety Set 
Table 14.3.11.2 
Summary of Shift in Serum Chemistry Results 
during the Study by Study Period and Study Visit 
Period-specific Safety Set  
Table 14.3.11.3 
Summary of Potentially Clinically Significant 
Liver Function Tests by Study Period 
Period-specific Safety Set  
Table 14.3.11.4 
Summary of Potentially Clinically Significant 
Serum Chemistry (excluding LFT) Results by 
Study Period 
Period-specific Safety Set  
Table 14.3.12.1 
Summary of Hematology Results by Study 
Period and Study Visit 
Period-specific Safety Set 
Table 14.3.12.2 
Summary of Shift in Hematology Results during 
the Study by Study Period and Study Visit 
Period-specific Safety Set  
Table 14.3.12.3 
Summary of Potentially Clinically Significant 
Hematology Results by Study Period 
Period-specific Safety Set  
Table 14.3.13.1 
Summary of Urinalysis Results by Study Period 
and Study Visit – Quantitative Results 
Period-specific Safety Set  
Table 14.3.13.2 
Summary of Urinalysis Results by Study Period 
and Study Visit – Qualitative Results  
Period-specific Safety Set  
Table 14.3.14.1 
Summary of Coagulation Results by Study Period 
and Study Visit  
Period-specific Safety Set 
Table 14.3.15.1 
Summary of Vital Signs by Study Period and 
Study Visit 
Period-specific Safety Set 
Table 14.3.15.2 
Summary of Potentially Clinically Significant 
Vital Signs by Study Period 
Period-specific Safety Set 
Table 14.3.15.3 
Summary of Orthostatic Vital Signs (Supine – 
Standing) by Study Period and Study Visit 
Period-specific Safety Set 
Table 14.3.16.1 
Summary of ECG Data by Study Period and 
Study Visit 
Period-specific Safety Set 
Table 14.3.16.2 
Summary of Abnormal ECG per Investigator 
Assessment by Study Period and Study Visit 
Period-specific Safety Set 
Table 14.3.16.3 
Summary of Potentially Clinically Significant 
QTcF in ECG Data by Study Period 
Period-specific Safety Set 
Table 14.3.17.1 
Summary of Shift from Baseline in Columbia 
Suicide Severity Rating Scale (C-SSRS) Suicidal 
Ideation and Suicidal Behavior Data by Study 
Period and Study Visit 
Period-specific Safety Set 
Table 14.3.17.2 
Summary of Columbia-Suicide Severity Rating 
Scale (C-SSRS) on Suicidal Ideation and Suicidal 
Behavior Data by Study Period 
Period-specific Safety Set 
Table 14.3.17.3 
Summary of Shift from Baseline in C-SSRS 
Maximum Severity Score in Suicidal Ideation at 
Any Time Post-Baseline by Study Period 
Period-specific Safety Set 
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Index of Figures 
Figure Number 
Title 
Analysis Set 
Figure 14.2.1.1.1 
Kaplan-Meier Plot of Time to First Retreatment 
(Days) 
Study-specific Safety Set 
Figure 14.2.1.1.2 
Kaplan-Meier Plot of Time to First Retreatment 
(Days) 
Safety Set 
Figure 14.2.1.2 
Kaplan-Meier Plot of Time to First Treatment in 
this Protocol Since ICF (Days) 
Enrolled Set 
Figure 14.2.1.3 
Kaplan-Meier Plot of Time to First Treatment in 
this Protocol Since Last Dose of Blinded 
Investigational Product in Parent Study (Days) 
Enrolled Set 
Figure 14.2.1.4 
Kaplan-Meier Plot of Time to First Treatment in 
this Protocol Since Last Dose of Blinded 
Investigational Product in Parent Study (Days) 
by Assigned ADT at Baseline of Parent Study 
Enrolled Set 
Figure 14.2.2.1 
Line Plot of Mean (±SD) Change from Period-
Specific Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score over Time by 
Study Period 
Full Analysis Set 
Figure 14.2.2.2 
Line Plot of Mean (±SD) Percent Change from 
Period-Specific Baseline in Hamilton Rating 
Scale for Depression (HAM-D) Total Score over 
Time by Study Period 
Full Analysis Set 
Figure 14.2.2.3.1 
Bar Chart of Hamilton Rating Scale for 
Depression (HAM-D) Response over Time, by 
Study Period 
Full Analysis Set 
Figure 14.2.2.3.2 
Sensitivity Analysis: Bar Chart of Hamilton 
Rating Scale for Depression (HAM-D) Response 
over Time, by Study Period 
Full Analysis Set 
Figure 14.2.2.4.1 
Bar Chart of Hamilton Rating Scale for 
Depression (HAM-D) Remission over Time, by 
Study Period 
Full Analysis Set 
Figure 14.2.2.4.2 
Sensitivity Analysis: Bar Chart of Hamilton 
Rating Scale for Depression (HAM-D) 
Remission over Time, by Study Period 
Full Analysis Set 
Figure 14.2.3.1 
Line Plot of Mean (±SD) Change from Period-
Specific Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Core Subscale Score over 
Time by Study Period 
Full Analysis Set 
Figure 14.2.3.2 
Line Plot of Mean (±SD) Percent Change from 
Period-Specific Baseline in Hamilton Rating 
Scale for Depression (HAM-D) Core Subscale 
Score over Time by Study Period 
Full Analysis Set 
Figure 14.2.3.3 
Line Plot of Mean (±SD) Change from Period-
Specific Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Anxiety Subscale Score 
over Time by Study Period 
Full Analysis Set 
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Figure 14.2.3.4 
Line Plot of Mean (±SD) Percent Change from 
Period-Specific Baseline in Hamilton Rating 
Scale for Depression (HAM-D) Anxiety 
Subscale Score over Time by Study Period 
Full Analysis Set 
Figure 14.2.3.5 
Line Plot of Mean (±SD) Change from Period-
Specific Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Bech-6 Subscale Score 
over Time by Study Period 
Full Analysis Set 
Figure 14.2.3.6 
Line Plot of Mean (±SD) Percent Change from 
Period-Specific Baseline in Hamilton Rating 
Scale for Depression (HAM-D) Bech-6 Subscale 
Score over Time by Study Period 
Full Analysis Set 
Figure 14.2.3.7 
Line Plot of Mean (±SD) Change from Period-
Specific Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Maier Subscale Score over 
Time by Study Period 
Full Analysis Set 
Figure 14.2.3.8 
Line Plot of Mean (±SD) Percent Change from 
Period-Specific Baseline in Hamilton Rating 
Scale for Depression (HAM-D) Maier Subscale 
Score over Time by Study Period 
Full Analysis Set 
Figure 14.2.4.1 
Forest Plot of Change from Period-Specific 
Baseline at Day 15 in Hamilton Rating Scale for 
Depression (HAM-D) Total Score for Subgroups 
by Study Period 
Full Analysis Set  
Figure 14.2.4.2 
Forest Plot of Change from Period-Specific 
Baseline at Day 15 in Hamilton Rating Scale for 
Depression (HAM-D) Subscale Scores by Study 
Period 
Full Analysis Set  
Figure 14.2.5.1 
Line Plot of Mean (±SD) Change from Period-
Specific Baseline in Clinical Global Impression – 
Severity (CGI-S) Score over Time by Study 
Period 
Full Analysis Set  
Figure 14.2.6.1 
Bar Chart of Clinical Global Impression – 
Improvement (CGI-I) Response over Time, by 
Study Period 
Full Analysis Set 
Figure 14.2.6.2 
Sensitivity Analysis: Bar Chart of Clinical 
Global Impression – Improvement (CGI-I) 
Response over Time, by Study Period 
Full Analysis Set 
Figure 14.2.8.1 
Kaplan-Meier Plot of Durability of Response, 
Measured by HAM-D (Days), by Study Period 
Full Analysis Set 
Figure 14.2.8.3 
Kaplan-Meier Plot of Time to Relapse, by Study 
Period 
Full Analysis Set - 
Responders Only 
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Figure 14.2.9.3 
Kaplan-Meier Plot of Time to First New 
Anxiolytic Use since ICF 
Enrolled Set 
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Index of Listings 
Listing Number 
Title 
Analysis Set 
Listing 16.2.1.1 
Participant Disposition 
Enrolled Set 
Listing 16.2.1.2 
Premature Withdrawal from the Study or 
Premature Discontinuation from SAGE-217 
Enrolled Set 
Listing 16.2.1.3 
Participation by Study Period  
Study-specific Safety Set 
Listing 16.2.1.4 
Participation by Treatment Cycle 
Study-specific Safety Set 
Listing 16.2.2.1 
Protocol Deviations 
Enrolled Set 
Listing 16.2.3.1 
Demographics 
Enrolled Set 
Listing 16.2.3.2 
Baseline Characteristics 
Enrolled Set 
Listing 16.2.4.1 
Interim Medical and Surgical History 
Enrolled Set 
Listing 16.2.5.1 
Medical and Surgical History from Parent Study 
Enrolled Set 
Listing 16.2.5.2 
Disease History from Parent Study 
Enrolled Set 
Listing 16.2.5.3 
Participant History of Psychiatric Disorder from 
Parent Study 
Enrolled Set 
Listing 16.2.5.4 
Family History of Psychiatric Disorder from 
Parent Study 
Enrolled Set 
Listing 16.2.6.1 
Prior and Concomitant Psychotropic Medications 
Enrolled Set 
Listing 16.2.6.2 
Prior and Concomitant Non-Psychotropic 
Medications 
Enrolled Set 
Listing 16.2.6.3 
Use of Antidepressant Medication during the 
Study 
Enrolled Set 
Listing 16.2.6.4 
Use of Anxiolytics Medication during the Study 
Enrolled Set 
Listing 16.2.6.5 
Use of Anti-Insomnia Medication during the 
Study 
Enrolled Set 
Listing 16.2.6.6 
Concomitant Procedures 
Enrolled Set 
Listing 16.2.7.1 
SAGE-217 Administration 
Safety Set 
Listing 16.2.7.2 
SAGE-217 Exposure 
Safety Set 
Listing 16.2.7.3 
SAGE-217 Adherence 
Safety Set 
Listing 16.2.8.1 
Hamilton Rating Scale for Depression (HAM-D) 
Enrolled Set 
Listing 16.2.9.1 
Clinical Global Impression (CGI) – Improvement Enrolled Set 
Listing 16.2.10.1 
Clinical Global Impression (CGI) – Severity 
Enrolled Set 
Listing 16.2.11.1 
Patient Health Questionnaire (PHQ-9) 
Enrolled Set 
Listing 16.2.14.1 
Patient Health Questionnaire (PHQ-9) and 
Hamilton Rating Scale for Depression (HAM-D) 
Leading to Re-treatment 
Enrolled Set 
Listing 16.2.15.1 
Adverse Events 
Enrolled Set 
Listing 16.2.15.2 
Non-fatal Serious Adverse Events 
Enrolled Set 
Listing 16.2.15.3 
Adverse Events Leading to Death 
Enrolled Set 
Listing 16.2.15.4 
Adverse Events with Onset Prior to First Dose of 
SAGE-217 
Enrolled Set 
Listing 16.2.15.5 
Adverse Events leading to Premature 
Discontinuation of SAGE-217 
Safety Set 
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Listing 16.2.15.6 
Adverse Events leading to Premature Withdrawal 
from the Study 
Enrolled Set 
Listing 16.2.15.7 
Adverse Events leading to Dose Reduction 
Safety Set 
Listing 16.2.16.1.1 
Serum Chemistry Data 
Enrolled Set 
Listing 16.2.16.1.2 
Serum Chemistry Data that are Potentially 
Clinically Significant 
Enrolled Set 
Listing 16.2.16.2.1 
Hematology Data 
Enrolled Set 
Listing 16.2.16.2.2 
Hematology Data that are Potentially Clinically 
Significant 
Enrolled Set 
Listing 16.2.16.3 
Urinalysis Data 
Enrolled Set 
Listing 16.2.16.4 
Coagulation Data 
Enrolled Set 
Listing 16.2.16.5 
Pregnancy Test 
Enrolled Set 
Listing 16.2.16.6 
Drug and Alcohol Screening 
Enrolled Set 
Listing 16.2.17.1.1 
Vital Signs 
Enrolled Set 
Listing 16.2.17.1.2 
Vital Signs Data that are Potentially Clinically 
Significant 
Safety Set 
Listing 16.2.18.1.1 
Electrocardiogram (ECG) Data 
Enrolled Set 
Listing 16.2.18.1.2 
Electrocardiogram (ECG) Data that are 
Potentially Clinically Significant 
Enrolled Set 
Listing 16.2.19.1.1 
Columbia-Suicide Severity Rating Scale (C-
SSRS) – Suicidal Ideation 
Enrolled Set 
Listing 16.2.19.1.2 
Columbia-Suicide Severity Rating Scale (C-
SSRS) – Suicidal Behavior 
Enrolled Set 
Listing 16.2.20.1 
Physical Examination 
Enrolled Set 
Listing 16.2.21.1 
Montgomery-Åsberg Depression Rating Scale 
(MADRS) 
Enrolled Set 
 
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Prot_000.pdf: 
COVER PAGE 
Official Title: 
A Phase 3, Open-Label, 1-Year Study of the Safety, Tolerability, and Need 
for Re-Treatment with SAGE-217 in Adult Subjects with Major Depressive 
Disorder 
NCT Number: 
 NCT03864614 
Document Date: Protocol Version 7.0: 10 May 2021 
 
 


Clinical Protocol 
 
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217-MDD-303 v7.0 
 
CONFIDENTIAL 
 
 
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A PHASE 3, OPEN-LABEL, 1-YEAR STUDY OF THE SAFETY, 
TOLERABILITY, AND NEED FOR RE-TREATMENT WITH 
SAGE-217 IN ADULT SUBJECTS WITH MAJOR DEPRESSIVE  
DISORDER 
 
PROTOCOL NUMBER: 217-MDD-303 
 
Study Drug 
SAGE-217 
Clinical Phase 
Phase 3 
Sponsor 
Sage Therapeutics, Inc. 
215 First Street 
Cambridge, MA 02142 
Sponsor Contact 
Tel:
E-mail: 
Sponsor Medical Monitor 
MD  
Tel:
E-mail:
Date of Original Protocol 
Date of Amendment 1 
Date of Amendment 2 
Date of Amendment 3 
Version 1.0, 18 October 2018 
Version 2.0, 09 January 2019 
Version 3.0, 25 April 2019 
Version 4.0, 06 February 2020 
Date of Amendment 4 
Date of Amendment 5 
Date of Amendment 6 
Version 5.0, 19 March 2020 
Version 6.0, 24 November 2020 
Version 7.0, 10 May 2021 
 
Confidentiality Statement 
The confidential information in this document is provided to you as an Investigator or consultant 
for review by you, your staff, and the applicable Institutional Review Board. Your acceptance of 
this document constitutes agreement that you will not disclose the information contained herein 
to others without written authorization from Sage Therapeutics, Inc. 
 






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INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for SAGE-217. I have read the 
217-MDD-303 clinical protocol and agree to conduct the study as outlined. I agree to maintain 
the confidentiality of all information received or developed in connection with this protocol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
Date (DD MMM YYYY) 


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


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CONFIDENTIAL 
 
 
6 
 
2. 
SYNOPSIS 
Name of Sponsor/Company: 
Sage Therapeutics, Inc. (hereafter referred to as Sage Therapeutics, or Sage) 
Name of Study Drug: SAGE-217 Capsules 
Name of Active Ingredient: SAGE-217 
Title of Study:  
A Phase 3, Open-label, 1-year Study of the Safety, Tolerability, and Need for Re-treatment with 
SAGE-217 in Adult Subjects with Major Depressive Disorder 
Number of Sites and Study Location: This study will take place at approximately 75 sites in the 
United States; non-US sites may be included as needed. 
Phase of Development: 3 
Planned Duration of Subject Participation: 
For Part A de novo subjects, the planned duration of participation is approximately 56 weeks: 
Screening Period (28 days), Initial Treatment Period (14 days), Follow-up Period (14 days), and 
Observational Period (48 weeks). In Part B, rollover subjects will enter the study during the 
Observational Period, therefore the planned duration of participation is approximately 46 weeks. 
Additional 14-day treatment periods with SAGE-217 may occur during the Observational Period. 
The following objectives and endpoints will be evaluated in 2 separate study parts: Part A (de novo 
subjects who have their initial treatment cycle in the current study) and Part B (rollover subjects who 
have their initial treatment cycle in the parent study). 
Objectives: 
Primary: 
• 
To determine the safety and tolerability of initial treatment and/or re-treatment(s) with 
SAGE-217 in adults with Major Depressive Disorder (MDD) experiencing a major 
depressive episode (MDE) at study entry for de novo subjects or at entry in the parent 
study for rollover subjects over a 1-year period 
Secondary: 
• 
To assess the need for re-treatment with SAGE-217 following initial treatment in adults 
with MDD experiencing an MDE at study entry for de novo subjects or at entry in the 
parent study for rollover subjects over a 1-year period 
• 
To assess the response of initial treatment and/or re-treatment(s) with SAGE-217 
following an initial 2-week treatment period in adults with MDD experiencing an MDE at 
study entry for de novo subjects or at entry in the parent study for rollover subjects over a 
1-year period 
 
• 
 
 
• 
 


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


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






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exhibit maximal efficacy. Rollover subjects, therefore, will not be eligible to begin their first 
SAGE-217 treatment period until 56 days has elapsed from the date of last dose of blinded study drug 
(SAGE-217 or placebo) administered in the parent study. 
As this is the first study in which longitudinal re-treatment with SAGE-217 will be examined, and 
based on known withdrawal symptoms with other GABAergic drugs and non-clinical findings in a 
9-month study of SAGE-217 in dogs (Investigator’s Brochure), the potential for withdrawal-related 
events, including seizure, will be monitored following the guidelines outlined in Section 8.5.1, which 
include study drug discontinuation or dose reduction. 
If a subject exhibits suicidality at any time, they will return to the site as soon as possible for 
assessment by the Investigator. The assessments for the Screening Period and Treatment and Follow-
up Periods in Part A – de novo subjects are summarized in Table 1; the assessments for the 
Observational Period in Part A - de novo subjects are summarized in Table 2. The assessments for 
Screening and Observational Period in Part B - rollover subjects are summarized in Table 3; the 
assessments for the Treatment and Follow-Up Periods in Part B – rollover subjects are summarized in 
Table 4.  
Number of Subjects (Planned): In Part A, approximately 1200 de novo subjects will be dosed, with 
the expectation to achieve follow-up of 675 subjects for 6 months and 235 subjects for 1 year. In 
Part B, approximately 350 rollover subjects may be enrolled. 
Eligibility Criteria: 
Part A – de novo subjects 
Inclusion Criteria: 
Qualified de novo subjects will meet all of the following criteria: 
1. Subject has signed an ICF prior to any study-specific procedures being performed. 
2. Subject is a male or female between 18 and 75 years of age, inclusive. 
3. Subject is in good physical health and has no clinically significant findings, as determined by 
the Investigator, on physical examination, 12-lead ECG, or clinical laboratory tests. 
4. Subject agrees to adhere to the study requirements, including not participating in night shift 
work during any 14-day treatment period.  
5. Subject has a diagnosis of MDD as diagnosed by SCID-5-CT, with symptoms that have been 
present for at least a 4-week period.  
6. Subject has a MADRS total score of ≥28 and a HAM-D total score of ≥20 at Screening and 
Day 1 (prior to dosing).  
7. Subjects taking antidepressants indicated for the treatment of major depressive disorder must 
have been taking these medications at the same dose for at least 60 days prior to Day 1. 
Subjects who have stopped taking antidepressants must have done so for at least 60 days prior 
to Day 1. Subjects receiving psychotherapy must have been receiving therapy on a regular 
schedule for at least 60 days prior to Day 1. 
8. Female subject agrees to use at least one method of highly effective contraception as listed in 
Section 9.2.4 during participation in the study and for 30 days following the last dose of study 
drug, unless she is postmenopausal (at least 12 months of spontaneous amenorrhea without an 
alternative medical cause, with confirmatory follicular stimulation hormone [FSH] >40 


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mIU/mL), and/or surgically sterile (hysterectomy or bilateral oophorectomy, and/or bilateral 
salpingectomy), or does not engage in sexual relations which carry a risk of pregnancy. 
9. Male subject agrees to use an acceptable method of effective contraception for the duration of 
study and for 5 days after receiving the last dose of the study drug, unless the subject does not 
engage in sexual relations which carry a risk of pregnancy. Acceptable methods of effective 
contraception are listed in Section 9.2.4. 
10. Male subject is willing to abstain from sperm donation for the duration of the study and for 
5 days after receiving the last dose of the study drug. 
11. Subject agrees to refrain from drugs of abuse and alcohol for the duration of the study. 
Exclusion Criteria: 
De novo subjects who meet any of the following criteria are disqualified from participation in this 
study: 
1. Subject is currently at significant risk of suicide, as judged by the Investigator, or has 
attempted suicide associated with the current episode of MDD. 
2. Subject has a recent history or active clinically significant manifestations of metabolic, hepatic, 
renal, hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, 
dermatological, urogenital, neurological, or eyes, ears, nose, and throat disorders, or any other 
acute or chronic condition that, in the Investigator's opinion, would limit the subject's ability to 
complete or participate in this clinical study. A body mass index (BMI) ≤18 or ≥45 kg/m2 at 
Screening is exclusionary; a BMI of 40 to 44.9 kg/m2, inclusive, at Screening is subject to a 
broader evaluation of medical co-morbidities (such as sleep apnea, chronic obstructive 
pulmonary disease [COPD]), concomitant medications, and prior tolerability of sedating 
agents. 
3. Subject has treatment-resistant depression, defined as persistent depressive symptoms despite 
treatment with adequate doses of antidepressants within the current major depressive episode 
(excluding antipsychotics) from two different classes for at least 4 weeks of treatment. 
Massachusetts General Hospital Antidepressant Treatment Response Questionnaire will be 
used for this purpose. 
4. Subject has had vagus nerve stimulation, electroconvulsive therapy, or has taken ketamine 
(including esketamine) within the current major depressive episode. 
5. Subject is taking any of the following: 
a. benzodiazepines, barbiturates, or GABAA modulators (eg, eszopiclone, zopiclone, 
zaleplon, zolpidem, brexanolone) at Day -28, 
b. benzodiazepines, barbiturates, or GABAA modulators (eg, eszopiclone, zopiclone, 
zaleplon, zolpidem, brexanolone) daily or near-daily (≥4 days per week) for 1 year, in 
the year prior to first dose of study drug, 
c. benzodiazepine or GABAA modulator with a half-life of ≥48 hours (eg, diazepam) 
from 60 days prior to Day 1 
6. Subject is taking non-GABA anti-insomnia medications (eg, prescribed therapeutics 
specifically for insomnia, over-the-counter sleep aids, melatonin) first generation (typical) 
antipsychotics (eg, haloperidol, perphenazine), and/or second generation (atypical) 


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antipsychotics (eg, aripiprazole, quetiapine) at Day -14. Note that antihistamines used during 
the day solely for indication(s) other than insomnia are permitted. 
7. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds.  
8. Subject has a positive pregnancy test at Screening or on Day 1 prior to the start of study drug 
administration for any treatment cycle.  
9. Subject that is breastfeeding at Screening or on Day 1 (prior to administration of study drug) 
does not agree to temporarily cease giving breast milk to her child(ren) from just prior to 
receiving study drug on Day 1 until 7 days after the last dose of study drug in each treatment 
cycle.  
10. Subject has detectable hepatitis B surface antigen, anti-hepatitis C virus (HCV) and positive 
HCV viral load, or human immunodeficiency virus (HIV) antibody at Screening. 
11. Subject has a clinically significant abnormal 12-lead ECG at the Screening or baseline visits. 
NOTE: mean QT interval calculated using the Fridericia method (QTcF) of >450 msec in 
males or >470 msec in females will be the basis for exclusion from the study.  
12. Subject has active psychosis per Investigator assessment.  
13. Subject has a medical history of seizures.  
14. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder.  
15. Subject has a history of mild, moderate, or severe substance use disorder (including 
benzodiazepines) diagnosed using DSM-5 criteria in the 12 months prior to Screening. 
16. Subject has been taking chronic or as-needed psychostimulants (eg, methylphenidate, 
amphetamine) or opioids at Day -28. 
17. Subject has had exposure to another investigational medication or device within 30 days prior 
to Screening.  
18. Subject has previously participated in a SAGE-217 or a SAGE-547 (brexanolone) clinical trial.  
19. Use of any known strong inhibitors of cytochrome P450 (CYP)3A4 within 28 days or 5 half-
lives (whichever is longer) or consumed grapefruit juice, grapefruit, or Seville oranges, or 
products containing these within 14 days prior to the first dose of study drug for any 
SAGE-217 treatment cycle.  
20. Use of strong CYP3A inducers within 28 days prior to the first dose of study drug for any 
SAGE-217 treatment cycle or planned use during any treatment cycle. Examples include: 
rifampin, carbamazepine, enzalutamide, mitotane, phenytoin, and St John’s Wort. 
21. Subject has a positive drug and/or alcohol screen at Screening or on Day 1 prior to dosing of 
the initial treatment cycle. 
22. Subject plans to undergo elective surgery during the initial treatment and follow-up period.  
23. Subject has been diagnosed with and/or treated for any type of cancer (excluding basal cell 
carcinoma and in situ melanoma) within the past year prior to Screening. 


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


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3. Subject has a recent history or active clinically significant manifestations of metabolic, hepatic, 
renal, hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, 
dermatological, urogenital, neurological, or eyes, ears, nose, and throat disorders, or any other 
acute or chronic condition that, in the investigator’s opinion, would limit the subject’s ability 
to complete or participate in this clinical study. 
4. Subject has had vagus nerve stimulation, electroconvulsive therapy, or has taken ketamine 
(including esketamine) since enrolling in the parent study 
5. Subject is taking first generation (typical) antipsychotics (eg, haloperidol, perphenazine), 
and/or second generation (atypical) antipsychotics (eg, aripiprazole, quetiapine) at Screening 
or within the time period between completion of the parent study and Screening. 
6. Subject has taken an antidepressant other than sertraline, escitalopram, citalopram, duloxetine 
or desvenlafaxine within 60 days prior to screening, including within the time period between 
completion of the parent study and Screening. 
7. Subject has a known allergy to SAGE-217, brexanolone, allopregnanolone, or related 
compounds. 
8. Subject has a positive pregnancy test at Screening. 
9. Subject that is breastfeeding at Screening does not agree to temporarily cease giving breast 
milk to her child(ren) from just prior to receiving study drug on Day 1 until 7 days after the 
last dose of study drug in each treatment cycle, if applicable. 
10. Subject has active psychosis per Investigator assessment. 
11. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder. 
12. Subject has a new history of mild, moderate, or severe substance use disorder (including 
benzodiazepines) diagnosed using DSM-5 criteria from the time of enrollment in the parent 
study or within the time period between completion of the parent study and Screening. 
13. Subject has taken psychostimulants (eg, methylphenidate, amphetamine) or opioids during the 
parent study or within the time period between completion of the parent study and Screening. 
14. Subject has had exposure to another investigational medication (other than SAGE-217) or 
device during the parent study or within the time period between completion of the parent 
study and Screening. 
15. Subject has a positive drug and/or alcohol screen at Screening. 
16. Subject has been diagnosed with and/or treated for any type of cancer (excluding basal cell 
carcinoma and in situ melanoma) during the parent study or within the time period between 
completion of the parent study and Screening. 
17. History of poor compliance with the study drug and/or procedures in the parent study as 
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SAGE-217 Dosage and Mode of administration:  
SAGE-217 is available as hard gelatin capsules for oral administration. Available dose strengths are as 
30-mg or 20-mg capsules, with single or multiple capsules administered as appropriate to achieve the 
total daily dose of 50 mg or 40 mg specified per all treatment cycles (initial or re-treatment).  
Reference Therapy, Dosage and Mode of Administration:  
Not applicable 
Duration of Treatment:  
In Part A, all de novo subjects will receive a daily oral dose of SAGE-217 from Day 1 through Day 14 
of the first treatment cycle.  
In Part B, rollover subjects will enter the current study after completing a 14-day double-blind 
treatment period and 4-week follow-up in the parent study.  
According to the re-emergence of depressive symptoms, SAGE-217 may be administered to both de 
novo and rollover subjects in subsequent 14-day treatment periods. 
Statistical Methods: 
Separate statistical analysis plans (SAP) will be generated for each part of the study and will provide a 
detailed description of the analyses to be performed in the study. For Part B- rollover subjects, the 
parent study database will be used in analysis. 
The SAP for each study part will be finalized and approved prior to database lock for respective parts. 
The data for Part A – de novo subjects may be analyzed and reported prior to database lock for Part B 
– rollover subjects. Any deviations from or changes to the SAPs following database lock will be 
described in detail in the clinical study report.   
General Considerations 
For the purpose of all analyses where applicable, baseline will be defined as the latest value before the 
first dose of SAGE-217 Cycle 1 for de novo subjects. A period-specific baseline will be defined as the 
latest value before the first dose of SAGE-217 in each 14-day treatment cycle.  
Every attempt will be made to avoid missing data. All subjects will be used in the analyses, as per the 
analysis populations, using all non-missing data available. 
Analysis Sets 
The Safety Set for both Part A and Part B is defined as all subjects administered study drug. 
The Full Analysis Set for de novo subjects is defined as all subjects in the Safety Set who completed 
Treatment Cycle 1 and moved on to Observational Period 1 (ie, these subjects had HAM-D response 
by Day 15 and did not discontinue the study for any reason within Treatment Cycle 1). 
The Full Analysis Set for rollover subjects is defined as all subjects in the Safety Set who have at least 
one HAM-D total score available after the first dose of study drug within this protocol. 
In addition, the cohorts of subjects who started with the 30-mg dose versus the 50-mg dose may be 
analyzed separately for de novo subjects. 
Determination of Sample Size 
The sample size is not based on a formal sample size calculation. The sample size of 1200 de novo 
subjects in Part A was chosen in order to have at least 675 subjects complete 24 weeks of the study and 
at least 235 subjects complete through 56 weeks, consistent with the objective of assessing SAGE-217 


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long-term safety. Approximately 350 subjects are expected to roll over from the parent study and 
enroll in Part B. 
Analysis of Primary Endpoint 
Safety and tolerability of SAGE-217 will be evaluated by incidence and severity of adverse 
events/serious adverse events, concomitant medication usage, vital signs, clinical laboratory 
evaluations, and 12-lead ECG. Suicidality will be monitored by the C-SSRS. In addition to overall 
study results, the results from each treatment cycle will be provided separately whenever applicable. 
Safety analyses will use the Safety Set for overall safety.  
A study period is defined as a treatment cycle and its subsequent observation period; the Safety Set for 
a given study period includes subjects in the Safety Set who are dosed in the respective study period. 
Safety analyses will be provided based on the Safety Set for each study period when appropriate. 
Analysis of Secondary Endpoints 
Using the Full Analysis Set, Kaplan-Meier (KM) survival curve will be provided for time to first re-
treatment; the estimand is the median time to first re-treatment, and it will be estimated from KM 
analysis.  
Number and percentage of subjects needing at least one re-treatment (ie, meeting the criteria for re-
treatment, but not necessarily retreated) will be provided. Number of re-treatment cycles per subject 
will be summarized. 
Change from baseline and/or from period-specific baseline, when appropriate, in HAM-D total score 
and subscale scores will be summarized by each treatment cycle. HAM-D response (defined as ≥50% 
reduction from baseline in HAM-D total score) and HAM-D remission (defined as HAM-D total score 
of ≤7) will be summarized for each treatment cycle. Change from baseline and/or from period-specific 
baseline, when appropriate, in CGI-S will be summarized for each treatment period. CGI-I will be 
summarized for each treatment cycle. 
 
  
 


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


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Study Drug Dispensation 
 
X 
X 
 
 
Study Drug Administration 
 
X (Day 1 through Day 14) 
 
Study Drug Accountability/Return 
 
 
X 
X 
 
Adverse Events/SAEst 
X 
Prior/Concomitant Medicationsu 
X 
CGI-I = Clinical Global Impression - Improvement; CGI-S – Clinical Global Impression - Severity; C-SSRS = 
Columbia Suicide Severity Rating Scale; D = day; ET = early termination; ECG = electrocardiogram; EOT = end of 
treatment; FSH = follicle stimulating hormone; HAM-D = Hamilton Rating Scale for Depression, 17-item; HIV = 
human immunodeficiency virus; ICD-10 = International Statistical Classification of Diseases and Related Health 
Problems version 10; 
 MADRS = Montgomery-Åsberg Depression Rating Scale; 
MGH ATRQ = Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; O = Optional; 
SCID-5 = Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; 
PHQ-9 = 9-item Patient Health Questionnaire; 
SAE = serious adverse event; 
wt = weight 
a Screening procedures are to be conducted before initial (Cycle 1) treatment period only. 
c Each cycle is 28 days (±1 day) and is comprised of a 14-day treatment period and a 14-day follow-up period. The 
initial treatment is considered Cycle 1 and re-treatments will be numbered sequentially. Each re-treatment cycle 
will begin with Day 1 (eg, the first day of the first re-treatment will be Day 1 of Cycle 2). 
d Subjects who discontinue treatment early should return to the site for an end of treatment (EOT) visit as soon as 
possible, preferably the day after treatment is discontinued. The follow-up visit should occur 14 days after the last 
dose of treatment. Subjects who discontinue treatment due to tolerability should be followed without any further 
administration of study drug in any subsequent cycle. If at any time after the EOT visit, a subject decides to 
terminate the study, the subject should return for an early termination (ET) visit. The EOT and ET visits can be on 
the same day if a subject discontinues study drug and terminates the study on the same day during a clinic visit; in 
this case, all events scheduled for the EOT visit will be conducted. 
e Subjects will be asked to authorize that their unique subject identifiers be entered into a registry 
(www.subjectregistry.com) with the intent of identifying subjects who may meet exclusion criteria for 
participation in another clinical study. 
f A serum FSH test will be conducted at Screening for female subjects who are not surgically sterile to confirm 
whether a female subject with ≥12 months of spontaneous amenorrhea meets the protocol-defined criteria for 
being post-menopausal. 
g A full physical examination will be conducted at Screening and abbreviated physical examinations will be 
conducted thereafter. A full physical examination includes assessment of body systems (eg, head, eye, ear, nose, 
and throat; heart; lungs; abdomen; and extremities). 
h Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. 
i Urine toxicology for selected drugs of abuse (as per the laboratory manual) and breath test for alcohol. 
j Serum pregnancy test at Screening and urine pregnancy test thereafter.  
m Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing). 
Heart rate and blood pressure to be collected in supine position at all scheduled time points after the subject has 
been resting for 5 minutes and then after approximately 3 minutes in the standing position. Vital signs may be 


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


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


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


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


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


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


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b Subjects who discontinue treatment early should return to the site for an end of treatment (EOT) visit as soon as 
possible, preferably the day after treatment is discontinued. The follow-up visit should occur 14 days after the last 
dose of treatment. Subjects who discontinue treatment due to tolerability should be followed without any further 
administration of study drug in any subsequent cycle. If at any time after the EOT visit, a subject decides to 
terminate the study, the subject should return for an early termination (ET) visit. The EOT and ET visits can be on 
the same day if a subject discontinues study drug and terminates the study on the same day during a clinic visit; in 
this case, all events scheduled for the EOT visit will be conducted. 
c Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. 
d Urine toxicology for selected drugs of abuse (as per the laboratory manual) and breath test for alcohol. 
e Urine pregnancy test.  
g Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing). 
Heart rate and blood pressure to be collected in supine position at all scheduled time points after the subject has 
been resting for 5 minutes and then after approximately 3 minutes in the standing position. Vital signs may be 
repeated at the discretion of the Investigator as clinically indicated. When vital signs are scheduled at the same 
time as blood draws, vital signs should be obtained first.  
h Triplicate ECGs will be collected. When ECG and blood draws are scheduled at the same time, ECG should be 
performed before blood draws.  
i The “Since Last Visit” C-SSRS form will be completed at any time of day. 
j The HAM-D is to be completed as early during the visit as possible. 
k The assessment timeframe for the HAM-D scale will refer to the past 7 days (1 week). 
l Adverse events will be collected starting at the time of informed consent and throughout the duration of the 
subject’s participation in the study. 
m See Section 9.2.1.  
 
 
 
 
 


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


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


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


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


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


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


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


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5. 
INTRODUCTION 
5.1. 
Background of Major Depressive Disorder and Unmet Medical Need 
The World Health Organization (WHO) has identified depression as the leading cause of 
disability worldwide, and as a major contributor to the overall global burden of disease 
(http://www.who.int/mediacentre/factsheets/fs369/en/). Globally, depression has been estimated 
to affect over 300 million people. 
In the United States, the economic burden of depression, including workplace costs, direct costs, 
and suicide-related costs, was estimated to be $210.5 billion in 2010 (Greenberg 2015). As per 
WHO statistics, over 800,000 people die due to suicide every year, and suicide is the second 
leading cause of death in 15- to 29-year-olds. The rate of US adults making a suicide attempt has 
increased (0.62% from 2004 to 2005 to 0.79% from 2012 to 2013), with a shift to more attempts 
among younger adults (42% to 50%, respectively) and among those with a depressive disorder 
(26% to 54%, respectively; Olfson 2017). 
In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5, American 
Psychiatric Association 2013), depression refers to an overarching set of diagnoses, including 
major depressive disorder (MDD). Diagnostic criteria for MDD includes a set of at least 5 
depressive symptoms out of 9, including depressed mood and/or loss of interest or pleasure, and 
other changes affecting appetite or weight, sleep, psychomotor activity, energy level, feelings of 
guilt, concentration ability, and suicidality during the same 2-week period, that represents a 
change from previous functioning (DSM-5). 
Antidepressants are a mainstay of pharmacological treatment for depressive disorders. Selective 
serotonin uptake inhibitors, serotonin norepinephrine reuptake inhibitors, tricyclic 
antidepressants, monoamine oxidase inhibitors, and other compounds that affect monoaminergic 
neurotransmission, such as mirtrazapine and bupropion, represent the major classes of 
antidepressants. While antidepressants are widely used, large scale studies have demonstrated 
their limited efficacy, including low remission rates and untreated symptoms (Trivedi 2006; 
Conradi 2011; Romera 2013). 
5.2. 
SAGE-217 
SAGE-217 is a synthetic positive allosteric modulator of GABAA receptors, the major class of 
inhibitory neurotransmitter receptors in the brain. In pharmacokinetic (PK) studies in mice and 
rats, SAGE-217 demonstrated rapid penetration and equilibrium across the blood brain barrier 
and is generally expected to have good extravascular exposure. In exploratory in vitro receptor 
and ion channel assays and in vivo safety pharmacology studies, SAGE-217 was highly selective 
for GABAA receptors, and, consistent with the actions of other GABAA receptor potentiators 
(Rudolph 2011), exhibits potent anticonvulsant, anxiolytic, and sedative activity when 
administered in vivo. 
SAGE-217 has been generally well tolerated in clinical studies to date. The most common 
treatment-emergent adverse events (TEAEs) associated with SAGE-217 (overall) were sedation, 
somnolence, and dizziness; most adverse events were reported as mild or moderate in intensity. 
Refer to the Investigator’s Brochure for a detailed description of the chemistry, pharmacology, 
efficacy, and safety of SAGE-217.  


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5.3. 
Potential Risks and Benefits 
The apparent risks of SAGE-217 are based on clinical data reports of adverse events in 
completed and ongoing studies and the known pharmacology of the drug. Sedation, somnolence, 
and dizziness were identified as adverse drug reactions. Most AEs were reported as mild or 
moderate in intensity and reversible. 
SAGE-217 may present a treatment option for MDD that has more rapid onset of action (days 
instead of weeks), when compared to available therapies. 
Based on nonclinical findings, embryo-fetal toxicity and withdrawal effects are considered 
important potential risk for SAGE-217. Risk mitigation measures in this study include 
monitoring for adverse effects, monitoring for potential withdrawal effects, requiring highly 
effective contraceptive measures for study participants, and inclusion of dose adjustment criteria 
and individual subject stopping criteria (Section 8.5.1). Finally, due to the sedation/somnolence 
observed, SAGE-217 is administered in the evening in this study. 
Given the outcome of the completed studies of SAGE-217 in subjects with MDD and PDD, the 
current significant unmet need in the treatment of depression, and a favorable benefit-risk 
profile, further investigation of SAGE-217 in adults with MDD is justified. 
5.4. 
Dose Justification 
To date, the current capsule utilized in clinical studies is not associated with a maximum 
tolerated dose (MTD). Initial MTD assessments were performed using SAGE-217 in an oral 
solution (OS) at steady-state in healthy subjects, which provided an MTD with a Cmax of 
125 ng/mL at 30 mg OS. While re-identification of the MTD using the capsule formulations was 
not conducted, steady-state 30 mg capsules provide a model-derived Cmax approximately 50% 
lower (64 ng/mL) than the concentration associated with the MTD of 30 mg OS (125 ng/mL).  
Studies 217-MDD-201 and 217-PPD-201, employing 30 mg capsules administered each evening 
for 14 days, demonstrated significant reduction in symptoms of depression, anxiety and 
insomnia. The safety profile in these studies is consistent with the GABAA neurosteroid 
mechanism, including adverse drug reactions (ADRs) of somnolence, sedation, and dizziness at 
rates of 4% to 15%; the majority with mild intensity. Phase 3 studies in a broader patient 
population demonstrate activity of SAGE-217 associated with improvement in depressive 
symptoms, however, both the efficacy and safety findings support investigation of a higher dose, 
with predictable ADRs expected to be within an acceptable range. 
Study 217-MDD-301A, a randomized, multi-center, 3-arm study examining SAGE-217 20 and 
30 mg capsules compared to placebo, found significant anti-depressant effects compared to 
placebo at Days 3, 8, and 12 but not Day 15 (primary endpoint) for the 30 mg dose. The 20 mg 
dose did not separate from placebo at any timepoint. The rates of expected ADRs of somnolence, 
sedation and dizziness in the 30 mg arm were each less than 10%; rates of discontinuation for 
adverse events were lower with SAGE-217 30 mg (2.1%) than with placebo (3.2%). No 
clinically relevant changes in vital signs, laboratory results, electrocardiogram measures, or 
suicidal thinking were observed in either 217-MDD-301A or across the full SAGE-217 program, 
now with over 2000 subjects exposed to treatment. Relevant results from 217-MDD-301A are 
available in the SAGE-217 Investigator’s Brochure.  


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Direct and modeled data from completed studies to date (including efficacy studies 
217-MDD-201 and 217-PPD-201) in addition to 217-MDD-301A (through Day 42 of the 
double-blind period), have been used to assess and predict the efficacy and safety outcomes at 
SAGE-217 concentrations expected with higher doses of SAGE-217 capsules (eg, 40 and 
50 mg).  
Direct safety data come from more than 140 subjects exposed to concentrations of SAGE-217 
that are higher than those achieved with a 30-mg capsule daily dose, primarily in the clinical 
pharmacology program. No serious adverse events were reported in association with any of these 
higher exposures. Consistent with the pharmacological action of SAGE-217 at the GABAA 
receptor, reports of somnolence, dizziness and sedation were increased at increased plasma 
concentrations. Results from a clinically-complete study that evaluated the effects of SAGE-217 
on driving performance (217-CLP-113), in which subjects (n=59) were exposed to 4 days of 
30 mg capsules, followed by a single dose of 60 mg capsules administered the evening prior to a 
driving simulation test, are illustrative. During treatment with 30 mg capsules daily (Days 1 to 
4), the rates of somnolence and dizziness were 8.5% and 13.6%, respectively. After a single dose 
of 60 mg on Day 5, the rates of somnolence and dizziness increased to 13.8% and 22.4%, 
respectively. For these ADRs, the events were mild or moderate in intensity, and no 
discontinuations due to the adverse events occurred. No events of sedation were reported but 
could be reflected as events of fatigue, which were reported at a rate of 3.4% with 30 mg (Day 1 
to 4) and 13.8% after a dose of 60 mg on Day 5. In addition, in this study, while there was an 
increase in incidence of somnolence, dizziness and fatigue at 60 mg, there was not an increase in 
the severity of events. Additional data from Study 217-CLP-113 are provided in the 
Investigator’s Brochure. 
Direct evidence related to efficacy and safety outcomes following administration of SAGE-217 
capsules at doses above 30 mg is further provided by results from a Phase 1, placebo-controlled 
study in healthy subjects using a 5-hour phase advance model of insomnia (Study 
217-EXM-101). Administration of single doses of SAGE-217 up to 45 mg improved sleep 
efficiency, duration, maintenance, and sleep quality compared with placebo. Evening 
administration of SAGE-217 was generally well tolerated, with an acceptable safety and 
tolerability profile. All reported TEAEs were mild and all resolved. Additional data from Study 
217-EXM-101 are provided in the Investigator’s Brochure. 
Using exposure-response models developed for both efficacy and safety outcomes, the benefit-
risk profile of SAGE-217 at doses of 40 or 50 mg capsules is expected to be acceptable. In 
Figure 1, the predicted concentrations of SAGE-217 following doses of 30, 40 or 50 mg capsules 
once daily are shown relative to two important concentration markers: Cavg as a marker for 
efficacy, identified based on pharmacodynamic biomarker modeling and clinical effectiveness 
(40 ng/mL) and Cmax as a marker for safety, associated with the maximally tolerated dose of the 
oral solution (125 ng/mL).  


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Figure 1: 
Predicted SAGE-217 concentrations (Cavg and Cmax) following dosing of 30 to 
50 mg daily 
 
Dashed vertical lines represent target concentrations for efficacy (Cavg >40 ng/mL) and safety (Cmax<125 
ng/mL). Percentage next to dashed lines indicate the percentages with Cavg>40 ng/mL or with Cmax>124 ng.  
The selection of 50 mg dosed daily was based first on efficacy, enabling the largest number of 
subjects to achieve a steady-state Cavg over 40 ng/mL. Figure 1 shows a dose of 50 mg will allow 
>90% subjects to maintain the target Cavg yet remain within the range of acceptable tolerability. 
With respect to Cmax, less than 1 in 5 (19%) subjects at the 50 mg dose level are expected to 
exceed a Cmax over 125 ng/mL, a level observed in Phase 1 studies which utilized oral solution 
and which was associated with a greater rate of sedation events.  
Increased granularity of the exposure-efficacy relationship is provided in Figure 2. Across 
Studies 217-MDD-201B, 217-MDD-301A, and 217-PPD-201, increased concentrations of 
SAGE-217 were associated with a larger reduction in depressive symptoms (Figure 2). Based on 
linear regression modeling, effect sizes for HAM-D were dose dependent, with a 50 mg dose 
administered once daily for 14 days predicted to provide greater therapeutic benefit compared to 
daily doses of 40 and 30 mg. Based on the 217-MDD-301A results, a dose of 30 mg may be 
considered the minimally effective dose.  


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


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


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dosing phase, were associated with exposures 7- to 11-fold above clinically relevant Cmax 
following administration of 30 mg capsules. Similar margin calculations for adverse effect levels 
in dogs to potential higher SAGE-217 dose levels (40 or 50 mg/day) remain at or above 4.5x for 
both Cmax and AUC. All non-clinical findings are provided in the SAGE-217 Investigator’s 
Brochure. The totality of the nonclinical safety data supports the use of SAGE-217 for the 
treatment of patients at the higher clinical dose regimen, particularly in the context of the current 
safety database of over 2000 subjects exposed to SAGE-217 treatment. 
In summary, recent results from a large, multicenter trial of SAGE-217 in MDD 
(217-MDD-301A) support the need for higher steady-state concentrations of SAGE-217 to allow 
subjects to experience maximum anti-depressant, anti-anxiety, and anti-insomnia benefits. Doses 
of SAGE-217 40 and 50 mg will be utilized in this trial, as well as all other ongoing trials with 
SAGE-217, under the 14 day regimen of an initial evening dose of 50 mg with reduction to 
40 mg as needed based on tolerability. These higher doses of SAGE-217 are expected to exhibit 
a favorable benefit-risk profile in the context of 30 mg now being identified as a minimally 
effective dose. While higher rates of ADRs may be anticipated, SAGE-217 is expected to 
maintain an acceptable tolerability profile, based on a current safety database of over 2000 
subjects exposed across different doses/concentrations. In addition, higher doses offer the 
potential for improved therapeutic benefit over the short 14-day treatment course.  
According to the DSM-5, a period of 8 weeks is required to establish ‘full remission’ of a 
depressive episode (American Psychiatric Association 2013). Further, available antidepressant 
therapies (ADT) often take up to 8 weeks to exhibit maximal efficacy. Thus, a minimum period 
of 8 weeks (56 days) is required between the end of a 14-day treatment period and the beginning 
of a new SAGE-217 treatment cycle.  


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


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


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






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approximately 1 week from the PHQ-9 score ≥10. In all subjects, the End of Study/Week 52 
Visit is mandatory if another scheduled on site visit does not fall in the Week 52 window. 
A minimum period of 8 weeks (56 days) is required between SAGE-217 treatment periods. This 
is based on the period of 8 weeks establishing ‘full remission’ of a depressive episode 
(American Psychiatric Association 2013) and is aligned with the treatment period which would 
be required for any available antidepressant (ADT) to exhibit maximal efficacy. Rollover 
subjects, therefore, will not be eligible to begin their first SAGE-217 treatment period until 
56 days has elapsed from the date of last dose of blinded study drug (SAGE-217 or placebo) 
administered in the parent study. 
Details guiding the use of as-needed benzodiazepines and GABA-modulators for insomnia (eg, 
eszopiclone, zopiclone, zaleplon, and zolpidem), new ADT use, or increases in concomitant 
medication ADT dose are provided in Section 9.2.1. 
As this is the first study in which longitudinal re-treatment with SAGE-217 will be examined, 
and based on known withdrawal symptoms with other GABAergic drugs and non-clinical 
findings in a 9-month study of SAGE-217 in dogs (Investigator’s Brochure), the potential for 
withdrawal-related events, including seizure, will be monitored following the guidelines outlined 
in Section 8.5.1, which include study drug discontinuation or dose reduction. 
If a subject exhibits suicidality at any time, they will return to the site as soon as possible for 
assessment by the Investigator. 
The assessments for the Screening Period and Treatment and Follow-up Periods in Part A – de 
novo subjects are summarized in Table 1; the assessments for the Observational Period in Part A 
- de novo subjects are summarized in Table 2. The assessments for Screening and Observational 
Period in Part B - rollover subjects are summarized in Table 3; the assessments for the Treatment 
and Follow-Up Periods in Part B – rollover subjects are summarized in Table 4. 
7.2. 
Number of Subjects 
In Part A, approximately 1200 de novo subjects will be dosed (Section 13.7). An estimated 25% 
will not exhibit response/remission during the first treatment exposure, leaving 900 to be 
followed for 1 year, expected to result in at least 675 subjects followed for 6 months and 
235 subjects followed for 1 year. In Part B, approximately 350 rollover subjects may be enrolled. 
7.3. 
Treatment Assignment 
This is an open-label study in which all subjects will receive SAGE-217. 
7.4. 
Dose Adjustment Criteria 
During the treatment period, subjects will be able to receive study drug as long as there are no 
dose limiting safety/tolerability concerns. Subjects who cannot tolerate 50 mg will receive 40 mg 
for the remainder of the treatment period. If a subject has been shown to not tolerate the 50 mg 
dose, and has previously been dose reduced to 40 mg, they may be started at the 40 mg dose for 
any needed subsequent re-treatments, as determined by the investigator. 
At the discretion of the investigator, subjects who cannot tolerate the 40-mg dose at any time 
may be discontinued from dosing upon completion of an end of treatment (EOT) visit as soon as 


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possible. These subjects should be followed without any further administration of study drug in 
any subsequent cycle, and complete assessments per the schedules of events (Table 1, Table 2 
Table 3, and Table 4). 
7.5. 
Criteria for Study Termination 
Sage Therapeutics may terminate this study or any portion of the study at any time for safety 
reasons including the occurrence of AEs or other findings suggesting unacceptable risk to 
subjects, or for administrative reasons. In the event of study termination, Sage Therapeutics will 
provide written notification to the Investigator. Investigational sites must promptly notify their 
IRB and initiate withdrawal procedures for participating subjects.  


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria – Part A de novo subjects 
Qualified de novo subjects will meet all of the following criteria: 
1. Subject has signed an ICF prior to any study-specific procedures being performed. 
2. Subject is a male or female between 18 and 75 years of age, inclusive. 
3. Subject is in good physical health and has no clinically significant findings, as 
determined by the Investigator, on physical examination, 12-lead ECG, or clinical 
laboratory tests. 
4. Subject agrees to adhere to the study requirements, including not participating in night 
shift work during any 14-day treatment period.  
5. Subject has a diagnosis of MDD as diagnosed by SCID-5-CT, with symptoms that have 
been present for at least a 4-week period.  
6. Subject has a MADRS total score of ≥28 and a HAM-D total score of ≥20 at Screening 
and Day 1 (prior to dosing).  
7. Subjects taking antidepressants used to treat major depressive disorder must have been 
taking these medications at the same dose for at least 60 days prior to Day 1. Subjects 
who have stopped taking antidepressants must have done so for at least 60 days prior to 
Day 1. Subjects receiving psychotherapy must have been receiving therapy on a regular 
schedule for at least 60 days prior to Day 1. 
8. Female subject agrees to use at least one method of highly effective contraception as 
listed in Section 9.2.4 during participation in the study and for 30 days following the last 
dose of study drug, unless she is postmenopausal (at least 12 months of spontaneous 
amenorrhea without an alternative medical cause, with confirmatory follicular stimulation 
hormone [FSH] >40 mIU/mL), and/or surgically sterile (hysterectomy or bilateral 
oophorectomy, and/or bilateral salpingectomy), or does not engage in sexual relations 
which carry a risk of pregnancy. 
9. Male subject agrees to use an acceptable method of effective contraception for the 
duration of study and for 5 days after receiving the last dose of the study drug, unless the 
subject does not engage in sexual relations which carry a risk of pregnancy. Acceptable 
methods of effective contraception are listed in Section 9.2.4.  
10. Male subject is willing to abstain from sperm donation for the duration of the study and 
for 5 days after receiving the last dose of the study drug. 
11. Subject agrees to refrain from drugs of abuse and alcohol for the duration of the study. 
8.2. 
Subject Exclusion Criteria – Part A de novo subjects 
De novo subjects who meet any of the following criteria are disqualified from participation in 
this study: 


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1. Subject is currently at significant risk of suicide, as judged by the Investigator, or has 
attempted suicide associated with the current episode of MDD. 
2. Subject has a recent history or active clinically significant manifestations of metabolic, 
hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, 
musculoskeletal, dermatological], urogenital, neurological, or eyes, ears, nose, and throat 
disorders, or any other acute or chronic condition that, in the Investigator's opinion, 
would limit the subject's ability to complete or participate in this clinical study. A body 
mass index (BMI) ≤18 or ≥45 kg/m2 at Screening is exclusionary; a BMI of 40 to 
44.9 kg/m2, inclusive, at Screening is subject to a broader evaluation of medical co-
morbidities (such as sleep apnea, chronic obstructive pulmonary disease [COPD]), 
concomitant medications, and prior tolerability of sedating agents. 
3. Subject has treatment-resistant depression, defined as persistent depressive symptoms 
despite treatment with adequate doses of antidepressants within the current major 
depressive episode (excluding antipsychotics) from two different classes for at least 4 
weeks of treatment. Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire will be used for this purpose. 
4. Subject has had vagus nerve stimulation, electroconvulsive therapy, or has taken 
ketamine (including esketamine) within the current major depressive episode. 
5. Subject is taking any of the following: 
a. benzodiazepines, barbiturates, or GABAA modulators (eg, eszopiclone, zopiclone, 
zaleplon, zolpidem, brexanolone) at Day -28,  
b. benzodiazepines, barbiturates, or GABAA modulators daily or near-daily (≥4 days per 
week) for 1 year, in the year prior to first dose of study drug,  
c. benzodiazepine or GABAA modulator with a half-life of ≥48 hours (eg, diazepam) 
from 60 days prior to Day 1 
6. Subject is taking non-GABA anti-insomnia medications (eg, prescribed therapeutics 
specifically for insomnia, over-the-counter sleep aids, melatonin), first generation 
(typical) antipsychotics (eg, haloperidol, perphenazine) and/or second generation 
(atypical) antipsychotics (eg, aripiprazole, quetiapine) at Day -14. Note that 
antihistamines used during the day solely for indication(s) other than insomnia are 
permitted. 
7. Subject has a known allergy to SAGE-217, allopregnanolone, or related compounds.  
8. Subject has a positive pregnancy test at Screening or on Day 1 prior to the start of study 
drug administration for any treatment cycle.  
9. Subject that is breastfeeding at Screening or on Day 1 (prior to administration of study 
drug) does not agree to temporarily cease giving breast milk to her child(ren) from just 
prior to receiving study drug on Day 1 until 7 days after the last dose of study drug in 
each treatment cycle.  
10. Subject has detectable hepatitis B surface antigen, anti-hepatitis C virus (HCV) and 
positive HCV viral load, or human immunodeficiency virus (HIV) antibody at Screening. 


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11. Subject has a clinically significant abnormal 12-lead ECG at the Screening or baseline 
visits. NOTE: mean QT interval calculated using the Fridericia method (QTcF) of 
>450 msec in males or >470 msec in females will be the basis for exclusion from the 
study.  
12. Subject has active psychosis per Investigator assessment.  
13. Subject has a medical history of seizures.  
14. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder.  
15. Subject has a history of mild, moderate, or severe substance use disorder (including 
benzodiazepines) diagnosed using DSM-5 criteria in the 12 months prior to Screening. 
16. Subject has been taking chronic or as-needed psychostimulants (eg, methylphenidate, 
amphetamine) or opioids at Day -28. 
17. Subject has had exposure to another investigational medication or device within 30 days 
prior to Screening.  
18. Subject has previously participated in a SAGE-217 or a SAGE-547 (brexanolone) clinical 
trial.  
19. Use of any known strong inhibitors of cytochrome P450 (CYP)3A4 within 28 days or 
5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, or Seville 
oranges, or products containing these within 14 days prior to the first dose of study drug 
for any SAGE-217 treatment cycle.  
20. Use of strong CYP3A4 inducers within 28 days prior to the first dose of study drug for 
any SAGE-217 treatment cycle or planned use during any treatment cycle. Examples 
include: rifampin, carbamazepine, enzalutamide, mitotane, phenytoin, and St John’s 
Wort. 
21. Subject has a positive drug and/or alcohol screen at Screening or on Day 1 prior to dosing 
of the initial treatment cycle. 
22. Subject plans to undergo elective surgery during the initial treatment and follow-up 
period. 
23. Subject has been diagnosed with and/or treated for any type of cancer (excluding basal 
cell carcinoma and in situ melanoma) within the past year prior to Screening. 
24. Subject has a history of sleep apnea. 
25. Subject has had gastric bypass surgery, has a gastric sleeve or lap band, or has had any 
related procedures that interfere with gastrointestinal transit. 
26. Subject ≥65 years of age has a history of cognitive impairment, increased risk for falls 
(including but not limited to impaired balance and/or gait), or is already taking ≥2 CNS 
active drugs as per the American Geriatrics Society 2015 Updated Beers Criteria for 
Potentially Inappropriate Medication Use in Older Adults. 


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


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5. Subject is taking first generation (typical) antipsychotics (eg, haloperidol, perphenazine), 
and/or second generation (atypical) antipsychotics (eg, aripiprazole, quetiapine) at 
Screening or within the time period between completion of the parent study and 
Screening. 
6. Subject has taken an antidepressant other than sertraline, escitalopram, citalopram, 
duloxetine or desvenlafaxine within 60 days prior to Screening, including within the time 
period between completion of the parent study and Screening. 
7. Subject has a known allergy to SAGE-217, brexanolone, allopregnanolone, or related 
compounds. 
8. Subject has a positive pregnancy test at Screening. 
9. Subject that is breastfeeding at Screening does not agree to temporarily cease giving 
breast milk to her child(ren) from just prior to receiving study drug on Day 1 until 7 days 
after the last dose of study drug in each treatment cycle, if applicable. 
10. Subject has active psychosis per Investigator assessment. 
11. Subject has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder. 
12. Subject has a new history of severe substance use disorder (including benzodiazepines) 
diagnosed using DSM-5 criteria within the 12 months prior to Screening or within the 
time period between completion of the parent study and Screening; or subject has a 
history of mild or moderate substance use disorder not in sustained remission for at least 
6 months prior to Screening. 
13. Subject has taken psychostimulants (eg, methylphenidate, amphetamine) or opioids 
during the parent study or within the time period between completion of the parent study 
and Screening. 
14. Subject has had exposure to another investigational medication (other than SAGE-217) or 
device during the parent study or within the time period between completion of the parent 
study and Screening. 
15. Subject has a positive drug and/or alcohol screen at Screening. 
16. Subject has been diagnosed with and/or treated for any type of cancer (excluding basal 
cell carcinoma and in situ melanoma) during the parent study or within the time period 
between completion of the parent study and Screening. 
17. History of poor compliance with the study drug and/or procedures in the parent study as 
determined by the Investigator 
8.5. 
Subject Withdrawal Criteria 
Subjects may withdraw from the study drug or terminate from the study at any time for any 
reason. The Investigator may withdraw the subject from the study drug or from the study for any 
of the following reasons: 
• The subject is unwilling or unable to adhere to the protocol 


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• The subject experiences an intolerable AE  
• Other medical or safety reason, including suicidality, at the discretion of the 
Investigator  
The Investigator must notify the Sponsor and/or the Medical Monitor immediately when a 
subject withdraws from study drug or terminates the study for any reason. The reason must be 
recorded in the subject’s electronic case report form (eCRF).  
If a subject is persistently noncompliant, the Investigator may withdraw the subject from the 
study at his/her discretion. Any reasons for unwillingness or inability to adhere to the protocol 
must be recorded in the subject’s eCRF, including: 
• missed visits 
• interruptions in the schedule of study drug administration 
• non-permitted medications (see Section 9.2). 
Subjects who discontinue the study due to an AE, regardless of Investigator-determined 
causality, should be followed until the event is resolved, considered stable, or the Investigator 
determines the event is no longer clinically significant.  
Subjects who discontinue study drug early during a treatment period should return to the site for 
an end of treatment (EOT) visit as soon as possible, preferably the day after treatment is 
discontinued. The follow-up visit should take place 14 days after the last dose of treatment. 
Thereafter the subject should continue the observational period as scheduled (Table 2 or 
Table 3). 
If at any time during a follow-up period or the observational period, a subject decides to 
terminate the study, the subject should contact the site and complete their remote assessments at 
an early termination (ET) visit. An ET visit may be on the same day as an EOT visit if a subject 
discontinues study drug and terminates the study on the same day during a treatment period; in 
this case, all events scheduled for the EOT visit will be conducted.  
A subject will be deemed lost to follow-up after attempts at contacting the subject have been 
unsuccessful. 
8.5.1. 
Individual Subject Stopping Criteria 
This is the first study in which longitudinal re-treatment with SAGE-217 will be examined. 
Based on known withdrawal symptoms with other GABAergic drugs and non-clinical findings in 
a 9-month study of SAGE-217 in dogs (Investigator’s Brochure), there is a potential for 
withdrawal-related events, including seizure. The following guidelines for study drug 
discontinuation or dose reduction are presented to support subject safety: 
1. Any subject reporting a confirmed or suspected seizure at any time will be discontinued 
from treatment and will not be eligible for another treatment cycle but will continue to be 
followed in the study. 
2. Following the first treatment period, the Investigator should monitor the course of 
CNS-based signs and symptoms suggestive of a seizure which are not accounted for by 
comorbid psychiatric or medical conditions. Examples of reported serious or severe 


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


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9.
TREATMENT OF SUBJECTS
9.1. 
Study Drug
In treatment cycles initiated prior to 217-MDD-303 Protocol Amendment 3, subjects were to 
self-administer SAGE-217 (30 mg or reduced dose of 20 mg, per criteria in Section 7.4) orally 
once daily in the evening with food for 14 days. 
After 217-MDD-303 Protocol Amendment 4, in all treatment cycles all subjects will self-
administer SAGE-217 50 mg (or reduced dose of 40 mg, per criteria in Section 7.4) orally once 
daily at approximately 8 PM with fat-containing food for 14 days. The 50-mg dose will be 
administered as 2 capsules per dose (one 30-mg capsule and one 20-mg capsule). If the dose is 
reduced to 40 mg, it will be administered as two 20-mg capsules. 
9.2. 
Prior Medications, Concomitant Medications, and Restrictions 
9.2.1. 
Prior and Concomitant Medications and/or Supplements 
The start and end dates, route, dose/units, frequency, and indication for all medications and/or 
supplements taken within 30 days prior to Screening (for subjects in Part A only) and throughout 
the duration of the study (for all subjects) will be recorded. In addition, antidepressant therapies 
taken in the 3 years prior to Screening will be recorded for subjects in Part A only. 
Any medication and/or supplement determined necessary for the welfare of the subject may be 
given at the discretion of the Investigator at any time during the study.  
For Part A de novo subjects, antidepressants that have been taken at the same dose for at least 
60 days prior to Day 1 are permitted if the subject intends to continue the stable dose through the 
initial treatment and follow-up period (through Day 28 of Cycle 1). De novo subjects who have 
stopped taking antidepressants must have done so for at least 60 days prior to Day 1. 
For Part B rollover subjects, antidepressant use within 60 days prior to Screening other than 
sertraline, escitalopram, citalopram, duloxetine or desvenlafaxine is not permitted. Use of these 
antidepressants throughout the study is permitted. 
See Table 5 for allowed concomitant psychotropic medications during each period of the study 
for both study parts. 
9.2.1.1. 
Medication use for depressive symptom worsening following a SAGE-217 
treatment cycle 
Study 217-MDD-201, Part B, found that for subjects achieving remission or response at Day 15 
(78.6%), 6.1% had a HAM-D ≥22 at Day 42; another 18.2% had a HAM-D score of 16 to 21 at 
Day 42 (Data on File, Sage Therapeutics). This indicates that most subjects who may experience 
a new MDE will have this experience after they reach the minimal required period (8 weeks or 
56 days) before a new SAGE-217 treatment cycle. Because of this, most subjects will be eligible 
(ie, PHQ-9 ≥10 and HAM-D ≥20 confirmed over 2 weeks) for a SAGE-217 treatment cycle 
when needed; a 2-week period is required to establish a new MDE (DSM-5).  
For de novo subjects who experience worsening depressive symptoms after Day 28 or for 
rollover subjects who experience worsening depressive symptoms after Screening and are not yet 


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eligible for a new SAGE-217 treatment cycle, there are 2 intervention options: as-needed 
medications (limited to a maximum of 4 days per week) and/or introduction of a new ADT or an 
increase in the dose of a current ADT (Table 5). To maintain equivalence in clinical status across 
all ADT use (ie, new SAGE-217, new ADT, or increase dose of current ADT), a requirement for 
PHQ-9 ≥10 and HAM-D ≥20 confirmed over 2 weeks will be required in all ADT use 
conditions. If a subject on a stable ADT is experiencing worsening depressive symptoms 
(PHQ-9 ≥10), it is recommended that only as-needed medications be used if the HAM-D score is 
<20; if the HAM-D score is ≥20, the current dose may be increased or a new ADT may be 
introduced. Furthermore, clinicians should consider an individual subject’s initial experience 
with SAGE-217 when starting any new ADT, as it may substantially reduce the likelihood that 
the subject will be eligible for a new SAGE-217 treatment cycle once time allows (ie, HAM-D 
may be <20). There is no PHQ-9 or HAM-D score requirement for as-needed medication use. 
Permitted as-needed medications for symptom management include benzodiazepines, 
GABA-modulators for insomnia (eg, eszopiclone, zopiclone, zaleplon, and zolpidem), and 
non-GABA treatments for insomnia; use of such treatments should be limited to a maximum of 
4 days per week.  
If as-needed medications and/or a new ADT was introduced or the dose of a current ADT was 
increased and the subject continues to exhibit a HAM-D ≥20, a new SAGE-217 treatment cycle 
can be initiated at Day 70 or later. After completion of a new SAGE-217 cycle, continued use of 
any intervention(s) used during the previous Observational Period will be at the investigator’s 
discretion. 
Any benzodiazepines and/or GABA-modulating medication use during the Observational Period 
must be stopped 7 days prior to any new SAGE-217 treatment cycle. As-needed non-GABA 
modulating medication use must be discontinued 1 day prior to any new SAGE-217 treatment 
cycle.  
Medications intended for contraception are permitted for female subjects (see Section 8.1). 
 


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


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


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completion of the parent study and Screening, and throughout the duration of the 
study. 
• For Part A de novo subjects, exposure to another investigational medication or device 
from 30 days prior to Screening and throughout the duration of the study; for Part B 
rollover subjects, exposure to another investigational medication (other than 
SAGE-217) or device is prohibited during the parent study, within the time period 
between completion of the parent study and Screening, and throughout the duration of 
the study. 
• Any known strong inhibitors of CYP3A4 within 28 days or 5 half-lives (whichever is 
longer) prior to a cycle of SAGE-217 and any time during a SAGE-217 treatment 
cycle. 
• Use of strong CYP3A inducers such as rifampin, carbamazepine, enzalutamide, 
mitotane, phenytoin, and St John’s Wort within 28 days prior to a cycle of SAGE-217 
and any time during a SAGE-217 treatment cycle. 
9.2.3. 
Other Restrictions 
The consumption of grapefruit juice, grapefruit, or Seville oranges, or products containing these 
is prohibited within 14 days prior to a cycle of SAGE-217 and at any time during a treatment 
cycle. 
Consumption of alcohol or use of drugs of abuse is discouraged throughout the duration of the 
study. 
Female subjects that are lactating or actively breastfeeding must stop giving breast milk to the 
baby(ies) from just prior to receiving study drug until 7 days after the last dose of study drug 
following each treatment period, if applicable. 
Elective surgeries are prohibited during the initial treatment and follow-up period (through 
Day 28 of Cycle 1; Part A de novo subjects only). 
Subjects must not participate in night shift work during any 14-day treatment period. 
Subjects who are feeling sedated, somnolent, or dizzy, are to refrain from driving or engaging in 
any activity requiring alertness. 
De novo subjects receiving psychotherapy on a regular schedule for at least 60 days prior to 
Day 1 are permitted if the subject intends to continue the therapy through at least the first 14-day 
follow-up period. Rollover subjects receiving psychotherapy on a regular schedule at Screening 
are permitted. 
9.2.4. 
Acceptable Forms of Contraception 
Acceptable forms of highly effective contraception for participants of childbearing potential or 
for partners of male participants who are of childbearing potential include: 
• Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation 


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• Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation  
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Laparoscopic or abdominal occlusion procedure (including bilateral tubal ligation) 
• Hysteroscopic bilateral tubal occlusion procedure performed at least 3 months prior to 
Screening 
• Vasectomized partner (performed at least 3 months prior to Screening) 
Acceptable forms of contraception for male participants include: 
• Sexual abstinence (no sexual intercourse) 
• History of vasectomy (performed at least 3 months prior to Screening) 
• Condom with spermicide used together with highly effective female contraceptive 
methods if the female partner(s) is of childbearing potential (see above for list of 
acceptable female contraceptive methods) 
9.3. 
Treatment Adherence 
SAGE-217 will be self-administered by subjects once daily at approximately 8 PM with 
fat-containing food during the 14-day treatment periods (see Section 10.5). Sites will dispense 
study drug to the subjects to take at home with instructions for use (see Section 10.6, Table 1, 
and Table 4).  
Subjects will be instructed to bring their dosing kit to the site as outlined in Table 1 and Table 4, 
at which time the Investigator or designee will be responsible for ensuring the kit contains 
sufficient doses for the duration of the treatment period.  
All subjects should be reinstructed about dosing instructions at clinic visits during any 
SAGE-217 treatment period. The authorized study personnel conducting the re-education must 
document the process in the subject source records. 
The Investigator(s) will record any reasons for non-compliance in the source documents. 
9.4. 
Randomization and Blinding 
This is an open-label study in which all subjects will receive SAGE-217. 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Description of Study Drug 
SAGE-217 is available as hard gelatin capsules containing a white to off-white powder. In 
addition to the specified amount of SAGE-217 Drug Substance, active SAGE-217 Capsules 
contain croscarmellose sodium, mannitol, silicified microcrystalline cellulose, colloidal silicon 
dioxide, and sodium stearyl fumarate as excipients. Capsules will be available in 20-mg and 
30-mg dose strengths.  
10.2. 
Study Drug Packaging and Labeling 
SAGE-217 will be provided to the clinic pharmacist and/or designated site staff responsible for 
dispensing the study drug in appropriately labeled, subject-specific kits containing sealed unit 
doses. Each unit dose for 30-mg treatment cycles consists of 1 capsule, and each unit dose for 
40-mg and 50-mg treatment cycles consists of 2 capsules. Additional information regarding the 
packaging and labeling is provided in the Pharmacy Manual.  
Study drug labels with all required information and conforming to all applicable FDA Code of 
Federal Regulations and Good Manufacturing Practices/Good Clinical Practices guidelines will 
be prepared by the Sponsor. 
10.3. 
Study Drug Storage 
SAGE-217 is to be stored at room temperature (59 to 86°F; 15 to 30°C), safely and separately 
from other drugs. 
10.4. 
Study Drug Preparation 
Not applicable. 
10.5. 
Study Drug Administration 
SAGE-217 is to be administered orally once daily at approximately 8 PM with fat-containing 
food (eg, within 1 hour of an evening meal which contains fat, or with a fat-containing snack). 
Examples of fat-containing snacks include nuts, peanut butter, avocado, eggs, and cheese.  
If a subject misses a dose, the subject should skip that dose (ie, they should not take the dose in 
the morning) and take the next scheduled dose the next evening. 
10.6. 
Study Drug Accountability 
Upon receipt of study drug, the Investigator(s), or the responsible pharmacist or designee, will 
inspect the study drug and complete and follow the instructions regarding receipt in the 
Pharmacy Manual. A copy of the shipping documentation will be kept in the study files. 
The designated site staff will dispense the supplied subject-specific kits to subjects at the planned 
dispensation visit intervals outlined in Table 1 and Table 4.   
Site staff will access the interactive response technology (IRT) at the Screening Visit to obtain a 
subject ID number for each subject. On Day 1, site staff will access the IRT and provide the 


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necessary subject-identifying information, including the subject ID number assigned at 
Screening, to enroll the eligible subject into the initial treatment cycle 1 and obtain the 
medication ID number for the study drug to be dispensed to that subject. The medication ID 
number and the number of capsules dispensed must be recorded. 
At the subsequent study drug-dispensing visits for any other treatment cycles, the investigator or 
designee will access the IRT, providing the same subject ID number assigned at Screening, to 
obtain the medication ID number for the study drug to be dispensed at that visit. The medication 
ID number, the number of capsules dispensed, and the number of capsules returned by the 
subject at this visit must be recorded. 
If dispensing errors or discrepancies are discovered by site staff or sponsor’s designee, the 
Sponsor must be notified immediately. 
The study drug provided is for use only as directed in this protocol. After the study is completed, 
all unused study drug must be returned as directed or destroyed on site per the Sponsor’s 
instructions. The Investigator or designee must keep a record of all study drug received, 
dispensed and discarded.  
Sage Therapeutics will be permitted access to the study supplies at any time and with appropriate 
notice during or after completion of the study to perform drug accountability and reconciliation. 
10.7. 
Study Drug Handling and Disposal 
At the end of the study, all used and unused study drug will be reconciled and returned to Sage 
Therapeutics for destruction or destroyed locally; disposition of study drug will be documented. 
A copy of the inventory record and a record of any clinical supplies that have been received, 
dispensed or destroyed must be documented by the site as directed. This documentation must 
include at least the information below:  
• the number of dispensed units 
• the number of unused units 
• the number of units destroyed at the end of the study 
• the date, method, and location of destruction. 
10.8. 
Product Complaints 
A product complain is any written, electronic, or verbal expression of dissatisfaction regarding 
the identity, quality, reliability, safety, purity, potency, effectiveness or performance (applicable 
for approved marketed products) of a drug product after it is released for distribution. In the 
course of conduct of the study, study personnel may become aware of a product complaint 
associated with the use of a Sage product. Personnel shall notify Sage within 24 hours by 
forwarding the product complaint information via the contact information listed in the table on 
page 5. Where possible, personnel should segregate any product, materials or packaging 
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11. 
ASSESSMENT OF EFFICACY 
All assessments will be conducted according to the schedules of events (Table 1, Table 2 
Table 3, and Table 4). Assessments that involve subject interviews, including the HAM-D and 
SCID-5-CT, may be audiotaped for independent quality control purposes. All assessments must 
be conducted by raters that have been trained and certified to conduct assessments in this study. 
Every effort should be made for the same rater to perform the assessments at all visits for a 
particular subject. For rollover subjects, assessments in the current study should, if possible, be 
conducted by a different rater than the one who performed the assessments in the parent study.  
11.1. 
Response Parameters 
11.1.1. 
Hamilton Rating Scale for Depression 
The 17-item HAM-D will be used to rate the severity of depression in subjects who are already 
diagnosed as depressed (Williams 2013a; Williams 2013b). The 17-item HAM-D comprises 
individual ratings related to the following symptoms: depressed mood (sadness, hopeless, 
helpless, worthless), feelings of guilt, suicide, insomnia (early, middle, late), work and activities, 
retardation (slowness of thought and speech; impaired ability to concentrate; decreased motor 
activity), agitation, anxiety (psychic and somatic), somatic symptoms (gastrointestinal and 
general), genital symptoms, hypochondriasis, loss of weight, and insight. An assessment 
timeframe of 7 days will be used for all visits. 
The HAM-D total score will be calculated as the sum of the 17 individual item scores.  
The HAM-D subscale scores will be calculated as the sum of the items comprising each 
subscale. A response will be defined as having a 50% or greater reduction from baseline in 
HAM-D total score. Remission will be defined as having a HAM-D total score of ≤7.  
11.1.2. 
Clinical Global Impression  
The CGI is a validated measure often utilized in clinical trials to allow clinicians to integrate 
several sources of information into a single rating of the subject’s condition. The CGI scale 
consists of 3 items. Only the first 2 items are being used in this study.  
The CGI-S uses a 7-point Likert scale to rate the severity of the subject’s illness at the time of 
assessment, relative to the clinician’s past experience with subjects who have the same diagnosis. 
Considering total clinical experience, a subject is assessed on severity of mental illness at the 
time of rating as 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately 
ill; 5=markedly ill; 6=severely ill; and 7=extremely ill (Busner 2007a).  
The CGI-I employs a 7-point Likert scale to measure the overall improvement in the subject’s 
condition posttreatment. The Investigator will rate the subject’s total improvement whether or 
not it is due entirely to drug treatment. Response choices include: 0=not assessed, 1=very much 
improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 
6=much worse, and 7=very much worse (Busner 2007b). The CGI-I is only rated at 
posttreatment assessments. By definition, all CGI-I assessments are evaluated against baseline 
conditions. CGI-I response will be defined as having a CGI-I score of “very much improved” or 
“much improved.”  


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11.1.4. 
PHQ-9 
The PHQ-9 is a subject-rated depressive symptom severity scale. To monitor severity over time 
for newly diagnosed subjects or subjects in current treatment for depression, subjects may 
complete questionnaires at baseline and at regular intervals thereafter. Scoring is total based on 
responses to specific questions, as follows: 0=not at all; 1=several days; 2=more than half the 
days; and 3=nearly every day.  
The PHQ-9 total score will be calculated as the sum of the 9 individual item scores. The PHQ-9 
total score will be categorized as follows: 1 to 4=minimal depression, 5 to 9=mild depression, 
10 to 14=moderate depression, 15 to 19=moderately severe depression; and 20 to 27=severe 
depression. 


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


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12.1.4. 
COVID-19 Questions  
Information regarding diagnosis, isolation, and/or hospitalization due to COVID-19 will be 
documented as part of medical history, AE collection, and prior/concomitant 
medication/procedure collection throughout the study. Questions to be asked are as follows:  
• Were you diagnosed with COVID-19 by a healthcare professional?  
− If the answer is “no”, no further questions. 
− If the answer is “yes”, the following questions are asked:  
 Did you have a test? If yes, was the result positive, negative or 
inconclusive?  
 Were you isolated? If yes, what were the dates of isolation?  
 Were you hospitalized? If yes, what were the dates of hospitalization? 
12.1.5. 
Vital Signs 
Vital signs comprise both supine and standing for systolic and diastolic blood pressure and heart 
rate measurements. Heart rate and blood pressure are to be collected in supine position after the 
subject has been resting for 5 minutes and then after approximately 3 minutes in the standing 
position. Respiratory rate and temperature are collected once, in either position. Vital signs will 
be documented. When vital signs are scheduled at the same time as blood draws, vital signs will 
be obtained first. 
Any abnormality in vital signs will be interpreted by the Investigator as abnormal, NCS or 
abnormal, CS in source documents. New or worsening abnormalities that are judged to be 
clinically significant will be recorded as AEs, assessed according to Section 12.2.1.1.  
12.1.6. 
Electrocardiogram  
Supine 12-lead ECGs will be performed in triplicate at all scheduled time points. The standard 
parameters (heart rate, PR, QRS, QT, and QTcF) as well as any rhythm abnormalities will be 
recorded.  
Any abnormality in ECG intervals will be interpreted by the Investigator as abnormal, NCS; or 
abnormal, CS in source documents. New or worsening abnormalities that are judged to be CS 
will be recorded as AEs, assessed according to Section 12.2.1.1. 
12.1.7. 
Laboratory Assessments 
Samples will be collected in accordance with acceptable laboratory procedures detailed in the 
laboratory manual.  
The clinical laboratory tests to be performed are listed in Table 6. 


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




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thereafter, as outlined in Table 1 and Table 2, including the ET visit for subjects who 
prematurely discontinue.  
In Part B, for rollover female subjects who complete the Screening Visit on the same day as the 
final, end-of-study visit in the parent study, a pregnancy test does not need to be repeated. If the 
Screening Visit is not conducted on the same day as the final, End of Study Visit in the parent 
study, a urine pregnancy test should be conducted. Urine pregnancy tests will be performed in 
females who are not surgically sterile and do not meet the protocol-defined criteria for being 
post-menopausal at all other scheduled timepoints, as outlined in Table 3 and Table 4 including 
the ET Visit for subjects who prematurely discontinue. 
12.1.8. 
Columbia-Suicide Severity Rating Scale  
Suicidality will be monitored during the study using the C-SSRS (Posner 2011). This scale 
consists of a baseline evaluation that assesses the lifetime experience of the subject with suicidal 
ideation and behavior, and a post-baseline evaluation that focuses on suicidality since the last 
study visit. The C-SSRS includes ‘yes’ or ‘no’ responses for assessment of suicidal ideation and 
behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being 
the most severe).  
In Part A, the “Baseline/Screening” C-SSRS form will be completed at Screening (lifetime 
history and past 24 months). The “Since Last Visit” C-SSRS form will be completed at all 
subsequent time points in Part A and in Part B, as outlined in Table 1, Table 2, Table 3, and 
Table 4. 
12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Definition of Adverse Events 
12.2.1.1. Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the use of a 
medicinal (investigational) product whether or not related to the medicinal (investigational) 
product. In clinical studies, an AE can include an undesirable medical condition occurring at any 
time, including baseline or washout periods, even if no study treatment has been administered. 
A TEAE is an AE that occurs after the first administration of any study drug. The term study 
drug includes any Sage investigational product, a comparator, or a placebo administered in a 
clinical trial. 
Laboratory abnormalities and changes from baseline in vital signs, ECGs, and physical 
examinations are considered AEs if they result in discontinuation or interruption of study 
treatment, require therapeutic medical intervention, meet protocol specific criteria (if applicable) 
and/or if the Investigator considers them to be CS. Laboratory values and vital signs that meet 
the criteria for an SAE should be reported in an expedited manner. Laboratory abnormalities and 
changes from baseline in vital signs, ECGs, and physical examinations that are clearly 


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attributable to another AE do not require discrete reporting (eg, electrolyte disturbances in the 
context of dehydration, chemistry and hematologic disturbances in the context of sepsis). 
All AEs that occur after any subject has signed the ICF and throughout the duration of the study, 
whether or not they are related to the study, must be reported to Sage Therapeutics. 
12.2.1.2. Serious Adverse Event  
A serious adverse event is any untoward medical occurrence that at any dose: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Results in a congenital abnormality or birth defect 
An SAE may also be any other medically important event that, in the opinion of the Investigator 
may jeopardize the subject or may require medical intervention to prevent one of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization). 
All SAEs that occur after any subject has signed the ICF and throughout the duration of the 
study, whether or not they are related to the study, must be recorded on the SAE report form 
provided by Sage Therapeutics within 24 hours of first awareness (Section 12.5). Serious adverse 
events occurring after a subject’s final visit (including the last follow-up visit) should be reported 
to Sage or designee only if the Investigator considers the SAE to be related to study treatment.  
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the subject is hospitalized. The site must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was scheduled 
(or on a waiting list to be scheduled) prior to obtaining the subject’s consent to participate 
in the study 
• The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress, in the opinion of the 
Investigator, between the subject’s consent to participate in the study and at the time of 
the procedure or treatment.  
12.3. 
Relationship to Study Drug 
The Investigator must make the determination of relationship to the study drug for each adverse 
event (not related, possibly related or probably related). The Investigator should decide whether, 
in his or her medical judgment, there is a reasonable possibility that the event may have been 
caused by the investigational product. If no valid reason exists for suggesting a relationship, then 
the adverse event should be classified as “not related.” If there is any valid reason, even if 
undetermined, for suspecting a possible cause-and-effect relationship between the investigational 


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product and the occurrence of the adverse event, then the adverse event should be considered at 
least “possibly related.”  
Table 7: 
Relationship to Study Drug 
Relationship 
Definition 
Not Related: 
No relationship between the experience and the administration of study drug; related to 
other etiologies such as concomitant medications or subject’s clinical state. 
Possibly Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug.  
The reaction might have been produced by the subject’s clinical state or other modes of 
therapy administered to the subject, but this is not known for sure. 
Probably Related: 
A reaction that follows a plausible temporal sequence from administration of the study drug 
and follows a known response pattern to the suspected study drug.  
The reaction cannot be reasonably explained by the known characteristics of the subject’s 
clinical state or other modes of therapy administered to the subject. 
If the relationship between the adverse event/serious adverse event and the investigational 
product is determined to be “possible” or “probable”, the event will be considered related to the 
investigational product for the purposes of expedited regulatory reporting. 
12.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. For subjects in Part B, ongoing adverse events with onset during the parent 
study will also be recorded at the Screening Visit. The AE term should be reported in standard 
medical terminology when possible. For each AE, the investigator will evaluate and report the 
onset (date and time), resolution (date and time), intensity, causality, action taken, serious 
outcome (if applicable), and whether or not it caused the subject to discontinue the study drug or 
withdraw early from the study. 
Intensity will be assessed according to the following scale: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities) 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.2.1.2. An AE of severe intensity 
may not be considered serious. 
If a female subject becomes pregnant during this study, pregnancy information must be collected 
and recorded on the Sage Therapeutics pregnancy form and submitted to the sponsor within 
24 hours of learning of the pregnancy. The investigator will also attempt to collect pregnancy 
information on any male subject’s female partner who becomes pregnant while the male subject 
is participating in study. After obtaining the necessary signed informed consent from the 
pregnant female partner directly, the investigator will follow the same pregnancy reporting 
procedures specified for pregnant female subjects. 


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The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) must be followed up and documented on the Sage Therapeutics 
pregnancy outcome form, even if the subject was discontinued from the study. If the pregnancy 
ends for any reason before the anticipated date, the investigator should notify Sage.  
Pregnancy in itself is not regarded as an AE unless there is a suspicion that a study drug may 
have interfered with the effectiveness of a contraceptive medication. If the outcome of the 
pregnancy meets the criteria for immediate classification as an SAE (ie, postpartum 
complication, spontaneous abortion, stillbirth, neonatal death, or congenital anomaly/birth 
defects), the investigator should follow the procedures for reporting an SAE.  
12.5. 
Reporting Serious Adverse Events 
All SAEs must be reported to Sage, or designee, immediately. A written account of the SAE 
must be sent to Sage, or designee, within 24 hours of the first awareness of the event by the 
investigator and/or his staff. The Investigator must complete, sign and date the SAE report form, 
verify the accuracy of the information recorded on the SAE report form with the corresponding 
source documents, and send a copy to Sage, or designee.  
Additional follow-up information, if required or available, should all be sent to Sage 
Therapeutics, or designee, within 24 hours of receipt on a follow-up SAE report form and placed 
with the original SAE information and kept with the appropriate section of the case report form 
and/or study file. 
Any SAEs discovered by the Investigator after the designated follow up time for the study, 
should be promptly reported to Sage, or designee, according to the timelines noted above.  
The contact information for reporting SAEs and/or pregnancies is located in the study reference 
manual.  
Sage, or designee, is responsible for notifying the relevant regulatory authorities of certain 
events. It is the Principal Investigator’s responsibility to notify the IRB of all SAEs that occur at 
his or her site. Investigators will also be notified of all suspected, unexpected, serious, adverse 
reactions (SUSARs) that occur during the clinical study. Institutional Review Boards will be 
notified of SAEs and/or SUSARs as required by local law.  
12.6. 
Overdose 
Overdoses, regardless of presence of associated clinical manifestation(s) (eg, headache, 
abnormal laboratory value), will be considered an AE and recorded as such on the eCRF. Any 
clinical manifestation(s) of overdose must also be recorded as an AE on the eCRF. In addition, 
overdoses must be recorded on an Overdose form and sent to Sage or designee within 24 hours 
of the site becoming aware of the overdose. 


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13. 
STATISTICS 
Separate statistical analysis plans (SAP) will be generated for each part of the study and will 
provide a detailed description of the analyses to be performed in the study. For Part B rollover 
subjects, the parent study database will be used in analysis. The SAP for each study part will be 
finalized and approved prior to database lock for respective parts. The data for Part A de novo 
subjects may be analyzed and reported prior to database lock for Part B rollover subjects. Any 
deviations from or changes to the SAPs following database lock will be described in detail in the 
clinical study report. 
13.1. 
Data Analysis Sets 
Part A (de novo subjects) 
The Safety Set is defined as all subjects administered study drug.  
The Full Analysis Set (FAS) s is defined as all subjects in the Safety Set who completed 
Treatment Cycle 1 and moved on to Observational Period 1 (ie, these subjects had HAM-D 
response at Day 15 and did not discontinue the study for any reason within Treatment Cycle 1). 
In addition, the cohorts of subjects who started with the 30-mg dose versus the 50-mg dose may 
be analyzed separately for de novo subjects. 
Part B (rollover subjects) 
The Safety Set is defined as all subjects administered study drug. 
The FAS is defined as all subjects in the Safety Set who have at least one HAM-D total score 
available after the first dose of study drug within this protocol.  
13.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data. All subjects will be used in the analyses, as 
per the analysis populations, using all non-missing data available.  
13.3. 
General Considerations 
For the purpose of all analyses where applicable, baseline will be defined as the latest value 
before the first dose of study drug in Cycle 1 for de novo subjects. A period-specific baseline 
will be defined as the latest value before the first dose of study drug in each treatment cycle.  
For rollover subjects, the first cycle of treatment in this study will be marked in the database as 
Cycle 2. For purposes of analysis, the treatment cycles and study periods within this protocol 
will be renumbered as 1-4 for subjects who received placebo in the parent study.  
Continuous endpoints will be summarized with number (n), mean, standard deviation (SD), 
median, minimum, and maximum. In addition, change from baseline and/or period-specific 
baseline values will be calculated at each time point and summarized descriptively. For 
categorical endpoints, descriptive summaries will include counts and percentages.  


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13.4. 
Demographics and Baseline Characteristics 
Demographic data (Section 12.1.1) and baseline characteristics, such as height, weight, and body 
mass index, will be summarized using the Safety Set.  
Hepatitis, HIV, drug and alcohol, and pregnancy screening results will be listed, but not 
summarized as they are considered part of the inclusion/exclusion criteria.  
Medical/family history, including interim medical history for Part B rollover subjects (see 
Section 12.1.1), will be listed by subject. 
13.5. 
Response Analyses 
For de novo subjects, response analyses for the first treatment cycle will be provided based on 
the Safety Set. Subjects who do not achieve HAM-D response at Day 15 (at least 50% reduction 
from baseline HAM-D total score or missing Day 15 HAM-D) will be discontinued from the 
study after the 14-day follow-up period with treatment cycle 1. 
Using the Full Analysis Set, Kaplan-Meier (KM) survival curve will be provided for time to first 
re-treatment; the estimand is the median time to first re-treatment -time from the last dose of 
study drug in Cycle 1 to first dose of study drug in Cycle 2- for de novo subjects and will be 
estimated from KM analysis. Number and percentage of subjects needing at least one 
re-treatment (ie, meeting the criteria for re-treatment, but not necessarily retreated) will be 
provided. Number of treatment cycles per subject will be summarized. 
For rollover subjects, using the Full Analysis Set, KM survival curve will be provided for time to 
first re-treatment; the estimand is the median time to first re-treatment -time from the last dose of 
study drug in Cycle 1 to first dose of study drug in Cycle 2 - and will be estimated from KM 
analysis. Number and percentage of subjects needing at least one re-treatment (ie, meeting the 
criteria for re-treatment, but not necessarily retreated) will be provided. Number of treatment 
cycles per subject will be summarized. 
Change from baseline, and/or from period-specific baseline when appropriate, in HAM-D total 
score and subscale scores will be summarized by each treatment cycle. HAM-D response 
(defined as ≥50% reduction from baseline in HAM-D total score) and HAM-D remission 
(defined as HAM-D total score of ≤7) will be summarized for each treatment cycle. Change from 
baseline, and/or from period-specific baseline when applicable, in CGI-S will be summarized for 
each treatment cycle. CGI-I will be summarized for each treatment cycle.  
 
13.6. 
Safety Analyses 
The primary endpoint, the safety and tolerability of SAGE-217, will be evaluated by incidence 
and severity of AEs/SAEs, concomitant medication usage, vital signs, clinical laboratory 
evaluations, and 12-lead ECG. Suicidality will be monitored by the C-SSRS. In addition to 
overall study results, the results from each treatment cycle will be provided separately whenever 
applicable. Safety analyses will use the Safety Set for overall safety.  
A study period is defined as a treatment cycle and its subsequent observation period; the Safety 
Set for a given study period includes subjects in the Safety Set who are dosed in the respective 


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study period. Safety analyses will be provided based on the Safety Set for each study period 
within this protocol when appropriate.  
13.6.1. 
Adverse Events 
The analysis of adverse events will be based on the concept of TEAEs. The incidence of TEAEs 
will be summarized overall and by Medical Dictionary for Regulatory Activities Version 21.0 or 
higher, System Organ Class, and preferred term. Incidences will be presented in order of 
decreasing frequency. In addition, summaries will be provided by intensity (mild, moderate, 
severe) and by causality (related, not related) to study drug (see Section 12.3).  
Any TEAEs leading to discontinuation and SAEs with onset after the start of study drug will also 
be summarized.  
All AEs and SAEs (including those with onset or worsening before the start of study drug) 
through the end of the study will be listed).  
13.6.2. 
Clinical Laboratory Evaluations 
Results of clinical laboratory parameters in each scheduled visit and mean changes from baseline 
and/or modified baseline will be summarized in standard units for each treatment cycle. Normal 
range of each parameter is provided by the laboratory; shift from baseline (and/or period-specific 
baseline) to post-baseline values in abnormality of results will be provided. Potentially CS values 
will be summarized. Any abnormal values deemed clinically significant by the investigator will 
be reported as an AE (see Section 12.2). Clinical laboratory results will be listed by subject and 
timing of collection. 
13.6.3. 
Physical Examinations 
Any clinically significant observation in physical examination will be reported as an AE (see 
Section 12.2). 
13.6.4. 
Vital Signs 
Results from each visit and mean changes from baseline and/or period-specific baseline in vital 
signs will be summarized for each treatment cycle. Any abnormality deemed CS by the 
Investigator will be reported as an AE (see Section 12.2). Potentially CS values will be 
summarized. Vital sign results will be listed by subject and timing of collection. 
13.6.5. 
12-Lead Electrocardiogram 
The following ECG parameters will be listed for each of the triplicate ECGs for each subject: 
heart rate, PR, QRS, QT, and QTcF; the derived mean of each parameter will also be listed. Any 
CS abnormalities or changes in mean ECGs should be reported as an AE (see Section 12.2). 
Mean ECG data will be summarized by visit for each treatment cycle. Potentially CS values of 
QTcF will be summarized. Electrocardiogram findings will be listed by subject and visit for each 
treatment cycle.  


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13.6.6. 
Prior and Concomitant Medications 
Medications will be recorded at each study visit during the study and will be coded using World 
Health Organization-Drug dictionary September 2015, or later.  
The medications taken prior to the initiation of the start of study drug within each part of the 
study will be denoted “Prior”. Those medications taken prior to the initiation of the study drug 
and continuing beyond the initiation of the study drug or those medications started at the same 
time or after the initiation of the study drug will be denoted “Concomitant” (ie, those with a start 
date on or after the first dose of study drug, or those with a start date before the first dose of 
study drug that are ongoing or with a stop date on or after the first dose of study drug).  
Medications will be presented according to whether they are “Prior” or “Concomitant” as 
defined above. If medication dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant.  
Details of prior and concomitant medications will be listed by subject, start date, and verbatim 
term.  
Anxiolytics, anti-insomnia, and/or antidepressant drug use between treatment cycles will be 
summarized, and such use may be explored with respect to the need for re-treatment with 
SAGE-217, response to SAGE-217, and safety of SAGE-217. In particular, for de novo subjects 
only, the time to first anxiolytic or anti-insomnia use, and time to first antidepressant use will be 
provided with KM plots. . 
13.6.7. 
Columbia Suicide Severity Rating Scale 
Suicidality data collected on the C-SSRS at baseline (or period-specific baseline) and by visit 
during the treatment cycle will be summarized by treatment cycle. Listings will include all data, 
including behavior type and/or category for Suicidal Ideation and Suicidal Behavior of the 
C-SSRS.  
13.7. 
Determination of Sample Size 
The sample size is not based on a formal sample size calculation. The sample size of 1200 de 
novo subjects in Part A was chosen in order to have at least 675 subjects complete 24 weeks of 
the study and at least 235 subjects complete through 56 weeks, consistent with the objective of 
assessing SAGE-217 long-term safety. Approximately 350 subjects are expected to rollover from 
the parent study and enroll in Part B.  


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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Before an investigational site can enter a subject into the study, a representative of Sage 
Therapeutics (or designee) will visit the investigational study site per Sage Standard Operating 
Procedures to: 
• Determine the adequacy of the facilities 
• Discuss with the investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Sage Therapeutics or its representatives. 
This will be documented in a Clinical Trial Agreement between Sage Therapeutics and 
the investigator. 
During the study, a monitor from Sage Therapeutics or representative will have regular contacts 
with the investigational site, for the following: 
• Provide information and support to the investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product 
accountability checks are being performed 
• Perform source data verification. This includes a comparison of the data in the case report 
forms with the subject’s medical records at the hospital or practice, and other records 
relevant to the study. This will require direct access to all original records for each 
subject (eg, clinic charts). 
• Record and report any protocol deviations not previously sent to Sage Therapeutics. 
• Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to Sage Therapeutics and those SAEs that met criteria for 
reporting have been forwarded to the IRB. 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
14.2. 
Audits and Inspections 
Authorized representatives of Sage Therapeutics, a regulatory authority, an Institutional Review 
Board (IRB) may visit the site to perform audits or inspections, including source data 
verification. The purpose of a Sage Therapeutics audit or inspection is to systematically and 
independently examine all study-related activities and documents to determine whether these 
activities were conducted, and data were recorded, analyzed, and accurately reported according 
to the protocol, Good Clinical Practice guidelines of the International Conference on 
Harmonization, and any applicable regulatory requirements. The investigator should contact 
Sage Therapeutics immediately if contacted by a regulatory agency about an inspection. 


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14.3. 
Institutional Review Board  
The Principal Investigator must obtain IRB approval for the investigation. Initial IRB approval, 
and all materials approved by the IRB for this study including the subject consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 


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


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


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


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



SAP_001.pdf: 
COVER PAGE 
Official Title: 
A Phase 3, Open-Label, 1-Year Study of the Safety, Tolerability, and Need 
for Re-Treatment with SAGE-217 in Adult Subjects with Major Depressive 
Disorder 
NCT Number: 
 NCT03864614 
Document Date: Part A SAP Version 3.0: 21 July 2023 
 
 


  
 
 
 
 
SAGE THERAPEUTICS INCORPORATED 
Statistical Analysis Plan 
Methods 
Protocol Number 217-MDD-303 
[SAP for Part A – De Novo Subjects Only] 
 
 STUDY TITLE: A PHASE 3, OPEN-LABEL, 1-YEAR STUDY OF THE SAFETY, 
TOLERABILITY, AND NEED FOR RE-TREATMENT WITH SAGE-217 IN 
ADULT SUBJECTS WITH MAJOR DEPRESSIVE DISORDER 
Author of SAP: 
 
Version: 3.0 
Version Date of SAP: 21 July 2023 
Sponsor: Sage Therapeutics, Inc. 
   215 First Street 
  Cambridge, Massachusetts 02142 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written consent of 
Sage Therapeutics Incorporated is strictly prohibited except to the extent required under applicable laws or regulations.  
Persons to whom the information is disclosed must be informed that the information is confidential and may not be further 
disclosed by them. 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................. 3 
LIST OF ABBREVIATIONS ...................................................................................... 6 
1. 
INTRODUCTION .................................................................................... 8 
2. 
STUDY OBJECTIVES ............................................................................ 9 
2.1. 
Primary Objective ..................................................................................... 9 
2.2. 
Secondary Objective ................................................................................. 9 
9 
3. 
STUDY ENDPOINTS ............................................................................ 10 
3.1. 
Primary Endpoints .................................................................................. 10 
3.2. 
Secondary Endpoints .............................................................................. 10 
10 
4. 
STUDY DESIGN ................................................................................... 12 
4.1. 
Overall Design ........................................................................................ 12 
4.2. 
Sample Size and Power .......................................................................... 14 
4.3. 
Randomization ........................................................................................ 14 
4.4. 
Blinding and Unblinding ........................................................................ 14 
5. 
MODIFICATIONS ................................................................................. 15 
5.1. 
Modifications to the Approved Clinical Study Protocol ........................ 15 
5.2. 
Modifications to the Approved Statistical Analysis Plan ....................... 15 
5.3. 
Modifications to the Approved DMC Charter ........................................ 15 
6. 
ANALYSIS SETS .................................................................................. 16 
6.1. 
Enrolled Set ............................................................................................ 16 
6.2. 
Safety Set ................................................................................................ 16 
6.3. 
Period-specific Safety Set ....................................................................... 16 
6.4. 
Full Analysis Set ..................................................................................... 16 
6.5. 
Dose Switch Set ...................................................................................... 16 
7. 
STATISTICAL ANALYSIS .................................................................. 17 
7.1. 
General Considerations ........................................................................... 17 
7.1.1. 
Study Day Definition .............................................................................. 18 
7.1.2. 
Study Period Definition .......................................................................... 18 
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7.1.3. 
Subject Completion Status ...................................................................... 19 
7.1.3.1. 
Eligible/Qualified for Re-treatment for Safety Set ................................. 20 
7.1.4. 
Missing Data ........................................................................................... 21 
7.2. 
Background Characteristics .................................................................... 21 
7.2.1. 
Subject Disposition ................................................................................. 21 
7.2.2. 
Protocol Deviations ................................................................................ 22 
7.2.3. 
Demographics and Baseline Characteristics ........................................... 23 
7.2.4. 
Medical/Surgical History ........................................................................ 24 
7.2.5. 
Prior and Concomitant Medications / Concomitant Procedures ............. 25 
7.2.6. 
Study Drug Exposure .............................................................................. 26 
7.2.7. 
Study Drug Adherence ........................................................................... 27 
7.3. 
Efficacy Analysis .................................................................................... 28 
7.3.1. 
Definition of Response Variables ........................................................... 28 
7.3.1.1. 
Hamilton Rating Scale for Depression (HAM-D) .................................. 29 
7.3.1.2. 
Clinical Global Impression – Improvement (CGI-I) .............................. 30 
7.3.1.3. 
Clinical Global Impression – Severity (CGI-S) ...................................... 30 
31 
7.3.1.5. 
Patient Health Questionnaire (PHQ-9) ................................................... 31 
31 
 32 
32 
7.3.2. 
Visit Windows ........................................................................................ 33 
7.3.3. 
Analysis of Response Variable(s) ........................................................... 34 
7.3.4. 
Time to Relapse and Durability of Study Drug Effect ........................... 37 
7.4. 
Safety Analysis ....................................................................................... 38 
7.4.1. 
Adverse Events ....................................................................................... 39 
7.4.2. 
Clinical Laboratory ................................................................................. 45 
7.4.3. 
Vital Signs .............................................................................................. 48 
7.4.4. 
Electrocardiogram ................................................................................... 49 
7.4.5. 
Physical Examination ............................................................................. 50 
7.4.6. 
Columbia Suicide Severity Rating Scale (C-SSRS) ............................... 50 
8. 
SUMMARY OF INTERIM AND DMC ANALYSES .......................... 52 
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9. 
REFERENCES ....................................................................................... 53 
10. 
LIST OF APPENDICES......................................................................... 54 
10.1. 
Appendix A: Schedule of Assessments (Screening, Treatment, and 
Follow-up Periods) ................................................................................. 54 
10.2. 
Appendix B: Schedule of Events (Observational Period) ...................... 57 
10.3. 
Appendix C: Handling of Missing Dates ................................................ 59 
10.4. 
Appendix D: Algorithms ........................................................................ 61 
10.5. 
Appendix E: List of Displays ................................................................. 67 
 
LIST OF TABLES 
Table 1: 
Diagnostic Screening Test Results ......................................................... 24 
Table 2: 
HAM-D Subscale Score Calculations .................................................... 29 
Table 3: 
Visit Windows for Efficacy Analysis (with respect to each treatment 
cycle) ....................................................................................................... 33 
Table 4: 
Safety endpoints and variables in the summary tables ........................... 39 
Table 5: 
Clinical Laboratory Tests ....................................................................... 45 
Table 6: 
Laboratory Parameters – Criteria for PCS Values .................................. 47 
Table 7: 
Vital Signs – Criteria for PCS Values .................................................... 49 
Table 8: 
ECG Parameters – Criteria for PCS and PCSC Values .......................... 50 
 
LIST OF FIGURES 
Figure 1: 
 Study Design Schematic ........................................................................ 13 
 
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LIST OF ABBREVIATIONS 
Abbreviation or specialist term 
Explanation 
ADT 
Antidepressant therapy 
AE 
adverse event 
ATC 
anatomical therapeutic chemical 
BLQ 
below the limit of quantitation 
BMI 
body mass index 
CGI-I 
Clinical Global Impression scale for improvement 
CGI-S 
Clinical Global Impression scale for severity 
CS 
Clinical significant 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DSM-5  
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition  
ECG 
Electrocardiogram 
eCRF  
electronic case report form  
EDC 
Electronic data capture 
EOT 
end of treatment 
ET 
early termination 
FSH  
follicle stimulating hormone  
GABA 
γ-aminobutyric acid 
HAM-D 
Hamilton Depression Rating Scale 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
 
 
LFT 
Liver Function Tests 
LLOQ 
lower limit of quantification 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MDD 
major depressive disorder 
MDE 
major depressive episode 
MedDRA 
Medical Dictionary for Regulatory Activities 
PCS 
 
Potentially clinically significant  
PCSC 
potentially clinically significant change 
PHQ-9 
Patient health Questionnaire 
 
 
PT 
preferred term 
QTcF 
QT corrected according to Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCID-5-CT 
Structured Clinical Interview for Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition for clinical trials 
SD 
standard deviation 
 
 
SE 
standard error 
SI 
International System of Units 
SOC 
system organ class 
SpO2 
pulse oximetry 
TEAE 
treatment-emergent adverse event 
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Abbreviation or specialist term 
Explanation 
WHO 
World Health Organization  
 
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1. 
INTRODUCTION 
Study 217-MDD-303 has two parts – Part A for de novo subjects, and Part B for subjects rolling over 
from 217-MDD-305 (a double-blind placebo-controlled study).  This statistical analysis plan (SAP) is 
for the final analysis of Study 217-MDD-303 Part A, and is based on clinical study protocol, version 
7.0, dated 10 May 2021.  The SAP for Part B will be provided separately along with its own CSR. 
The purpose of the SAP is to describe in detail the statistical methodology and the statistical analyses 
to be conducted for the above-mentioned protocol for de novo subjects.  The SAP will be approved 
and finalized before database lock. 
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2. 
STUDY OBJECTIVES  
2.1. 
Primary Objective 
To determine the safety and tolerability of initial treatment and/or re-treatment(s) with 
SAGE-217 in adults with Major Depressive Disorder (MDD) experiencing a major 
depressive episode (MDE) at study entry for de novo participants over a 1-year period. 
2.2. 
Secondary Objective 
The secondary objectives of Study 217-MDD-303A are: 
  To assess the need for re-treatment with SAGE-217 following initial treatment in 
adults with MDD experiencing an MDE at study entry for de novo participants 
over a 1-year period 
  To assess the response of initial treatment and/or re-treatment(s) with SAGE-217 
following an initial 2-week treatment period in adults with MDD experiencing an 
MDE at study entry for de novo participants over a 1-year period  
 
 
 
 
 
 
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3. 
STUDY ENDPOINTS 
3.1. 
Primary Endpoints 
  The safety and tolerability of the initial treatment with SAGE-217 and re-
treatment with SAGE-217, as assessed by the incidence and severity of adverse 
events/serious adverse events; changes from baseline in clinical laboratory 
measures, vital signs, and electrocardiograms (ECGs); and suicidal ideation and 
behavior using the Columbia Suicide Severity Rating Scale (C-SSRS) 
3.2. 
Secondary Endpoints 
  The need for re-treatment with SAGE-217 as assessed by:  
  Time to first re-treatment (Kaplan-Meier curves) 
  Number of subjects achieving the requirements for re-treatment 
 Number of re-treatment cycles for each subject 
   The response of initial treatment and/or re-treatment as assessed by:  
  Change from baseline in the 17-item Hamilton Rating Scale for Depression 
(HAM-D) total score at the end of each 14-day treatment (initial and/or re-
treatment) period 
  HAM-D response at the end of each 14-day treatment (initial and/or re-
treatment) period, defined as a ≥50% reduction in HAM-D score from 
baseline 
  HAM-D remission at the end of each 14-day treatment (initial and/or re-
treatment) period, defined as HAM-D total score ≤7 
  Clinical Global Impression - Improvement (CGI-I) response, defined as 
“much improved” or “very much improved”, at the end of each 14-day 
treatment (initial and/or re-treatment) period 
  Change from baseline in Clinical Global Impression - Severity (CGI-S) score 
at the end of each 14-day treatment (initial and/or re-treatment) period 
 
 
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4. 
STUDY DESIGN  
4.1. 
Overall Design  
This is an open-label, long-term, longitudinal study in adult subjects with MDD currently 
experiencing an MDE. See Figure 1 for a schematic of the study design. 
The Screening Period begins with the signature of the informed consent form (ICF); the ICF 
must be signed prior to beginning any screening activities.  
The diagnosis of MDD must be made according to Structured Clinical Interview for DSM-5 
Clinical Trial Version (SCID-5-CT) performed by a qualified healthcare professional. 
Subjects will undergo preliminary screening procedures at the Screening Visit to determine 
eligibility, including completion of the MADRS, HAM-D, and CGI-S. 
Before Protocol Amendment 3 (dated 06 February 2020), all participants received SAGE-217 
30 mg. After Protocol Amendment 3, all newly enrolled participants and all ongoing 
participants for subsequent treatment periods received SAGE-217 50 mg. Note: no 
participants were dosed under Amendment 3; the first participants who received 50 mg were 
enrolled under Protocol Amendment 4 (19 March 2020). 
Subjects achieving response with SAGE-217 followed for 48 weeks 
Beginning on Day 1, qualified subjects self-administer SAGE-217 30 mg or 50 mg 
(depending on the amendment the subject has consented to) orally once daily in the evening 
for 14 days. A follow-up visit will be conducted after the completion of the 14-day treatment 
period. 
If a subject does not exhibit a response to SAGE-217 by Day 15 of the initial treatment, 
defined as a ≥50% reduction in HAM-D score from baseline, the subject will be terminated 
from the study upon completion of the 14-day follow-up period. 
After the initial treatment period, the HAM-D responders will be followed naturalistically for 
48 weeks. Subjects will return to the site every 8 weeks (Day 70 is the first 8-week visit – 56 
days after the 14-day treatment period, irrespective of when the subject completed treatment 
period) during the 48-week observational period for clinical assessments. 
SAGE-217 treatment cycles 
Each 14-day treatment period of SAGE-217 and corresponding 14-day follow-up period is 
considered a cycle (Day 28). The initial treatment is Cycle 1 and re-treatments will be 
numbered sequentially. Each cycle will begin with Day 1 (eg, the first day of the first re-
treatment period will be Day 1 of Cycle 2). A maximum of 5 treatment cycles is permitted; a 
new re-treatment cycle cannot start after Week 48.  
The need for re-treatment will be assessed every 14 days via remote assessments during the 
48-week observational period based on the results of the subject-reported PHQ-9; if the 
PHQ-9 score is ≥10, the subject will return to the site to be assessed by the clinician-
administered HAM-D. New SAGE-217 cycles may be initiated for subjects with a HAM-D 
score ≥20 assessed approximately 1 week from the PHQ-9 score ≥10. In all subjects, the End 
of Study (EOS)/Week 52 Visit is mandatory if another scheduled on-site visit does not fall in 
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the Week 52 window. A minimum period of 8 weeks (56 days) is required between SAGE-
217 treatment periods, i.e. first dose date of Cycle X – last dose date of Cycle (X-1) +1 >=56.  
One time dose reduction is permitted within a treatment cycle at the discretion of the 
investigator if the safety of the subject is of concern; for subjects who start with 30mg this 
reduced dose is 20mg, while for subjects who start with 50mg this reduced dose is 40mg. If a 
subject was treated with 40mg in any treatment cycle, they may be assigned 50mg or 40mg at 
the start of a subsequent treatment cycle, according to the discretion of the investigator. 
Details guiding the use of as-needed benzodiazepines and GABA-modulators for insomnia 
(eg, eszopiclone, zopiclone, zaleplon, and zolpidem), new ADT use, or increases in 
concomitant medication ADT dose are provided in protocol Section 9.2.1. The potential for 
withdrawal-related events, including seizure, is monitored following the guidelines outlined 
in protocol Section 8.5.1, which include study drug discontinuation or dose reduction. If a 
subject exhibits suicidality at any time, they will return to the site as soon as possible for 
assessment by the Investigator. 
The assessments for the Screening Period and Treatment and Follow-up Periods are 
summarized in Section 10.1, Appendix A; the assessments for the observational period and 
any unscheduled visits are summarized in Section 10.2, Appendix B.  
SAGE-217 study periods 
An observation period is defined as the time between end of one treatment cycle (marked by 
Day 28 visit date or Day 28 11:59 pm if Day 28 visit date is not available) and the beginning 
of the next treatment cycle (marked by the first dose date/time in the treatment cycle).  A 
study period is defined as a treatment cycle, plus the observation period immediately 
following. Algorithms for study period derivations are discussed in Section 10.4, Appendix 
D. 
Figure 1: 
 Study Design Schematic 
 
Note: The Observation period only applies to those subjects that exhibit a HAM-D response by Day 15 with the 
initial treatment, defined as a ≥50% reduction in HAM-D score from baseline. Subjects that do not exhibit a 
HAM-D response by Day 15 of Cycle 1 will be terminated from the study upon completion of the Day 28 
follow-up visit. Subjects who exhibit a HAM-D response by Day 15 of Cycle 1 will be eligible for re-treatment 
at Day 70 or later. 
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4.2. 
Sample Size and Power 
The sample size is not based on a formal sample size calculation. The sample size of 1200 de 
novo subjects was chosen in order to have at least 675 subjects complete 24 weeks of the 
study and at least 235 subjects complete through 56 weeks.   
4.3. 
Randomization 
Study 217-MDD-303 is an open-label design, hence randomization does not apply.  
4.4. 
Blinding and Unblinding 
All subjects who receive any study drug in this study will receive SAGE-217 in an open-
label manner; hence blinding/unblinding does not apply. 
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5. 
MODIFICATIONS  
5.1. 
Modifications to the Approved Clinical Study Protocol 
There is no modification in the analysis of data compared to what has been written in the 
approved clinical study protocol. 
5.2. 
Modifications to the Approved Statistical Analysis Plan 
This is the first version of the SAP for the final analysis. 
5.3. 
Modifications to the Approved DMC Charter 
Not applicable. 
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6. 
ANALYSIS SETS 
6.1. 
Enrolled Set 
The Enrolled Set is defined as all subjects who signed the ICF and are not a screen failure. 
6.2. 
Safety Set 
The Safety Set is defined as all subjects who are administered study drug. 
6.3. 
Period-specific Safety Set 
The Period-specific Safety Set includes subjects in the Safety Set who are administered study 
drug in the corresponding treatment cycle.  
6.4. 
Full Analysis Set 
The Full Analysis Set (FAS) is defined as all subjects in the Safety Set who have HAM-D 
response at Day 15 in treatment cycle 1 and discontinuation from study date, if it exists, is 
after the end of treatment cycle 1.    
Programming algorithms for period-specific Safety Set and FAS derivations are discussed in 
Section 10.4, Appendix D. 
6.5. 
Dose Switch Set 
The Dose Switch Set is defined as all subjects in the safety set who received 30mg in 
Treatment Cycle 1, Day 1 and received 50mg on Day 1 in a subsequent re-treatment cycle.   
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7. 
STATISTICAL ANALYSIS 
7.1. 
General Considerations 
Unless otherwise specified, continuous endpoints will be summarized with n, mean, standard 
deviation (SD), median, minimum (min) and maximum (max).  The minimum and maximum 
will be reported with the same degree of precision (i.e., the same number of decimal places) 
as the observed data.  Measures of location (mean and median) will be reported to 1 degree 
of precision more than the observed data and measures of spread (standard deviation) will be 
reported to 2 degrees of precision more than the observed data.  
For categorical endpoints, descriptive summaries will include counts and percentages.  
Percentages will be presented to 1 decimal place unless otherwise specified; the denominator 
of percentages will be the number of subjects in the analysis set used unless specified 
otherwise.  
All analyses and summary outputs will be generated using SAS® 9.4 or higher. 
All subject data, including those derived, to support tables and figures will be presented in 
the subject data listings.  In general, the subject data listings will be sorted by dose cohort, 
subject number and assessment visit and date (and time, if applicable).  The summary tables 
will be presented descriptively for the analysis population by dose cohort and/or by treatment 
cycle/study period.  Displays on Dose Switch Set will be presented by first dose received in 
each cycle.  A listing of dose cohort for each subject and first dose (mg) for each subject in 
each study period will be provided. 
For the purpose of all safety and response analyses, unless specified otherwise, baseline is 
defined as the last non-missing measurement prior to the first dose of study drug. Period-
specific baseline is defined as the last non-missing measurement before the first dose of study 
drug in each 14-day treatment cycle.  If the time of an assessment is collected, baseline will 
be the latest assessment prior to first dose of study drug administration time; if the time of an 
assessment is not collected, the assessment on Day 1 is assumed to be prior to dosing if the 
protocol or study manual mentions that this assessment needs to be before dosing or it is 
collected as “pre-dose”.   
Cohorts of this study are defined based on treatment received per dose dispensation as 
follows: 
 High dose cohort is defined as subjects who received 50mg of SAGE-217 in 
Treatment Cycle 1, Day 1. 
 Low dose cohort is defined as subjects who received 30mg of SAGE-217 in 
Treatment Cycle 1, Day 1 and received 30mg or 20mg of SAGE-217 as the last 
dose dispensed. 
 Dose Switch cohort is defined as the subjects who received 30mg of SAGE-217 
in Treatment Cycle 1, Day 1 and received 50mg of SAGE-217 in Treatment Cycle 
X, Day 1, where X>1. This is the same set of subjects who are in Dose Switch 
Set. 
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 30mg cohort is defined as the subjects who received 30mg of SAGE-217 in 
Treatment Cycle 1, Day 1 and combines the Low Dose and Dose Switch cohorts.  
Whenever possible, data will be presented for the 3 cohorts (high dose cohort, low dose 
cohort, dose switch cohort) separately, in addition to all groups together as SAGE-217 
Overall cohort.  In addition, when appropriate, data will also be presented for 30mg cohort, 
which refers to the first dose in first cycle, and thus combines the Low Dose and Dose Switch 
cohorts.  For Dose Switch Set, the data will be presented by study period, by the Treatment 
Cycle X, Day 1 dose received per dose dispensation in the specific period as well as for 
SAGE-217 Overall (irrespective of dose received). All displays will be presented based on 
treatment received, with no consideration for planned treatment. 
All assessments, including unscheduled assessments or un-windowed assessments, are 
included in the derivation for last value on treatment, last value in the study period, and 
potentially clinically significant (PCS) values. 
7.1.1. 
Study Day Definition 
It is to be noted that the study drug is administered in the evening with food.  The 
assessments at the clinic on Day 1 are hence before the first dose of study drug. 
Study day will be defined as follows:  
  The day of subject receiving the first dose of study drug is designated as Day 1. 
  For visit days on or 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”. 
Study day from the first dose of study drug within specific study period will be calculated as: 
visit date – first dose date in the specific period +1. 
7.1.2. 
Study Period Definition 
 Treatment Period X starts with first dose of study drug date/time in Study Period 
X and ends with last dose of study drug in Study Period X (both with >0 capsules 
consumed) + 1 day. 
  Follow-up Period X starts after the end of Treatment Period X and ends on Day 
28 visit date/time from vitals; or if vital signs are not assessed, Day 28 HAM-D 
date/time is to be used. If none of these have a recorded time available, Day 28 
vitals date will be used; if no vitals date, Day 28 HAM-D date will be used.  If 
Day 28 does not exist in either vitals or HAM-D, then the earlier of (treatment 
period X start date/time + 28 days, study completion/discontinuation date) is to be 
used. 
 Treatment Cycle Period X starts with start of Treatment Period X and ends with 
end of Follow-up Period X. 
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 Observation Period X starts right after the end of Treatment Cycle X and ends 
right before the first dose of study drug in the Treatment Cycle X+1.  Observation 
Period X end date/time: Right before the first dose of study drug in the Treatment 
Cycle X+1 if such treatment cycle exists, or study completion/discontinuation 
date if no X+1 cycle exists. 
 Study period X starts with start of Treatment Period X and ends with end of 
Observation Period X. 
The definitions for periods may be slightly different for different endpoints. For details of the 
algorithm used for defining the periods for concomitant medication, please refer to Section 
7.2.5 and Section 10.4, Appendix D. 
Except for AEs, which has been described separately in Section 7.4.1, if the start date is the 
same as treatment start date but time for either the evaluation or the treatment start is 
missing, consider this evaluation according to the nominal visit designation (e.g. Cycle 1 or 
OBS1 will be assigned Study period 1); if the nominal visit designation is ambiguous, then 
assign in Study Period X-1, not in Study Period X,  
7.1.3. 
Subject Completion Status 
Subject completion status for the Safety Set is classified in the following manner: 
Completer for the study:  
 Study Conclusion CRF Page: indicates completion of the study AND  
 Subject dosing status: must have been dosed with SAGE-217 within this protocol  
Prematurely withdrawn from the study:  
 Study Conclusion CRF Page: indicates premature withdrawal from the study 
AND  
 Subject dosing status: must have been dosed with SAGE-217 within this protocol  
Prematurely withdrew from study period X, where X=1,2,3,4,5: 
 Study Conclusion CRF Page: indicates premature withdrawal from the study 
AND 
 Subject dosing status: Subject is dosed in study period X and not dosed in study 
period X+1 if X+1 is viable in the study, and the study discontinuation date is on 
or after the first dose of study period X 
For details of study discontinuation date derivation, refer to Section 10.4, Appendix D. 
Completed study period X, where X=1,2,3,4,5: 
 If the participant is dosed in Study period X+1 when X+1 is viable OR  
 Study period X is the last period the participant is dosed and the participant did 
not prematurely withdraw in study period X per the previous definition  
Discontinued treatment cycle X, where X=1, 2, 3, 4, 5:  
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 Study Conclusion CRF Page: indicates premature withdrawal from the study 
AND  
 Subject dosing status: Subject is dosed in cycle X and not dosed in cycle X+1 if 
X+1 is viable in the study, and the study discontinuation date is on or before the 
treatment cycle X end date  
For details of study discontinuation date derivation, refer to Section 10.4, Appendix D. 
Completed treatment cycle X, where X=1, 2, 3, 4,5:  
 If the subject is dosed in cycle X+1 when X+1 is viable OR  
 Cycle X is the last cycle the subject is dosed and the subject did not prematurely 
withdraw in treatment cycle X per the previous definition  
A subject is counted at the beginning of Observation Period X if the subject has completed 
the treatment cycle X. 
7.1.3.1. 
Eligible/Qualified for Re-treatment for Safety Set 
Subjects eligible/qualified for re-treatment for Safety Set are defined as follows: 
A subject is eligible for re-treatment in treatment cycle X if (discontinuation/completion date 
- treatment end date in cycle X-1 >=56).   
A subject is qualified for re-treatment in treatment cycle X if the subject is eligible for re-
treatment in treatment cycle X AND there exists at least one HAM-D total score >=20 after 
treatment cycle X-1 end date (i.e., any time after 14 days from the treatment end date in cycle 
X-1)  and must be before 
 The first dose in treatment cycle X when treatment cycle X start date/time is non-
missing OR 
 last day in the study 
Subjects reached threshold of re-treatment in Cycle X based on HAM-D>=20 on or after 56 
days from the treatment end date in Cycle X-1: 
A subject reached the threshold of re-treatment in Cycle X based on HAM-D>=20 in Cycle X-1 
if the subject is eligible for re-treatment in Cycle X AND there exists at least one HAM-D total 
score >=20 on or after 56 days from the treatment end date in Cycle X-1 and this HAM-D 
evaluation must be before treatment start date/time in Cycle X if the subject received treatment in 
Cycle X.  If the subject did not receive treatment in Cycle X, then the date of study 
discontinuation/completion will be used. 
Subjects reached threshold PHQ-9>=10 after 14 days from the treatment end date in Cycle X: 
A subject reached the threshold of re-treatment in Cycle X based on PHQ-9 >=10 in Cycle X if 
the subject is in FAS and continuing in observation period in Cycle X and there exists at least one 
PHQ-9 score >=10 after 14 days from the treatment end date in Cycle X (ie., in observation 
period X) and this PHQ-9 evaluation must be before treatment start date/time in Cycle X+1 if the 
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subject received treatment in Cycle X+1.  If the subject did not receive treatment in Cycle X+1, 
then the date of study discontinuation/completion will be used. 
7.1.4. 
Missing Data 
All subjects will be used in the analyses, as per the analysis populations, using all non-
missing data available; this may include windowing of unscheduled visits when scheduled 
visit data is missing.  For windowing algorithm, please see Section 7.3.2, Imputation of 
missing data in scoring of questionnaires is discussed in respective sections below.  Handling 
of missing or incomplete dates is discussed in Section 10.3, Appendix C. 
7.2. 
Background Characteristics  
7.2.1. 
Subject Disposition 
The analyses of subject disposition will use all subjects who provided written inform consent 
to the study. 
The summaries of subject disposition will include the number of subjects who were screened, 
screen failed, enrolled, did not receive study drug, and who received any study drug, and the 
number and percentage of subjects who completed treatment cycle 1, who prematurely 
withdrew from the study during treatment cycle 1 and associated primary reason for 
discontinuation, who prematurely discontinued study treatment during treatment period 1 and 
associated primary reason for discontinuation, who completed the study, who prematurely 
withdrew from the study and primary reasons for not completing the study, and who 
switched the dose from 30 mg to 50 mg for the first time by study period. If a subject is 
rescreened because the subject had been a screen failure the first time, the status of the 
subject will be determined from the second screening. In the count of screened subjects, this 
subject will be counted only once. 
The number and percentage of subjects in each analysis set will be provided, using Safety Set 
as the denominator. 
The summaries of subject disposition by study period will include the number of subjects at 
the beginning of each observation period, the number and percentage of subjects dosed in the 
treatment cycle, who discontinued treatment during the 14-day treatment period, primary 
reason for discontinuing the treatment, and who completed the treatment in the study period. 
This will use Full Analysis Set. 
The number and percentage of subjects by the length of study participation (through study 
completion/discontinuation date) since the time of first dose will be provided in category of 
months: < 3 months, ≥3 months but less than 6 months, ≥6 months but less than 9 months, ≥9 
months. This will use Safety Set. Below is the definition of the cut off for the category, where 
start date varies based on the analysis:  
 End of 3-month period: start date + 90 days  
 End of 6-month period: start date + 181 days  
 End of 9-month period: start date + 272 days  
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The number and percentage of subjects initiating the latest re-treatment cycle X will be 
provided, along with the number and percentage of subjects who have not needed any re-
treatment.  This will use Safety Set.  
A separate data listing will be provided for all subjects who prematurely discontinued 
treatment or prematurely withdrew from the study with reasons, number of days on study 
drug, etc. Separate data listings will be provided for subject participation by study period, 
and by treatment cycle. 
A separate data listing will be provided for all subjects regarding screen failure status (Y/N), 
whether they meet all eligibility criteria (if not, which ones are not met) and reason for screen 
failure, if applicable. 
A summary of subject progression, including information on how many subjects progressed 
from one cycle to another will be provided.  A separate summary for subjects who 
discontinued treatment prematurely or withdrew from the study will be provided by study 
period to include the duration on the study and the latest HAM-D total score available. 
A summary of the number and percentage of Safety Set subjects who discontinued the study 
in < 3 months , ≥3 months but less than 6 months, ≥6 months but less than 9 months, ≥9 
months, with primary reason for discontinuation, will be summarized for the high dose and 
30 mg dose cohorts; for those in the study for <3 months, the summarization will be further 
subset for those who discontinued from Day 1-15, Day 16-28, and after Day 28.  The 
summary will also include the number and percentage of Safety Set subjects who completed 
the study overall and subset by the number of treatment cycles initiated. 
A summary of the number and percentage of subjects who discontinued the study and with 
associated reason for discontinuation and the number and percentage of subjects who 
completed the study overall and subset by the number of treatment cycles initiated will be 
presented for Full Analysis Set subjects who were HAM-D responders at Day 15 in 
Treatment Cycle 1. 
The latest available HAM-D (continuous and categories of none [<=7], mild [8-13], 
moderate [14-19], severe [20-25], and very severe [>=26]), latest available PHQ-9 
(continuous and categories of minimal [0-4], mild [5-9], moderate [10-14], moderately severe 
[15-19], and severe [20-27]), and latest available CGI-S (continuous and categories of 
normal/borderline [1-2], mild [3], moderate [4], severe [5], and very severe [6]), and days 
since the start of the most recent treatment cycle to last day on study will be summarized for 
the high dose and 30 mg cohorts and overall for the Full Analysis Set.  This summary will be 
presented for those who completed the study and those who prematurely discontinued the 
study. 
7.2.2. 
Protocol Deviations 
Protocol deviations identified during site monitoring will be captured on eCRF and 
categorized by the study team as major (efficacy, safety and GCP, separately) and minor 
deviations. The major deviations will be summarized by type. 
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7.2.3. 
Demographics and Baseline Characteristics 
The following analyses will be done for the Safety Set and the FAS separately. 
Demographic data (age, race, sex, ethnicity, employment status, highest education level, 
marital/civil status) and baseline characteristics, such as height, weight, and body mass index 
(BMI), will be summarized. Highest education level will be categorized in the summary 
tables as follows: 
 Less than or equal to12th grade, but no diploma 
 12th grade diploma or GED 
 Some college but no degree 
 Associate degree 
 Bachelor’s degree 
 Master’s degree 
 Professional degree 
 Doctoral degree 
The severity of the depressive episode upon entry into the study will be evaluated using the 
Montgomery-Åsberg Depression Rating Scale (MADRS). The MADRS is a 10-item 
diagnostic questionnaire used to measure the severity of depressive episodes in subjects with 
mood disorders.  MADRS is collected at Screening and at Day 1 (prior to dosing). Each 
MADRS item ranges from 0 to 6; higher MADRS scores indicate more severe depression.  
The MADRS total score will be calculated as the sum of the 10 individual item scores, which 
ranges from 0 to 60. If more than two individual items are missing, the MADRS total score 
will not be calculated and will be left as missing. If less than or equal to two individual item 
scores are missing, the missing item scores will be imputed by the mean of all other available 
item scores to calculate the MADRS total score. MADRS scores from Screening and Day 1 
pre-dose will be summarized. 
Subgroups of interest at baseline will be summarized for the following categories: 
  Sex (Male, Female) 
  Race (Black or African American, White, Other) 
  Age (18-24, 25-50, 51-64, ≥65 years) 
 Elderly/Non-elderly: Age >=65 years, Age <65 years 
  Baseline antidepressant use (Yes, No) 
[Antidepressant medications are identified by ATC3 level code of N06A]  
  BMI (≤18.4, 18.5-24.9, 25-29.9, ≥30 kg/m2) 
 Baseline HAM-D total score (<22, >=22) 
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 Baseline Anxious Depression Status (Yes, No) 
[Baseline HAM-D Anxiety Subscale standardized score >=39 (same as HAM-D 
Anxiety subscale raw score >=7)] 
Diagnostic labs are part of screening; a data listing using Safety Set will be provided. The 
following diagnostic screening test results will be included in this listing.  
Table 1: 
Diagnostic Screening Test Results 
Diagnostic  
 
 
 
Serum 
Urine 
Breathalyzer 
 
Hepatitis B 
Hepatitis C 
Reflex HCV RNA 
HIV-1 and -2 
Female subjects that are not 
surgically sterile and do 
not meet the protocol-
defined criteria for being 
post-menopausal: serum 
hCG 
Female subjects, if 
menopause is suspected 
and not surgically sterile: 
FSH 
Drug screen including: 
amphetamines, 
barbiturates, 
benzodiazepines, 
cannabinoids, cocaine, 
opiates, phencyclidine 
Female subjects that are not 
surgically sterile and do 
not meet the protocol-
defined criteria for being 
post-menopausal: urine 
hCG  
Alcohol 
 
 
7.2.4. 
Medical/Surgical History 
The following analyses will use the Safety Set and FAS.  
The history related to MDD (date of initial diagnosis of MDD, antidepressant usage, 
information of depressive episodes, etc.) will be collected.  Years since initial diagnosis of 
MDD, Antidepressant usage, and information of depressive episodes will be summarized. 
Years since initial diagnosis of MDD, days since start of current episode and days since start 
of first episode will be calculated using:   First dose date of the study drug – Date of interest. 
For imputation of incomplete dates in medical history, please see Section 10.3. When a 
subject reports the current episode to be the first one, the number of episodes will be imputed 
as 1 for summary purposes. 
The following analyses will use the Safety Set. 
Medical/surgical history collected at screening will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA), Version 24.0.  
Medical/surgical history data will be summarized by system organ class (SOC) and preferred 
term (PT). A summary of medical/surgical history that are ongoing at the time of screening 
will be provided separately.   
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Subject history of psychiatric disorders and family psychiatric history will be summarized.  
7.2.5. 
Prior and Concomitant Medications / Concomitant Procedures 
The following analyses will use the Safety Set. 
All medications taken and procedures undergone during the study will be recorded; in 
addition, psychotropic medications taken within 6 months prior to screening, and non-
psychotropic medications taken within 30 days prior to screening will also be collected.  
Psychotropic and non-psychotropic medications are collected on the same CRF page with 
prior or current psychotropic medication question answered “Yes” for psychotropic 
medication and “No” for non-psychotropic medication.  All medications will be coded using 
World Health Organization-Drug dictionary (WHO-DD) March 2021. 
Medications will be presented according to whether they are being taken prior to and/or 
during the study (concomitant).  Prior medications are defined as those taken prior to the 
initiation of the start of study drug.  Concomitant medications are defined as those with a 
start date on or after the first dose of study drug or those with a start date before the first dose 
of study drug that are ongoing or with a stop date on or after the first dose of study drug.  If 
medication dates are incomplete and it is not clear whether the medication was concomitant, 
it will be assumed concomitant.  For imputation of missing concomitant medication dates, 
please refer to Section 10.3, Appendix C. Note that it is possible for a medication to be both 
‘prior’ and ‘concomitant’. Algorithms for concomitant medication period derivations are 
discussed in Section 10.4, Appendix D. Concomitant medications will also be defined by 
study period as follows: all medications with a start date on or after the first dose of study 
drug in the study period X but before the first dose of study drug in the study period X+1, or 
those with a start date before the first dose of study drug that were ongoing at the time of first 
dose of study drug in the study period X or with a stop date on or after the first dose of study 
drug in the study period X.  These will be further divided by study period as follows (if time 
is missing, the date will be used for this algorithm):  
 On-treatment concomitant medications in study period X are all medications with 
a start date on or after the first dose of study drug in the study period X AND the 
start date on or before the last dose of study drug in the study period X or those 
with a start date before the first dose of study drug that were ongoing at the time 
of first dose of study drug in the study period X,  
 Post-treatment concomitant medications in study period X are all medications 
with a start date after the last dose of study drug in the study period X but before 
the first dose of study drug in the study period X+1. 
For further details on the programming algorithm of concomitant medication periods, please 
refer to Section 10.4, Appendix D. 
Prior and concomitant non-psychotropic medication use will be summarized by anatomical 
therapeutic chemical (ATC) level 1 and Standard Medication Name. Similar summary tables 
will be provided for psychotropic medications. The differentiation of non-psychotropic 
versus psychotropic medications are based on the answer to the prior or current psychotropic 
medication question on CRF page.   
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On-treatment and post-treatment concomitant medications by study period will be 
summarized – psychotropic and non-psychotropic medications separately. 
Antidepressants that have been taken at the same dose for at least 60 days prior to the first 
dose of study drug are permitted if the subject intends to continue the stable dose through the 
initial treatment and follow-up period (through Day 28 of Cycle 1).  Antidepressant 
medications are identified by ATC3 level code of N06A.  A summary of Antidepressant 
concomitant medication use at period-specific baseline and any change in these medications 
post-baseline (including the observation period) will be provided by study period. 
Anxiolytic and anti-insomnia medication use at Baseline will be summarized. Anxiolytic 
medications are identified by ATC3 level code of N05B. Anti-insomnia medications are 
identified by ATC3 level code of N05C or standard medication name is in (TRAZODONE, 
MIRTAZAPINE) or ATC Level 4 = R06AA. A summary of anxiolytic concomitant 
medication use at period-specific baseline and any change in these medications post-baseline 
(including the observational period) will be provided by study period.  A summary of anti-
insomnia concomitant medication use at period-specific baseline and any change in these 
medications post-baseline (including the observation period) will be provided by study 
period. 
Baseline use of antidepressant, anxiolytic, or anti-insomnia medication in Study Period X are 
the medications specified above respectively with a start date before the first dose of study 
drug in the study period X AND they were ongoing or with a stop date on or after the first 
dose of study drug in the study period X. 
Time to first anxiolytic, time to first anti-insomnia use, and 
 
 
 
 
 
 
 
. Changes to 
dose of antidepressants taken at baseline vs. post-baseline, including dose increases, are not 
counted as new antidepressant. For the analyses of time to first anxiolytic and time to first 
anti-insomnia, only the medications started on or after the first dose date of study drug in the 
study are considered.  A subject will be censored at the subject’s last day in the study if the 
subject has not taken the specified medication after the first treatment. Programming 
algorithms for censoring are discussed in Section 10.4, Appendix D. 
Concomitant procedures are recorded on a separate eCRF page; this will be presented in a 
listing by subject, and will not be summarized. The study day for the end date of the 
procedure will be provided, when a complete end date is available. 
7.2.6. 
Study Drug Exposure 
The following analyses will use the Safety Set. 
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Total drug exposure (in mg) is defined as the total study drug in mg for SAGE-217 that was 
taken during the study period.  If the patient skips the dose on any of the days, the dose taken 
is 0 mg. Total drug exposure for the entire study is the sum of period-specific total drug 
exposure.  
In the 50/40mg dose regimen, the daily dose is 2 capsules – 30+20 for 50mg, 20+20 for 
40mg.  The capsules are blinded for the strength.  If one capsule is taken within 50mg dosing 
in a day, 30mg exposure will be assumed for that day. If one capsule is taken within 40mg 
dosing in a day, 20mg exposure is unambiguous for that day.   
Total exposure duration to study drug (in days) for each study period is defined as:  Date of 
last dose in the specific period – date of first dose in the specific period + 1. Note that this 
does not exclude days when the dose has been missed.  Total exposure duration to study drug 
for the entire study is the sum of exposure duration over all study periods. 
Percent of the planned exposure received is defined as the total drug exposure, divided by 
planned exposure, times 100.  Planned exposure will be based on actual duration of treatment 
within the specific study period for the subject, based on whether there was a dose reduction 
in the 30mg or 50mg dosing days:   
1.  If the subject discontinues treatment within Day 2 and Day 14 (both inclusive) 
without a dose reduction, the planned exposure is: last dose day of study drug x initial 
dose in the cycle 
2.  If the subject discontinues treatment within Day 2 and Day 14 (both inclusive), but 
the subject has undergone a dose reduction on Day X, the planned exposure is: (X-1) 
x initial dose in the cycle + (last dose day of study drug – X + 1) x reduced dose in 
mg. 
3.  If the subject does not discontinue treatment and does not have a dose reduction, the 
planned exposure is: 14 x initial dose in the cycle.  
4. If the subject does not discontinue treatment but has undergone a dose reduction on 
Day X, the planned exposure is: (X-1) x initial dose in the cycle + (14 – X + 1) x 
reduced dose in mg. 
Planned exposure for the entire study is the sum of period-specific planned exposure and will 
be used as the denominator for the percent calculation for the entire study. 
Total drug exposure, total exposure duration and percent of the planned exposure received 
for the entire study will be summarized descriptively. 
Study drug exposure will also be summarized descriptively by study period. 
7.2.7. 
Study Drug Adherence 
The following analyses will use the Full Analysis Set. 
Study drug adherence (%) is defined as the number of capsules taken, divided by the number 
of capsules planned to be taken, times 100.   
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The schedule of study drug is one capsule per day for 30/20mg dose regimen, and 2 capsules 
per day for 50/40mg regimen.   
1.  If the subject discontinues treatment within Day 2 and Day 14 (both inclusive), the 
planned number of capsules is the last dose day of study drug, times x, where x=1 for 
30/20mg dose regimen, =2 for 50/40mg dose regimen. 
2.  If the subject does not discontinue treatment, the planned number of capsules is 14 
for 30/20mg dose regimen, 28 for 50/40mg dose regimen. 
The planned number of capsules to be taken is the sum of period-specific planned number of 
days the study drug should be taken, and will be used as the denominator for the calculation 
of adherence. 
Study drug adherence will be summarized descriptively by study period. Number and 
percentage of subjects with study drug adherence in categories - <75%, 75-100%, >100% - 
will be provided by study period. 
Any dose reduction from 30mg to 20mg or 50mg to 40mg will be listed by treatment cycle. 
7.3. 
Efficacy Analysis  
Using the FAS, Kaplan-Meier (KM) survival curve by dose cohort will be provided for time 
to first re-treatment; median will be provided from KM estimates – for SAGE-217 Overall, 
High Dose, Low Dose and Dose Switch cohorts. A subject will be censored at the date of 
study discontinuation/completion if the subject did not re-treat; algorithms for censoring are 
discussed in Section 10.4, Appendix D. In addition to median, the first and third quartile will 
be provided.  A similar plot will be provided for the High Dose cohort versus 30 mg cohort. 
The number and percentage of subjects eligible for at least 1 re-treatment, qualified for at 
least 1 re-treatment, dosing in at least 1 re-treatment, and dosing in exactly X re-treatments, 
and the number of re-treatment cycles per participant and time between treatment cycles will 
be summarized. Number of treatment cycles per subject will also be summarized. This 
summary will be repeated by antidepressant use at Study Period 1 Baseline. Box plots 
corresponding to the time to dosing in Treatment Cycle X+1 since the last dose in Treatment 
Cycle X (in days) by at least X re-treatments/exactly X re-treatments will be presented. 
A listing of PHQ-9 and HAM-D scores leading to re-treatment will be provided. A listing of 
treatment cycles, including treatment cycle number, dates of each treatment start and end 
dates (including first treatment), duration of treatment, date of 28-day follow-up visit, and 
last day on study (only populated on last re-treatment) will be provided. 
All efficacy analyses will be performed for the FAS unless otherwise specified. For Study 
Period 1 efficacy analyses may be performed on Safety Set. 
7.3.1. 
Definition of Response Variables 
The efficacy variables are defined below. 
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7.3.1.1. 
 Hamilton Rating Scale for Depression (HAM-D) 
The 17-item HAM-D will be used to rate the severity of depression in subjects already 
diagnosed as depressed.  HAM-D is collected during the clinic visit on Days 1, 8, 15, 28 
during each treatment cycle, and then once every 8 weeks (Q8W) during the observation 
periods. The 17-item HAM-D comprises of individual ratings related to the following 
symptoms: depressed mood (sadness, hopeless, helpless, worthless), feelings of guilt, suicide, 
insomnia (early, middle, late), work and activities, retardation (slowness of thought and 
speech; impaired ability to concentrate; decreased motor activity), agitation, anxiety (psychic 
and somatic), somatic symptoms (gastrointestinal and general), genital symptoms, 
hypochondriasis, loss of weight, and insight.  Each item is scored in a range of 0 to 2 or 0 to 
4, with higher scores indicating a greater degree of depression.  The score for each item will 
be summed to compute a total score, which ranges from 0 to 52, rounded to a whole number.  
If more than 3 individual items are missing a response, the HAM-D total score will not be 
calculated and will be left as missing.  If less than or equal to 3 individual item scores are 
missing, the missing item scores will be imputed by the mean of all other available item 
scores, or the maximum possible values for the missing responses, whichever is smaller, to 
calculate the HAM-D total score.   
Four HAM-D subscale scores will be calculated as the sum of the individual rating scores 
related to each subscale, divided by the total possible score within the subscale, multiplied by 
100, and rounded to a whole number.  If more than one item is missing or HAM-D total score 
is missing, the subscale score is left as missing; if one item on a particular subscale is 
missing, but has been imputed for the calculation of total score, the imputed value from total 
score calculation will be used in subscale score calculation for that item.  Following table 
describes the subscale score calculation: 
Table 2: 
HAM-D Subscale Score Calculations 
HAM-D Subscales 
Items 
Calculation 
Core 
Depressed mood 
Feeling of guilt 
Suicide 
Work and activities 
Retardation 
Sum of the 5-item responses/20 x 100.   
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale.  
Anxiety 
Anxiety psychic 
Anxiety somatic 
Somatic symptoms gastrointestinal 
Somatic symptoms general 
Hypochondriasis 
Insight 
Sum of the 6-item responses/18 x 100.   
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale.  
Bech-6 
Depressed mood 
Feeling of guilt 
Sum of the 6-item responses/22 x 100.   
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HAM-D Subscales 
Items 
Calculation 
Work and activities 
Retardation 
Anxiety psychic 
Somatic symptoms general 
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale.  
Maier 
Depressed mood 
Feeling of guilt 
Work and activities 
Retardation 
Agitation 
Anxiety psychic 
Sum of the 6-item responses/24 x 100.   
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale.  
HAM-D response will be defined as having a 50% or greater reduction from baseline in 
HAM-D total score; only subjects who have non-missing total score of HAM-D at baseline 
as well as the visit will be considered in HAM-D response evaluation.  HAM-D remission 
will be defined as having a HAM-D total score of ≤7; if HAM-D total score is missing at the 
visit, remission will not be defined. For a sensitivity analysis the worst-case scenario 
imputation will be used, i.e. missing values for HAM-D response (remission) will be 
considered as “No response” (“No remission”). 
7.3.1.2. 
 Clinical Global Impression – Improvement (CGI-I) 
The Clinical Global Impression Improvement (CGI-I) employs a 7-point Likert scale to 
measure the overall improvement in the subject’s condition post-treatment. The Investigator 
will rate the subject’s total improvement. Response choices include: 0=not assessed, 1=very 
much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally 
worse, 6=much worse, and 7=very much worse. The CGI-I is rated at post-treatment 
assessments on Days 8, 15, 28 during each treatment cycle, and Q8W visit during the 
observation periods. By definition, all CGI-I assessments are evaluated against baseline 
conditions. CGI-I response will be defined as having a CGI-I score of “very much improved” 
or “much improved.” Missing CGI-I at the visit will not be evaluated for response. For a 
sensitivity analysis the worst-case scenario imputation will be used, i.e. missing values for 
CGI-I response will be considered as “No response”. 
7.3.1.3. 
 Clinical Global Impression – Severity (CGI-S) 
The Clinical Global Impression Severity (CGI-S) uses a 7-point Likert scale to rate the 
severity of the subject’s illness at the time of assessment, relative to the clinician’s past 
experience with subjects who have the same diagnosis. Considering total clinical experience, 
a subject is assessed on severity of mental illness at the time of rating as 1=normal, not at all 
ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 
and 7=extremely ill.  CGI-S is collected at Screening, Days 1, 8, 15, 28 during each treatment 
cycle, and at Q8W visit during the observation periods. 
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7.3.1.5. 
Patient Health Questionnaire (PHQ-9)  
The PHQ-9 is a 9-item subject-rated depressive symptom severity scale. It is collected during 
the clinic visit on Days 1, 8, 15, 28 during each treatment cycle, at Q2W (remote), and at 
Q8W visit during the observation periods. Scoring is based on responses to specific 
questions, as follows: 0=not at all; 1=several days; 2=more than half the days; and 3=nearly 
every day.  
The PHQ-9 total score will be calculated as the sum of the 9 individual item scores. If more 
than 1 individual item is missing, the PHQ-9 total score will not be calculated and will be left 
as missing.  If 1 individual item score is missing, the missing item score will be imputed by 
the mean of all other available item scores to calculate the PHQ-9 total score. The PHQ-9 
total score will be categorized as follows: 0 to 4=minimal depression, 5 to 9=mild 
depression, 10 to 14=moderate depression, 15 to 19=moderately severe depression; and 20 to 
27=severe depression. 
 
 
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7.3.2. 
Visit Windows 
The scheduled visits within a treatment cycle will not be windowed and will be used at 
nominal visit value for analysis purposes.  Observation period (scheduled and unscheduled), 
unscheduled, end-of-treatment (EOT), and early termination (ET) visits will be mapped to a 
scheduled visit for analysis.  In order to accommodate as much data as possible into analysis, 
these windows have been widened compared to protocol-specified operational window, to 
have no gap between them; these windows are used for analysis purposes only. 
Once analysis visit windows are assigned, all visits, including scheduled visits, unscheduled 
visits, and EOT/ET visits will be eligible for being flagged as the “analyzed record” within 
the analysis window; a subject’s individual analysis visit window could potentially contain 
more than 1 visit.  In the event of multiple visits falling within an analysis window or in case 
of a tie, the following rules will be used in sequence to determine the “analyzed record” for 
the analysis visit window: 
 If the data from the scheduled visit is available, except for observational visits, 
then the scheduled visit data will be used.  
 If there is no data from the scheduled visit available, the data closest to the 
scheduled study day for that window will be used.  
 If there is a tie between the data in the number of days before and after the 
scheduled day, the later data will be used.  
 If there is a tie on the target day, the record with later time will be used.  
The summary by visit will use the “analyzed records” only – at most one per subject.  The 
data not flagged as the “analyzed record” will be included in listings. An unscheduled visit 
that does not fall under any analysis window (e.g. in case one is available after Week 52) will 
remain in the database and will be included in the listings.   
Table 3 displays windows for response analysis.  
Table 3: 
Visit Windows for Efficacy Analysis (with respect to each treatment 
cycle) 
Scheduled Visit 
Target Study Day  
Study Day Window for Visit  
Baseline / Period-specific Baseline 
Day 1  
Latest available before the first dose in 
Treatment Cycle 1 / in Treatment Cycle X 
Day 8 (1 day) 
Day 8 
Day 2 – Day 11 
Day 15 (1 day) 
Day 15 
Day 12 – Day 18 
Day 28 (3 day) 
Day 28 (last dose date 
+ 14 days) 
Day 19 – Day 37 (last dose date + 5 days, 
+23 days) 
Q8W (±3 days) 
Day 70  
Day 126  
 Day 63 – Day 77 
Day 119 – Day 133 
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Scheduled Visit 
Target Study Day  
Study Day Window for Visit  
Day 182 
Day 238 
Day 294 
Day 350 
Day 175 – Day 189 
Day 231 – Day 245 
Day 287 – Day 301 
Day 343 – Day 357 
Notes: Parenthesized study day window are for Observation period visits (scheduled or unscheduled), 
unscheduled visits, EOT, and ET for subjects who have discontinued treatment prematurely and only when such 
visit date is more than 4 days from the last dose of study drug intake (visit date – last dose date +1 >4) within 
the same treatment cycle. If the date does not fall in the parenthesized window days, the visit will be matched 
against the Observation period visit only (Q8W) within the same study period.  If the visit date is less than or 
equal to 4 days from the last dose date, or the visit comes from subjects who completed the treatment, 
parenthesized window days do not apply; the visit will be matched against the non-parenthesized window for 
treatment cycle as well as observation period visits, as appropriate, within the same study period. 
 
End-of-Study (EOS) visit is a scheduled visit which is to be done for subjects who completed 
one year of follow up (target date from first cycle first dose date = Day 364).  If the data from 
EOS visit is available, then scheduled visit data will be used.  If EOS scheduled visit is not 
available, and there are visits (observational period visit, unscheduled visit, EOT or ET) that 
first cannot be windowed to a cycle-specific day, they will then be evaluated for EOS 
window for the completers (per study conclusion CRF page) (≥Day 358 counting from cycle 
1 first dose date) and in case of multiple visits the one closest to the target date of Day 364 
(from cycle 1 first dose date) will be used in analysis. In summaries by study period, EOS 
visit will be presented within the last study period the subject had been treated with SAGE-
217.   
7.3.3. 
Analysis of Response Variable(s) 
Response analyses for the first treatment cycle will be provided based on the Safety Set. The 
FAS will be used for all response summary tables by study period. Subjects who do not 
achieve HAM-D response at Day 15 (at least 50% reduction from baseline HAM-D total 
score or missing Day 15 HAM-D) will be discontinued from the study after the 14-day 
follow-up period with treatment cycle 1. 
The following response endpoints will be summarized descriptively by scheduled assessment 
time point – for study period 1 and by each study period separately, for SAGE-217 Overall 
and by dose cohort: 
 HAM-D total score – observed, change from baseline, percent change from 
baseline, change from period-specific baseline, percent change from period-
specific baseline  
 HAM-D subscale scores – observed, change from baseline, percent change from 
baseline, change from period-specific baseline, percent change from period-
specific baseline 
 HAM-D individual item score – observed, change from baseline, percent change 
from baseline, change from period-specific baseline, percent change from period-
specific baseline  
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 HAM-D response – missing response not accounted (bar chart will also be 
provided) 
 HAM-D response – missing response counted as No response (bar chart will also 
be provided) 
 HAM-D remission – missing remission not accounted (bar chart will also be 
provided) 
 HAM-D remission – missing remission counted as No remission (bar chart will 
also be provided) 
 CGI-I score -observed  
 CGI-I response – missing response not accounted 
 CGI-I response – missing response counted as No response  
 CGI-S scores – observed and change from baseline, change from period-specific 
baseline 
 
 
 
 
 
 
Line plot of mean and standard deviation (SD) over time will be prepared for change from 
baseline in HAM-D total score, HAM-D subscale scores, and 
 separately for each 
study period, and HAM-D total score separately for different combination of each study 
period and anti-depressant use at baseline combination. For line plots of these efficacy 
endpoints and bar charts of HAM-D response and remission by study period, for each time 
point on X axis, the number of participants withdrawing from the study between last time 
point and this time point will be provided in a row below the X-axis.  For time points beyond 
Day 70, another row of numbers indicating how many participants got retreated (and thus are 
no longer continuing within this study period) between the last time point and this time point 
will be provided; this number should be ‘not applicable’ (NA) at time points before Day 70 
within each period. In line plots, a vertical line at Day 70 will be provided to indicate in 
footnote that this is when a participant becomes eligible for re-treatment; for bar charts, Day 
70 will be starred and footnoted in a similar way. 
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Forest plot for change from period-specific baseline in HAM-D scores at Day 15 – means, 
confidence interval – will be provided for total score by subgroup and by study period. 
Similar plot will be provided for change from period-specific baseline in subscale score of 
HAM-D by study period. 
To explore how the antidepressant use affects HAM-D results, the following summaries will 
be provided, and corresponding line plots for total score and bar charts for HAM-D response 
and remission will be provided: 
 HAM-D total score for each study period, by use of antidepressant at period-
specific baseline, using FAS subjects who were dosed in the specific study period 
 HAM-D total score for Treatment Cycle 1, by use of antidepressant at baseline, 
using Safety set  
 HAM-D Response for each study period, by use of antidepressant at period-
specific baseline, using FAS subjects who were dosed in the specific study period 
 HAM-D Response for Treatment Cycle 1, by use of antidepressant at baseline, 
using Safety set  
 HAM-D Remission for each study period, by use of antidepressant at period-
specific baseline, using FAS subjects who were dosed in the specific study period 
 HAM-D Remission for Treatment Cycle 1, by use of antidepressant at baseline, 
using Safety set  
 Summary of select efficacy endpoints – HAM-D total score, HAM-D response, 
HAM-D remission, CGI-S, CGI-I scores, CGI-I response, 
, 
 
 and 
 - by study periods will be presented for Dose Switch Set by 
the first dose of 30mg, 40mg or 50mg in the respective re-treatment study period. 
Following subgroup summaries by study period will be provided for HAM-D total score: 
 Sex (Male, Female) 
  Race (Black or African American, White, Other) 
  Age (18-24, 25-50, 51-64, ≥65 years) 
 BMI (≤18.4, 18.5-24.9, 25-29.9, ≥30 kg/m2) 
 Anxious Depression status at Baseline (Yes, No) 
In addition, for FAS who were dosed in study period X (X>1), the summary of  HAM-D total 
score, HAM-D subscale scores, CGI-S score and 
 will be provided for Baseline, Day 
8, Day 15, Day 28 and any scheduled visit in the current and previous study periods.  Line 
plot of percent change from period-specific baseline will be provided for HAM-D total score 
and HAM-D subscale scores for FAS who were dosed in study period X for current and 
previous study periods on the same page. 
For exploratory purposes, responders from Day 15 (>=50% decrease from period-specific 
baseline) in Treatment Cycle X will be followed to the end of the study through line plot of 
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HAM-D total score at scheduled visits, by dose group (only High and Low dose groups) and 
over subsequent cycles. To support the figure, summary tables will be provided.   
A line plot of HAM-D total score for responders of cycle X who needed exactly X number of 
treatments will be provided by over time since the first dose in the latest treatment cycle, by 
dose group (only High and Low Dose groups). To support the figure, summary tables will be 
provided. Bar charts for percentage of responders and non-responders at Day 15 in each 
study period along with the percent of responders (separately for non-responders) at the 
previous cycle among each group will be presented. 
7.3.4. 
Time to Relapse and Durability of Study Drug Effect  
Time to relapse in each study period: 
Time to relapse is defined as follows: Take only the HAM-D responders (HAM-D total 
score, change from period-specific baseline <= -50%) in study period X on D15 – safety set 
for study period 1, FAS for study periods 2-5.  A relapse is defined as a subject having a 
HAM-D total score after D15 where HAM-D total score >=20 and there exists a PHQ-9 
>=10 within 10 days prior to this HAM-D.  Time to relapse is defined as the number of days 
from Day 15 in study period X to relapse for the first time within study period X.  
Responders in study period X who do not experience relapse within study period X will be 
censored at the latest HAM-D evaluation date before the first dose in study period X+1 if it 
exists or the last HAM-D evaluation in the study if there is no further treatment cycle for the 
subject. Time to relapse will be calculated only for the subset of D15 HAM-D responders in 
Cycle X who have at least one HAM-D after Day 15 HAM-D date. 
Durability of study drug effect in each study period: 
Durability measured by HAM-D: Take only the HAM-D responders (HAM-D total score, 
change from period-specific baseline <= -50%) in study period X on D15 – safety set for 
study period 1, FAS for study periods 2-5.  Durability of study drug effect measured by 
HAM-D criterion is defined as the number of days between Day 15 in study period X to the 
first period-specific study day when the reduction in the HAM-D total score from the period-
specific baseline within the study period X is less than 50%.  A subject who does not have 
any HAM-D showing less than 50% reduction in HAM-D total score from the period-
specific baseline after Day 15 in the study period X will be censored at the latest HAM-D 
evaluation date before the first dose in study period X+1 if it exists or the last HAM-D 
evaluation in the study if there is no further treatment cycle for the subject. Durability 
measured by HAM-D will be calculated only for the subset of D15 HAM-D responders in 
Cycle X who have at least one HAM-D after Day 15 HAM-D date. 
Durability measured by PHQ-9: Take only the HAM-D responders (HAM-D total score, 
change from period-specific baseline <= -50%) in study period X on D15 safety set for study 
period 1, FAS for study periods 2-5.  Durability of study drug effect measured by PHQ-9 
criterion is defined as the number of days from Day 15 in study period X to the first PHQ-9 
after Day 15 when PHQ-9 score >=10 within the study period X.  A subject who does not 
have any PHQ-9 showing score >=10 post Day 15 within the study period X will be censored 
at the latest PHQ-9 evaluation date before the first dose in study period X+1 if it exists or the 
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last PHQ-9 evaluation in the study if there is no further treatment cycle for the subject. 
 
. 
 
 
 
. In addition, for each study period, number of HAM-D 
evaluations post Day 15 per subject, percent of HAM-D evaluations post Day 15 per subject 
with >=50% reduction from period-specific baseline, number of PHQ-9 evaluations post Day 
15 per subject and percent of PHQ-9 evaluations post Day 15 per subject with score <10 will 
be summarized by dose cohort. 
7.4. 
Safety Analysis 
The primary objective is to evaluate the safety and tolerability of SAGE-217 as assessed by 
the incidence and severity of adverse events; changes from baseline in clinical laboratory 
measures, vital signs, and ECGs; and suicidal ideation and behavior using the C-SSRS. 
Safety analyses will use the Safety Set for overall safety.  Safety analyses will be provided 
based on the Safety Set for each study period when appropriate.  
The safety endpoints evaluated at scheduled visits are taken as done in nominal visit, without 
any windowing.  If a value is available for a nominal scheduled visit, that value will be used 
in summary by visit.  Unscheduled visits, EOT and ET visits will be windowed using the 
same window days outlined in Table 3 for efficacy endpoints.  If scheduled visit value is not 
available, a value from the specific visit window will be included in summary, the choice of 
the record following the same rule as described in Section 7.3.2. 
Last value on treatment and Last value in the study period will be included in the summaries 
whenever indicated in the relevant sections below.  Last value on treatment is defined as the 
last post-baseline value between the first dose of study drug (exclusive) and up to last dose of 
study drug + 1 day (inclusive) within the study period. Last value on study within study 
period is defined as the last post-baseline value after the first dose of study drug within the 
study period.  
Potentially clinically significant (PCS) values for parameters in lab, vital signs and ECG have 
been identified by the medical personnel in the team ahead of the analysis.  These are listed 
in the respective sections below.  
The safety endpoints and variables considered in the summary tables for this study are 
summarized in Table 4.   
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Table 4: 
Safety endpoints and variables in the summary tables 
Safety 
Evaluation 
Incidence 
Observed 
Value 
Change/ 
Period-
specific 
change from 
Baseline 
Abnormality/Clinical 
Significance (CS) 
Potentially Clinical 
Significance (PCS) 
AEs 
X 
 
 
 
 
Labs 
 
X 
X  
Z 
X 
ECGs 
 
X 
X 
Z 
X 
Vital Signs 
 
X 
X  
 
X 
C-SSRS 
X 
X 
X 
 
 
Note: PCS criteria are outlined in sections 7.4.2-7.4.4 
X = to be summarized in tables 
Z = to be presented in listings only 
7.4.1. 
Adverse Events 
Adverse events (AEs) are collected starting at the time of informed consent and throughout 
the duration of the subject’s participation in the study.  All adverse events will be coded 
using MedDRA version 24.0.  
A treatment-emergent adverse event (TEAE) is defined as an adverse event with onset on or 
after the first dose of study drug. The TEAEs will be further categorized by study period of 
occurrence as follows: 
A TEAE for study period X is defined as an adverse event with onset on or after the first 
dose of study drug in the treatment cycle X until prior to the first dose of study drug in the 
subsequent study period X+1.  
 A treatment period TEAE in study period X is defined as an adverse event with 
onset on or after the first dose of study drug in the treatment cycle X but within 1 
day since the last dose of study drug in the same treatment cycle.   
 A follow up period TEAE in the study period X is defined as an adverse event 
with onset after 1 day from the last dose of study drug in the same treatment cycle 
but on or before 14 days after the last dose in the same study period (typically 
Day 28 visit day).  
 A treatment cycle TEAE in the study period X includes treatment period TEAEs 
and follow-up period TEAEs within the study period X. 
 An observation period TEAE in the study period X is defined as an adverse event 
with onset after 14 days after the last dose within study period X and before start 
of subsequent study period X+1. 
If the date of an adverse event is incomplete and an unambiguous determination could not be 
made with respect to its onset time versus the first dose of study drug and/or last dose of 
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study drug, the adverse event will be assumed to be a TEAE and a treatment period AE in the 
cycle in which it started (or assigned to Cycle 1 if cycle of AE start could not be determined).  
For imputation of missing AE dates, please refer to Section 10.3, Appendix C. For further 
details on the programming algorithm of AE periods, please refer to Section 10.4, Appendix 
D. 
An overview summary table of TEAEs will present the number and percentage of subjects as 
well as the number of events using Safety Set for the following: 
 TEAE 
 TEAEs by maximum severity (severe>moderate>mild) 
 TEAE leading to dose reduction 
 TEAE leading to dose interruption 
 TEAE leading to dose reduction or dose interruption 
 TEAE leading to discontinuation of study drug 
 TEAE leading to withdrawal from the study 
 Death 
 Serious Adverse Event (SAE) 
An overview summary table of TEAE by study period will present the number and 
percentage of subjects as well as the number of events for the following, and this summary 
will be repeated by period-specific baseline use of antidepressant subgroups: 
 TEAE  
 Treatment Cycle Period TEAE 
 Treatment Period TEAE 
 Follow-up Period TEAE 
  Observation Period TEAE 
 TEAEs by maximum severity (severe>moderate>mild) 
 Treatment Cycle Period TEAE 
 Treatment Period TEAE 
 Follow-up Period TEAE 
 Observation Period TEAE 
 TEAE leading to dose interruption 
 Treatment Cycle Period TEAE 
 TEAE leading to Dose Reduction 
 Treatment Cycle Period TEAE 
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 TEAE leading to Dose Reduction or Dose Interruption 
 Treatment Cycle Period TEAE 
 TEAE leading to discontinuation of study drug 
 Treatment Cycle Period TEAE 
 TEAE leading to withdrawal from the study 
 Treatment Cycle Period TEAE 
 Treatment Period TEAE 
 Follow-up Period TEAE 
 Observation Period TEAE 
 Death 
 Treatment Cycle Period TEAE 
 Treatment Period TEAE 
 Follow-up Period TEAE 
 Observation Period TEAE 
 Serious Adverse Event (SAE) 
 Treatment Cycle Period TEAE 
 Treatment Period TEAE 
 Follow-up Period TEAE 
 Observation Period TEAE 
Incidence of TEAEs will be provided by SOC and PT.  A subject is counted only once under 
each SOC and PT in case of multiple occurrences of the same AE. These summaries will be 
sorted by decreasing frequency of overall column, then by High Dose column, then 
alphabetically – for SOC first, then within SOC by PT.  
For observation period TEAE summaries, the below rules will be used for the denominator in 
calculating the percentage: 
 Study Period 1: number of subjects in the Safety Set at the beginning of the 
observation period in the study period 1 will be used as the denominator in 
calculating the percentage. (This is because the study terminates some subjects by 
design from follow up beyond treatment cycle 1) 
  Study Period 2 to 5: number of subjects in the Safety Set for the specific study 
period will be used as the denominator in calculating the percentage. 
Refer to SAP Section 7.1.3 regarding a subject counted at the beginning of Observation 
Period X.  
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Incidence of TEAEs in the following categories will be provided by SOC and PT for the 
entire study as well as for the specific period using Safety Set, unless specified otherwise:  
 TEAE 
 Treatment Cycle Period TEAE 
 Treatment Period TEAE 
 Follow-up Period TEAE 
 Observation Period TEAE 
 TEAEs by maximum severity (overall only) 
 Treatment Cycle Period TEAEs by maximum severity (“by study period” 
only) 
 Treatment Period TEAEs by maximum severity (“by study period” only)  
 Follow-up Period TEAEs by maximum severity (“by study period” only)  
 Observation Period TEAEs by maximum severity (“by study period” only)  
 TEAEs by relationship (overall only) 
 Treatment Cycle Period TEAEs by relationship to study drug (“by study 
period” only)  
 Treatment Period TEAEs by relationship to study drug (“by study period” 
only)  
 Follow-up Period TEAEs by relationship to study drug (“by study period” 
only)  
 Observation Period TEAEs by relationship to study drug (“by study period” 
only)  
 Serious TEAEs (overall only) 
 Serious TEAEs by study period  
 Serious TEAEs by relationship (overall and by study period) 
 Treatment Cycle Period Serious TEAEs (overall and by study period)  
 Treatment Period Serious TEAE (overall and by study period) 
 Follow-up Period Serious TEAE (overall and by study period)  
 Observation Period Serious TEAE (overall and by study period) 
 TEAEs leading to discontinuation of study drug 
 TEAEs leading to dose reduction of study drug (including a row for number of 
subjects who completed treatment in the study period with dose reduction)  
  TEAEs leading to dose interruption of study drug 
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  TEAEs leading to dose reduction or interruption of study drug 
 TEAEs leading to withdrawal from the study  
 Treatment Cycle Period TEAEs leading to withdrawal from the study (“by study 
period” only) 
 Treatment Period TEAEs leading to withdrawal from the study (“by study 
period” only) 
 Follow-up Period TEAEs leading to withdrawal from the study (“by study 
period” only) 
Incidence of TEAEs in the following categories in each study period will be provided by 
dose cohort, SOC, and PT.   
 Treatment Cycle Period TEAEs 
 Treatment Period TEAEs 
 Follow-up Period TEAEs 
 Observation Period TEAEs 
 Treatment Cycle Period TEAEs by maximum severity 
 Treatment Cycle Period TEAEs by relationship to study drug 
 TEAEs leading to discontinuation of study drug 
 TEAEs leading to dose reduction of study drug 
 Treatment Cycle Period Serious TEAEs 
 Treatment Period Serious TEAEs 
 Follow-up Period Serious TEAEs 
 Observation Period Serious TEAEs 
 Treatment Period most common TEAEs (PT only) 
Listing of AEs with onset prior to first dose of study drug will be provided.  All listings on 
TEAEs will provide the study period and period designation for each AE.   
A summary of most common TEAE (defined as incidence more than 5%) by preferred term will 
be provided, overall and by study period, sorted by decreasing frequency using Safety Set. 
Similarly summary of most common treatment cycle period TEAE by preferred term,  and 
summary of most common treatment period TEAE by preferred term will also be provided. 
Using Dose Switch Set, a summary of TEAEs by SOC/PT and by study period (starting at 
Study period 2, because by definition, subjects in Dose Switch Set would have had 30mg 
starting dose in study period 1) will be provided by the first dose in the specific re-treatment 
study period (as well as for SAGE-217 Any Dose) for the following: 
 Treatment Cycle Period TEAE 
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 Treatment Cycle Period Serious TEAE 
 Treatment Cycle Period TEAEs by maximum severity 
 Treatment Cycle Period TEAEs by relationship to study drug 
 TEAEs leading to dose reduction of study drug 
 TEAEs leading to discontinuation of study drug 
 TEAEs leading to withdrawal from the study 
 Most common (5% in any dose cohort) Treatment Period TEAE 
For maximum severity, subjects will be counted only once within each SOC and PT at the 
maximum severity in the following order: severe> moderate> mild; an AE with missing 
severity will be omitted from severity presentation.  For relationship to study drug, ‘related’ 
is defined as relationship being “possible” or “probable” or missing. A subject will be 
counted only once within each SOC and PT at the strongest relationship to study drug in the 
following order: related, not related.  
In tables which present dose cohorts in columns, the incidences will be presented by 
descending frequency of SOC within SAGE-217 Overall, then by high dose cohort, then by 
dose switch cohort, then by low dose cohort; In tables which present study periods in 
columns, the incidence will be presented by descending frequency of SOC within Study 
Period 1, then by Study Period 2, etc.   For tables using Dose Switch Set, the incidence will 
be presented by descending frequency of SOC within SAGE-217 Any Dose column, then by 
50mg, then by 40mg, then by 30/20mg.  Within an SOC, the incidence will be sorted by 
descending frequency, in the same order as done for SOC.  In case of a tie in incidence, 
sorting will be in alphabetical order.   
Adverse events with onset before the first dose of study drug will be provided in a separate 
listing.  Separate data listing for deaths and non-fatal SAEs will be provided. 
In addition, Treatment Cycle Period TEAE summary by SOC/PT by study period will also be 
presented by the following subgroups: 
 Age group:18-24, 25-50, 51-64, ≥65 years 
 Sex: Male, Female  
 Race: White, Black or African American, Other 
 Antidepressant use at Period-specific Baseline: Yes, No 
 Anxious depression status at baseline: Yes, No 
In addition, the following summaries will be provided by SOC/PT by study period for age 
group <65 years (non-elderly), and >=65 years (elderly): 
 Treatment Cycle Period TEAE 
 Treatment Period TEAEs 
 Follow-up Period TEAEs 
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 Observation Period TEAEs 
 Treatment Cycle Period TEAEs by maximum severity  
 Treatment Cycle Period Serious TEAEs 
 Treatment Period TEAEs leading to discontinuation of study drug 
 Treatment Period TEAEs leading to dose reduction of study drug 
 Treatment Period TEAEs leading to dose interruption of study drug 
 Treatment Period TEAEs leading to dose reduction or dose interruption of study 
drug 
7.4.2. 
Clinical Laboratory 
The clinical laboratory tests to be performed for monitoring of safety are listed in Table 5.  
They are collected at Screening, Days 1, 8, 15 of each study period, and Q8W. 
Table 5: 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Coagulation 
Red blood cell count 
Hemoglobin  
Hematocrit  
White blood cell count  
   with differential  
Platelet count 
Red blood cell  
    morphology 
Alanine aminotransferase  
Albumin  
Alkaline phosphatase  
Aspartate aminotransferase  
Total bilirubin  
Direct bilirubin  
Indirect bilirubin  
Total protein  
Creatinine  
Blood urea nitrogen  
Creatine kinase  
Gamma-glutamyl transferase  
Potassium  
Sodium  
Lactate dehydrogenase  
Glucose  
Chloride  
Bicarbonate  
Calcium  
Phosphorus  
Triglycerides  
Thyroid stimulating hormone  
pH  
Specific gravity  
Protein  
Glucose  
Red blood cell  
Nitrite  
Leukocyte 
esterase  
Ketones  
Bilirubin  
Urobilinogen  
Activated partial 
 Thromboplastin 
  time  
Prothrombin time  
International 
  normalized ratio  
All parameters will be converted to consistent units according to the International System of 
Units (SI) before presentation. 
For the laboratory results that are “< or = x”, where x is a number as collected in the data, the 
numeric part of the result will be used in calculation in the summary tables.  Same is true if 
the result is presented as below the limit of quantification (BLQ) and a lower limit of 
quantification  (LLOQ) value is provided – LLOQ value will be used for calculation in the 
summary tables.  The actual results as collected will be displayed in the listings. 
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Summary tables on lab parameters will be done by study period, and will include descriptive 
statistics for the observed values, changes from baseline, and period-specific changes from 
baseline by scheduled assessment timepoint in hematology, serum chemistry, coagulation 
and quantitative urinalysis test results.  It will also include the summary of last post-baseline 
values on treatment and on study within study period.  The parameter values which are 
produced only if another parameter is abnormal will be included in data listings, but not 
summarized. 
If a normal range is provided for the parameter, out-of-range values will be flagged as low or 
high, where applicable, in the subject data listings.  A shift table for these parameters will 
include the Out-of-range values for the period-specific baseline, then the shift from normal at 
period-specific baseline to high or low at any time during treatment (on or after first dose and 
on or before last dose + 1 day) and any time post-baseline during the study period (on or after 
first dose in the respective period but before the first dose of next study period). Qualitative 
urinalysis parameters will be summarized descriptively using number and percentage of 
subjects. 
The number and percentage of subjects with PCS values will be provided in separate displays 
in hematology, serum chemistry, and liver function tests for such occurrence any time post-
baseline (i.e. after first dose of the study drug, irrespective of whether it happens in scheduled 
or unscheduled assessments) during the entire study. Potentially clinically significant values 
will be identified for specific laboratory parameters as outlined in Table 6: Laboratory 
Parameters – Criteria for PCS Values.  For each study period, an occurrence of PCS values 
any time in the treatment period, the last value during the treatment period, any time in the 
treatment cycle, the last value during the treatment cycle and any time during the study 
period will be summarized. 
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Table 6: 
Laboratory Parameters – Criteria for PCS Values  
Laboratory  
Parameter 
Sex 
Units 
Criteria for PCS Values (Observed values) 
 
 
 
High  
Low  
Hematology 
 
 
 
 
Hemoglobin                    Male 
g/L  
>185  
<115 
 
Female 
g/L  
>170 
<100 
Hematocrit    
Male 
Fraction of 1 
>0.55  
<0.385  
 
Female 
Fraction of 1 
>0.49 
<0.345 
Platelet count  
 
10^9/L  
>600 
<125 
White blood cell 
 
10^9/L  
>15  
<2.5  
Basophils  
 
10^9/L  
>0.5 
NA 
Eosinophils 
 
10^9/L  
>1.5 
NA 
Neutrophils  
 
10^9/L  
NA  
<1.5  
Lymphocytes  
 
10^9/L  
>6.0  
<0.5  
Monocytes  
 
10^9/L  
>1.4 
NA 
 
 
 
 
 
Serum Chemistry 
 
 
 
 
Albumin  
 
g/L  
>70  
<28  
Blood urea nitrogen  
 
mmol/L 
>10.71 
NA 
Calcium 
 
mmol/L 
>2.75 
<2.0 
Chloride 
 
mmol/L 
>120 
<90 
Creatinine 
 
mmol/L 
>3xULN or >3x Baseline 
 
Gamma Glutamyl 
Transferase  
 
 
>3xULN 
 
Glucose 
 
mmol/L 
>13.9 
<2.8 
Sodium  
 
mmol/L  
>150  
<132  
Potassium  
 
mmol/L  
>5.4  
<3.3  
Protein  
 
g/L 
 
<45 
Bicarbonate  
 
mmol/L  
>34  
<18  
Chloride  
 
mmol/L  
>120  
<90  
Phosphorus  
 
mmol/L 
>1.94 
<0.61 
Liver Function Tests 
(LFT) 
 
 
 
 
Total Bilirubin  
 
μmol/L  
>2xULN  
NA  
Aspartate 
Aminotransferase  
 
U/L  
>3xULN  
NA  
Alanine 
Aminotransferase  
 
U/L  
>3xULN  
NA  
Alkaline Phosphatase  
 
U/L  
>1.5xULN  
NA  
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Liver function tests will be monitored more closely than above for potentially clinically 
significant values, and will be summarized by each study period for an occurrence of PCS 
values any time in the treatment period, the last value during the treatment period, any time 
in the treatment cycle, the last value during the treatment cycle and any time during the study 
period,  for the following parameters for these PCS threshold (for condition involving more 
than one parameter, the results need to be from the same timepoint): 
Alanine Aminotransferase: >3xULN, >5xULN, >10xULN 
Aspartate Aminotransferase: >3xULN, >5xULN, >10xULN 
Alanine Aminotransferase or Aspartate Aminotransferase: >3xULN, >5xULN, >10xULN 
Alkaline Phosphatase: >1.5xULN, >2xULN 
Total Bilirubin: >1.5xULN, >2xULN 
Total Bilirubin > 2xULN AND (Alanine Aminotransferase or Aspartate Aminotransferase 
>3xULN) [any time post-baseline, does not need to be measured at the same time point of 
assessment] 
[(Total Bilirubin >2xULN) AND Alkaline Phosphatase <2xULN (any time post-baseline, 
measured at the same time point of assessment)] AND [(ALT or AST >3xULN) AND 
Alkaline Phosphatase <2xULN, any time post-baseline, measured at the same time point of 
assessment], refer to algorithm in Section 10.4, Appendix D.  
Any lab results considered clinically significant by the investigator will be captured as 
adverse events, hence will show up in AE displays. 
Pregnancy test results will be listed but not summarized.  
7.4.3. 
Vital Signs 
Vital signs for the following parameters – respiratory rate (breaths/minute), oral temperature 
(degrees C), supine heart rate (beats/minute), supine systolic blood pressure (mmHg), supine 
diastolic blood pressure (mmHg), standing heart rate (beats/minute), standing systolic blood 
pressure (mmHg), and standing diastolic blood pressure (mmHg) are collected at Screening, 
Days 1, 8, 15, 28 of each study period, and Q8W. Descriptive summaries of observed values, 
changes from baseline, and changes from baseline period-specific baseline will be provided 
for vital sign parameters – by scheduled assessment time point within each study period.  It 
will also include the last values on treatment and on study within study period assessments. 
The orthostatic vital sign – the change from supine to standing (Supine – Standing)– heart 
rate, systolic and diastolic blood pressure – will also be summarized by study period and 
scheduled assessment timepoint. 
Potentially clinically significant values will be identified for vital sign parameters as outlined 
in Table 7, Vital Signs – Criteria for PCS Values.  For each study period, an occurrence of 
PCS values any time in the treatment period, the last value during the treatment period, any 
time in the treatment cycle, the last value during the treatment cycle and any time during the 
study period will be summarized. 
 
 
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Table 7: 
Vital Signs – Criteria for PCS Values 
 
 
Criteria for PCS Values 
Vital Sign 
Units 
 Observed values 
Change from Baseline values 
 
 
High  
Low  
Increase  
Decrease  
Heart rate (supine and 
standing) 
Beats/min  
>120  
<40  
NA 
NA 
Systolic Blood Pressure 
(supine and standing)  
mmHg  
>180 
<90  
≥30 
≥30 
Diastolic Blood pressure 
(supine and standing)  
mmHg  
>110 
<50  
≥20 
≥20  
Supine – Standing 
Systolic Blood Pressure 
mmHg 
≥20 
 
 
 
Supine – Standing 
Diastolic Blood Pressure 
mmHg 
≥10 
 
 
 
Possible Orthostatic 
hypotension: supine – 
standing SBP and DBP 
mmHg 
SBP >= 20 
and DBP 
>= 10 
 
 
 
 
mmHg 
SBP >= 20 
or DBP >= 
10 
 
 
 
Any vital signs results considered clinically significant by the investigator will be captured as 
adverse events, hence will show up in AE displays. 
7.4.4. 
Electrocardiogram 
Supine 12-lead ECGs will be performed in triplicate, and are collected at Screening, Days 1, 
15 and Q8W. The following ECG parameters will be collected for each subject: heart rate 
(beats per minute), PR (msec), QRS (msec), QT (msec), and QTcF (msec).     
The average of the triplicate values will be used in the summary, including baseline ECG 
values.  The observed value at each time point, change from baseline, and change from 
period-specific baseline at each post-baseline scheduled time point will be summarized.  This 
summary will also include the last values on treatment and on study within study period. 
Each ECG is evaluated as ‘normal’, ‘abnormal, not clinically significant’ and ‘abnormal, 
clinically significant’; the number and percentage of subjects with at least one of the 
triplicate values in the categories of ‘abnormal, clinically significant’ and ‘abnormal, not 
clinically significant’ will be provided by period-specific baseline and each post-baseline 
scheduled assessment time point (plus the end of treatment and EOS assessments, if any). 
Potentially clinically significant values will be identified for ECG parameters as outlined in 
the following table.  This analysis includes triplicate values individually, and is not based on 
the average value (note: for the PCS values derived from change from Baseline: Baseline is the 
average of the triplicate values).  For each study period, an occurrence of PCS values any time 
in the treatment period, the last value during the treatment period, any time in the treatment 
cycle, the last value during the treatment cycle and any time during the study period will be 
summarized. 
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The maximum value of QTcF if within any of the PCS criteria will also be summarized by 
study period. 
Table 8: 
ECG Parameters – Criteria for PCS and PCSC Values 
 
 
Criteria for PCS Values 
ECG 
Units 
 Observed values 
 Change from Baseline 
 
 
High  
Low  
Increase  
Decrease  
QTcF 
Interval 
msec  
>450 but <=480, >480 but <=500,  
>500 
NA  
>=30 to 60 
>60 
 
NA  
7.4.5. 
Physical Examination  
Physical examination is scheduled at Screening, Day 1 and Q8W. Only clinically significant 
abnormalities are captured in the database – for post-baseline observations, these will be 
reported as adverse events, hence these will be included in AE displays; for pre-baseline 
observations, these will be reported as medical history, hence these will be included in 
Medical History displays.  The dates of physical examination will be listed to confirm that 
the examination was done. 
7.4.6. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
Suicidality data collected on the C-SSRS is collected during the clinical visits at Screening, 
Days 1, 8, 15, 28, and Q8W. The C-SSRS includes ‘yes’ or ‘no’ responses for assessment of 
suicidal ideation and behavior as well as numeric ratings for severity of ideation, if present 
(from 1 to 5, with 5 being the most severe).  
The subject’s non-suicidal self-injurious behaviors is also assessed separately as part of C-
SSRS. The “Baseline/Screening” C-SSRS form will be completed at Screening (lifetime 
history and past 24 months). The “Since Last Visit” C-SSRS form will be completed at all 
subsequent time points.   
The assessments for suicidal ideation are ranked as follows with 5 being the worst: 
1. Wish to be dead 
2. Non-specific active suicidal thoughts 
3. Active suicidal ideation with any methods 
4. Active suicidal ideation with some intent 
5. Active suicidal ideation with specific plan 
The assessments for suicidal behavior are ranked as follows with 5 being the worst: 
1. Preparatory acts or behavior 
2. Aborted attempt 
3. Interrupted attempt 
4. Actual attempt (non-fatal) 
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5. Completed suicide 
Suicidal behavior is considered worse than suicidal ideation.   
Baseline for each question is defined as the worst of the assessments done before the first 
dose of study drug, excluding the lifetime version.  This will typically include the ‘past 24-
month version’ from screening and ‘since last visit version’ from Day 1, as well as any 
unscheduled visits done before the first dose of study drug; any Yes will make the baseline 
value as Yes. 
Period-specific baseline is defined as the latest value on or before the first dose of the 
specific period but after the last study drug dose of the last study period, except for period 1 
in which case Baseline defined above is same as Period 1 baseline. 
The number and percentage of subjects with at least one response of ‘Yes’ to any C-SSRS 
suicidal ideation or suicidal behavior item, as well as for Subject’s non-suicidal self-injurious 
behavior, will be summarized for period-specific baseline and any time post-baseline (period-
specific) separately within each study period. 
Summary of shift from period-specific baseline in C-SSRS suicidal ideation and suicidal 
behavior will be presented for the following categories (no suicidal ideation/behavior, 
suicidal ideation, suicidal behavior) for each scheduled assessment time point within each 
study period. If the answer to all available assessments in suicidal ideation and all available 
assessments in suicidal behavior is ‘No’ then the category for the table is considered as ‘No 
suicidal ideation/behavior’.  If any of the assessments in suicidal behavior is Yes, the 
category is considered as ‘Suicidal behavior’.  If any of the assessments in suicidal ideation is 
Yes but all available assessments in suicidal behavior is No, the category is considered as 
‘Suicidal ideation’.  
In addition, a summary of shift in suicidal ideation from period-specific baseline maximum 
rank score for any time post-baseline (period-specific) maximum rank score will be presented 
by study period. Maximum score 0 refers to all No for all assessments in the desired period 
for all 5 questions on suicidal ideation. 
  
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8. 
SUMMARY OF INTERIM AND DMC ANALYSES 
This is an open-label study.  An interim data cut with data cleaned to a pre-specified level (in 
data management documentation, as agreed by the study team, ahead of the interim data cut) 
was  undertaken at the time of NDA submission.  Analyses from this snapshot of data was 
included in the original NDA submission. 
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9. 
REFERENCES 
Clinical study protocol, version 5.0, 19 March 2020, Company: Sage Therapeutics Inc. 
American Psychiatric Association. Diagnostic and statistical manual of mental disorders (5th 
edition, DSM-5). Arlington, VA: American Psychiatric Publishing. 2013. 
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10. 
LIST OF APPENDICES 
10.1. 
Appendix A: Schedule of Assessments (Screening, Treatment, and Follow-up Periods) 
 
Screening 
Perioda, b 
Cyclec 
Open-label Treatment Period 
(Initial and Re-treatments) 
Follow-up 
Days 
D-28 to D-1 
D1 
D8 
(+1d) 
D15 
(±1d)/ 
EOTd 
D28 
(±1d)  
and/or 
ET 
Study Procedure 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
Duplicate Subject Checke 
X 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
Demographics 
X 
 
 
 
 
Medical/Family History 
X 
 
 
 
 
SCID-5 
X 
 
 
 
 
ICD-10 
X 
 
 
 
 
MGH ATRQ 
X 
 
 
 
 
Serum FSH testf 
X 
 
 
 
 
Physical Examinationg 
X 
X 
 
 
 
Body Weight/Height 
X 
 
 
X (wt only) 
 
Clinical Laboratory Assessmentsh 
X 
X 
X 
X 
 
Drug & Alcohol Screeni 
X 
X 
X 
X 
 
Pregnancy Testj 
X 
X 
 
Xk 
 
Hepatitis & HIV Screen 
X 
 
 
 
 
Vital Signsn 
X 
X 
X 
X 
 
12-Lead ECGo 
X 
X 
 
X 
 
C-SSRSp 
X 
X 
X 
X 
X 
MADRS 
X 
X 
 
 
 
HAM-Dq, r 
 
X 
X 
X 
Xs 
CGI-S 
X 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
PHQ-9 
 
X 
X 
X 
X 
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Study Drug Dispensation 
 
X 
X 
 
 
Study Drug Administration 
 
X (Day 1 through Day 14) 
 
Study Drug Accountability/Return 
 
 
X 
X 
 
Adverse Events/SAEsu 
X 
Prior/Concomitant Medicationsv 
X 
CGI-I = Clinical Global Impression – Improvement; CGI-S – Clinical Global Impression – Severity; C-SSRS = Columbia Suicide Severity Rating Scale; D = day; ET = early 
termination; ECG = electrocardiogram; EOT = end of treatment; FSH = follicle stimulating hormone; HAM-D = Hamilton Rating Scale for Depression, 17-item; HIV = 
human immunodeficiency virus; ICD-10 = International Statistical Classification of Diseases and Related Health Problems version 10; 
 
MADRS = Montgomery-Åsberg Depression Rating Scale; MGH ATRQ = Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; O = 
Optional; SCID-5 = Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; PHQ-9 = 9-item Patient Health Questionnaire; 
SAE = serious adverse event; 
 wt = weight 
a Screening procedures are to be conducted before initial (Cycle 1) treatment period only. 
 
c Each cycle is 28 days (±1 day) and is comprised of a 14-day treatment period and a 14-day follow-up period. The initial treatment is considered Cycle 1 and re-treatments 
will be numbered sequentially. Each re-treatment cycle will begin with Day 1 (eg, the first day of the first re-treatment will be Day 1 of Cycle 2). 
d Subjects who discontinue treatment early should return to the site for an end of treatment (EOT) visit as soon as possible, preferably the day after treatment is discontinued. 
The follow-up visits should occur 14 days after the last dose of treatment. If at any time after the EOT visit, a subject decides to terminate the study, the subject should 
return for an early termination (ET) visit. The EOT and ET visits can be on the same day if a subject discontinues study drug and terminates the study on the same day 
during a clinic visit; in this case, all events scheduled for the EOT visit will be conducted. 
e Subjects will be asked to authorize that their unique subject identifiers be entered into a registry (www.subjectregistry.com) with the intent of identifying subjects who may 
meet exclusion criteria for participation in another clinical study. 
f A serum FSH test will be conducted at Screening for female subjects that are not surgically sterile to confirm whether a female subject with ≥12 months of spontaneous 
amenorrhea meets the protocol-defined criteria for being post-menopausal. 
g A full physical examination will be conducted at Screening and abbreviated physical examinations will be conducted thereafter. A full physical examination includes 
assessment of body systems (eg, head, eye, ear, nose, and throat; heart; lungs; abdomen; and extremities). 
h Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis. 
i Urine toxicology for selected drugs of abuse (as per the laboratory manual) and breath test for alcohol. 
j Serum pregnancy test at screening and urine pregnancy test thereafter. 
k Female subjects who prematurely discontinue will have a pregnancy test performed at the ET visit. 
n Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing). Heart rate and blood pressure to be collected in supine 
position at all scheduled time points after the subject has been resting for 5 minutes and then in the standing position. Vital signs may be repeated at the discretion of the 
Investigator as clinically indicated. 
o Triplicate ECGs will be collected.  
p 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. 
q The HAM-D is to be completed as early during the visit as possible. 
r The assessment timeframe for the HAM-D scale will refer to the past 7 days (1 week). 
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s Subjects that do not exhibit a response to SAGE-217 by Day 15 of the initial treatment, defined as a ≥50% reduction in HAM-D score from baseline, will be terminated 
from the study upon completion of the 14-day follow-up period.  
u Adverse events will be collected starting at the time of informed consent and throughout the duration of the subject’s participation in the study. 
v Prior medications will be collected at Screening and concomitant medications will be collected at each subsequent visit. 
 
 
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10.2. 
Appendix B: Schedule of Events (Observational Period)  
 
Observational Perioda 
(Day 29 through Week 52) 
EOS/Week 52 (±7 d) 
 
Remote Assessment 
Q2W (±1 d) 
Visit Q8W/ET (± 3 d) 
Unscheduled Visit 
(as needed)b 
Study Procedure 
 
 
 
 
PHQ-9c 
Xd 
X 
X 
X 
Abbreviated Physical Examination 
 
X 
 
X 
Body Weight 
 
X 
 
X 
Clinical Laboratory Assessments 
 
X 
  
X 
Drug & Alcohol Screen 
 
X 
 
X 
Pregnancy Test 
 
X  
 
X  
Vital Signs 
 
X 
 
X 
12-Lead ECG 
 
X 
 
X 
C-SSRS 
 
X 
 
X 
HAM-De 
 
X 
X 
X 
CGI-S 
 
X 
 
X 
CGI-I 
 
X 
 
X 
Concomitant Medicationsf 
 
X 
X 
X 
Adverse Events/SAEsh 
X 
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Observational Perioda 
(Day 29 through Week 52) 
EOS/Week 52 (±7 d) 
 
Remote Assessment 
Q2W (±1 d) 
Visit Q8W/ET (± 3 d) 
Unscheduled Visit 
(as needed)b 
Study Procedure 
 
 
 
 
ECG = electrocardiogram; ET = early termination; d = days; EOS = end of study; HAM-D = Hamilton Rating Scale for Depression, 
17-item; 
 O = optional; PHQ-9 = 9-item Patient Health Questionnaire; Q2W = once every 2 weeks; 
Q8W = once every 8 weeks; 
 SAE = serious adverse event 
 
a Within an Observational Period, the Q2W remote assessments will begin on Day 42 (±1 day) and occur every 2 weeks (14 days) thereafter. The Q8W 
visits will begin on Day 70 (±3 days) and occur every 8 weeks (56 days) thereafter. 
b A subject will return to the site outside of the Q8W visit schedule if the PHQ-9 score is ≥10 and/or upon any suicidal thoughts or behaviors.  
c All PHQ-9 assessments will be performed via 
. 
d The subject will take the PHQ-9 every 14 days; if the PHQ-9 score is ≥10, then the subject will return to the site to be assessed by the clinician-
administered HAM-D in approximately one week. If the HAM-D score is <20, the subject will take the PHQ-9 on a weekly basis: the subject will return to 
the site to be assessed by the HAM-D each week that the PHQ-9 score remains ≥10; if the PHQ-9 score is <10, the subject will take the PHQ-9 every 2 
weeks thereafter. 
e If the HAM-D score is ≥20 (assessed approximately one week from having a PHQ-9 score ≥10) and it has been at least 8 weeks since the last treatment day 
of the previous SAGE-217 treatment cycle (ie, Day 70 or later), the subject will begin a 14-day re-treatment period with a 14-day follow-up visit (see 
Appendix A). If the HAM-D score is ≥20 but it has been less than 8 weeks since the last treatment day of the previous SAGE-217 treatment cycle (ie, Day 
69 or earlier), see Section 9.2.1 for guidance on allowable interventions; the subject will take the PHQ-9 on a weekly basis until the 8-week period has 
lapsed, at which time the subject may begin a re-treatment period with SAGE-217 (see Appendix A), or until the PHQ-9 score is <10. 
f Concomitant medications will be collected at each in-clinic visit. 
h Adverse events will be collected starting at the time of informed consent and throughout the duration of the subject’s participation in the study. 
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10.3. 
Appendix C: Handling of Missing Dates 
Dates missing the day or both the day and month of the year will adhere to the following conventions in order to classify TEAEs 
and to classify prior and concomitant medications.  
In general, listings will present the actual partial or missing values rather than the imputed values that may be used in derivation. 
In instances where imputed values will be presented, imputed values will be flagged.  
 Adverse Events 
If the AE start date is completely missing, do not impute a date but consider it as TEAE, unless the AE end date is before the 
initiation of treatment, in which case the AE will be considered prior. 
For partial AE start dates: 
 When the year is known, but the month and day is unknown, then: 
 If the year matches the year of first dose date and the end date (if present) is after first dose date, or AE is ongoing, 
then impute the month as the month of the first dose date, and day as the day of the first dose date + 1 day. 
 If the year of AE onset < year of initiation of the treatment, then the month and day will be set to December 31st .  
 If the year of AE onset > the year of initiation of treatment, then the month and day will be set to January 1st. 
 If the year and month are known, but the day is unknown, then: 
 If the year of AE onset = the year of initiation of the treatment and: 
 
the month of AE onset = the month of initiation of the treatment, then the day will be set to the day of first dose day + 
1 day. 
 
the month of AE onset < the month of initiation of the treatment, then the day will be set to the last day of month. 
 
if the month of AE onset > the month of initiation of the treatment, then the day will be set to the 1st day of month. 
 If the year of AE onset < the year of initiation of the treatment, then the day will be set to the last day of month. 
 If the year of AE onset > the year of initiation of the treatment, then the day will be set to the 1st day of month. 
 
If the imputed AE onset date is after the AE stop date, then the onset date will be set to the stop date. 
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 When the year and day are present and the month is missing, treat it as if the day is missing, and only year is 
present.  Follow the imputation rules for “year is known, but the month and day is unknown”. 
 When the year is missing, but the month and/or day is known, treat this date as missing; do not impute. 
Prior and Concomitant Medications 
If the conmed start date is completely missing, do not impute a date but consider it as a concomitant medication, unless the 
conmed end date is before the initiation of treatment, in which case the conmed will be considered prior. 
For the partial start date of medication: 
 If the year is present and the month and day are missing, then the month and day will be set to January 1. 
 If the year and day are present and the month is missing, then treat it as if the day is also missing.  Set the month 
and day to be January 1. 
 If the year and month are present and the day is missing, then the day will be set to the 1st day of month. 
 If the imputed start date of medication is after the non-imputed end date of medication, then the start date will be set 
to the end date of medication. 
For the partial end date of medication: 
 If the year is present and the month and day are missing, then the month and day will be set to December 31. 
 If the year and day are present and the month is missing, then treat it as if the day is also missing.  Set the month 
and day to be December 31. 
 If the year and month are present and the day is missing, then the day will be set to the last day of the month. 
Dates in Disease History (Dates of diagnosis, current episode, first episode) 
 If the year is present and the month and day are missing, then the month and day will be set to January 1. 
 If the year and day are present and the month is missing, then treat it as if the day is also missing.  Set the month 
and day to be January 1. 
 If the year and month are present and the day is missing, then the day will be set to the 1st day of month. 
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10.4. 
Appendix D: Algorithms 
Defining Analysis Datasets / Dose Cohorts 
Safety Set for Period X: Subjects who had Treatment Period X start date non-missing 
Full Analysis Set: Subjects who had HAM-D total score at Day 15 less than 50% of HAM-D total score at baseline in Treatment 
Cycle 1, and the discontinuation from study date/time, if the subject discontinued from the study prematurely, from study 
conclusion page is not equal to or before Treatment Cycle 1 end date/time. (This is the set who enters Obs Period 1 and is subject 
to re-treatment.) 
High Dose Cohort: Subjects who received 50mg of SAGE-217 in Treatment Cycle 1, Day 1. 
Low Dose Cohort: Subjects who received 30mg of SAGE-217 in Treatment Cycle 1, Day 1 and received 30mg or 20mg of SAGE-
217 as the last dose received. 
Dose Switch cohort: Subjects who received 30mg of SAGE-217 in Treatment Cycle 1, Day 1 and received 50mg of SAGE-217 in 
Treatment Cycle X, Day 1, where X>1. 
30 mg cohort: Combination of Low Dose and Dose Switch cohorts. 
Adverse Event Periods 
Pre-treatment AE: AE onset date before Treatment Cycle 1 start date/time 
TEAE: AE onset date on or after Treatment Cycle 1 start date/time 
Treatment Period AE in Study Period X: AE onset date/time on or after Treatment Cycle X start date/time and on or before last 
dose date + 1 day in Treatment Cycle X (Note that time does not matter for the end of this period.) 
Follow-up Period AE in Study Period X: AE onset date after last dose date +1 day and on or before last dose date + 14 days in 
Treatment Cycle X (Typically, Day 16 through Day 28 – time does not matter) 
Observation Period AE in Study Period X: AE onset date after last dose date + 14 days in Study Period X and before Study Period 
X+1 start date/time 
Treatment Cycle AE in Study Period X: All AEs that are flagged as either Treatment Period or Follow-up Period AE in Study 
Period X 
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If an AE start date is the same as start of Treatment Cycle X, but time is missing in AE start or treatment start, then AE is 
considered in Cycle X.   
Concomitant Medication Periods 
Prior: Conmeds with start date before Treatment Cycle 1 start date/time 
On-treatment in Study Period X: Conmed start date on or after Treatment Cycle X start date and on or before the last dose date in 
Treatment Cycle X, OR Conmed start date before Treatment Cycle X start date and conmed end date either missing or on or after 
the Treatment Cycle X start date 
Post-treatment in Study Period X: Conmed start date after last dose date in Treatment Cycle X and before the Treatment Cycle 
X+1 start date 
Concomitant in Study Period X: All Conmeds that are flagged as either on-treatment or post-treatment in Study Period X 
Baseline use of antidepressant, anxiolytic, or anti-insomnia medication in Study Period X are the medications with a start date 
before the first dose of study drug in the study period X AND they were ongoing or with a stop date on or after the first dose of 
study drug in the study period X.  
The below rules apply to antidepressant, anxiolytic, or anti-insomnia medication during observation period derivation. If the end 
date of a period is the same as the start date of the next period, and  
a.  the medication start date falls on this date, then consider the medication as occurring in the next period.  
b.  the medication end date falls on this date, then consider the medication concomitant in the next period in addition to 
being concomitant the current period. 
For antidepressant, anxiolytic, or anti-insomnia medication records, any switch from period-specific baseline is determined by the 
period: Treatment period, Follow Up period and Observation period, where follow-up period is same as Treatment Cycle. For 
definitions of periods, please refer to Section 7.1.2. 
Censoring for Time-To Event Analysis 
For any time-to analysis, define time to event/censor and a censor variable = 1/0 
For any time-to analysis, each subject must have a non-missing time to event and a non-missing censor value.  Time is calculated 
in Days with no respect to time component. 
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These general rules will apply in all cases, except for time to relapse and durability of study drug effect in each study period.  Time 
to relapse and durability of study drug effect for Study Period X will be computed and summarized only for those subjects who are 
HAM-D responders at Day 15 in Study Period X and who have at least one HAM-D (for time to relapse and durability of study 
drug effect by HAM-D) or at least one PHQ-9 (
) after the Day 15 date. 
Time to first re-treatment: Ref Date – Date of last dose date in Treatment Cycle 1 + 1, where  
Ref Date = Date of first dose in Treatment Cycle 2 (CENSOR = 0), OR 
= Date of Study Discontinuation or Completion if the subject has Study Conclusion page filled in and Treatment Cycle 2 dosing 
did not occur (CENSOR=1) 
Time to relapse in Study Period X: (Ref Date – Date of Day 15 visit in Study Period X) + 1, where Ref Date  
= Date of first relapse in Study Period X where relapse is defined as a subject having a HAM-D total score after Day 15 where 
HAM-D total score >=20 and there exists a PHQ-9 >=10 within 10 days prior to this HAM-D (CENSOR = 0) 
= Date of the latest HAM-D evaluation before the first dose in Study Period X+1 if it exists (CENSOR = 1) 
= Date of the last HAM-D evaluation in the study if there is no further treatment cycle for the subject (CENSOR = 1) 
Durability of study drug effect by HAM-D in Study Period X: (Ref Date – Date of Day 15 visit in Study Period X) + 1, where 
Ref Date  
= First date after Day 15 within Study Period X when the reduction in HAM-D total score from the period-specific baseline is less 
than 50% (CENSOR = 0) 
or, for subjects without any HAM-D showing less than 50% reduction in HAM-D total score from the period-specific baseline 
after Day 15 in the Study Period X 
= Date of the latest HAM-D evaluation after Day 15 within Study Period X and before the first dose in Study Period X+1 if it 
exists (CENSOR = 1)  
= Date of the last HAM-D evaluation after Day 15 within Study Period X and in the study if there is no further treatment cycle for 
the subject (CENSOR = 1) 
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Time to first anxiolytic med use: Ref Date – Date of first dose in Treatment Cycle 1 +1, where Ref Date is 
= Start Date of first anxiolytic med use on or after the first dose date of SAGE-217 (CENSOR=0) if there exists one in the 
database, OR 
= Date of Study Discontinuation or Completion if the subject has Study Conclusion page filled in and there is no evidence of  
anxiolytic medication use in the database (CENSOR=1) if the reason for discontinuation is not lost-to-follow-up 
= Date of last contact from the Study Conclusion page if the reason for discontinuation is lost-to-follow up 
Anxiolytic med is determined by ATC Level 3 = N05B.   
Time to first anti-insomnia med use: Ref Date – Date of first dose in Treatment Cycle 1 +1, where Ref Date is 
= Start Date of first anti-insomnia med use on or after the first dose date of SAGE-217 (CENSOR=0), OR 
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= Date of Study Discontinuation or Completion if the subject has Study Conclusion page filled in and there is no evidence of anti-
insomnia medication use in the database (CENSOR=1) if the reason for discontinuation is not lost-to-follow-up 
= Date of last contact from the Study Conclusion page if the reason for discontinuation is lost-to-follow up 
Anti-insomnia med is determined by: [ATC Level 3 = N05C or standard medication name is in (TRAZODONE, 
MIRTAZAPINE)] or ATC Level 4 = R06AA 
Time to end of follow-up: Ref Date – Date of first dose in Treatment Cycle 1 + 1, where  
Ref Date = Study discontinuation/completion date, defined from the study conclusion CRF page from the same variable, except 
when the subject is discontinued for the reason of lost-to-follow-up, in which case the date of discontinuation is defined as the date 
of last contact from the study conclusion page (CENSOR = 0)  
Time to first HAM-D total score >=20 after Cycle 1 Day 15 Response: (Ref Date – Date of Cycle 1 Day 15 visit) + 1, where 
Ref Date = Date of first HAM-D total score >=20 after Cycle 1 Day 15 (CENSOR = 0), OR 
=Date of the last HAM-D evaluation before the first dose in Cycle 2 if it exists (CENSOR = 1) 
=Date of the last HAM-D evaluation in the study if there is no further treatment cycle for the subject (CENSOR = 1) 
Time to first HAM-D total score >=20 after Cycle 1 Day 15 response will be computed only for those subjects who are HAM-D 
responders at Day 15 in Cycle 1 and who have at least one HAM-D after Day 15 date. 
Study discontinuation/completion date:  
Study discontinuation/completion date is defined from the study conclusion page from the same variable, except when the 
participant is discontinued for the reason of Lost-to-follow-up, in which case the date of discontinuation is defined as the date of 
last contact from the study conclusion page.  
Calculation of Month:  
 a year is counted as 365.2425 days  
 a month is counted as 365.2425/12 = 30.436875 days  
“<3 months” = “Study Day 91 or less”  
“>=3 months and <6 months” = “Study Day >=92 and , <=182”  
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“>=6 months and <9 months” = “Study Day >=183, <=273”  
“>= 9 months” = “Study Day >=274”  
where Start Day is calculated as: End Date-Start Date +1  
Derivation of PCS for liver function test based on combination results of Total Bilirubin, Alkaline Phosphatase, Alanine 
Aminotransferase or Aspartate Aminotransferase:  
 [(Total Bilirubin >2xULN) AND Alkaline Phosphatase <2xULN (any time post-baseline, measured at the same time 
point of assessment)] AND [(ALT or AST >3xULN) AND Alkaline Phosphatase <2xULN, any time post-baseline, 
measured at the same time point of assessment]  
In order to derive the records which met the above criteria, the participants should meet both of the following 2 criteria:  
1. Total Bilirubin >2xULN AND Alkaline Phosphatase <2xULN (any time post-baseline, measured at the same time point of 
assessment)  
2. (ALT or AST >3xULN) AND Alkaline Phosphatase <2xULN (any time post-baseline, measured at the same time point of 
assessment)  
Time point of assessments in Criterion 1 and Criterion 2 do not have to be the same. However, in order to summarize by the time 
frame (for example, any time in the treatment period, the last value during the treatment period, etc.), the time point in both criteria 
should fall into the same time frame. Note that the above PCS criterion cannot be evaluated for last value on treatment unless both 
condition happens to be satisfied on the last assessment. 
 
 
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10.5. 
Appendix E: List of Displays 
 
Following is a list of table numbering not used for the study: 
 
14.2.1.1 
14.2.2.11.2 
14.2.2.11.5 
14.2.2.11.8 
14.2.2.11.11 
14.2.2.11.14 
 
 
 
 
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Index of Tables 
 
Number 
Title 
Analysis Set 
Table 14.1.1.1 
Summary of Subject Disposition 
All Subjects 
Table 14.1.1.2 
Summary of Subject Disposition by Study Period 
Full Analysis Set 
Table 14.1.1.3 
Summary of Subject Progression 
Safety Set 
Table 14.1.1.4 
Summary of Study Duration and HAM-D Total Scores for Subjects who Discontinued Study 
or Treatment  
Safety Set 
Table 14.1.1.5 
Summary of Study Participation 
Safety Set 
Table 14.1.1.6 
 
Summary of Completion and Discontinuation of Subjects from the Study by Interval of Time 
Safety Set 
Table 14.1.1.7 
 
Summary of Discontinuation of Subjects who were HAM-D Day 15 Responders in 
Treatment Cycle 1 
Full Analysis Set 
Table 14.1.1.8 
Summary of the Latest Severity of Depression by Study Completion Status 
Full Analysis Set 
Table 14.1.1.9 
Summary of Reaching Threshold in Cycle X based on HAM-D >= 20 
Full Analysis Set 
Table 14.1.1.9.1 
Summary of Reaching Threshold in Cycle x based on PHQ-9 >= 10 
Full Analysis Set 
Table 14.1.2.1 
Summary of Major Protocol Deviations 
Safety Set 
Table 14.1.3.1 
Summary of Demographics and Baseline Characteristics 
Safety Set 
Table 14.1.3.2 
Summary of Baseline Subgroups 
Safety Set 
Table 14.1.3.3 
Summary of Demographics and Baseline Characteristics 
Full Analysis Set  
Table 14.1.3.4 
Summary of Baseline Subgroups 
Full Analysis Set  
Table 14.1.4.1 
Summary of Disease History 
Safety Set 
Table 14.1.4.2 
Summary of Disease History 
Full Analysis Set 
Table 14.1.5.1 
Summary of Medical and Surgical History 
Safety Set 
Table 14.1.5.2 
Summary of Medical and Surgical History Ongoing at Screening 
Safety Set 
Table 14.1.6.1 
Summary of Subject History of Psychiatric Disorder 
Safety Set 
Table 14.1.6.2 
Summary of Family History of Psychiatric Disorder 
Safety Set 
Table 14.1.7.1 
Summary of Prior Non-Psychotropic Medications  
Safety Set 
Table 14.1.7.2 
Summary of Concomitant Non-Psychotropic Medications  
Safety Set 
Table 14.1.7.3 
Summary of Prior Psychotropic Medications 
Safety Set 
Table 14.1.7.4 
Summary of Concomitant Psychotropic Medications 
Safety Set 
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Table 14.1.7.5 
Summary of On-Treatment Concomitant Non-Psychotropic Medications by Study Period 
Safety Set 
Table 14.1.7.6 
Summary of Post-Treatment Concomitant Non-Psychotropic Medications by Study Period 
Safety Set 
Table 14.1.7.7 
Summary of On-Treatment Concomitant Psychotropic Medications by Study Period 
Safety Set 
Table 14.1.7.8 
Summary of Post-Treatment Concomitant Psychotropic Medications by Study Period 
Safety Set 
Table 14.1.7.9 
Summary of Use of Concomitant Antidepressant Medications by Study Period 
Safety Set 
Table 14.1.7.10 
Summary of Use of Concomitant Anxiolytic Medications by Study Period 
Safety Set 
Table 14.1.7.11 
Summary of Use of Concomitant Anti-insomnia Medications by Study Period 
Safety Set 
Table 14.1.8.1 
Summary of Study Drug Exposure by Study Period 
Safety Set 
Table 14.1.8.2 
Summary of Study Drug Adherence by Study Period 
Full Analysis Set 
Table 14.2.1.2 
Summary of Re-treatments 
Full Analysis Set 
Table 14.2.1.3 
Summary of Re-treatment for Subjects With Exactly X Treatments 
Full Analysis Set 
Table 14.2.1.4 
Summary of Re-treatments by Antidepressant Use at Study Period 1 Baseline 
Full Analysis Set 
Table 14.2.2.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score – Study Period 1 
Safety Set 
Table 14.2.2.2.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Study Period 
Full Analysis Set 
Table 14.2.2.3 
Summary of Hamilton Rating Scale for Depression (HAM-D) Subscale Scores – Study 
Period 1 
Safety Set 
Table 14.2.2.4 
Summary of Hamilton Rating Scale for Depression (HAM-D) Subscale Score by Study 
Period  
Full Analysis Set 
Table 14.2.2.5 
Summary of Hamilton Rating Scale for Depression (HAM-D) Individual Item Score – Study 
Period 1 
Safety Set 
Table 14.2.2.6 
Summary of Hamilton Rating Scale for Depression (HAM-D) Individual Item Score by 
Study Period 
Full Analysis Set 
Table 14.2.2.7.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Response – Study Period 1 
Safety Set 
Table 14.2.2.7.2 
Sensitivity Analysis: Summary of Hamilton Rating Scale for Depression (HAM-D) Response 
– Study Period 1 
Safety Set 
Table 14.2.2.8.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Response by Study Period 
Full Analysis Set 
Table 14.2.2.8.2 
Sensitivity Analysis: Summary of Hamilton Rating Scale for Depression (HAM-D) Response 
by Study Period 
Full Analysis Set 
Table 14.2.2.8.2.1 
 
Sensitivity Analysis: Summary of Hamilton Rating Scale for Depression (HAM-D) Response 
by Study Period and Antidepressant Use at Period-specific Baseline 
Full Analysis Set 
Table 14.2.2.9.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Remission – Study Period 1 
Safety Set 
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Table 14.2.2.9.2 
Sensitivity Analysis: Summary of Hamilton Rating Scale for Depression (HAM-D) 
Remission – Study Period 1 
Safety Set 
Table 14.2.2.9.2.1 
 
Sensitivity Analysis: Summary of Hamilton Rating Scale for Depression (HAM-D) 
Remission, by Antidepressant Use at Baseline - Study Period 1 
Safety Set 
Table 14.2.2.10.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Remission by Study Period 
Full Analysis Set 
Table 14.2.2.10.2 
Sensitivity Analysis: Summary of Hamilton Rating Scale for Depression (HAM-D) 
Remission by Study Period 
Full Analysis Set 
Table 14.2.2.10.2.1 
 
Sensitivity Analysis: Summary of Hamilton Rating Scale for Depression (HAM-D) 
Remission by Study Period and Antidepressant Use at Period-specific Baseline 
Full Analysis Set 
Table 14.2.2.11.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Study Period 
and Antidepressant Use at Period-specific Baseline 
Full Analysis Set 
Table 14.2.2.11.3 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Antidepressant 
Use at Baseline – Study Period 1 
Safety Set 
Table 14.2.2.11.4 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Study Period 
and Age 
Full Analysis Set 
Table 14.2.2.11.6 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Age – Study 
Period 1 
Safety Set 
Table 14.2.2.11.7 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Study Period 
and Sex 
Full Analysis Set 
Table 14.2.2.11.9 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Sex – Study 
Period 1 
Safety Set 
Table 14.2.2.11.10 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Study Period 
and Race 
Full Analysis Set 
Table 14.2.2.11.12 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Race – Study 
Period 1 
Safety Set 
Table 14.2.2.11.13 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Study Period 
and BMI 
Full Analysis Set 
Table 14.2.2.11.15 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by BMI – Study 
Period 1 
Safety Set 
Table 14.2.2.11.16 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Study Period 
and Anxious Depression Status at Baseline  
Full Analysis Set 
Table 14.2.2.11.17 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by Anxious 
Depression Status at Baseline – Study Period 1 
Safety Set 
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Table 14.2.2.12.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score by the First Dose 
in the Study Period 
Dose Switch Set 
Table 14.2.2.12.2 
Summary of Hamilton Rating Scale for Depression (HAM-D) Response by First Dose in the 
Study Period 
Dose Switch Set 
Table 14.2.2.12.3 
Summary of Hamilton Rating Scale for Depression (HAM-D) Remission by First Dose in the 
Study Period 
Dose Switch Set 
Table 14.2.2.13.1A 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score for Current and 
Past Study Periods using Subjects Dosed in Study Period 2 
Full Analysis Set 
Table 14.2.2.13.1B 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score for Current and 
Past Study Periods using Subjects Dosed in Study Period 3 
Full Analysis Set 
Table 14.2.2.13.1C 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score for Current and 
Past Study Periods using Subjects Dosed in Study Period 4 
Full Analysis Set 
Table 14.2.2.13.1D 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score for Current and 
Past Study Periods using Subjects Dosed in Study Period 5 
Full Analysis Set 
Table 14.2.2.13.2A1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Core Subscale Score for 
Current and Past Study Periods using Subjects Dosed in Study Period 2 
Full Analysis Set 
Table 14.2.2.13.2A2 
Summary of Hamilton Rating Scale for Depression (HAM-D) Core Subscale Score for 
Current and Past Study Periods using Subjects Dosed in Study Period 3 
Full Analysis Set 
Table 14.2.2.13.2A3 
Summary of Hamilton Rating Scale for Depression (HAM-D) Core Subscale Score for 
Current and Past Study Periods using Subjects Dosed in Study Period 4 
Full Analysis Set 
Table 14.2.2.13.2A4 
Summary of Hamilton Rating Scale for Depression (HAM-D) Core Subscale Score for 
Current and Past Study Periods using Subjects Dosed in Study Period 5 
Full Analysis Set 
Table 14.2.2.13.2B1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Anxiety Subscale Score for 
Current and Past Study Periods using Subjects Dosed in Study Period 2 
Full Analysis Set 
Table 14.2.2.13.2B2 
Summary of Hamilton Rating Scale for Depression (HAM-D) Anxiety Subscale Score for 
Current and Past Study Periods using Subjects Dosed in Study Period 3 
Full Analysis Set 
Table 14.2.2.13.2B3 
Summary of Hamilton Rating Scale for Depression (HAM-D) Anxiety Subscale Score for 
Current and Past Study Periods using Subjects Dosed in Study Period 4 
Full Analysis Set 
Table 14.2.2.13.2B4 
Summary of Hamilton Rating Scale for Depression (HAM-D) Anxiety Subscale Score for 
Current and Past Study Periods using Subjects Dosed in Study Period 5 
Full Analysis Set 
Table 14.2.2.13.2C1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Bech-6 Subscale Score for 
Current and Past Study Periods using Subjects Dosed in Study Period 2 
Full Analysis Set 
Table 14.2.2.13.2C2 
Summary of Hamilton Rating Scale for Depression (HAM-D) Bech-6 Subscale Score for 
Current and Past Study Periods using Subjects Dosed in Study Period 3 
Full Analysis Set 
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Table 14.2.2.13.2C3 
Summary of Hamilton Rating Scale for Depression (HAM-D) Bech-6 Subscale Score for 
Current and Past Study Periods using Subjects Dosed in Study Period 4 
Full Analysis Set 
Table 14.2.2.13.2C4 
Summary of Hamilton Rating Scale for Depression (HAM-D) Bech-6 Subscale Score for 
Current and Past Study Periods using Subjects Dosed in Study Period 5 
Full Analysis Set 
Table 14.2.2.13.2D1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Maier Subscale Score for 
Current and Past Study Periods using Subjects Dosed in Study Period 2 
Full Analysis Set 
Table 14.2.2.13.2D2 
Summary of Hamilton Rating Scale for Depression (HAM-D) Maier Subscale Score for 
Current and Past Study Periods using Subjects Dosed in Study Period 3 
Full Analysis Set 
Table 14.2.2.13.2D3 
Summary of Hamilton Rating Scale for Depression (HAM-D) Maier Subscale Score for 
Current and Past Study Periods using Subjects Dosed in Study Period 4 
Full Analysis Set 
Table 14.2.2.13.2D4 
Summary of Hamilton Rating Scale for Depression (HAM-D) Maier Subscale Score for 
Current and Past Study Periods using Subjects Dosed in Study Period 5 
Full Analysis Set 
Table 14.2.2.14.1A 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score for Current and 
Subsequent Study Periods for Responders at Day 15 in Treatment Cycle 2 
Full Analysis Set 
Table 14.2.2.14.1B 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score for Current and 
Subsequent Study Periods for Responders at Day 15 in Treatment Cycle 3 
Full Analysis Set 
Table 14.2.2.14.1C 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score for Current and 
Subsequent Study Periods for Responders at Day 15 in Treatment Cycle 4 
Full Analysis Set 
Table 14.2.2.14.1D 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score for Current and 
Subsequent Study Periods for Responders at Day 15 in Treatment Cycle 5 
Full Analysis Set 
Table 14.2.2.14.2A 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score over Time for 
Responders at Day 15 at Treatment Cycle 1 for Subjects who Had Been Dosed in Exactly 1 
Treatment Cycle  
Full Analysis Set 
Table 14.2.2.14.2B 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score over Time for 
Responders at Day 15 at Treatment Cycle 2 for Subjects who Had Been Dosed in Exactly 2 
Treatment Cycles  
Full Analysis Set 
Table 14.2.2.14.2C 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score over Time for 
Responders at Day 15 at Treatment Cycle 3 for Subjects who Had Been Dosed in Exactly 3 
Treatment Cycles  
Full Analysis Set 
Table 14.2.2.14.2D 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score over Time for 
Responders at Day 15 at Treatment Cycle 4 for Subjects who Had Been Dosed in Exactly 4 
Treatment Cycles 
Full Analysis Set 
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Table 14.2.2.14.2E 
Summary of Hamilton Rating Scale for Depression (HAM-D) Total Score over Time for 
Responders at Day 15 at Treatment Cycle 5 for Subjects who Had Been Dosed in Exactly 5 
Treatment Cycles  
Full Analysis Set 
Table 14.2.2.15.1 
Summary of Relapse – Study Period 1 
Safety Set – HAM-
D Responders at 
Day 15 in Cycle 1 
Table 14.2.2.15.2 
Summary of Relapse by Study Period 
Full Analysis Set – 
HAM-D 
Responders at Day 
15 in Cycle X 
Table 14.2.2.16.1 
Summary of Durability of Study Drug Effect, Measured by HAM-D – Study Period 1 
Safety Set – HAM-
D Responders at 
Day 15 in Cycle 1 
Table 14.2.2.16.2 
Summary of Durability of Study Drug Effect, Measured by HAM-D, by Study Period 
Full Analysis Set – 
HAM-D 
Responders at Day 
15 in Cycle X 
Table 14.2.2.18.1 
Summary of Hamilton Rating Scale for Depression (HAM-D) Response by Antidepressant 
Use at Baseline – Study Period 1 
Safety Set 
Table 14.2.2.18.1.2 
Sensitivity Analysis: Summary of Hamilton Rating Scale for Depression (HAM-D) 
Response, by Antidepressant Use at Baseline – Study Period 1 
Safety Set 
Table 14.2.2.18.2 
Summary of Hamilton Rating Scale for Depression (HAM-D) Response by Antidepressant 
Use at Period-Specific Baseline, by Study Period 
Full Analysis Set 
Table 14.2.2.18.3 
Summary of Hamilton Rating Scale for Depression (HAM-D) Remission by Antidepressant 
Use at Baseline – Study Period 1 
Safety Set 
Table 14.2.2.18.4 
Summary of Hamilton Rating Scale for Depression (HAM-D) Remission by Antidepressant 
Use at Period-Specific Baseline, by Study Period 
 
Full Analysis Set 
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Table 14.2.3.1 
Summary of Clinical Global Impression – Improvement (CGI-I) – Study Period 1 
Safety Set 
Table 14.2.3.2 
Summary of Clinical Global Impression – Improvement (CGI-I) – by Study Period 
Full Analysis Set 
Table 14.2.3.3 
Summary of Clinical Global Impression – Improvement (CGI-I) – by the First Dose in the 
Study Period 
Dose Switch Set  
Table 14.2.3.4 
Summary of Clinical Global Impression – Improvement (CGI-I) Response – Study Period 1 
Safety Set 
Table 14.2.3.4.1 
Sensitivity Analysis: Summary of Clinical Global Impression – Improvement (CGI-I) 
Response – Study Period 1 
Safety Set 
Table 14.2.3.5 
Summary of Clinical Global Impression – Improvement (CGI-I) Response by Study Period 
Full Analysis Set 
Table 14.2.3.5.1 
Sensitivity Analysis: Summary of Clinical Global Impression – Improvement (CGI-I) 
Response by Study Period 
Full Analysis Set 
Table 14.2.3.6 
Summary of Clinical Global Impression – Improvement (CGI-I) Response by the First Dose 
in the Study Period 
Dose Switch Set 
Table 14.2.3.6.1 
Sensitivity Analysis: Summary of Clinical Global Impression – Improvement (CGI-I) 
Response by the First Dose in the Study Period 
Dose Switch Set 
Table 14.2.4.1 
Summary of Clinical Global Impression – Severity (CGI-S) – Study Period 1 
Safety Set 
Table 14.2.4.2 
Summary of Clinical Global Impression – Severity (CGI-S) by Study Period  
Full Analysis Set 
Table 14.2.4.3 
Summary of Clinical Global Impression – Severity (CGI-S) by the First Dose in the Study 
Period 
Dose Switch Set 
Table 14.2.4.4A 
Summary of Clinical Global Impression – Severity (CGI-S) Score for Current and Past Study 
Periods using Subjects Dosed in Study Period 2 
Full Analysis Set 
Table 14.2.4.4B 
Summary of Clinical Global Impression – Severity (CGI-S) Score for Current and Past Study 
Periods using Subjects Dosed in Study Period 3 
Full Analysis Set 
Table 14.2.4.4C 
Summary of Clinical Global Impression – Severity (CGI-S) Score for Current and Past Study 
Periods using Subjects Dosed in Study Period 4 
 
Full Analysis Set 
Table 14.2.4.4D 
Summary of Clinical Global Impression – Severity (CGI-S) Score for Current and Past Study 
Periods using Subjects Dosed in Study Period 5 
Full Analysis Set 
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Table 14.3.1.1 
Overview of Treatment-Emergent Adverse Events 
Safety Set 
Table 14.3.1.2 
Overview of Treatment-Emergent Adverse Events by Study Period 
Safety Set 
Table 14.3.1.3 
Overview of Treatment-Emergent Adverse Events by Study Period by Period-Specific 
Baseline Use of Antidepressant 
Safety Set 
Table 14.3.2.1 
Summary of Treatment Emergent Adverse Events by System Organ Class and Preferred 
Term  
Safety Set 
Table 14.3.2.2 
Summary of Treatment Emergent Adverse Events by System Organ Class and Preferred 
Term by Study Period 
Safety Set 
Table 14.3.2.3 
Summary of Treatment Cycle Period Treatment Emergent Adverse Events by System Organ 
Class and Preferred Term by Study Period 
Safety Set 
Table 14.3.2.3.1 
Summary of Treatment Cycle Period Treatment Emergent Adverse Events by System Organ 
Class and Preferred Term by Dose Cohort 
Safety Set 
Table 14.3.2.3.2 
Summary of Treatment Cycle Period Treatment Emergent Adverse Events by System Organ 
Class and Preferred Term by the First Dose in the Study Period 
Dose Switch Set 
Table 14.3.2.3.3 
Summary of Treatment Cycle Period Treatment Emergent Adverse Events by System Organ 
Class and Preferred Term 
Safety Set 
Table 14.3.2.4 
Summary of Treatment Period Treatment Emergent Adverse Events by System Organ Class 
and Preferred Term by Study Period 
Safety Set 
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Table 14.3.2.4.1 
Summary of Treatment Period Treatment Emergent Adverse Events by System Organ Class 
and Preferred Term by Dose Cohort 
Safety Set 
Table 14.3.2.4.2 
Summary of Treatment Period Treatment Emergent Adverse Events by System Organ Class 
and Preferred Term 
Safety Set 
Table 14.3.2.5 
Summary of Follow-up Period Treatment Emergent Adverse Events by System Organ Class 
and Preferred Term by Study Period  
Safety Set 
Table 14.3.2.5.1 
Summary of Follow-up Period Treatment Emergent Adverse Events by System Organ Class 
and Preferred Term by Dose Cohort 
Safety Set 
Table 14.3.2.5.2 
Summary of Follow-up Period Treatment Emergent Adverse Events by System Organ Class 
and Preferred Term 
Safety Set 
Table 14.3.2.6 
Summary of Observation Period Treatment Emergent Adverse Events by System Organ 
Class and Preferred Term by Study Period 
Safety Set 
Table 14.3.2.6.1 
Summary of Observation Period Treatment Emergent Adverse Events by System Organ 
Class and Preferred Term by Dose Cohort 
Safety Set 
Table 14.3.2.6.2 
Summary of Observation Period Treatment Emergent Adverse Events by System Organ 
Class and Preferred Term 
Safety Set 
Table 14.3.3.1 
Summary of Treatment Emergent Adverse Events by System Organ Class, Preferred Term, 
and Maximum Severity 
Safety Set 
Table 14.3.3.2 
Summary of Treatment Cycle Period Treatment Emergent Adverse Events by System Organ 
Class, Preferred Term, and Maximum Severity by Study Period 
Safety Set 
Table 14.3.3.2.1 
Summary of Treatment Cycle Period Treatment Emergent Adverse Events by System Organ 
Class, Preferred Term, and Maximum Severity by Dose Cohort 
Safety Set 
Table 14.3.3.2.2 
Summary of Treatment Cycle Period Treatment Emergent Adverse Events by System Organ 
Class, Preferred Term, and Maximum Severity by the First Dose in the Study Period 
Dose Switch Set 
Table 14.3.3.3 
Summary of Treatment Period Treatment Emergent Adverse Events by System Organ Class, 
Preferred Term, and Maximum Severity by Study Period 
Safety Set 
Table 14.3.3.4 
Summary of Follow-up Period Treatment Emergent Adverse Events by System Organ Class, 
Preferred Term, and Maximum Severity by Study Period 
Safety Set 
Table 14.3.3.5 
Summary of Observation Period Treatment Emergent Adverse Events by System Organ 
Class, Preferred Term, and Maximum Severity by Study Period 
Safety Set 
Table 14.3.4.1 
Summary of Treatment Emergent Adverse Events by System Organ Class, Preferred Term, 
and Relationship to Study Drug 
Safety Set 
Table 14.3.4.2 
Summary of Treatment Cycle Period Treatment Emergent Adverse Events by System Organ 
Class, Preferred Term, and Relationship to Study Drug by Study Period 
Safety Set 
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Table 14.3.4.2.1 
Summary of Treatment Cycle Period Treatment Emergent Adverse Events by System Organ 
Class, Preferred Term, and Relationship to Study Drug by Dose Cohort 
Safety Set 
Table 14.3.4.2.2 
Summary of Treatment Cycle Period Treatment Emergent Adverse Events by System Organ 
Class, Preferred Term and Relationship to Study Drug by the First Dose in the Study Period 
Dose Switch Set 
Table 14.3.4.3 
Summary of Treatment Period Treatment Emergent Adverse Events by System Organ Class, 
Preferred Term, and Relationship to Study Drug by Study Period 
Safety Set 
Table 14.3.4.4 
Summary of Follow-up Period Treatment Emergent Adverse Events by System Organ Class, 
Preferred Term, and Relationship to Study Drug by Study Period 
Safety Set 
Table 14.3.4.5 
Summary of Observation Period Treatment Emergent Adverse Events by System Organ 
Class, Preferred Term, and Relationship to Study Drug by Study Period 
Safety Set 
Table 14.3.5.1 
Summary of Treatment Emergent Adverse Events leading to Discontinuation of Study Drug 
by System Organ Class and Preferred Term 
Safety Set 
Table 14.3.5.2 
Summary of Treatment Emergent Adverse Events leading to Discontinuation of Study Drug 
by System Organ Class and Preferred Term by Study Period 
Safety Set 
Table 14.3.5.2.1 
Summary of Treatment Emergent Adverse Events leading to Discontinuation of Study Drug 
by System Organ Class and Preferred Term by Dose Cohort 
Safety Set 
Table 14.3.5.2.2 
Summary of Treatment Emergent Adverse Events leading to Discontinuation of Study Drug 
by System Organ Class and Preferred Term by the First Dose in the Study Period 
Dose Switch Set 
Table 14.3.5.3 
Summary of Treatment Emergent Adverse Events leading to Dose Reduction of Study Drug 
by System Organ Class and Preferred Term by Study Period 
Safety Set 
Table 14.3.5.3.1 
Summary of Treatment Emergent Adverse Events leading to Dose Reduction of Study Drug 
by System Organ Class and Preferred Term by Dose Cohort 
Safety Set 
Table 14.3.5.3.2 
Summary of Treatment Emergent Adverse Events leading to Dose Reduction of Study Drug 
by System Organ Class and Preferred Term by the First Dose in the Study Period 
Dose Switch Set 
Table 14.3.5.4 
Summary of Treatment Emergent Adverse Events leading to Dose Reduction of Study Drug 
in Any Study Period by System Organ Class and Preferred Term 
Safety Set 
Table 14.3.5.5 
Summary of Treatment Emergent Adverse Events leading to Dose Interruption of Study 
Drug by System Organ Class and Preferred Term by Study Period 
Safety Set 
Table 14.3.5.5.1 
Summary of Treatment Emergent Adverse Events leading to Dose Interruption of Study 
Drug by System Organ Class and Preferred Term by Dose Cohort 
Safety Set 
Table 14.3.5.5.2 
Summary of Treatment Emergent Adverse Events leading to Dose Interruption of Study 
Drug by System Organ Class and Preferred Term by the First Dose in the Study Period 
Dose Switch Set 
Table 14.3.5.6 
Summary of Treatment Emergent Adverse Events leading to Dose Interruption of Study 
Drug in Any Study Period by System Organ Class and Preferred Term 
Safety Set 
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Table 14.3.5.7 
Summary of Treatment Emergent Adverse Events leading to Dose Reduction or Dose 
Interruption of Study Drug by System Organ Class and Preferred Term by Study Period 
Safety Set 
Table 14.3.5.7.1 
Summary of Treatment Emergent Adverse Events leading to Dose Reduction or Dose 
Interruption of Study Drug by System Organ Class and Preferred Term by Dose Cohort 
Safety Set 
Table 14.3.5.7.2 
Summary of Treatment Emergent Adverse Events leading to Dose Reduction or Dose 
Interruption of Study Drug by System Organ Class and Preferred Term by the First Dose in 
the Study Period 
Dose Switch Set 
Table 14.3.5.8 
Summary of Treatment Emergent Adverse Events leading to Dose Reduction or Dose 
Interruption of Study Drug in Any Study Period by System Organ Class and Preferred Term 
Safety Set 
Table 14.3.6.1 
Summary of Treatment Emergent Adverse Events leading to Withdrawal from the Study by 
System Organ Class and Preferred Term 
Safety Set 
Table 14.3.6.2 
Summary of Treatment Emergent Adverse Events leading to Withdrawal from the Study by 
System Organ Class and Preferred Term by Study Period 
Safety Set 
Table 14.3.6.2.1 
Summary of Treatment Emergent Adverse Events leading to Withdrawal from the Study by 
System Organ Class and Preferred Term by the First Dose in the Study Period 
Dose Switch Set 
Table 14.3.6.2.2 
Summary of Treatment Cycle Period Treatment Emergent Adverse Events leading to 
Withdrawal from the Study by System Organ Class and Preferred Term by Study Period 
Safety Set 
Table 14.3.6.2.3 
Summary of Treatment Period Treatment Emergent Adverse Events leading to Withdrawal 
from the Study by System Organ Class and Preferred Term by Study Period 
Safety Set 
Table 14.3.6.2.4 
Summary of Follow-up Period Treatment Emergent Adverse Events leading to Withdrawal 
from the Study by System Organ Class and Preferred Term by Study Period 
Safety Set 
Table 14.3.7.1 
Summary of Treatment Emergent Serious Adverse Events by System Organ Class and 
Preferred Term 
Safety Set 
Table 14.3.7.1.1 
Summary of Treatment Emergent Serious Adverse Events by System Organ Class and 
Preferred Term and Relationship to Study Drug 
Safety Set 
Table 14.3.7.1.2 
Summary of Treatment Emergent Serious Adverse Events by System Organ Class, Preferred 
Term, and Relationship to SAGE-217 by Study Period 
Safety Set 
Table 14.3.7.1.3 
Summary of Treatment Emergent Serious Adverse Events by System Organ Class and 
Preferred Term by Study Period 
Safety Set 
Table 14.3.7.2 
Summary of Treatment Cycle Period Treatment Emergent Serious Adverse Events by 
System Organ Class and Preferred Term by Study Period 
Safety Set 
Table 14.3.7.2.1 
Summary of Treatment Cycle Period Treatment Emergent Serious Adverse Events by 
System Organ Class and Preferred Term by Dose Cohort 
Safety Set 
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Table 14.3.7.2.2 
Summary of Treatment Cycle Period Treatment Emergent Serious Adverse Events by 
System Organ Class and Preferred Term by the First Dose in the Study Period 
Dose Switch Set 
Table 14.3.7.2.3 
Summary of Treatment Cycle Period Treatment Emergent Serious Adverse Events by 
System Organ Class and Preferred Term 
Safety Set 
Table 14.3.7.3 
Summary of Treatment Period Treatment Emergent Serious Adverse Events by System 
Organ Class and Preferred Term by Study Period 
Safety Set 
Table 14.3.7.3.1 
Summary of Treatment Period Treatment Emergent Serious Adverse Events by System 
Organ Class and Preferred Term by Dose Cohort 
Safety Set 
Table 14.3.7.3.2 
Summary of Treatment Period Treatment Emergent Serious Adverse Events by System 
Organ Class and Preferred Term 
Safety Set 
Table 14.3.7.4 
Summary of Follow-up Period Treatment Emergent Serious Adverse Events by System 
Organ Class and Preferred Term by Study Period  
Safety Set 
Table 14.3.7.4.1 
Summary of Follow-up Period Treatment Emergent Serious Adverse Events by System 
Organ Class and Preferred Term by Dose Cohort 
Safety Set 
Table 14.3.7.4.2 
Summary of Follow-up Period Treatment Emergent Serious Adverse Events by System 
Organ Class and Preferred Term 
Safety Set 
Table 14.3.7.5 
Summary of Observation Period Treatment Emergent Serious Adverse Events by System 
Organ Class and Preferred Term by Study Period 
Safety Set 
Table 14.3.7.5.1 
Summary of Observation Period Treatment Emergent Serious Adverse Events by System 
Organ Class and Preferred Term by Dose Cohort 
Safety Set 
Table 14.3.7.5.2 
Summary of Observation Period Treatment Emergent Serious Adverse Events by System 
Organ Class and Preferred Term 
Safety Set 
Table 14.3.8.1 
Summary of Treatment Period Most Common (>5% in Any Cohort) Treatment Emergent 
Adverse Events by Preferred Term 
Safety Set 
Table 14.3.8.2 
Summary of Treatment Period Most Common (>5% in Any Cohort) Treatment Emergent 
Adverse Events by Preferred Term by Study Period 
Safety Set 
Table 14.3.8.2.1 
Summary of Treatment Period Most Common (>5% in Any Dose Cohort and Study Period) 
Treatment Emergent Adverse Events by Preferred Term by Dose Cohort 
Safety Set 
Table 14.3.8.2.2 
Summary of Treatment Period Most Common (> 5% in Any Study Period and First Dose 
Level) Treatment Emergent Adverse Events by Preferred Term by the First Dose in the 
Study Period 
Dose Switch Set 
Table 14.3.8.3.1 
Summary of Treatment Cycle Period Treatment Emergent Adverse Events by System Organ 
Class, Preferred Term and Age Group by Study Period 
Safety Set 
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Table 14.3.8.3.2 
Summary of Treatment Cycle Period Treatment Emergent Adverse Events by System Organ 
Class, Preferred Term and Sex by Study Period 
Safety Set 
Table 14.3.8.3.3 
Summary of Treatment Cycle Period Treatment Emergent Adverse Events by System Organ 
Class, Preferred Term and Race Group by Study Period 
Safety Set 
Table 14.3.8.3.4 
Summary of Treatment Cycle Period Treatment Emergent Adverse Events by System Organ 
Class, Preferred Term and ADT use at Period-Specific Baseline, by Study Period  
Safety Set 
Table 14.3.8.3.5 
Summary of Treatment Cycle Period Treatment Emergent Adverse Events by System Organ 
Class, Preferred Term and Anxious Depression Status at Baseline, by Study Period 
Safety Set 
Table 14.3.8.4.1 
Summary of Treatment Cycle Period Treatment Emergent Adverse Events by System Organ 
Class, Preferred Term and Elderly Group by Study Period 
Safety Set 
Table 14.3.8.4.2 
Summary of Treatment Cycle Period Treatment Emergent Adverse Events by System Organ 
Class, Preferred Term, Maximum Severity and Elderly Group by Study Period 
Safety Set 
Table 14.3.8.4.3 
Summary of Treatment Cycle Period Treatment Emergent Serious Adverse Events by 
System Organ Class, Preferred Term, and Elderly Group by Study Period 
Safety Set 
Table 14.3.8.4.4 
Summary of Treatment Period Treatment Emergent Adverse Events Leading to 
Discontinuation of Study Drug, by System Organ Class, Preferred Term, and Elderly Group 
by Study Period 
Safety Set 
Table 14.3.8.4.5 
Summary of Treatment Period Treatment Emergent Adverse Events Leading to Dose 
Reduction of Study Drug, by System Organ Class, Preferred Term, and Elderly Group by 
Study Period 
Safety Set 
Table 14.3.8.4.6 
Summary of Treatment Period Treatment Emergent Adverse Events Leading to Dose 
Interruption of Study Drug, by System Organ Class, Preferred Term, and Elderly Group by 
Study Period 
Safety Set 
Table 14.3.8.4.7 
Summary of Treatment Period Treatment Emergent Adverse Events Leading to Dose 
Reduction or Dose Interruption of Study Drug, by System Organ Class, Preferred Term, and 
Elderly Group by Study Period 
Safety Set 
Table 14.3.8.4.8 
Summary of Treatment Period Treatment Emergent Adverse Events by System 
Organ Class, Preferred Term and Elderly Group by Study Period 
Safety Set 
Table 14.3.8.4.9 
Summary of Follow-up Period Treatment Emergent Adverse Events by System 
Organ Class, Preferred Term and Elderly Group by Study Period 
Safety Set 
Table 14.3.8.4.10 
Summary of Observation Period Treatment Emergent Adverse Events by System 
Organ Class, Preferred Term and Elderly Group by Study Period 
Safety Set 
Table 14.3.8.5.1 
Summary of Most Common (>5% in any dose cohort) Treatment Emergent Adverse Events 
by Preferred Term 
Safety Set 
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Table 14.3.8.5.2 
Summary of Most Common (>5% in any dose cohort) Treatment Emergent Adverse Events 
by Preferred Term by Study Period 
Safety Set 
Table 14.3.8.5.3 
Summary of Most Common (>5% in any dose cohort) Treatment Cycle Period Treatment 
Emergent Adverse Events by Preferred Term 
Safety Set 
Table 14.3.8.5.4 
Summary of Most Common (>5% in any dose cohort) Treatment Cycle Period Treatment 
Emergent Adverse Events by Preferred Term by Study Period 
Safety Set 
Table 14.3.9.1 
Summary of Serum Chemistry Results by Study Period and Study Visit 
Safety Set 
Table 14.3.9.2 
Summary of Shift from Normal Baseline in Serum Chemistry Results during the Study by 
Study Period and Study Visit 
Safety Set 
Table 14.3.9.3 
Summary of Potentially Clinically Significant Liver Function Tests by Study Period 
Safety Set 
Table 14.3.9.4 
Summary of Potentially Clinically Significant Serum Chemistry (excluding LFT) Results by 
Study Period 
Safety Set 
Table 14.3.10.1 
Summary of Hematology Results by Study Period and Study Visit 
Safety Set 
Table 14.3.10.2 
Summary of Shift from Normal Baseline in Hematology Results during the Study by Study 
Period and Study Visit 
Safety Set 
Table 14.3.10.3 
Summary of Potentially Clinically Significant Hematology Results by Study Period 
Safety Set 
Table 14.3.11.1 
Summary of Urinalysis Results by Study Period and Study Visit – Quantitative Results 
Safety Set 
Table 14.3.11.2 
Summary of Urinalysis by Study Period and Study Visit – Qualitative Results 
Safety Set 
Table 14.3.12.1 
Summary of Coagulation Results by Study Period and Study Visit 
Safety Set 
Table 14.3.13.1 
Summary of Vital Signs by Study Period and Study Visit 
Safety Set 
Table 14.3.13.2 
Summary of Potentially Clinically Significant Vital Signs by Study Period 
Safety Set 
Table 14.3.13.3 
Difference in Supine to Standing Vital Signs (Supine minus Standing) by Study Period and 
Study Visit 
Safety Set 
Table 14.3.14.1 
Summary of ECG data by Study Period and Study Visit 
Safety Set 
Table 14.3.14.2 
Summary of Abnormal ECG by Study Period and Study Visit 
Safety Set 
Table 14.3.14.3 
Summary of Potentially Clinically Significant QTcF in ECG Data by Study Period 
Safety Set 
Table 14.3.15.1 
Summary of Shift from Period-specific Baseline in Columbia-Suicide Severity Rating Scale 
(C-SSRS) Suicidal Ideation and Suicidal Behavior Data by Study Period and Study Visit 
Safety Set 
Table 14.3.15.2 
Summary of Columbia-Suicide Severity Rating Scale (C-SSRS) on Suicidal Ideation and 
Suicidal Behavior Data by Study Period 
Safety Set 
Table 14.3.15.3 
Summary of Shift from Baseline in C-SSRS Maximum Severity Score in Suicidal Ideation at 
Any Time Post-Baseline by Study Period 
Safety Set 
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Index of Listings 
 
Number 
Title 
Analysis Set 
Listing 16.1.7 
Subject Dosing Groups 
Safety Set 
Listing 16.2.1.1 
Subject Disposition 
All Subjects 
Listing 16.2.1.2 
Premature Withdrawal from Study or Premature Discontinuation from Study Drug 
Safety Set 
Listing 16.2.1.3 
Subject Participation by Study Period 
Safety Set 
Listing 16.2.1.4 
Subject Participation by Treatment Cycle 
Full Analysis Set 
Listing 16.2.2.1 
Protocol Deviations 
All Subjects 
Listing 16.2.3.1 
Inclusion/Exclusion Criteria  
All Subjects 
Listing 16.2.4.1 
Demographics 
Safety Set 
Listing 16.2.4.2 
Baseline Characteristics 
Safety Set 
Listing 16.2.4.3 
Montgomery-Asberg Depression Rating Scale (MADRS) 
Full Analysis Set 
Listing 16.2.5.1 
Medical and Surgical History 
Safety Set 
Listing 16.2.5.2 
Disease History 
Safety Set 
Listing 16.2.5.3 
Subject History of Psychiatric Disorder 
Safety Set 
Listing 16.2.5.4 
Family History of Psychiatric Disorder 
Safety Set 
Listing 16.2.6.1 
Prior and Concomitant Psychotropic Medications 
Safety Set 
Listing 16.2.6.2 
Prior and Concomitant Non-Psychotropic Medications 
Safety Set 
Listing 16.2.6.3 
Use of Antidepressant during the Study 
Safety Set 
Listing 16.2.6.4 
Use of Anxiolytics during the Study 
Safety Set 
Listing 16.2.6.5 
Use of Anti-insomnia during the Study 
Safety Set 
Listing 16.2.6.6 
Concomitant Procedures 
Safety Set 
Listing 16.2.7.1 
Study Drug Administration 
Safety Set 
Listing 16.2.7.2 
Study Drug Exposure 
Safety Set 
Listing 16.2.7.3 
Study Drug Adherence 
Safety Set 
Listing 16.2.7.4 
Study Drug Dose Reduction 
Safety Set 
Listing 16.2.8.1 
Hamilton Rating Scale for Depression (HAM-D) 
Safety Set 
Listing 16.2.9.1 
Clinical Global Impression (CGI) – Improvement 
Safety Set 
Listing 16.2.10.1 
Clinical Global Impression (CGI) – Severity 
Safety Set 
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Listing 16.2.16.1 
Patient Health Questionnaire (PHQ-9) and Hamilton Rating Scale for Depression (HAM-D) 
Leading to Re-treatment 
Full Analysis Set 
Listing 16.2.17.1 
Adverse Events 
Safety Set 
Listing 16.2.17.2 
Non – fatal Serious Adverse Events 
Safety Set 
Listing 16.2.17.3 
Adverse Events Leading to Death 
Safety Set 
Listing 16.2.17.4 
Adverse Events with Onset Prior to First Dose of Study Drug 
Safety Set 
Listing 16.2.17.5 
Adverse Events Leading to Premature Discontinuation of Study Drug 
Safety Set 
Listing 16.2.17.6 
Adverse Events Leading to Premature Withdrawal from the Study 
Safety Set 
Listing 16.2.17.7 
Adverse Events for Subjects who Experienced Dose Reduction 
Safety Set 
Listing 16.2.18.1.1 
Serum Chemistry Data (Excluding Liver Function Tests) 
Safety Set 
Listing 16.2.18.1.2 
Serum Chemistry Data (Excluding Liver Function Tests) that are Potentially Clinically 
Significant 
Safety Set 
Listing 16.2.18.1.3 
Serum Chemistry Data, Liver Function Tests 
Safety Set 
Listing 16.2.18.1.4 
Potentially Clinically Significant Values of Liver Function Tests 
Safety Set 
Listing 16.2.18.2.1 
Hematology Data 
Safety Set 
Listing 16.2.18.2.2 
Hematology Data that are of Potential Clinical Concern 
Safety Set 
Listing 16.2.18.3 
Urinalysis Data 
Safety Set 
Listing 16.2.18.4 
Coagulation Data 
Safety Set 
Listing 16.2.18.5 
Pregnancy Test 
Safety Set 
Listing 16.2.18.6 
Diagnostic Screening Laboratory Tests 
Safety Set 
Listing 16.2.19.1.1 
Vital Signs 
Safety Set 
Listing 16.2.19.1.2 
Vital Signs that are of Potential Clinical Concern 
Safety Set 
Listing 16.2.20.1.1 
Electrocardiogram (ECG) data 
Safety Set 
Listing 16.2.20.1.2 
Electrocardiogram (ECG) data that are of Potential Clinical Concern 
Safety Set 
Listing 16.2.21.1 
Columbia-Suicide Severity Rating Scale (C-SSRS) – Suicidal Ideation  
Safety Set 
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Listing 16.2.21.2 
Columbia-Suicide Severity Rating Scale (C-SSRS) – Suicidal Behavior 
Safety Set 
Listing 16.2.22 
Physical Examination 
Safety Set 
 
 
 
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Index of Figures 
 
Figure 14.2.2 
Kaplan-Meier Plot of Time to First Anxiolytic Medication Use (Days) 
Full Analysis Set 
Figure 14.2.2.1 
 
Kaplan-Meier Plot of Time to First Anxiolytic Medication Use (Days) - High Dose vs 30mg 
Cohort 
Full Analysis Set 
Figure 14.2.3 
Kaplan-Meier Plot of Time to First Anti-insomnia Medication Use (Days) – High Dose vs 
30mg Cohort 
Full Analysis Set 
Figure 14.2.3.1 
 
Kaplan-Meier Plot of Time to First Anti-insomnia Medication Use (Days) - High Dose vs 
30mg Cohort 
Full Analysis Set 
Figure 14.2.4 
Kaplan-Meier Plot of Time to First Re-treatment (Days) 
Full Analysis Set 
Figure 14.2.4.1 
Kaplan-Meier Plot of Time to First Re-treatment (Days) - High Dose vs 30mg Cohort 
Full Analysis Set 
Figure 14.2.4.2 
Box Plot of Time to Re-treatment from Last Cycle (Days) 
Full Analysis Set 
Figure 14.2.4.3 
 
Box Plot of Time to Re-treatment from Last Cycle (Days) for Subjects With Exactly X 
Treatments 
Full Analysis Set 
Figure 14.2.5 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Response over Time, by Study 
Period 
Full Analysis Set 
Figure 14.2.5.1 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Response over Time – Study 
Period 1 
Safety Set 
Figure 14.2.5.2 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Response over Time, by 
Antidepressant Use at Baseline – Treatment Cycle 1 
Safety Set 
Figure 14.2.5.3 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Response at Day 15 over 
Different Study Periods, by Antidepressant Use at Period-Specific Baseline 
Safety Set for Study 
Period 1, Full Analysis 
Set for Study Periods 2-5 
Figure 14.2.5.4 
Sensitivity Analysis: Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Response 
over Time, by Study Period 
Full Analysis Set 
Figure 14.2.5.5 
Sensitivity Analysis: Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Response 
over Time – Study Period 1 
Safety Set 
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Figure 14.2.5.6 
Sensitivity Analysis: Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Response 
over Time, by Antidepressant Use at Baseline – Study Period 1 
Safety Set 
Figure 14.2.5.7 
Sensitivity Analysis: Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Response 
at Day 15 over Study Periods, by Antidepressant Use at Period-Specific Baseline 
Full Analysis Set 
Figure 14.2.6 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Remission over Time, by Study 
Period 
Full Analysis Set 
Figure 14.2.6.1 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Remission over Time – Study 
Period 1 
Safety Set 
Figure 14.2.6.2 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Remission over Time, by 
Antidepressant Use at Baseline – Treatment Cycle 1 
Safety Set 
Figure 14.2.6.3 
Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Remission at Day 15 over 
Different Study Periods, by Antidepressant Use at Period-Specific Baseline 
Safety Set for Study 
Period 1, Full Analysis 
Set for Study Periods 2-5 
Figure 14.2.6.4 
Sensitivity Analysis: Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Remission 
over Time, by Study Period 
Full Analysis Set 
Figure 14.2.6.5 
Sensitivity Analysis: Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Remission 
over Time – Study Period 1 
Safety Set 
Figure 14.2.6.6 
Sensitivity Analysis: Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Remission 
over Time, by Antidepressant Use at Baseline – Study Period 1 
Safety Set 
Figure 14.2.6.7 
Sensitivity Analysis: Bar Chart of Hamilton Rating Scale for Depression (HAM-D) Remission 
at Day 15 over Study Periods, by Antidepressant Use at Period-Specific Baseline 
Full Analysis Set 
Figure 14.2.7 
Line Plot of Mean (±SD) Change from Period-Specific Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score over Time by Study Period 
Full Analysis Set 
Figure 14.2.7.1 
Line Plot of Mean (±SD) Change from Period-Specific Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score over Time by Study Period – High Dose vs 30mg Cohort 
Full Analysis Set 
Figure 14.2.7.2 
Line Plot of Mean (±SD) Percent Change from Period-Specific Baseline in Hamilton Rating 
Scale for Depression (HAM-D) Total Score over Time by FAS Subjects Dosed in Each Study 
Period 
Full Analysis Set 
Figure 14.2.7.2.1 
 
Line Plot of Mean (±SD) Percent Change from Period-Specific Baseline in Hamilton Rating 
Scale for Depression (HAM-D) Total Score over Time by FAS Subjects Dosed in Each Study 
Period - High Dose vs 30mg Cohort 
Full Analysis Set 
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Figure 14.2.7.3 
 
Line Plot of Mean (±SD) Change from Period-Specific Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score over Time – Study Period 1 
Safety Set 
Figure 14.2.8 
Line Plot of Mean (±SD) Change from Period-Specific Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Core Subscale Score over Time by Study Period 
Full Analysis Set 
Figure 14.2.8.1 
Line Plot of Mean (±SD) Change from Period-Specific Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Core Subscale Score over Time by Study Period – High Dose vs 30mg 
Cohort 
Full Analysis Set 
Figure 14.2.8.2 
 
Line Plot of Mean (±SD) Percent Change from Period-Specific Baseline in Hamilton Rating 
Scale for Depression (HAM-D) Core Subscale Score over Time by FAS Subjects Dosed in 
Each Study Period 
Full Analysis Set 
Figure 14.2.8.2.1 
 
Line Plot of Mean (±SD) Percent Change from Period-Specific Baseline in Hamilton Rating 
Scale for Depression (HAM-D) Core Subscale Score over Time by FAS Subjects Dosed in 
Each Study Period - High Dose vs 30mg Cohort 
Full Analysis Set 
Figure 14.2.9 
Line Plot of Mean (±SD) Change from Period-Specific Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Anxiety Subscale Score over Time by Study Period 
Full Analysis Set 
Figure 14.2.9.1 
Line Plot of Mean (±SD) Change from Period-Specific Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Anxiety Subscale Score over Time by Study Period – High Dose vs 
30mg Cohort 
Full Analysis Set 
Figure 14.2.9.2 
 
Line Plot of Mean (±SD) Percent Change from Period-Specific Baseline in Hamilton Rating 
Scale for Depression (HAM-D) Anxiety Subscale Score over Time by FAS Subjects Dosed in 
Each Study Period 
Full Analysis Set 
Figure 14.2.9.2.1 
 
Line Plot of Mean (±SD) Percent Change from Period-Specific Baseline in Hamilton Rating 
Scale for Depression (HAM-D) Anxiety Subscale Score over Time by FAS Subjects Dosed in 
Each Study Period - High Dose vs 30mg Cohort 
Full Analysis Set 
Figure 14.2.10 
Line Plot of Mean (±SD) Change from Period-Specific Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Bech-6 Subscale Score over Time by Study Period 
Full Analysis Set 
Figure 14.2.10.1 
Line Plot of Mean (±SD) Change from Period-Specific Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Bech-6 Subscale Score over Time by Study Period – High Dose vs 
30mg Cohort 
Full Analysis Set 
Figure 14.2.10.2 
 
Line Plot of Mean (±SD) Percent Change from Period-Specific Baseline in Hamilton Rating 
Scale for Depression (HAM-D) Bech-6 Subscale Score over Time by FAS Subjects Dosed in 
Each Study Period 
Full Analysis Set 
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Figure 14.2.10.2.1 
 
Line Plot of Mean (±SD) Percent Change from Period-Specific Baseline in Hamilton Rating 
Scale for Depression (HAM-D) Bech-6 Subscale Score over Time by FAS Subjects Dosed in 
Each Study Period - High Dose vs 30mg Cohort 
Full Analysis Set 
Figure 14.2.11 
Line Plot of Mean (±SD) Change from Period-Specific Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Maier Subscale Score over Time by Study Period 
Full Analysis Set 
Figure 14.2.11.1 
Line Plot of Mean (±SD) Change from Period-Specific Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Maier Subscale Score over Time by Study Period – High Dose vs 30mg 
Cohort 
Full Analysis Set 
Figure 14.2.11.2 
 
Line Plot of Mean (±SD) Percent Change from Period-Specific Baseline in Hamilton Rating 
Scale for Depression (HAM-D) Maier Subscale Score over Time by FAS Subjects Dosed in 
Each Study Period 
Full Analysis Set 
Figure 14.2.11.2.1 
 
Line Plot of Mean (±SD) Percent Change from Period-Specific Baseline in Hamilton Rating 
Scale for Depression (HAM-D) Maier Subscale Score over Time by FAS Subjects Dosed in 
Each Study Period - High Dose vs 30mg Cohort 
Full Analysis Set 
Figure 14.2.12 
Line Plot of Mean (±SD) Change from Period-Specific Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score over Time by Study Period and Antidepressant Use at 
Period-specific Baseline 
Full Analysis Set 
Figure 14.2.12.1 
Line Plot of Mean (±SD) Change from Period-Specific Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score over Time by Study Period and Antidepressant Use at 
Period-Specific Baseline – High Dose vs 30mg Cohort 
Full Analysis Set 
Figure 14.2.12.2 
 
Line Plot of Mean (±SD) Change from Period-Specific Baseline in Hamilton Rating Scale for 
Depression (HAM-D) Total Score over Time by Antidepressant Use at Baseline - Study 
Period 1 
Safety Set 
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Figure 14.2.14.1 
Forest Plot of Change from Period-Specific Baseline at Day 15 in Hamilton Rating Scale for 
Depression (HAM-D) Total Score for Subgroups by Study Period 
Full Analysis Set 
Figure 14.2.14.2 
Forest Plot of Change from Period-Specific Baseline at Day 15 in Hamilton Rating Scale for 
Depression (HAM-D) Subscale Scores by Study Period 
Full Analysis Set 
Figure 14.2.14.3 
Forest Plot of Change from Period-Specific Baseline at Day 15 in Hamilton Rating Scale for 
Depression (HAM-D) Total Score for Subgroups - Study Period 1 
Safety Set 
Figure 14.2.14.4 
Forest Plot of Change from Period-Specific Baseline at Day 15 in Hamilton Rating Scale for 
Depression (HAM-D) Subscale Scores - Study Period 1 
Safety Set 
Figure 14.2.15 
Line Plot of Mean (±SD) Change from Period-Specific Baseline in Clinical Global Impression 
– Severity (CGI-S) Score over Time by Study Period 
Full Analysis Set 
Figure 14.2.15.1 
Line Plot of Mean (±SD) Change from Period-Specific Baseline in Clinical Global Impression 
- Severity (CGI-S) Score over Time by Study Period – High Dose vs 30mg Cohort 
Full Analysis Set 
Figure 14.2.15.2 
 
Line Plot of Mean (±SD) Percent Change from Period-Specific Baseline in Clinical Global 
Impression - Severity (CGI-S) Score over Time by FAS Subjects Dosed in Each Study Period 
Full Analysis Set 
Figure 14.2.15.2.1 
 
Line Plot of Mean (±SD) Percent Change from Period-Specific Baseline in Clinical Global 
Impression - Severity (CGI-S) Score over Time by FAS Subjects Dosed in Each Study Period 
- High Dose vs 30mg Cohort 
Full Analysis Set 
Figure 14.2.16.1 
Line Plot of Mean (±SD) of HAM-D Total Score over Current and Subsequent Study Periods 
for Responders at Day 15 from Current Treatment Cycle   
Full Analysis Set 
Figure 14.2.16.1.1 
 
Line Plot of Mean (±SD) of HAM-D Total Score over Current and Subsequent Study Periods 
for Responders at Day 15 from Current Treatment Cycle - High Dose vs 30mg Cohort 
Full Analysis Set 
Figure 14.2.16.2 
Line Plot of HAM-D Total Score over Time for Responders at Day 15 of the Latest Treatment 
Cycle by Subjects who Had Been Dosed in Exactly X Treatment Cycles   
Full Analysis Set 
Figure 14.2.16.2.1 
 
Line Plot of HAM-D Total Score over Time for Responders at Day 15 of the Latest Treatment 
Cycle by Subjects who Had Been Dosed in Exactly X Treatment Cycles - High Dose vs 30mg 
Cohort 
Full Analysis Set 
Figure 14.2.16.3 
Bar Chart of HAM-D Responders/Non-Responders at Day 15 with % of Non-Responders at 
Day 15 in Previous Cycle 
Full Analysis Set 
Figure 14.2.16.4 
Bar Chart of HAM-D Responders/Non-Responders at Day 15 with % of Responders at Day 
15 in Previous Cycle 
Full Analysis Set 
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Figure 14.2.17.1 
Kaplan-Meier Plot of Relapse (Days) by Study Period 
Safety Set for Study 
Period 1, Full Analysis 
Set for Study Periods 2-5 
Figure 14.2.17.1.1 
 
Kaplan-Meier Plot of Relapse (Days) by Study Period - High Dose vs 30 mg Cohort 
Safety Set for Study 
Period 1, Full Analysis 
Set for Study Periods 2-5 
Figure 14.2.17.2 
Kaplan-Meier Plot of Durability of Study Drug Effect, Measured by HAM-D (Days), by 
Study Period 
Safety Set for Study 
Period 1, Full Analysis 
Set for Study Periods 2-5 
Figure 14.2.17.2.1 
 
Kaplan-Meier Plot of Durability of Study Drug Effect, Measured by HAM-D (Days), by 
Study Period - High Dose vs 30 mg Cohort 
Safety Set for Study 
Period 1, Full Analysis 
Set for Study Periods 2-5 
Figure 14.2.18 
Kaplan-Meier Plot of Time to End of Follow-up (Days) 
Full Analysis Set 
Figure 14.2.18.1 
Kaplan-Meier Plot of Time to End of Follow-up (Days) - High Dose vs 30mg Cohort 
Full Analysis Set 
Figure 14.2.19 
Kaplan-Meier Plot of Time to First HAM-D total score >=20 after Cycle 1 Day 15 Response  
Full Analysis Set 
Figure 14.2.19.1 
Kaplan-Meier Plot of Time to First HAM-D total score >=20 after Cycle 1 Day 15 Response - 
High Dose vs 30mg Cohort 
Full Analysis Set 
 
 
 
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