Clinical trial NCT04442503
Conditions: Depression, Postpartum
Keywords: SAGE-217 Postpartum depression
Sponsor: Biogen
Start date: 2020-06-08; Completion date: 2022-04-12
Enrollment: 200 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine if treatment with SAGE-217 reduces depressive symptoms in females with severe postpartum depression (PPD) as compared to placebo.

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

Arms: arm 1: Participants received SAGE-217 matched-placebo capsules, orally, once daily for 14 days. arm 2: Participants received SAGE-217, 50 mg, capsules, orally, once daily for 14 days.
Interventions: intervention 1: SAGE-217 intervention 2: Placebo
Intervention descriptions: intervention 1: SAGE-217 oral capsules. intervention 2: SAGE-217 matched-placebo oral capsules.

Protocol documents:
Prot_000.pdf: 
Official Title: A Randomized, Double-Blind, Placebo-Controlled Study Evaluating the 
Efficacy and Safety of Sage-217 in the Treatment of Adults With 
Severe Postpartum Depression 
NCT Number: NCT04442503  
Document Date: Protocol Version 2: 02 February 2021 








Clinical Protocol 
Sage Therapeutics, Inc. 
217-PPD-301, Version 2 
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INVESTIGATOR’S AGREEMENT 
I have received and read the Investigator’s Brochure for SAGE-217. I have read the 
217-PPD-301 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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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Sage Therapeutics, Inc. (hereafter referred to as Sage Therapeutics, or Sage) 
Name of Investigational Product: 
SAGE-217 
Name of Active Ingredient: 
SAGE-217 
Title of Study:  
A Randomized, Double-Blind, Placebo-controlled Study Evaluating the Efficacy and Safety of 
SAGE-217 in the Treatment of Adults with Severe Postpartum Depression 
Number of Sites and Study Location: This study will take place at approximately 90 sites globally. 
Phase of Development: Phase 3 
Planned Duration for each Study Participant: 
The duration of participation for each participant will be up to 76 days, including screening, treatment 
period and follow-up period. 
Objectives and Endpoints: 
Objectives: 
Primary:  
• 
To determine if treatment with SAGE-217 reduces depressive symptoms in adults with severe 
postpartum depression (PPD) compared to placebo 
Secondary:  
• 
To determine if treatment with SAGE-217 reduces anxiety symptoms compared to placebo 
• 
To assess self-report of depressive symptoms 
• 
To evaluate the safety and tolerability of SAGE-217  
 
  
Endpoints: 
Primary: 
• 
Change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D) total 
score at Day 15 
Key Secondary: 
• 
Change from baseline in HAM-D total score at Day 3, Day 28, and Day 45 
• 
Change from baseline in Clinical Global Impressions – Severity (CGI-S) score at Day 15 
Other Secondary: 
• 
HAM-D response at Day 15 and Day 45 
• 
HAM-D remission at Day 15 and Day 45 
• 
Clinical Global Impressions – Improvement (CGI-I) response at Day 15 
• 
Change from baseline in Hamilton Anxiety Rating Scale (HAM-A) total score at Day 15 




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complete the remaining study visits as scheduled through Day 45 (ie, relative to Day 1) unless the 
participant withdraws consent or loses the capacity to grant consent. If a participant withdraws from 
the study/stops study participation early, an early termination visit should be conducted. 
Number of Participants (planned): Approximately 192 participants, with a total of approximately 
96 per treatment group (SAGE-217 or placebo)  
Eligibility Criteria:  
Inclusion Criteria: 
1. Participant has signed an ICF prior to any study-specific procedures being performed. 
2. Participant is an ambulatory female between 18 and 45 years of age, inclusive. 
3. Participant is in good physical health and has no clinically significant findings, as determined 
by the investigator, on physical examination, 
. 
4. Participant agrees to adhere to the study requirements, including not participating in night 
shift work. 
5. Participant has ceased lactating or agrees not to provide breastmilk to her infant(s) from just 
prior to receiving IP on Day 1 until 7 days after the last dose of IP. 
6. Participant must have a negative pregnancy test at screening and Day 1 prior to the start of IP 
administration. 
7. Participant has had a major depressive episode that began no earlier than the third trimester 
and no later than the first 4 weeks following delivery, and meets criteria for major depressive 
episode per DSM-5, diagnosed by SCID-5-CT. 
8. Participant has a HAM-D total score of ≥26 at screening and Day 1 (prior to randomization). 
9. Participant is ≤12 months postpartum at screening and Day 1. 
10. Participants taking antidepressants must have been taking these medications at the same dose 
for at least 30 days prior to Day 1. Participants who have stopped taking antidepressants 
within 30 days must have stopped for longer than 5 half-lives of the antidepressant prior to 
Day 1, and will be stratified into the “no antidepressant group”. Participants receiving 
psychotherapy must have been receiving therapy on a regular schedule for at least 30 days 
prior to Day 1. 
11. Participant is willing to delay the start of other antidepressant or antianxiety medications and 
any new pharmacotherapy regimens, including as-needed benzodiazepine anxiolytics and 
sleep aids, until after completion of the Day 45 visit.  
12. Participant agrees to use at least 1 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 IP, 
unless she is surgically sterile (bilateral oophorectomy, hysterectomy, and/or bilateral 
salpingectomy), or does not engage in sexual relations which carry a risk of pregnancy (does 
not include abstinence). 
13. Participant agrees to refrain from drugs of abuse and alcohol for the duration of the study. 
Exclusion Criteria: 
1. Participant is currently at significant risk of suicide, as judged by the investigator or has 
attempted suicide associated with the current episode of PPD. 
2. Participant has a recent history of active clinically significant manifestations of metabolic, 
hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, 


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dermatological, urogenital, neurological, or eye, ears, nose, and throat disorders, or any other 
acute or chronic condition that, in the investigator’s opinion, would limit the participant’s 
ability to participate in or complete the 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 comorbidities (eg,  chronic obstructive pulmonary 
disease [COPD]), concomitant medications, and prior tolerability of sedating agents. 
3. Participant has a clinically significant abnormal 
 at the screening or Day 1 visit. 
NOTE: a mean 
 calculated using the 
 of >470 msec will 
be the basis for exclusion from the study. 
4. Participant has a known allergy to SAGE-217, allopregnanolone, or related compounds. 
5. Participant has active psychosis per investigator assessment. 
6. Participant’s index pregnancy resulted in a miscarriage, still birth, or neonatal/infant death; or 
participant has terminated parental rights (eg, child has been placed for adoption). 
7. Participant has a medical history of nonfebrile seizures. 
8. Participant has a medical history of bipolar disorder, schizophrenia, and/or schizoaffective 
disorder. 
9. Participant 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.  
10. Participant has had exposure to another investigational medication or device within 30 days 
prior to screening. 
11. Participant has previously participated in this study or any other study employing SAGE-217 
or SAGE-547 (brexanolone), ganaxolone, any other compound containing allopregnanolone, 
or has previously been treated with ZULRESSO™ (brexanolone).  
12. Participant has a history of sleep apnea. 
13. Participant has had vagus nerve stimulation, electroconvulsive therapy, or has taken ketamine 
within the current PPD episode. 
14. Participant has had gastric bypass surgery, has a gastric sleeve or lap band, or has had any 
related procedures that interfere with gastrointestinal transit. 
15. Participant is taking benzodiazepines, barbiturates, or γ-aminobutyric acid (GABA)A receptor 
modulators (eg, eszopiclone, zopiclone, zaleplon, and zolpidem) within 28 days prior to 
Day 1 or has been using these agents daily or near-daily (≥4 times per week) for more than 
1 year. Participant is taking any benzodiazepine or GABA modulator with a half-life of 
≥48 hours (eg, diazepam) from 30 days prior to Day 1. 
16. Participant is taking non-GABA anti-insomnia medications (eg, melatonin, Benadryl 
[antihistamines], trazodone), or first or second generation (typical/atypical) antipsychotics 
within 14 days prior to Day 1.  
17. Participant has been diagnosed with and/or treated for any type of cancer (excluding basal 
cell carcinoma and melanoma in situ) within the past year prior to screening. 


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18. Participant is taking psychostimulants (eg, methylphenidate, amphetamine) or opioids, 
regularly or as needed, within 28 days prior to Day 1. 
19. Use of any known strong inhibitors of cytochrome P450 (CYP)3A4 within 14 days or 
5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, Seville oranges, or 
products containing these within 14 days prior to receiving the first dose of IP.  
20. Participant has a positive urine drug test and/or alcohol screen at screening or on Day 1 prior 
to dosing.  
21. Use of any strong CYP3A inducer, such as rifampin, carbamazepine, enzalutamide, mitotane, 
phenytoin, or St. John’s Wort within 14 days or 5 half-lives (whichever is longer) prior to the 
first dose of IP.  
22. Participant plans to undergo elective surgery during participation in the study. 
23. Participant is a dependent of the sponsor, investigator, investigator’s deputy, or study site 
staff. 
24. Participant is involuntarily confined or detained in a penal institution or other institution 
under court order. 
Investigational Product Dosage and Mode of Administration:  
SAGE-217 and placebo will be provided as hard gelatin capsules for oral administration. Available 
dose strengths of SAGE-217 are: 
• 
50-mg with the option to reduce to 40-mg for intolerable AEs 
Duration of Treatment:  
SAGE-217 or placebo will be administered once daily for 14 days. 
Statistical Methods:  
Detailed description of the analyses to be performed in the study will be provided in the statistical 
analysis plan (SAP). The SAP will be finalized and approved prior to database lock.  
General Considerations 
For the purpose of all primary and secondary analyses where applicable, baseline is defined as the last 
measurement prior to receipt of IP.  
Continuous endpoints will be summarized with number (n), mean, standard deviation, median, 
minimum, and maximum. In addition, change from baseline values will be calculated at each time 
point and summarized descriptively. For categorical endpoints, descriptive summaries will include 
counts and percentages.  
Analysis Sets 
The Safety Set will include all participants administered IP.  
The Full Analysis Set will include all randomized participants who received any amount of IP and 
have a valid baseline and at least one valid postbaseline HAM-D total score.  
The Per Protocol Set is defined as all participants in the Full Analysis Set without any major protocol 
deviations that could affect efficacy.  The review of major protocol deviations will be completed, and 
the decision on whether the deviation affects efficacy will be documented before database unblinding. 
Determination of Sample Size 
Using a 2-sided test at an alpha level of 0.05, a sample size of approximately 86 evaluable 
participants per treatment group would provide 90% power to detect a placebo-adjusted treatment 






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Table 2: 
Schedule of Assessments 
Study Procedure 
Study Period / Visit Day 
Screening 
Period 
Treatment Perioda 
Follow-up Period 
D-28 to -1 
D1 
(assessments 
completed 
predose) 
D3 
(±1 d) 
D8  
(+1 d) 
D15 
(+1 d) 
 
D18 
(±1 d) 
D21 
(±1 d) 
D28 
(±3 d) 
D45/ET 
(±3 d) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Duplicate Participant 
Check b 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
SCID-5-CT 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical/Family History c 
X 
 
 
 
 
 
 
 
 
Participant training d 
X 
X 
 
 
 
 
 
 
 
Physical Examination e 
X 
 
 
X 
X 
 
X 
 
Xf  
Body Weight/Height 
X 
 
 
 
X 
(weight 
only) 
 
X 
(weight 
only) 
 
X (weight 
only) f 
Drug & Alcohol Screen h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test i 
X 
X 
 
 
X 
 
 
 
X 
Hormone Sample j 
O 
 
 
O 
O 
 
 
 
 
Genetic Sample k 
O 
 
 
 
 
 
 
 
 
 CGI-I 
 
 
X 
X 
X 
 
X 
X 
X 
CGI-S 
X 
X 
X 
X 
X 
 
X 
X 
X 
HAM-A o 
 
X 
X 
X 
X 
 
X 
X 
X 
HAM-D o, p 
X 
X 
X 
X 
X 
 
X 
X 
X 
MADRS 
 
X 
 
X 
X 
 
 
X 
X 
EPDS 
X 
X 
X 
X 
X 
 
X 
X 
X 
PHQ-9 
X 
X 
X 
X 
X 
 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
Dispense IP 
 
X 
 
X 
 
 
 
 
 




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r As local regulations permit, IP administration will be monitored via a medication adherence monitoring platform used on 
smartphones to visually confirm IP ingestion. IP adherence will not be captured after participants discontinue IP. Optional 
consent may be required in regions with restricted regulations. 
s Prior medications will be collected at screening and concomitant medications and/or procedures will be collected at each 
subsequent visit (see Section 9.2.1). 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
CONTACT INFORMATION ..........................................................................................................5 
2. 
SYNOPSIS ...................................................................................................................6 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............16 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................21 
5. 
INTRODUCTION ......................................................................................................23 
5.1. 
SAGE-217 ...................................................................................................................23 
5.2. 
Potential Risks and Benefits .......................................................................................24 
5.3. 
Dose Justification ........................................................................................................24 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................30 
6.1. 
Study Objective ..........................................................................................................30 
6.1.1. 
Primary Objective .......................................................................................................30 
6.1.2. 
Secondary Objectives .................................................................................................30 
 
30 
6.2. 
Endpoints ....................................................................................................................30 
6.2.1. 
Primary Endpoint ........................................................................................................30 
6.2.2. 
Key Secondary Endpoints ...........................................................................................30 
6.2.3. 
Other Secondary Endpoints ........................................................................................30 
 
31 
7. 
INVESTIGATIONAL PLAN .....................................................................................32 
7.1. 
Overall Study Design ..................................................................................................32 
7.2. 
Number of Participants ...............................................................................................33 
7.3. 
Treatment Assignment ................................................................................................33 
7.4. 
Dose Adjustment Criteria ...........................................................................................33 
7.5. 
Criteria for Study Termination ...................................................................................33 
8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS .....................................34 
8.1. 
Participant Inclusion Criteria ......................................................................................34 
8.2. 
Participant Exclusion Criteria .....................................................................................34 
8.3. 
Screen Failures ............................................................................................................36 


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8.4. 
Investigational Product Discontinuation and Early Termination from the 
Study ...........................................................................................................................36 
8.4.1. 
Investigational Product Discontinuation .....................................................................37 
8.4.2. 
Early Termination from the Study ..............................................................................37 
8.4.3. 
Loss to Follow-up .......................................................................................................37 
8.4.4. 
Replacement of Participants .......................................................................................37 
9. 
TREATMENT OF PARTICIPANTS .........................................................................38 
9.1. 
Description of Investigational Product .......................................................................38 
9.2. 
Prior Medications, Concomitant Medications, Restrictions, and 
Contraception Requirements ......................................................................................38 
9.2.1. 
Prior and Concomitant Medications and/or Supplements ..........................................38 
9.2.2. 
Prohibited Medications ...............................................................................................38 
9.2.3. 
Other Restrictions .......................................................................................................39 
9.2.4. 
Acceptable Forms of Contraception ...........................................................................40 
9.3. 
Intervention after the End of the Study .......................................................................40 
9.4. 
Treatment Adherence ..................................................................................................40 
9.5. 
Randomization and Blinding ......................................................................................41 
9.5.1. 
Emergency Unblinding ...............................................................................................41 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............42 
10.1. 
Investigational Product ...............................................................................................42 
10.2. 
Investigational Product Packaging and Labeling .......................................................42 
10.3. 
Investigational Product Storage ..................................................................................42 
10.4. 
Investigational Product Preparation ............................................................................42 
10.5. 
Investigational Product Administration ......................................................................42 
10.6. 
Investigational Product Accountability, Handling, and Disposal ...............................42 
10.7. 
Product Complaints ....................................................................................................43 
11. 
EFFICACY AND CLINICAL PHARMACOLOGY ASSESSMENTS ....................44 
11.1. 
Efficacy Assessments .................................................................................................44 
11.1.1. 
Hamilton Rating Scale for Depression (HAM-D) ......................................................44 
11.1.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) ........................................44 
11.1.3. 
Hamilton Anxiety Rating Scale (HAM-A) .................................................................44 
11.1.4. 
Clinical Global Impressions .......................................................................................45 
11.1.5. 
Edinburgh Postnatal Depression Scale .......................................................................45 


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11.1.6. 
Patient Health Questionnaire ......................................................................................45 
11.2. 
Clinical Pharmacology Assessments ..........................................................................45 
 
46 
11.2.2. 
Blood Sample Collection ............................................................................................46 
11.2.3. 
Sample Analysis .........................................................................................................46 
11.2.4. 
Optional Blood Sample Collection for Hormones and Exploratory 
Biochemistry ...............................................................................................................46 
12. 
SAFETY ASSESSMENTS ........................................................................................48 
12.1. 
Safety Parameters .......................................................................................................48 
12.1.1. 
Demography and Medical History ..............................................................................48 
12.1.2. 
Weight and Height ......................................................................................................48 
12.1.3. 
Physical Examination .................................................................................................48 
12.1.4. 
COVID-19 Questions .................................................................................................48 
 
49 
 
49 
 
49 
 
.50 
 
51 
12.2. 
Adverse and Serious Adverse Events .........................................................................51 
12.2.1. 
Adverse Event Definition ...........................................................................................51 
12.2.2. 
Serious Adverse Event Definition ..............................................................................52 
12.2.3. 
Relationship to Investigational Product ......................................................................52 
12.2.4. 
Recording Adverse Events .........................................................................................53 
12.2.5. 
Reporting Serious Adverse Events .............................................................................53 
12.3. 
Pregnancy ...................................................................................................................54 
12.4. 
Overdose .....................................................................................................................54 
13. 
STATISTICS ..............................................................................................................55 
13.1. 
Data Analysis Sets ......................................................................................................55 
13.2. 
Handling of Missing Data ...........................................................................................55 
13.3. 
General Considerations ...............................................................................................55 
13.4. 
Demographics and Baseline Characteristics ...............................................................55 
13.5. 
Efficacy Analysis ........................................................................................................55 
13.6. 
Safety Analyses ..........................................................................................................57 


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13.6.1. 
Adverse Events ...........................................................................................................57 
 
57 
13.6.3. 
Physical Examinations ................................................................................................57 
 
57 
 
57 
13.6.6. 
Prior and Concomitant Medications ...........................................................................58 
 
58 
 
58 
13.7. 
Clinical Pharmacology Analyses ................................................................................58 
13.8. 
Sample Size and Power ..............................................................................................58 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................59 
14.1. 
Study Monitoring ........................................................................................................59 
14.2. 
Audits and Inspections ................................................................................................59 
14.3. 
Institutional Review Board or Independent Ethics Committee ..................................60 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................61 
16. 
ETHICS ......................................................................................................................62 
16.1. 
Ethics Review .............................................................................................................62 
16.2. 
Ethical Conduct of the Study ......................................................................................62 
16.3. 
Written Informed Consent ..........................................................................................62 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................64 
17.1. 
Inspection of Records .................................................................................................64 
17.2. 
Retention of Records ..................................................................................................64 
18. 
PUBLICATION POLICY ..........................................................................................65 
19. 
LIST OF REFERENCES ............................................................................................66 
 
 
LIST OF TABLES 
Table 1: 
Contact Information ......................................................................................................5 
Table 2: 
Schedule of Assessments ............................................................................................13 
Table 3: 
Abbreviations and Specialist Terms ...........................................................................21 
 
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LIST OF FIGURES 
Figure 1: 
Predicted SAGE-217 concentrations (Cavg and Cmax) following dosing of 
30 to 50 mg daily ........................................................................................................26 
Figure 2: 
Total score change on Day 15 (Studies 217-MDD-201B, 217-MDD-301, 
217-PPD-201) .............................................................................................................27 
Figure 3: 
Predicted incidence of sedation or somnolence by dose ............................................28 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 3: 
Abbreviations and Specialist Terms  
Abbreviation 
Definition 
ADR 
adverse drug reaction 
AE 
adverse event 
AUC 
area under the curve 
BMI 
body mass index 
CBD 
Cannabidiol 
CGI-I 
Clinical Global Impressions – Improvement 
CGI-S 
Clinical Global Impressions – Severity 
Cmax 
maximum observed concentration 
CS 
clinically significant 
CSR 
clinical study report 
CYP 
cytochrome P450 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
IEC 
independent ethics committee 
IRT 
interactive response technology 
eCRF 
electronic case report form 
EPDS 
Edinburgh Postnatal Depression Scale 
ET 
early termination 
FDA 
Food and Drug Administration 
GABA 
γ-aminobutyric acid 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GEE 
generalized estimating equation 
HAM-A 
Hamilton Rating Scale for Anxiety 
HAM-D 
Hamilton Rating Scale for Depression 
IB 
Investigator’s Brochure 
ICF 
informed consent form 


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Abbreviation 
Definition 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IP 
investigational product 
IRB 
institutional review board 
LDH 
lactate dehydrogenase 
LS 
least squares 
MADRS 
Montgomery Åsberg Depression Rating Scale 
MDD 
major depressive disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed-effects model for repeated measures 
MTD 
maximum tolerated dose 
NCS 
not clinically significant 
NOAEL 
no-observed-adverse-effect level 
OS 
oral solution 
PCS 
potentially clinically significant 
PHQ-9 
9-item Patient Health Questionnaire 
PPD 
postpartum depression 
PV 
Pharmacovigilance 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCID-5-CT 
Structured Clinical Interview for Diagnostic and DSM-5 Clinical Trial 
Version 
SD 
standard deviation 
SSRI 
selective serotonin reuptake inhibitors 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TSH 
thyroid stimulating hormone 
WHO 
World Health Organization 


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5. 
INTRODUCTION 
Postpartum depression (PPD) is defined as the occurrence of major depressive episode within 
4 weeks of delivery (DSM-IV 1994) or up to a year after giving birth (Okun 2013). In Diagnostic 
and Statistical Manual of Mental Disorders (DSM-5), the onset specifier includes the entire 
pregnancy as well as 4 weeks following delivery (DSM-5 2013). There are 2 entry criteria for the 
diagnosis of depression (depressed mood and/or loss of interest) and 7 associated symptoms of 
depression (appetite problems, sleep problems, motor problems, lack of concentration, loss of 
energy, poor self-esteem, and suicidality). To be diagnosed with severe PPD, women must 
present at least 5 symptoms of depression (DSM-5 2013). The estimated prevalence of PPD in 
the US is 11.5% (Ko 2017). Based on data from several studies, approximately 25% of PPD 
cases are considered severe (McCabe 2016; PACT Consortium 2015). If untreated, PPD can 
have devastating consequences for the woman and her family (Fihrer 2009; Verbeek 2012). 
PPD is characterized by significant functional impairment for the mother due to sadness and 
depressed mood, loss of interest in daily activities, changes in eating and sleeping habits, fatigue 
and decreased energy, inability to concentrate, and feelings of worthlessness, shame, or guilt. 
Postpartum depression also carries an increased risk for suicide (Savitz 2011; American 
Psychiatric Association 2013), which is the leading cause of maternal death following childbirth 
(Oates 2003) in developed countries. 
Current standard of care for severe PPD comprises cautious use of pharmacological therapies 
combined with a number of counseling, behavioral, and nonpharmacological therapy approaches 
(Altshuler 2001). Use of tricyclic antidepressants and/or selective serotonin reuptake inhibitors 
(SSRIs) is based on use in the general depressed population rather than any extensive studies in 
PPD (Austin 2013) Data to support the efficacy of MDD antidepressants in PPD are mixed (refer 
to Investigator’s Brochure for more information). SSRIs tend to be preferred due to better data 
on safety while breastfeeding (Altshuler 2001). Based on the level of evidence for 
antidepressants in MDD (Kirsch 2008; Fournier 2010), there is a considerable need for improved 
pharmacological therapy for PPD.  
In 2019, brexanolone, a positive allosteric modulator of γ-aminobutyric acid (GABA)A receptors, 
the major class of inhibitory neurotransmitter receptors in the brain, was approved by the FDA as 
a treatment for PPD. In clinical studies, intravenous infusion of brexanolone over 60 hours was 
more effective than placebo in improving depressive symptom scores in women with moderate 
to severe PPD (Kanes 2017; Meltzer-Brody 2018). These data suggest that augmenting 
extrasynaptic GABAA receptor function provides a therapeutic benefit in PPD. 
5.1. 
SAGE-217 
SAGE-217 is a synthetic positive allosteric modulator of GABAA receptors. 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. 


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Unlike other neurotropic medications that target GABAA receptors, SAGE-217 is an allosteric 
modulator of both synaptic as well as extrasynaptic GABAA receptors (Martinez Botella 2017). 
As such, SAGE-217 may represent a therapeutic advantage in the treatment of depressive 
disorders, including PPD, by resetting the GABAergic imbalance in depression by affecting both 
phasic and tonic inhibition. 
In a Phase 3 study of adults with severe PPD, rapid and significant improvements of depressive 
symptoms were observed over 14 days of treatment. The SAGE-217 treatment group began to 
show statistically significant improvement over the placebo group as early as Day 3. The odds 
ratios associated with response and remission were 2.6 and 2.5, respectively, favoring 
SAGE-217. This improvement over the placebo group was overall consistent across assessments 
(ie, HAM-D, MADRS, HAM-A, CGI-I) and was sustained after the treatment period was 
completed. 
5.2. 
Potential Risks and Benefits 
The apparent risks of SAGE-217 are based on both nonclinical and clinical data in completed 
and ongoing studies and the known pharmacology of the drug. SAGE-217 has been generally 
well-tolerated in clinical studies. Somnolence, sedation, and dizziness were identified as adverse 
drug reactions. Most AEs were reported as mild or moderate in intensity and reversible. The 
proposed 50-mg or 40-mg doses have not been studied in participants with PPD, but the 
benefit-risk profile is expected to be acceptable (see Section 5.3). Refer to the Investigator’s 
Brochure for a detailed description of the chemistry, pharmacology, efficacy, and safety of 
SAGE-217. SAGE-217 may present a treatment option for PPD that has more rapid onset of 
action (days instead of weeks) when compared to current standard of care. 
Based on nonclinical findings, embryo-fetal toxicity and withdrawal effects are considered 
important potential risks 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. 
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 adults with MDD and PPD, the 
current significant unmet need in the treatment of depression, and a favorable benefit-risk 
profile, further investigation of SAGE-217 in adults with PPD is justified. 
5.3. 
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 participants, which provided an MTD with a Cmax of 
125 ng/mL at 30 mg OS. While reidentification 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 


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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, multicenter, 3-arm study examining SAGE-217 20-and 
30-mg capsules compared to placebo, found significant antidepressant 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 time point. 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 participants exposed to treatment. Relevant results 
from 217-MDD-301A are available in the Investigator’s Brochure.  
Direct and modeled data from completed studies to date (including efficacy studies 
217-MDD-201 and 217-PPD-201) in addition to 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 participants 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 (SAEs) 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 participants (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 participants 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 


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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 2 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).  
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 
participants to achieve a steady-state Cavg over 40 ng/mL. Figure 1 shows a dose of 50 mg will 
allow >90% participants to maintain the target Cavg yet remain within the range of acceptable 
tolerability. With respect to Cmax, less than 1 in 5 (19%) participants 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-301, 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-301 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-301, 
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-301, 30-mg capsules MDD-301, 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-301, 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 the 
bar = absolute percentage of patients with sedation or somnolence during treatment with SAGE-217; 
percentage in parentheses = 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, participants 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 participants 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; area under the curve 
[AUC] = 936 ng⸱h/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 nonclinical findings are provided in the 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 participants exposed to SAGE-217 treatment. 
In summary, preliminary results through Day 42 of the double-blind period in Part A of Study 
217-MDD-301 in adults with MDD support the need for higher steady-state concentrations of 
SAGE-217 to allow participants to experience maximum anti-depressant, antianxiety, and 
anti-insomnia benefits. Doses of SAGE-217 40 and 50 mg will be utilized in this trial, as well as 
all other ongoing trials with SAGE-217, under the 14-day regimen of an initial evening dose of 
50 mg with reduction to 40 mg as needed based on tolerability. These higher doses of SAGE-217 
are expected to exhibit a favorable benefit-risk profile in the context of 30 mg now being 
identified as a minimally effective dose. While higher rates of ADRs may be anticipated, 
SAGE-217 is expected to maintain an acceptable tolerability profile, based on a current safety 
database of greater than 2000 participants exposed to SAGE-217 treatment across different 
doses/concentrations. In addition, higher doses offer the potential for improved therapeutic 
benefit over the short 14-day treatment course.  
 


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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Study Objective 
6.1.1. 
Primary Objective 
The primary objective is to determine if treatment with SAGE-217 reduces depressive symptoms 
in adults with severe postpartum depression (PPD) compared to placebo. 
6.1.2. 
Secondary Objectives 
Secondary objectives are: 
• To determine if treatment with SAGE-217 reduces anxiety symptoms compared to 
placebo 
• To assess self-report of depressive symptoms 
• To evaluate the safety and tolerability of SAGE-217  
 
 
 
• 
  
6.2. 
Endpoints 
6.2.1. 
Primary Endpoint 
• Change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D) 
total score at Day 15 
6.2.2. 
Key Secondary Endpoints 
• Change from baseline in HAM-D total score at Day 3, Day 28, and Day 45 
• Change from baseline in Clinical Global Impressions – Severity (CGI-S) score at 
Day 15 
6.2.3. 
Other Secondary Endpoints 
• HAM-D response at Day 15 and Day 45 
• HAM-D remission at Day 15 and Day 45 
• Clinical Global Impressions – Improvement (CGI-I) response at Day 15  
• Change from baseline in Hamilton Anxiety Rating Scale (HAM-A) total score at 
Day 15 
• Change from baseline in the Montgomery-Åsberg Depression Rating Scale 
(MADRS) total score at Day 15 
• Change from baseline in HAM-D subscale at Day 15 




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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a randomized, double-blind, placebo-controlled, parallel group study of the efficacy and 
safety of SAGE-217 in adults diagnosed with severe PPD. Participants, site staff, and sponsor 
personnel will be masked to treatment allocation.  
This study will consist of a Screening Period of up to 28 days, a 14-day double-blind Treatment 
Period and a Follow-up Period through Day 45.  
The Screening Period begins with the signing of the informed consent form (ICF); the ICF must 
be signed prior to beginning any screening activities. The diagnosis of depression will be 
determined using the Structured Clinical Interview for Diagnostic and Statistical Manual of 
Mental Disorders-5 (DSM-5) Axis I Disorders (SCID-5-CT). Participants will undergo 
preliminary screening procedures to determine eligibility. A full personal medical history will be 
taken including documentation of all major depression episodes, other Axis I disorders, and any 
prior PPD episodes. In addition, PPD episodes experienced by immediate female family 
members, including siblings, parents, and grandparents will be documented. 
During the study, a qualified lactation consultant will be made available upon request to 
participants who are breastfeeding.  
Psychotropic medications are permitted provided participants are on a stable dose for at least 
30 days prior to Day 1 and agree to continue on a stable dose through completion of the Day 45 
assessments. Initiation of new psychotropic medications that may potentially have an impact on 
efficacy and/or safety endpoints will not be allowed within 30 days prior to Day 1 through 
completion of the Day 45 assessments. On Day 1, eligible participants will be stratified based on 
use of antidepressant treatment (current/stable or not treated/withdrawn ≥30 days or 
>5 half-lives) and randomized within each stratum to one of 2 treatment groups (SAGE-217 
50 mg or matching placebo) in a 1:1 ratio. Participants will self-administer investigational 
product (IP) once daily at approximately 8 PM with fat-containing food (eg, within 1 hour of an 
evening meal which contains fat, or with a fat-containing snack), on an outpatient basis, for 
14 days. See Section 10.5 for examples of fat-containing snacks. As local regulations permit, IP 
administration will be monitored via a medication adherence monitoring platform used on 
smartphones to visually confirm IP ingestion. Participants will return to the study center during 
the treatment and follow-up periods as outlined in Table 2.  
During the treatment period, participants will be able to receive IP as long as there are no dose 
limiting safety/tolerability concerns. Participants who cannot tolerate 50 mg will receive 40 mg 
for the remainder of the treatment period. At the discretion of the investigator, participants who 
cannot tolerate the 40-mg dose will be discontinued from IP.  
Participants who discontinue IP early should complete the remaining study visits as scheduled 
through Day 45 (ie, relative to Day 1) unless the participant withdraws consent or loses the 
capacity to grant consent. If a participant withdraws from the study/stops study participation 
early, an early termination visit should be conducted.  


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7.2. 
Number of Participants 
Approximately 192 participants, with a total of approximately 96 per treatment group 
(SAGE-217 or placebo) will be randomized and dosed to obtain approximately 86 evaluable 
participants per treatment group. Additional participants may be randomized if the dropout rate is 
higher than anticipated (see Section 13.8). 
7.3. 
Treatment Assignment 
Participants will be randomly assigned to a treatment group on Day 1 and will be stratified based 
on use of antidepressant treatment (current/stable or not treated/withdrawn ≥30 days or 
>5 half-lives) at baseline. Randomization will be performed within each stratum in a 1:1 ratio to 
receive SAGE-217 50 mg or matching placebo. Additional details on randomization and blinding 
are provided in Section 9.5.  
7.4. 
Dose Adjustment Criteria 
During the treatment period, participants will be able to receive IP as long as there are no dose 
limiting safety/tolerability concerns. Participants who cannot tolerate 50 mg will receive 40 mg 
for the remainder of the treatment period.   
If dose adjustment is deemed necessary by the investigator at any time during the treatment 
period, the participant will return to the site to return any remaining IP and for the adjusted dose 
to be dispensed. 
At the discretion of the investigator, participants who cannot tolerate the 40-mg dose will be 
discontinued from IP (refer to Section 8.4.1 for procedures for early IP discontinuation). 
Participants are encouraged to continue to come in for assessments following IP discontinuation.  
7.5. 
Criteria for Study Termination 
Sage Therapeutics will 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 
participants, or for administrative reasons. In the event of study termination, Sage Therapeutics 
will provide written notification to the investigator. Investigational sites must promptly notify 
their institutional review board (IRB)/independent ethics committee (IEC), where required, and 
initiate withdrawal procedures for participating participants.  


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8. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
8.1. 
Participant Inclusion Criteria 
Participants must meet all of the following criteria to qualify for participation in this study: 
1. Participant has signed an ICF prior to any study-specific procedures being performed. 
2. Participant is an ambulatory female between 18 and 45 years of age, inclusive. 
3. Participant is in good physical health and has no clinically significant findings, as 
determined by the investigator, on physical examination, 
 
. 
4. Participant agrees to adhere to the study requirements, including not participating in night 
shift work. 
5. Participant has ceased lactating or agrees not to provide breastmilk to her infant(s) from 
just prior to receiving IP on Day 1 until 7 days after the last dose of IP. 
6. Participant must have a negative pregnancy test at screening and Day 1 prior to the start 
of IP administration. 
7. Participant has had a major depressive episode that began no earlier than the third 
trimester and no later than the first 4 weeks following delivery, and meets criteria for 
major depressive episode per DSM-5, diagnosed by SCID-5-CT. 
8. Participant has a HAM-D total score of ≥26 at screening and Day 1 (prior to 
randomization). 
9. Participant is ≤12 months postpartum at screening and Day 1. 
10. Participants taking antidepressants must have been taking these medications at the same 
dose for at least 30 days prior to Day 1. Participants who have stopped taking 
antidepressants within 30 days must have stopped for longer than 5 half-lives of the 
antidepressant prior to Day 1, and will be stratified into the “no antidepressant group”. 
Participants receiving psychotherapy must have been receiving therapy on a regular 
schedule for at least 30 days prior to Day 1. 
11. Participant is willing to delay the start of other antidepressant or antianxiety medications 
and any new pharmacotherapy regimens, including as-needed benzodiazepine anxiolytics 
and sleep aids, until after completion of the Day 45 visit.  
12. Participant 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 
IP, unless she is surgically sterile (bilateral oophorectomy, hysterectomy, and/or bilateral 
salpingectomy), or does not engage in sexual relations which carry a risk of pregnancy 
(does not include abstinence). 
13. Participant agrees to refrain from drugs of abuse and alcohol for the duration of the study. 
8.2. 
Participant Exclusion Criteria 
Participants who meet any of the following criteria are disqualified from participation in this 
study: 




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16. Participant is taking non-GABA anti-insomnia medications (eg, melatonin, Benadryl 
[antihistamines], trazodone), or first or second generation (typical/atypical) 
antipsychotics within 14 days prior to Day 1.  
17. Participant has been diagnosed with and/or treated for any type of cancer (excluding 
basal cell carcinoma and melanoma in situ) within the past year prior to screening. 
18. Participant is taking psychostimulants (eg, methylphenidate, amphetamine) or opioids, 
regularly or as needed, within 28 days prior to Day 1. 
19. Use of any known strong inhibitors of cytochrome P450 (CYP)3A4 within 14 days or 
5 half-lives (whichever is longer) or consumed grapefruit juice, grapefruit, Seville 
oranges, or products containing these within 14 days prior to receiving the first dose of 
IP.  
20. Participant has a positive urine drug test and/or alcohol screen at screening or on Day 1 
prior to dosing.  
21. Use of any strong CYP3A inducer, such as rifampin, carbamazepine, enzalutamide, 
mitotane, phenytoin, or St. John’s Wort within 14 days or 5 half-lives (whichever is 
longer) prior to the first dose of IP.  
22. Participant plans to undergo elective surgery during participation in the study. 
23. Participant is a dependent of the sponsor, investigator, investigator’s deputy, or study site 
staff. 
24. Participant is involuntarily confined or detained in a penal institution or other institution 
under court order. 
8.3. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently assigned to study intervention. A minimal set of screen failure information will 
be collected, including demography, screen failure details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Rescreened participants should be assigned a new participant number. 
8.4. 
Investigational Product Discontinuation and Early Termination from 
the Study 
A participant may withdraw from the study at any time at his/her own request for any reason. 
The investigator may discontinue a participant from the study and/or from IP for safety, 
behavioral, compliance, or administrative reasons. The investigator must discontinue a 
participant from IP for any of the following reasons: 
• The participant is unwilling or unable to adhere to the protocol 
• Other medical or safety reason, including suicidality, based on clinical judgment 
• The participant becomes pregnant during the treatment period 


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The investigator must also discontinue a participant from the study and from IP (if applicable) if 
the participant withdraws consent or loses the capacity to grant consent. 
The reason for IP discontinuation and/or the reason for early termination from the study must be 
documented in the participant’s study record and recorded in the participant’s electronic case 
report form (eCRF).  
The investigator must notify the sponsor and/or the medical monitor when a participant 
discontinues IP and/or stops participation in the study for any reason.  
8.4.1. 
Investigational Product Discontinuation 
Participants who discontinue IP early should complete the remaining study visits as scheduled 
through Day 45 (ie, relative to Day 1) unless the participant withdraws consent or loses the 
capacity to grant consent.  
8.4.2. 
Early Termination from the Study 
At the time of study withdrawal/stopping study participation, if possible, an ET visit should be 
conducted. The participant will be permanently discontinued both from the IP (if applicable) and 
from the study at that time. 
If the participant withdraws consent for disclosure of future information, the sponsor will retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
Participants 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.  
8.4.3. 
Loss to Follow-up 
A participant will be deemed lost to follow-up after 3 attempts at contacting the participant have 
been made and it has been at least 1 month since the last participant contact. All attempts at 
contact and the reason for discontinuation will be documented. If the investigator becomes aware 
of a change in the participant’s status or receives more information about a participant’s 
disposition, this information will be documented.  
8.4.4. 
Replacement of Participants 
Participants will not be replaced. Additional participants may be randomized if the dropout rate 
is higher than anticipated (Section 13.8). 


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9. 
TREATMENT OF PARTICIPANTS 
9.1. 
Description of Investigational Product 
Participants will self-administer SAGE-217 (50 mg or 40 mg [for dose adjustments only as 
permitted as described in Section 7.4]) or matching placebo orally once daily at approximately 
8 PM with food for 14 days. The 50-mg and 40-mg doses will be administered as 2 capsules per 
dose (50 mg, administered as one 30-mg capsule and one 20-mg capsule, and 40 mg, 
administered as two 20-mg capsules). Placebo will also be administered as 2 capsules to 
maintain the blind.  
9.2. 
Prior Medications, Concomitant Medications, Restrictions, and 
Contraception Requirements 
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 signing the ICF through the first dose of IP will be 
recorded. In addition, psychotropic medications taken 6 months prior to Screening will be 
recorded. 
All medications and/or supplements taken from the first dose of IP through the final study visit 
(including start and end dates route, dose/units, frequency, and indication) will be recorded on 
the eCRF. Any concomitant medication determined necessary for the welfare of the participant 
may be given at the discretion of the investigator at any time during the study.  
Antidepressants that have been taken at the same dose for at least 30 days prior to Day 1 are 
permitted if the participant intends to continue the stable dose for the duration of the study. 
The following medications intended for contraception are permitted for female participants: 
• Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation 
• Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation 
• Intrauterine device 
• Intrauterine hormone-releasing system 
9.2.2. 
Prohibited Medications 
Restrictions on specific classes of medications include the following and any use of these 
medications during the specified time periods must be documented as protocol deviations: 
• Initiation of new psychotropic medications, including antidepressant or antianxiety 
medications, and any new pharmacotherapy regimens that may potentially have an 
impact on efficacy and/or safety endpoints within 30 days prior to Day 1 through 
completion of the Day 45 visit 


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• Use of any benzodiazepines, barbiturates, GABAA modulators (eg, eszopiclone, 
zopiclone, zaleplon, and zolpidem) within 28 days prior to Day 1 through completion 
of the Day 45 visit (within 30 days prior to Day 1 through completion of the Day 45 
visit for benzodiazepine or GABA modulators with a half-life of ≥48 hours 
[eg, diazepam) 
• First generation (typical) antipsychotics (eg, haloperidol, perphenazine) and second 
generation (atypical) antipsychotics (eg, aripiprazole, quetiapine) within 14 days prior 
to Day 1 through completion of the Day 45 visit 
• Use of any non-GABA anti-insomnia medications (eg, melatonin, Benadryl 
[antihistamines], trazodone) within 14 days prior to Day 1 through completion of the 
Day 45 visit 
• Exposure to another investigational medication or device from 30 days prior to 
screening through completion of the Day 45 visit 
• Any known strong inhibitors of cytochrome P450 (CYP)3A4 within 14 days or 
5 half-lives (whichever is longer) within 14 days prior to receiving the first dose of IP 
through the 14-day treatment period 
• Use of any strong CYP3A inducer, such as rifampin, carbamazepine, enzalutamide, 
mitotane, phenytoin, or St John’s Wort within 14 days or 5 half-lives (whichever is 
longer) prior to receiving the first dose of IP through the 14-day treatment period 
• Use of any chronic or as-needed psychostimulants (eg, methylphenidate, 
amphetamine) or opioids from within 28 days prior to Day 1 through completion of 
the Day 45 visit 
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 receiving the first dose of IP and throughout the 14-day 
treatment period. 
Consumption of alcohol, use of drugs of abuse, or use of products containing cannabidiol (CBD) 
is discouraged throughout the duration of the study.  
Female participants who are lactating or actively breastfeeding must stop giving breast milk to 
the baby(ies) starting on Day 1 until 7 days after the last dose of IP. During the study, a qualified 
lactation consultant will be made available to participants upon request. 
Elective surgeries or procedures are prohibited through completion of the Day 45 visit. 
Vagus nerve stimulation and electroconvulsive therapy are prohibited through completion of the 
Day 45 visit. 
Participants must not participate in night shift work. 
Participants who are feeling sedated, somnolent, and/or dizzy are to refrain from driving or 
engaging in any activity requiring alertness. 


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Participants receiving psychotherapy on a regular schedule for at least 30 days prior to Day 1 are 
permitted if the participant intends to continue the regular schedule through the follow-up period 
(Day 45). 
9.2.4. 
Acceptable Forms of Contraception 
Acceptable forms of highly effective contraception for participants who are not surgically sterile 
include: 
• Combined (estrogen and progestogen containing) oral, intravaginal, or transdermal 
hormonal contraception associated with inhibition of ovulation 
• Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation  
• Intrauterine device 
• Intrauterine hormone-releasing system 
• 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) 
9.3. 
Intervention after the End of the Study 
No intervention following the end of the study is planned.  
9.4. 
Treatment Adherence 
SAGE-217 or placebo will be self-administered by participants once daily in the evening with 
food. Sites will dispense a weekly supply of IP to the participants to take at home with 
instructions for use (see Section 10.5 and Table 2).  
As local regulations permit, administration of IP will be monitored by a medication adherence 
monitoring platform used on smartphones to visually confirm medication ingestion. Participants 
will receive a reminder within a predefined time window to take IP while using the application. 
Participants will follow a series of prescribed steps in front of the front-facing webcam to 
visually confirm their ingestion of the medication. The application will record the date and time 
of IP administration by dose level, as well as missed doses. 
In addition, the participant will be instructed to bring their dosing kit to the site as outlined in 
Table 2, 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 participants should be reinstructed about the dosing requirement during study contacts. The 
authorized study personnel conducting the re-education must document the process in the 
participant source records. 
The investigator(s) will record any reasons for noncompliance in the source documents. 


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9.5. 
Randomization and Blinding 
This is a randomized double-blind, placebo-controlled study. Participants who meet the entrance 
criteria will be randomized in a stratified manner based on use of antidepressant treatment 
(current/stable or not treated/withdrawn ≥30 days) at baseline.  
Randomization will be done within each stratum in a 1:1 ratio to receive SAGE-217 50 mg or 
matched placebo.  
Participants, clinicians, and the study team will be blinded to treatment allocation. 
Randomization will be performed centrally via an interactive response technology (IRT) system. 
Randomization schedules will be generated by an independent statistician. The allocation to 
treatment group will be based on the randomization schedule. The randomization schedules will 
be kept strictly confidential, accessible only to authorized personnel until the time of unblinding. 
The blinding of the study will be broken after the database has been locked. 
9.5.1. 
Emergency Unblinding 
During the study, the blind is to be broken by the investigator via the IRT system only when the 
safety of a participant is at risk and the treatment plan is dependent on the study treatment 
received. Unless a participant is at immediate risk, the investigator should make attempts to 
contact Sage prior to unblinding the study treatment administered to a participant. The 
responsibility to break the treatment code in emergency situations resides solely with the 
investigator. If the unblinding occurs without Sage’s knowledge, the investigator must notify 
Sage within 24 hours of breaking the blind. All circumstances surrounding a premature 
unblinding must be clearly documented in the source records.   
In all cases where the IP allocation for a participant is unblinded, pertinent information 
(including the reason for unblinding) must be documented in the participant’s records and on the 
eCRF. At the time of withdrawal from the study/stopping participation, if possible, an EOT 
and/or ET visit should be conducted.  
 


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10. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
10.1. 
Investigational Product 
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.  
Matching placebo capsules are hard gelatin capsules containing only the excipients listed for the 
active capsule.  
10.2. 
Investigational Product Packaging and Labeling 
SAGE-217 capsules and matched placebo capsules will be provided to the clinic pharmacist 
and/or designated site staff responsible for dispensing the IP in appropriately labeled, 
participant-specific kits containing sealed unit doses. Each unit dose consists of 2 capsules (see 
Section 9.1). Additional information regarding the packaging and labeling is provided in the 
Pharmacy Manual.  
Investigational product 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. 
Investigational Product Storage 
SAGE-217 and matching placebo capsules are to be stored at room temperature (59°F to 86°F; 
15°C to 30°C), safely and separately from other drugs. 
10.4. 
Investigational Product Preparation 
Not applicable. 
10.5. 
Investigational Product 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 participant misses a dose, the participant should skip that dose (ie, they should not take the 
dose in the morning) and take the next scheduled dose in the evening the next day. 
10.6. 
Investigational Product Accountability, Handling, and Disposal 
Upon receipt of IP, the investigator(s), or the responsible pharmacist or designee, will inspect the 
IP and complete and follow the instructions regarding receipt and storage in the Investigator’s 
Brochure and (where applicable) in the pharmacy manual. A copy of the shipping documentation 
will be kept in the study files. 


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The designated site staff will dispense the supplied participant-specific kits to participants at the 
planned dispensation visit intervals outlined in Table 2.  
Site staff will access the IRT at the Screening Visit to obtain a participant identification (ID) 
number for each participant that has signed an ICF. On Day 1, site staff will access the IRT and 
provide the necessary participant-identifying information, including the participant ID number 
assigned at screening, to randomize the eligible participant into the study and obtain the 
medication ID number for the IP to be dispensed to that participant. The medication ID number 
and the number of capsules dispensed must be recorded. 
At the subsequent IP-dispensing visit, the investigator or designee will access the IRT, providing 
the same participant ID number assigned at Screening, to obtain the medication ID number for 
the IP to be dispensed at that visit. The medication ID number, the number of capsules 
dispensed, and the number of capsules returned by the participant 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 IP provided is for use only as directed in this protocol. The investigator or designee must 
keep a record of all IP received, used and returned/discarded. It must be clear from the records 
which participant received which dose of active or placebo treatment. 
Sage Therapeutics will be permitted access to the study supplies at any time with appropriate 
notice during or after completion of the study to perform drug accountability reconciliation.  
The investigator, pharmacist, or qualified designee is responsible for drug accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final disposition records). 
At the end of the study, any unused IP will be returned to Sage Therapeutics for destruction or 
destroyed locally per the site’s procedures; disposition of IP will be documented. 
10.7. 
Product Complaints 
A product complaint is any written, electronic, or verbal expression of dissatisfaction regarding 
the identity, quality, reliability, safety, purity, potency, effectiveness or performance (applicable 
for approved marketed products) of a drug product after it is released for distribution.  
In the course of conduct of the study, study personnel may become aware of a product complaint 
associated with the use of a Sage product. Personnel shall notify Sage within 24 hours by 
forwarding the product complaint information via the contact information listed in Table 1. 
Where possible, personnel should segregate and retain any product, materials, or packaging 
associated with the product complaint until further instruction is provided by Sage or its 
designated representative(s). 


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11. 
EFFICACY AND CLINICAL PHARMACOLOGY ASSESSMENTS 
11.1. 
Efficacy Assessments 
All assessments will be conducted according to the Schedule of Assessments (Table 2). Study 
assessments that involve participant interviews, including the HAM-D and SCID-5-CT, may be 
audiotaped for independent quality control purposes. All assessments must be conducted by 
raters that have been trained and certified to conduct assessments in this study. 
11.1.1. 
Hamilton Rating Scale for Depression (HAM-D) 
The primary outcome measure is the change from baseline in 17-item HAM-D total score at the 
end of the Treatment Period (Day 15). Every effort should be made for the same rater to perform 
all HAM-D assessments for an individual participant. An assessment timeframe of past 7 days 
(1 week) will be used at Screening and ‘Since Last Visit’ will be used for all other visits. 
The 17-item HAM-D will be used to rate the severity of depression in participants who are 
already diagnosed as depressed (Williams 2013a; Williams 2013b). The 17-item HAM-D 
comprises individual ratings related to the following symptoms: depressed mood (sadness, 
hopeless, helpless, worthless), feelings of guilt, suicide, insomnia (early, middle, late), work and 
activities, retardation (slowness of thought and speech; impaired ability to concentrate; decreased 
motor activity), agitation, anxiety (psychic and somatic), somatic symptoms (gastrointestinal and 
general), genital symptoms, hypochondriasis, loss of weight, and insight.  
The HAM-D total score will be calculated as the sum of the 17 individual item scores.  
In addition to the primary efficacy endpoint of change from baseline in HAM-D total score, 
several secondary efficacy endpoints will be derived for the HAM-D. Hamilton Rating Scale for 
Depression subscale scores will be calculated as the sum of the items comprising each subscale. 
Hamilton Rating Scale for Depression response will be defined as having a 50% or greater 
reduction from baseline in HAM-D total score. Hamilton Rating Scale for Depression remission 
will be defined as having a HAM-D total score ≤7.  
11.1.2. 
Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive 
episodes in participants with mood disorders. It was designed as an adjunct to the HAM-D that 
would be more sensitive to the changes brought on by antidepressants and other forms of 
treatment than the Hamilton Scale.  
Higher MADRS scores indicate more severe depression, and each item yields a score of 0 to 6. 
The overall score ranges from 0 to 60 (Williams 2008). 
The MADRS total score will be calculated as the sum of the 10 individual item scores.  
11.1.3. 
Hamilton Anxiety Rating Scale (HAM-A) 
The 14-item HAM-A will be used to rate the severity of symptoms of anxiety (Williams 2013c; 
Williams 2013d). Each of the 14 items is defined by a series of symptoms, and measures both 
psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical 
complaints related to anxiety). Scoring for HAM-A is calculated by assigning scores of 0 (not 






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The sponsor will store the deidentified samples in a secure storage space with adequate measures 
to protect participant confidentiality. Only the sponsor and those persons or entities working with 
the sponsor will have access to the samples and associated data.   


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12. 
SAFETY ASSESSMENTS 
12.1. 
Safety Parameters 
All assessments will be conducted according to the Schedule of Assessments (Table 2). 
12.1.1. 
Demography and Medical History 
Demographic characteristics (age, race, gender, ethnicity, employment status, highest education 
level, marital/civil status) and a full personal medical history, including: generalized anxiety 
disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder; bipolar 
disorder, persistent depressive disorder, postpartum depression, substance use disorder, alcohol 
use disorder, major depressive disorder with seasonal pattern, major depressive disorder with 
psychotic features, premenstrual dysphoric disorder, major depressive disorder with atypical 
features, schizophrenia, or schizoaffective disorder will be documented. The delivery date of the 
index pregnancy and any other prior pregnancies with associated postpartum depressive episodes 
will also be recorded. In addition, postpartum depression episodes experienced by immediate 
female family members, including siblings, parents, and grandparents will be documented.  
The diagnosis of PPD will be determined using the SCID-5-CT. If available, the disease code 
associated with the diagnosis of PPD based on the 10th revision of the International Statistical 
Classification of Diseases and Related Health Problems (ICD-10) should be recorded.  
12.1.2. 
Weight and Height 
Height (screening only) and weight will be measured and documented. BMI will be calculated 
and documented.  
12.1.3. 
Physical Examination 
Whenever possible, the same individual should perform all physical examinations. Physical 
examinations will include assessment of body systems (eg, head, eye, ear, nose and throat; heart; 
lungs; abdomen; and extremities) as well as cognitive and neurological examination and mental 
status examination. An abbreviated physical examination includes a brief medical history 
followed by a targeted physical examination. Unscheduled physical examinations may also be 
conducted per the investigator’s discretion. 
Any abnormality in physical examinations will be interpreted by an Investigator as abnormal, not 
clinically significant (NCS); or abnormal, clinically significant (CS) in source documents.  
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 at screening and throughout the study. Questions to be asked are 
as follows:  
• Were you diagnosed with COVID-19 by a healthcare professional?  
− If the answer is “no”, no further questions.  








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12.2.2. 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Places the participant at immediate risk of death (a life-threatening event); however, 
this does not include an event that, had it occurred in a more severe form, might have 
caused death  
• Requires inpatient 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 participant or may require medical intervention to prevent 1 of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization). 
All SAEs that occur after any participant 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. Any SAE that is ongoing when the participant completes their 
final study visit, will be followed by the investigator until the event has resolved, stabilized, 
returned to baseline status, or until the participant dies or is lost to follow up. 
A prescheduled or elective procedure or routinely scheduled treatment will not be considered an 
SAE, even if the participant 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 participant’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 an 
investigator, between the participant’s consent to participate in the study and at the 
time of the procedure or treatment. 
12.2.3. 
Relationship to Investigational Product 
The investigator must make the determination of relationship to the IP for each adverse event 
(not related, related). The following definitions should be considered when evaluating the 
relationship of AEs and SAEs to the IP.  
Not Related 
An AE will be considered “not related” to the use of the IP if there is not a reasonable 
possibility that the event has been caused by the IP. Factors pointing towards this 
assessment include but are not limited to: the lack of temporal relationship between 
administration of the IP and the event, the presence of biologically implausible 
relationship between the product and the AE, or the presence of a more likely 
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Related 
An AE will be considered “related” to the use of the IP if there is a reasonable 
possibility that the event may have been caused by the product under investigation. 
Factors that point towards this assessment include but are not limited to: a positive 
rechallenge, a reasonable temporal sequence between administration of the drug and 
the event, a known response pattern of the suspected drug, improvement following 
discontinuation or dose reduction, a biologically plausible relationship between the 
drug and the AE, or a lack of alternative explanation for the AE 
12.2.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the participant and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. The AE term should be reported in standard medical terminology when 
possible. For each AE, the investigator will evaluate and report the onset (date and time), 
resolution (date and time), intensity, causality, action taken, outcome, and seriousness (if 
applicable), and whether or not it caused the participant to discontinue the IP or withdraw early 
from the study. 
Intensity will be assessed according to the following scale: 
• Mild: symptom(s) barely noticeable to participant or does not make participant 
uncomfortable; does not influence performance or functioning; prescription drug not 
ordinarily needed for relief of symptom(s)  
• Moderate: symptom(s) of a sufficient severity to make participant uncomfortable; 
performance of daily activity is influenced; participant is able to continue in study; 
treatment for symptom(s) may be needed 
• Severe: symptom(s) cause severe discomfort; symptoms cause incapacitation or 
significant impact on participant’s daily life; severity may cause cessation of 
treatment with IP; treatment for symptom(s) may be given and/or participant 
hospitalized  
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 12.2.2. An AE of severe intensity 
may not necessarily be considered serious. 
12.2.5. 
Reporting Serious Adverse Events 
In order to adhere to all applicable laws and regulations for reporting an SAE(s), the study site 
must notify Sage or designee within 24 hours of the study site staff becoming aware of the 
SAE(s). 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 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 eCRF and/or study file. 


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Serious adverse events occurring after the designated follow-up time for the study, should be 
reported to Sage or designee according to the timelines noted above only if the investigator 
considers the SAE related to IP.   
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/IEC 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. IRBs/IECs will be notified of 
SAEs and/or SUSARs as required by local law. 
In addition, appropriate personnel in Sage Drug Safety and Pharmacovigilance or designee will 
unblind SUSARs for the purpose of regulatory reporting. Sage or designee will submit SUSARs 
(in blinded or unblinded fashion) to regulatory agencies according to local law. Sage, or 
designee, will submit SUSARS to investigators in a blinded fashion. 
12.3. 
Pregnancy 
If a participant becomes pregnant after the first administration of IP, pregnancy information must 
be collected and recorded on the Pregnancy form and submitted to the sponsor within 24 hours of 
learning of the pregnancy. Details will be collected for all pregnancies for which conception was 
likely to have occurred after the start of IP administration until 5 terminal half-lives following 
the last administration of IP or until the completion of the study whichever is longer. Any 
pregnancy occurring in that time frame will be followed until delivery or termination of the 
pregnancy.  
The participant will be followed to determine the outcome of the pregnancy. The outcome of all 
pregnancies (eg, spontaneous abortion, elective abortion, normal birth) must be followed and 
documented even if the participant was discontinued from the study. The investigator will collect 
follow-up information on the participant and the neonate, and the information will be forwarded 
to Sage or designee. Generally, follow up will not be required for longer than 6 to 8 weeks 
beyond the estimated delivery date. Any termination of pregnancy will be reported, regardless of 
fetal status (presence or absence of anomalies) or indication for the procedure. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an IP may have 
interfered with the effectiveness of a contraceptive medication. Any complication during 
pregnancy (eg, anemia, infections, preeclampsia) should be reported as an AE/SAE. If the 
outcome of the pregnancy meets the criteria for immediate classification as an SAE 
(ie, spontaneous abortion, stillbirth, neonatal death), the investigator should follow the 
procedures for reporting an SAE.  
12.4. 
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, 
all overdoses must be recorded on an Overdose form and sent to Sage or designee within 
24 hours of the site becoming aware of the overdose.  


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13. 
STATISTICS 
Detailed description of the analyses to be performed in the study will be provided in the 
statistical analysis plan (SAP). The SAP will be finalized and approved prior to database lock. 
Any changes/additions to the SAP following database lock will be described in detail in the 
clinical study report. 
13.1. 
Data Analysis Sets 
The Randomized Set is defined as all participants who are randomized. 
The Safety Set will include all participants administered IP.  
The Full Analysis Set will include all randomized participants who received any amount of IP 
and have a valid baseline and at least one valid postbaseline HAM-D total score.  
The Per Protocol Set is defined as all participants in the Full Analysis Set without any major 
protocol deviations that could affect efficacy. The review of major protocol deviations will be 
completed, and the decision on whether the deviation affects efficacy will be documented before 
database unblinding. 
13.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data. All participants will be used in the analyses, 
as per the analysis populations, using all nonmissing data available. No imputation process will 
be used to estimate missing data. A sensitivity analysis will be used to investigate the impact of 
missing data if ≥5% of participants in any treatment group have missing data. 
13.3. 
General Considerations 
For the purpose of all primary and secondary analyses where applicable, baseline is defined as 
the last measurement prior to receipt of IP.  
Continuous endpoints will be summarized with number (n), mean, standard deviation, median, 
minimum, and maximum. In addition, change from baseline values will be calculated at each 
time point and summarized descriptively. For categorical endpoints, descriptive summaries will 
include counts and percentages.  
13.4. 
Demographics and Baseline Characteristics 
Demographic data, such as age, race, and ethnicity, and baseline characteristics, such as height, 
weight, and BMI, will be summarized using the Safety Population.  
Pregnancy test results and drug screen results will be listed but not summarized.  
Medical history will be listed by participant.  
13.5. 
Efficacy Analysis  
The estimand for the primary efficacy analysis is defined as follows: 
1. The treatment regimen for participants is: placebo or SAGE-217 for 14 days. 


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2. The target population is adult participants with a diagnosis with severe PPD (baseline 
HAM-D total score ≥26). 
3. The variable of interest is the change from baseline in HAM-D total score at Day 15. 
4. The population summary level deals with the difference between SAGE-217 and placebo 
treatments in mean change from baseline in HAM-D total score at Day 15. 
5. The intercurrent events could be: 
a. The premature discontinuation of treatment for any reason, thus not having a Day 15 
HAM-D total score available. This will be handled by a sensitivity analysis using 
multiple imputation technique (details will be provided in the SAP).  
b. Certain medications including, but not limited to, new antidepressants or 
benzodiazepines are prohibited in the protocol until Day 45 follow-up; however, the 
treatment policy strategy dictates that the results following these prohibited 
medication use will not be manipulated, but will rather be used ‘as is’ in 
analysis. Please note that this protocol does not specify any rescue medication, hence 
there is no rescue medication to be considered.  
Data will be analyzed using a mixed-effects model for repeated measures (MMRM); the model 
will include treatment, baseline HAM-D total score, stratification factor, assessment time point, 
and time point-by-treatment as explanatory variables. All explanatory variables will be treated as 
fixed effects. All postbaseline time points will be included in the model. Model-based point 
estimates (ie, least squares means, 95% confidence intervals, and p values) will be reported 
where applicable. An unstructured covariance structure will be used to model the within-
participant errors. If there is a convergence issue with the unstructured covariance model, 
Toeplitz compound symmetry or Autoregressive (1) [AR(1)] covariance structure will be used, 
following this sequence until convergence is achieved. If the model still does not converge with 
AR(1) structure, no results will be reported. When the covariance structure is not UN, the 
sandwich estimator for the variance covariance matrix will be derived, using the EMPIRICAL 
option in the PROC MIXED statement in SAS.  
Similar to those methods described above for the primary endpoint, an MMRM will be used for 
the analysis of the change from baseline in other time points in HAM-D total score, MADRS 
total score, HAM-A total score, EPDS total score, PHQ-9 score, and selected individual items 
and/or subscale scores in HAM-D.  
Generalized estimating equation (GEE) methods will be used for the analysis of HAM-D 
response (defined as ≥50% reduction from baseline in HAM-D total score) and HAM-D 
remission (defined as HAM-D total score of ≤7.0). GEE models will include terms for treatment, 
baseline score, stratification factor, assessment time point, and time point-by-treatment as 
explanatory variables. The comparison of interest will be the difference between SAGE-217 and 
matching placebo at Day 15. Model-based point estimates (ie, odds ratios), 95% confidence 
intervals, and p values will be reported.  
A GEE method will also be used for the analysis of CGI-I response (defined as “much 
improved” or “very much improved”) including terms for treatment, baseline CGI-S score, 
stratification factor, assessment time point, and time point-by-treatment as explanatory variables. 
Descriptive summary statistics will be provided for other endpoints. 






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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Before an investigational site can enter a participant into the study, a representative of Sage 
Therapeutics 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 IP accountability checks are being 
performed 
• Perform source data verification. This includes a comparison of the data in the case report 
forms with the participant’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 
participant (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 or IEC. 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
14.2. 
Audits and Inspections 
Sage Therapeutics or authorized representatives of Sage Therapeutics, a regulatory authority, or 
an IEC or an IRB may visit the site to perform an audit(s) or inspection(s), including source data 
verification. The purpose of a Sage Therapeutics audit or a regulatory authority inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, GCP/ICH GCP guidelines, and any applicable 
regulatory requirements. The investigator should contact Sage Therapeutics immediately if 
contacted by a regulatory agency or IRB/IEC about an inspection. 


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14.3. 
Institutional Review Board or Independent Ethics Committee 
The principal investigator must obtain IRB (or IEC) approval for the clinical study prior to 
enrolling a participant. Initial IRB (or IEC) approval, and all materials approved by the IRB (or 
IEC) for this study including the participant 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 Practice and all applicable regulatory requirements, 
Sage Therapeutics may conduct a quality assurance audit(s) at the clinical site. Please see 
Section 14.2 for more details regarding the audit process. 
The investigator must have adequate quality control practices to ensure that the study is 
performed in a manner consistent with the protocol, GCP/ICH GCP guidelines, and applicable 
regulatory requirements. The investigator is responsible for reviewing all identified protocol 
deviations. Significant protocol deviations should be reported to the IRB/IEC per the IRB/IEC’s 
written procedures. 
The investigator is responsible for supervising any individual or party to whom the investigator 
delegates trial-related duties and functions conducted at the trial site. When the investigator 
retains the services of any individual or party to perform trial-related duties and functions, the 
investigator must ensure the individual or party is qualified to perform trial-related duties and 
functions and should implement procedures to ensure the integrity of the trial-related duties and 
functions performed, and any data generated.   
The investigator must maintain adequate and accurate source documents and trial records that 
include all pertinent observations on each of the site’s trial participants. Source data must be 
attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data 
should be traceable, should not obscure the original entry, and should be explained, if necessary 
to provide clarification. 
 


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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 
given a written and dated approval or favorable opinion by an IRB or IEC as appropriate. The 
investigator must obtain and document approval before he or she can enroll any participant into 
the study. The IRB or IEC must supply to the sponsor a list of the IRB/IEC membership and a 
statement to confirm that the IRB/IEC is organized and operates according to GCP and 
applicable laws and regulations. 
The principal investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB or IEC must approve all 
advertising used to recruit participants for the study. The protocol must be re-approved by the 
IRB or IEC upon receipt of amendments and annually, as local regulations require. 
The principal investigator is also responsible for providing the IRB or IEC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. Sage Therapeutics will provide this information to the principal investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. In addition, the principal investigator must 
inform the IRB/IEC and sponsor of any changes significantly affecting the conduct of the trial 
and/or increasing the risk to participants (eg, violations to the protocol or urgent safety measures 
taken for participant safety). 
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 ICH and GCP guidelines, as well as all 
applicable regional or national regulatory requirements. 
16.3. 
Written Informed Consent 
Prior to enrolling a trial participant, the investigator(s) will ensure that the participant is given 
full and adequate oral and written information about the nature, purpose, possible risk and 
benefit of the study. Participants must also be notified that they are free to discontinue from the 
study at any time. The participant should be given the opportunity to ask questions and allowed 
time to consider the information provided. 
When the participant decides to participate in the trial, the participant (or the participant’s, parent 
or legally authorized representative) must provide signed and dated informed consent. The 
written consent must be obtained before conducting any study procedures. The investigator must 
document the consent process in the participant’s source records. The investigator must maintain 
the original, signed Informed Consent Form. A copy of the signed Informed Consent Form must 
be given to the participant or to the participant’s parent or legally authorized representative. 
Throughout the trial participants should be informed of any changes made to the study and as 
new safety and or risk information becomes known. The provision of this information will be 


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documented in the participant’s source records, and when applicable, an updated ICF will be 
provided. 


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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Inspection of Records 
Sage Therapeutics or its representative(s) will be allowed to conduct site visits at the 
investigation facilities for the purpose of monitoring any aspect of the study. The investigator 
agrees to allow the monitor to inspect the facility, drug storage area, drug accountability records, 
participant charts and study source documents, and other records relative to study conduct. 
Inspection of the study by a Regulatory Authority may occur at any time. The investigator must 
agree to the inspection of study-related records and source documents by the Regulatory 
Authority representative(s).  
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, and until there are no pending or contemplated marketing applications in an ICH 
region or at least 2 years have elapsed since the formal discontinuation of clinical development 
of the investigational product. Sage is responsible to inform the investigator/institution as to 
when study documents no longer need to be retained.   
 


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


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19. 
LIST OF REFERENCES 
Altshuler LL, Cohen LS, Moline ML, et al. Treatment of depression in women: a summary of 
the expert consensus guidelines. J Psychiatr Pract. 2001;7(3):185-208. 
Austin MP, Middleton P, Reilly NM, et al. Detection and management of mood disorders in the 
maternity setting: the Australian Clinical Practice Guidelines. Women Birth. 2013;26(1):2-9. 
Busner J, Targum S. CGI-S. (2007a), as adapted from Kay, Stanley R, Positive and Negative 
Symptoms in Schizophrenia:Assessment and Research.  Clinical and Experimental Psychiatry, 
Monograph No. 5.  Brunner/Mazel, 1991.  Modified from Guy W. Clinical Global Impressions: 
In ECDEU Assessment Manual for Psychopharmacology. 1976; 218-22. Revised DHEW Pub. 
(ADM) Rockville, MD: National Institute for Mental Health.   
Busner J, Targum S. CGI-I.  (2007b), as adapted from Spearing, et al.  Psychiatry Research, 
1997;73:159-71.  Modified from Guy W. Clinical Global Impressions: In ECDEU Assessment 
Manual for Psychopharmacology. 1976; 218-22. Revised DHEW Pub. (ADM) Rockville, MD: 
National Institute for Mental Health.   
Cox JL, Holden JM, Sagovsky R.  Detection of postnatal depression.  Development of the 
10-item Edinburgh Postnatal Depression Scale.  Br J Psychiatry.  1987;150:782-6. 
DSM-5.  Diagnostic and statistical manual of mental disorders (5th ed.).  American Psychiatric 
Association 2013.  Arlington, VA: American Psychiatric Publishing. 
Fihrer I, McMahon CA, Taylor AJ. The impact of postnatal and concurrent maternal depression 
on child behaviour during the early school years. J Affect Disord. 2009;119(1-3):116-23. 
Fournier JC, DeRubeis RJ, Hollon SD, et al. Antidepressant drug effects and depression 
severity—a patient-level meta-analysis. JAMA. 2010;303:47-53. 
Kanes S, Colquhoun H, Gunduz-Bruce H, et al. Brexanolone (SAGE-547 injection) in post-
partum depression: a randomized controlled trial. Lancet. 2017 Jul 29;390(10093):480-489. 
Kirsch I, Deacon BJ, Huedo-Medina TB, et al. Initial severity and antidepressant benefits: A 
meta-analysis of data submitted to the Food and Drug Administration. PLoS Med. 
2008;5(2):e45. 
Ko JY, Rockhill KM, Tong VT, Morrow B, Farr SL. Trends in Postpartum Depressive 
Symptoms – 27 States, 2004, 2008, and 2012. MMWR Morb Mortal Wkly Rep 2017;66:153-
158. 
Martinez Botella G, Salituro FG, Harrison BL, et al. Neuroactive steroids. 2. 3α-hydroxy-3β-
methyl-21-(4-cyano-1H-pyrazol-1’-yl)-19-nor-5β-pregnan-20-one (SAGE-217): A clinical next 
generation neuroactive steroid positive allosteric modulator of the (γ-aminobutyric acid) A 
receptor. J Med Chem 2017;28;60(18):7810-19. 
McCabe-Beane, JE, Segre, LS, Perkhounkova, Y, Stuart, S, O’Hara, MW. The identification of 
severity ranges for the Edinburgh Postnatal Depression Scale. J Reprod Infant Psyc. 2016:34(3); 
293-303.Olfson M, Marcus SC, Shaffer D. Antidepressant drug therapy and suicide in severely 
depressed children and adults: A case-control study. Archives of general psychiatry. 
2006:63(8);865-872. 



SAP_001.pdf: 
Official Title: A Randomized, Double-Blind, Placebo-Controlled Study Evaluating the 
Efficacy and Safety of Sage-217 in the Treatment of Adults With 
Severe Postpartum Depression 
NCT Number: NCT04442503  
Document Dates: SAP Version 1.0: 13 April 2022 


Clinical Study Report 
 
217-PPD-301 
16.1 Study Information 
 
1 
 
 
  
 
9. 
STATISTICAL METHODS INTERIM ANALYSIS PLAN 
The following statistical analysis plan is provided: 
Statistical analysis plan Version 1.0, 11 April 2022 


  
 
 
 
SAGE THERAPEUTICS INCORPORATED  
Statistical Analysis Plan 
Methods 
Protocol Number 217-PPD-301 
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY 
EVALUATING THE EFFICACY AND SAFETY OF SAGE-217 IN THE 
TREATMENT OF ADULTS WITH SEVERE POSTPARTUM DEPRESSION 
 
Author of SAP: 
 
Version:  Final Version 1.0 
Version Date of SAP: 11 April 2022 
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 
1. 
LIST OF ABBREVIATIONS................................................................... 6 
2. 
INTRODUCTION .................................................................................... 7 
3. 
STUDY OBJECTIVES ............................................................................ 8 
3.1. 
Primary Objective ..................................................................................... 8 
3.2. 
Secondary Objective ................................................................................. 8 
 
 8 
4. 
STUDY ENDPOINTS .............................................................................. 8 
4.1. 
Efficacy Endpoints .................................................................................... 8 
4.1.1. 
Primary Efficacy Endpoint ....................................................................... 8 
4.1.2. 
Secondary Efficacy Endpoints .................................................................. 8 
4.1.2.1. 
Key Secondary Efficacy Endpoints .......................................................... 8 
4.1.2.2. 
Other Secondary Endpoints ...................................................................... 8 
 
 9 
5. 
STUDY DESIGN ..................................................................................... 9 
5.1. 
Overall Design .......................................................................................... 9 
5.2. 
Sample Size and Power .......................................................................... 10 
5.3. 
Randomization ........................................................................................ 10 
5.4. 
Blinding and Unblinding ........................................................................ 11 
6. 
MODIFICATIONS ................................................................................. 11 
6.1. 
Modifications to the Approved Clinical Study Protocol ........................ 11 
6.2. 
Modifications to the Approved Statistical Analysis Plan ....................... 11 
6.3. 
Modifications to the Approved DMC Charter ........................................ 12 
7. 
ANALYSIS SETS .................................................................................. 12 
7.1. 
Randomized Set ...................................................................................... 12 
7.2. 
Full Analysis Set ..................................................................................... 12 
7.3. 
Safety Set ................................................................................................ 12 
7.4. 
Per Protocol Set ...................................................................................... 12 
 
 12 
8. 
STATISTICAL ANALYSIS .................................................................. 12 


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8.1. 
General Considerations ........................................................................... 12 
8.1.1. 
Study Day Definition .............................................................................. 14 
8.1.2. 
Missing Data ........................................................................................... 14 
8.2. 
Background Characteristics .................................................................... 14 
8.2.1. 
Participant Disposition ............................................................................ 14 
8.2.2. 
Protocol Deviations ................................................................................ 15 
8.2.3. 
Demographics and Baseline Characteristics ........................................... 15 
8.2.4. 
Medical/Surgical History ........................................................................ 17 
8.2.5. 
Prior and Concomitant Medications ....................................................... 17 
8.2.6. 
Investigational Product Exposure ........................................................... 18 
8.2.7. 
Investigational Product Adherence ......................................................... 19 
8.3. 
Efficacy Analysis .................................................................................... 20 
8.3.1. 
Definition of Efficacy Variables ............................................................. 20 
8.3.1.1. 
Hamilton Rating Scale for Depression (HAM-D) .................................. 20 
8.3.1.2. 
Clinical Global Impression – Improvement (CGI-I) .............................. 21 
8.3.1.3. 
Clinical Global Impression – Severity (CGI-S) ...................................... 22 
8.3.1.4. 
Hamilton Anxiety Rating Scale (HAM-A) ............................................. 22 
8.3.1.5. 
Montgomery-Åsberg Depression Rating Scale (MADRS) .................... 22 
8.3.1.6. 
Edinburgh Postnatal Depression Scale (EPDS) ...................................... 22 
8.3.1.7. 
Patient Health Questionnaire (PHQ-9) ................................................... 23 
8.3.2. 
Visit Windows ........................................................................................ 23 
8.3.3. 
Analysis of Efficacy Variable(s) ............................................................ 24 
8.3.3.1. 
Mixed Effects Model for Repeated Measures ........................................ 26 
8.3.3.2. 
Generalized Estimating Equation (GEE) Models ................................... 28 
8.3.3.3. 
Sensitivity Analysis ................................................................................ 28 
8.3.3.4. 
Analysis of Time to First HAM-D Response/Remission ....................... 31 
8.3.3.5. 
Multiplicity Adjustment for Key Secondary Endpoints ......................... 32 
8.3.4. 
Characterization of Durability of SAGE-217 Treatment Effect ............. 32 
8.3.4.1. 
Durability of Clinically Meaningful Treatment Effect for SAGE-217 .. 32 
8.3.4.2. 
Durability of Treatment Effect at Day 45 via Statistical Comparison of 
SAGE-217 Versus Placebo ..................................................................... 33 
8.3.5. 
Anxious Subgroup Analysis ................................................................... 34 


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8.4. 
Safety Analysis ....................................................................................... 34 
8.4.1. 
Adverse Events ....................................................................................... 35 
 
 37 
 
 40 
 
 42 
8.4.5. 
Physical Examination ............................................................................. 42 
 
 42 
 
 44 
 
 44 
 
 44 
9. 
SUMMARY OF INTERIM AND DMC ANALYSES .......................... 44 
10. 
REFERENCES ....................................................................................... 44 
11. 
LIST OF APPENDICES......................................................................... 45 
11.1. 
Appendix A: Schedule of Assessments .................................................. 45 
11.2. 
Appendix B: Details of Statistical Methodology .................................... 48 
11.3. 
Appendix C: Handling of Missing Dates ................................................ 50 
11.4. 
Appendix D: List of Displays ................................................................. 53 
 
LIST OF TABLES 
Table 1: 
Diagnostic Screening Test ...................................................................... 16 
Table 2: 
HAM-D Subscale Calculation ................................................................ 20 
Table 3: 
Visit Windows for Efficacy Analysis ..................................................... 24 
Table 4: 
Safety Endpoints and Variables in the Summary Tables ........................ 35 
 
 37 
 
 
 39 
 
 
 41 
 
 
 42 
 
 


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1. 
LIST OF ABBREVIATIONS 
Abbreviation or specialist term 
Explanation 
AE 
adverse event 
AR 
Autoregressive 
ATC 
anatomical therapeutic chemical 
BMI 
body mass index 
CGI-I 
Clinical Global Impression scale for improvement 
CGI-S 
Clinical Global Impression scale for severity 
COVID-19 
A syndrome caused by infection with the SARS-CoV-2 virus 
CS 
Compound Symmetry 
DSM-5  
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition  
eCRF  
electronic case report form  
EOT 
end of treatment 
EPDS 
Edinburgh Postnatal Depression Scale 
ET 
early termination 
FAS 
Full Analysis Set 
FSH  
follicle stimulating hormone  
GEE  
generalized estimating equation  
HAM-A  
Hamilton Rating Scale for Anxiety  
HAM-D 
Hamilton Depression Rating Scale 
hCG 
human chorionic gonadotropin 
ICF 
informed consent form 
IRT 
interactive response technology  
IP 
Investigational product 
MADRS 
Montgomery-Åsberg Depression Rating Scale 
MMRM  
mixed effects model for repeated measures  
MedDRA 
Medical Dictionary for Regulatory Activities 


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Abbreviation or specialist term 
Explanation 
NCS 
not clinically significant 
PCS 
Potentially clinically significant  
PHQ-9 
Patient health Questionnaire 
PPD 
Postpartum depression 
PRO 
patient-reported outcome 
PT 
preferred term 
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 
TEAE 
treatment-emergent adverse event 
UN 
Unstructured 
WHO 
World Health Organization  
 
2. 
INTRODUCTION 
This statistical analysis plan (SAP) is for the final analysis of data from 217-PPD-301 study, 
and is based on clinical study protocol, version 2.0, dated 29 JAN 2021.  
The purpose of the SAP is to describe in detail the statistical methodology and analyses to be 
conducted for 217-PPD-301 protocol. The SAP will be approved and finalized before 
database lock. 
Any changes made to the SAP after the clinical database lock has occurred but before 
treatment unblinding will be documented and discussed in the clinical study report for this 
study. No changes can be made to the SAP after treatment unblinding. 


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3. 
STUDY OBJECTIVES  
3.1. 
Primary Objective 
The primary objective of Study 217-PPD-301 is to determine if treatment with SAGE-217 
reduces depressive symptoms in adults with severe postpartum depression (PPD) compared 
to placebo. 
3.2. 
Secondary Objective 
The secondary objectives of Study 217-PPD-301 are: 
 To determine if treatment with SAGE-217 reduces anxiety symptoms compared 
to placebo 
 To assess self-report of depressive symptoms 
 To evaluate the safety and tolerability of SAGE-217  
 
 
 
 
4. 
STUDY ENDPOINTS 
4.1. 
Efficacy Endpoints 
4.1.1. 
Primary Efficacy Endpoint  
The primary efficacy endpoint is the change from baseline in the 17-item Hamilton Rating 
Scale for Depression (HAM-D) total score at Day 15. Details of the estimand are provided in 
Section 8.3.3.1  . 
4.1.2. 
Secondary Efficacy Endpoints  
4.1.2.1. 
Key Secondary Efficacy Endpoints  
  Change from baseline in HAM-D total score at Day 3 
 Change from baseline in HAM-D total score at Day 28 
  Change from baseline in HAM-D total score at Day 45   
  Change from baseline in Clinical Global Impressions – Severity (CGI-S) score at 
Day 15 
4.1.2.2. 
Other Secondary Endpoints  
 HAM-D response at Day 15 and Day 45 


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 HAM-D remission at Day 15 and Day 45 
 Clinical Global Impressions – Improvement (CGI-I) response at Day 15 
 Change from baseline in Hamilton Anxiety Rating Scale (HAM-A) total score at 
Day 15 
 Change from baseline in Montgomery-Åsberg Depression Rating Scale 
(MADRS) total score at Day 15 
 Change from baseline in HAM-D subscale at Day 15 
 Change from baseline in self-reported measures of depressive symptoms, as 
assessed by the Edinburgh Postnatal Depression Scale (EPDS) total score and 9-
item Patient Health Questionnaire (PHQ-9) 
 Incidence of treatment-emergent adverse events (TEAEs) 
 
 
 
 
 
 
  
 
 
 
5. 
STUDY DESIGN  
5.1. 
Overall Design  
Study 217-PPD-301 is a randomized, double-blind, placebo-controlled, parallel group study 
of the efficacy and safety of SAGE-217 in adults diagnosed with severe PPD. Participants, 
site staff, and sponsor personnel will be masked to treatment allocation.  
This study will consist of a Screening Period of up to 28 days, a 14-day double-blind 
Treatment Period, and a Follow-up Period through Day 45.  
The diagnosis of depression must be determined according to the Structured Clinical 
Interview for Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) Axis I 
Disorders (SCID-5-CT) performed by a qualified healthcare professional. Participants will 
undergo preliminary screening procedures to determine eligibility. A full personal medical 
history will be taken including documentation of all major depression episodes, other Axis I, 
and any prior PPD episodes. In addition, PPD episodes experienced by immediate female 
family members, including siblings, parents, and grandparents will be documented. 
Psychotropic medications are permitted provided participants are on a stable dose for at least 
30 days prior to Day 1 and agree to continue a stable dose through the Day 45 assessments. 
Initiation of new psychotropic medications that may potentially have an impact on efficacy 


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and/or safety endpoints will not be allowed within 30 days prior to Day 1 through completion 
of the Day 45 assessments.  
On Day 1, eligible participants will be stratified based on antidepressant treatment use at 
baseline (Yes = current and stable; No = not treated or withdrawn (≥30 days or >5 half-
lives)) and randomized within each stratum to 1 of 2 treatment groups (SAGE-217 50 mg or 
matching placebo) in a 1:1 ratio.  
Participants will self-administer investigational product (IP) once daily at approximately 8 
PM with fat-containing food (eg, within 1 hour of an evening meal which contains fat, or 
with a fat-containing snack), on an outpatient basis, for 14 days. As local regulations permit, 
IP administration will be monitored via a medication adherence monitoring platform used on 
smartphones to visually confirm IP ingestion. 
During the treatment period, participants will be able to receive 50 mg IP as long as there are 
no dose limiting safety/tolerability concerns. Participants who cannot tolerate 50 mg will 
receive 40 mg for the remainder of the treatment period. At the discretion of the investigator, 
participants who cannot tolerate the 40-mg dose will be discontinued from IP.  
Participants who discontinue IP early should return to the site for the remaining study visits 
as scheduled (ie, relative to the first dose of IP) unless the participant withdraws consent or 
loses the capacity to grant consent. If a participant withdraws from the study/stops study 
participation early, an early termination visit should be conducted, if possible. 
5.2. 
Sample Size and Power 
Using a 2-sided test at an alpha level of 0.05, a sample size of approximately 86 evaluable 
participants per treatment group would provide 90% power to detect a placebo-adjusted 
treatment difference of approximately 4 points in the primary endpoint, change from baseline 
in HAM-D total score at Day 15 assuming standard deviation of 8 points.  
Assuming a 10% dropout and a 1:1 randomization ratio within each stratum (antidepressant 
treatment use at baseline, yes or no), approximately 192 randomized participants (96 per 
treatment group) will be required to obtain 86 evaluable participants per treatment group. 
Evaluable participants are defined as those randomized participants who receive IP and have 
a valid baseline and at least 1 postbaseline HAM-D assessment. Additional participants may 
be randomized if the dropout rate is higher than 10%. 
5.3. 
Randomization 
Participants who meet the eligibility criteria will be randomized in a stratified manner based 
on antidepressant treatment use at baseline (Yes = current and stable; No = not treated or 
withdrawn (≥30 days or > 5 half-lives)) at baseline; Randomization will be done within each 
stratum in a 1:1 ratio to receive SAGE-217 50 mg or matched placebo. 
Randomization schedules will be generated by an independent statistician. The allocation to 
treatment group (SAGE-217 50 mg, or placebo) will be based on the randomization schedule. 
Randomization will be performed centrally via an interactive response technology (IRT) 
system.   


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5.4. 
Blinding and Unblinding 
The Sponsor, site personnel and participants will remain blinded until the database lock after 
all participants have completed the Day 45 visit. 
During the study, the blind is to be broken only when the safety of a participant is at risk and 
the treatment plan is dependent on the study treatment received. Unless a participant is at 
immediate risk, the Investigator should make diligent attempts to contact Sage prior to 
unblinding the study treatment administered to a participant. Requests from the Investigator 
about the treatment administered to study participants should be discussed with the Sage 
Medical Monitor. If the unblinding occurs without Sage’s knowledge, the Investigator must 
notify Sage within 24 hours of breaking the blind.  
All circumstances surrounding a premature unblinding must be clearly documented in the 
source records.   
In all cases where the IP allocation for a participant is unblinded, pertinent information 
(including the reason for unblinding) must be documented in the participant’s records and on 
the eCRF. At the time of withdrawal from the study/stopping participation, if possible, an 
EOT and/or ET visit should be conducted.  
If a participant becomes unblinded to the participant’s treatment assignment before database 
lock, the participant will be excluded from the Per Protocol Set (see Section 7.4), but will be 
included in the Full Analysis Set (FAS) (see Section 7.2).  
6. 
MODIFICATIONS  
6.1. 
Modifications to the Approved Clinical Study Protocol 
 
The following statistical considerations have been added to the analysis plan compared to 
the statistical section of the Clinical Study Protocol, version 2.0, dated 29 Jan 2021 
1) Change from baseline in HAM-D total score at Day 3, 28, and 45, and change from 
baseline in CGI-S at Day 15 prespecified as key secondary endpoints and testing 
sequence defined 
2) Multiplicity adjustment procedure for strong control of type I error rate described 
3) The FAS definition is updated as ‘all randomized participants administered IP with 
valid baseline and at least 1 post-baseline total score in at least one of HAM-D, 
HAM-A, MADRS, CGI-S, EPDS and PHQ-9, or at least 1 post-baseline value of 
CGI-I. In the protocol, it is at least 1 post-baseline HAM-D assessment 
4) MADRS response and remission were added 
5) Analyses of durability of treatment effect were added 
6.2. 
Modifications to the Approved Statistical Analysis Plan 
This is first version of the SAP. 


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6.3. 
Modifications to the Approved DMC Charter 
Not applicable 
7. 
ANALYSIS SETS 
7.1. 
Randomized Set 
The Randomized Set is defined as all participants who are randomized. 
7.2. 
Full Analysis Set 
The FAS is defined as all randomized participants who are administered IP with valid 
baseline total score and at least 1 post-baseline total score in at least one of HAM-D, HAM-
A, MADRS, CGI-S, EPDS and PHQ-9, or at least 1 post-baseline value of CGI-I. 
7.3. 
Safety Set 
The Safety Set is defined as all participants who are administered IP. 
7.4. 
Per Protocol Set 
The Per Protocol Set is defined as all participants in the FAS without any major protocol 
deviations that could affect efficacy. For further details, see Section 8.2.2 . 
In addition, the Per Protocol Set will also exclude FAS participant with any of the following 
conditions: 
1.  Participants who consumed <22 capsules (ie, <80% of assigned number of capsules) 
2.  Participants who consumed incorrect IP (ie, IP other than that to which they were 
randomized to receive) at any time during the study 
3. Participants or study personnel who were unblinded to participant’s treatment assignment 
before database lock  
 
  
 
   
8. 
STATISTICAL ANALYSIS 
8.1. 
General Considerations 
Unless otherwise specified, continuous endpoints will be summarized with n, mean standard 
deviation (SD), median, minimum (min) and maximum (max). If the measurements in the 
source (raw) data are integers, then the corresponding mean and median will be presented to 
1 decimal place and the SD to 2 decimal places; If the raw scores are integers and the 
difference between two treatment groups is small, in result the rounded values for two 


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treatment groups are equal (for instance, if mean is 0.07 and 0.14 respectively, both groups 
would have reported as 0.1 even though one number is doubling of another) then two decimal 
places will be present. If the measurements are obtained to 1 decimal place, then the mean 
and median will be presented to 2 decimal places and the SD to 3 decimal places and so 
forth. Minimum and maximum will be displayed as reported in the source (raw) data. LS 
mean will be presented to 1 decimal place, and standard error (SE) will be presented to 2 
decimal places. P-value will be presented to 4 decimal places with p-values less than 0.0001 
reported as “<0.0001”. P-values larger than 0.9999 will be reported as “>0.9999”.    In 
addition, change from baseline values (visit value – baseline value) will be calculated at each 
time point and summarized descriptively.  
For categorical endpoints, descriptive summaries will include counts and percentages.  
Percentages will be presented to 1 decimal place unless otherwise specified; the denominator 
of percentages will be the number of participants in the analysis set used unless specified 
otherwise.  
All analyses and summary outputs will be generated using SAS® 9.4 or higher. 
All summaries and figures will be provided by treatment group: placebo and SAGE-217.  
Participants who are randomized to 50 mg treatment and received 40 mg dose due to dose 
reduction will be summarized under one treatment group.  For efficacy data analysis, 
participants’ data are analyzed by as randomized. For safety data analysis, participants’ data 
are analyzed per the actual treatment received, and this is determined as follows: if a 
participant received any dose of SAGE-217 at any point of time, the participant is assigned to 
actual treatment of SAGE-217. All participant data, including those derived, to support tables 
and figures will be presented in the participant data listings.  In general, the participant data 
listings will be sorted by participant number and assessment visit and date (and time, if 
applicable).  The treatment will be identified for each participant. 
For the purpose of all safety and efficacy analyses, baseline is defined as the last non-missing 
measurement including unscheduled visits prior to the first dose of investigational product, 
unless stated otherwise. If the time of an assessment is collected, baseline will be the latest 
assessment prior to first dose of IP administration time; if the time of an assessment is not 
collected, the assessment on Day 1 is assumed to be prior to dosing if the protocol mentions 
that this assessment needs to be before dosing or it is collected as “pre-dose”.  
Antidepressant treatment use at baseline (yes=current and stable; no=not treated or 
withdrawn (≥30 days or > 5 half-lives)) identified by ATC level 3 code of N06A will be used 
in the subgroup analysis and mixed effects model for repeated measures (MMRM). 
 
 
 
   


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8.1.1. 
Study Day Definition 
It is to be noted that the investigational product is administered in the evening with food.  
The assessments at the clinic on Day 1 are hence before the first dose of investigational 
product. 
Study day will be defined as follows:  
  The day of participant receiving the first dose of investigational product is 
designated as Day 1. 
  For visit days after Day 1, study day = visit date – Day 1 date + 1. 
  For visit days prior to Day 1, study day = visit date – Day 1 date.  Thus, study 
days for screening visit are negative numbers.  There is no “Day 0”. 
8.1.2. 
Missing Data 
All participants will be used in the analyses, as per the analysis populations, using all non-
missing data available.  Missing scheduled visit values may be replaced by windowing 
unscheduled visit values (see Section 8.3.2 ). Efficacy analyses will use sensitivity analyses 
to assess the impact of the assumptions made about missing data. Safety analyses will not 
impute missing data, unless specified.  Imputation of missing data in scoring of 
questionnaires is discussed in respective sections below.  Handling of missing or incomplete 
dates are described in Section 11.3 Appendix C.  
8.2. 
Background Characteristics  
All displays in this section will be presented by the treatment arms of placebo, SAGE-217 
and overall. 
8.2.1. 
Participant Disposition 
The analyses of participant disposition will use all participants who provided written 
informed consent to the study. 
The summaries of participant disposition will include the number of participants who were 
screened, number (%) screen failed, randomized, did and did not receive investigational 
product (IP), the number (%) of participants who completed the study, prematurely withdrew 
from the study, primary reasons for not completing the study, completed treatment, 
discontinued IP prematurely, and primary reasons for discontinuing IP.   
All percentages will be calculated based on the participants who were randomized and 
received IP. Treatment arm assignment will be according to the planned treatment. If a 
participant is rescreened because the participant has been a screen failure the first time, the 
status of the participant will be determined from the second screening. In the count of 
screened participants, this participant will be counted only once.   
A completer for the study is defined as one who completed the last follow up visit based on 
the study completion CRF page with the completion question answered Yes.  


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A participant is marked as completing the treatment if the complete treatment question on the 
study treatment completion CRF page is answered Yes. 
The number of participants in each analysis set will be provided.  Using Randomized Set, the 
reason for not being included in other analysis sets will be summarized. 
A separate data listing will be provided for all participants who prematurely discontinued IP 
or prematurely withdrew from the study with reasons, number of days on investigational 
product, date of withdrawal from the study, using the Safety Set. 
8.2.2. 
Protocol Deviations 
Protocol deviations identified during the study will be captured and categorized by the study 
review team as major and minor deviations without any unblinding information on an 
ongoing basis.   
All major protocol deviations will be summarized by randomized treatment using the FAS.  
The study team will identify the major protocol deviations related to efficacy or that may 
have impact on efficacy to determine the participants in the FAS to be excluded for the Per 
Protocol Set prior to database lock in a blinded fashion (some major protocol deviations may 
not lead to participants’ data to be excluded from the Per Protocol Set). 
In addition, COVID-19 related protocol deviations such as remoted telephone/video 
visit/assessment, home healthcare visit, missed visit/assessment, out of window 
visit/assessment, safety reporting, investigational product administration, and other will be 
documented and provided as a separate listing. 
All protocol deviations (major and minor) will be included in a data listing for randomized 
participants. Randomized treatment will be used.  
Any violation of inclusion/exclusion criteria will be presented with the randomized treatment 
in a separate data listing using the Randomized Set. 
8.2.3. 
Demographics and Baseline Characteristics 
The following analyses will use the Safety Set (using actual treatment received), and the FAS 
(using randomized treatment). 
Demographic data (age at informed consent [years]), race, ethnicity, employment status, 
highest education level, marital/civil status) and baseline characteristics, such as height (cm), 
weight (kg), and body mass index (BMI) (kg/m2), will be summarized by treatment group 
(randomized for the FAS and actual for the Safety Set) and overall.  
Baseline subgroups will be summarized for the following categories: 
  Race (Black or African American, White, Other) 
  Age (18-24, 25-45 years) 
  Baseline antidepressant use (Yes, No) (for definition of antidepressant, see 
Section 8.2.5) 
  BMI (≤18.4, 18.5-24.9, 25-29.9, ≥30 kg/m2) 


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 Baseline HAM-D total score (<median of baseline HAM-D total score, >= 
median of baseline HAM-D total score, median will be calculated on FAS) 
 Onset of PPD (3rd trimester vs. postpartum) 
 History of PPD (1st episode vs recurrent PPD episode) 
 COVID-19 History (not impacted, hospitalization, SARS-CoV-2 test positive, 
patient isolation, suspected COVID, COVID-19) (refer to Section 8.2.4 for 
details) 
 Depression with elevated anxiety based on baseline HAMD anxiety subscale (>=7 
vs. <7 or normalized score ≥39 vs.<39). 
 Depression with elevated anxiety based on baseline HAMA total score (>=20, 
<20). 
 Country (US, Rest of World) 
A separate listing for participants who were randomized under incorrect stratification of 
antidepressant use at baseline will be provided.  The antidepressant medications are 
identified from concomitant medication records with Anatomic Therapeutic Classification 
(ATC) level 3 = N06A. The stratum for antidepressant use at baseline is determined from the 
coding of antidepressant, comparing the start/end dates of the medication versus the date of 
first dose of investigational product.   Any deviation from the antidepressant stratum 
recorded at IRT system are part of protocol deviations and will be included in protocol 
deviation listing.  
Diagnostic labs are part of screening. The results of the diagnostic screening test in Table 1  
will be provided in a data listing using the Safety Set. 
Table 1: 
Diagnostic Screening Test 
 
Diagnostic 
 
Serum 
Urine 
Breathalyzer 
Participants that are not 
surgically sterile at screen: 
serum hCG 
Drug screen: including 
amphetamines, barbiturates, 
benzodiazepines, 
cannabinoids, cocaine, 
opiates, phencyclidine 
Alcohol 
Participants, if not surgically 
sterile at Screen: FSH 
Participants that are not 
surgically sterile at all other 
visits: urine hCG 
 
 
Abbreviations: FSH=follicle stimulating hormone; hCG=human chorionic gonadotropin;  


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8.2.4. 
Medical/Surgical History 
 
The following analyses will use the Safety Set.  
Time since initial diagnosis of PPD, antidepressant usage, any past PPD episodes, and onset 
of current PPD (3rd trimester, within 4 week of delivery) will be summarized. Time since 
initial diagnosis of PPD and days since start of current episode will be calculated using: First 
dose date of the investigational product – date of interest. For imputation of incomplete dates 
in medical history, please see Section 11.3.  
Disease history such as the diagnosis of PPD, ICD-10 code, current or past episode, date of 
delivery, start date of current PPD episode and Family history of PPD will be listed. 
Medical/surgical history collected at screening will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA), Version 23.0 or higher. Medical/surgical history data 
will be summarized by system organ class (SOC) and preferred term (PT). A summary of 
medical/surgical history that are ongoing at the time of screening will be provided separately.  
A Participant will be counted once within each level of summarization.  Medical/surgical 
history will also be listed. 
In addition, participant’s COVID-19 history will be collected via medical history eCRF page 
and will be coded by coded by MedDRA. COVID-19 history will be summarized by 
COVID-19 related preferred term (PT), low level term, high level term and reported term, in 
medical history data. For participants without COVID-19 related PT, the participants are 
categorized as ‘Not impacted’. If a participant had multiple PTs related to COVID-19, then 
the participant will be counted once under the worst case in the following order: 
Hospitalization > SARS-CoV-2 test positive > Patient isolation > Suspected COVID-19 > 
COVID-19.  
A participant history of psychiatric disorders and family history of postpartum depression 
episodes will be summarized and listed.   
8.2.5. 
Prior and Concomitant Medications  
The following analyses will use the Safety Set. 
All medications taken and procedures undergone during the study will be recorded; in 
addition, psychotropic medications taken within 6 months prior to screening, and non-
psychotropic medications taken within 30 days prior to screening will also be collected.  All 
medications will be coded using World Health Organization-Drug (WHO) Global B3 March 
2020 or later. 
Medications will be presented according to whether they are being taken prior to and/or 
during the study (concomitant).  Prior medications are defined as those taken prior to the 
initiation of the start of investigational product.  Concomitant medications are defined as 
those with a start date on or after the first dose of investigational product or those with a start 
date before the first dose of investigational product that are ongoing or with a stop date on or 
after the first dose of investigational product.  If medication dates are incomplete and it is not 
clear whether the medication was concomitant, it will be assumed concomitant.  For 


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imputation of missing concomitant medication dates, please refer to Appendix C, Section 
11.3. Note that medication taken before the initial dosing of investigational product and 
continued after the initial dosing will be categorized as a prior medication and separately as a 
concomitant medication. 
Concomitant medications will be further divided by usage period as follows:  
 On-treatment concomitant medications are those that have been used any time from 
start of first dose to the last dose of investigational product. 
  Post-treatment concomitant medications are those that have been started after the last 
dose of investigational product. 
Prior and concomitant non-psychotropic medication use will be summarized by anatomical 
therapeutic chemical (ATC) level 1 and Standard Medication Name. Similar summary tables 
will be provided for psychotropic medications. Separate but similar summaries will be 
provided for concomitant medication use for on-treatment and post-treatment periods as 
defined above. A Participant will be counted once within each level of summarization. 
In addition, for prior and concomitant psychotropic medication separate summaries will be 
provided by ATC level 1 and ATC level 4. 
Antidepressants that have been taken at the same dose for at least 30 days prior to the first 
dose of investigational product are permitted if the participant intends to continue the stable 
dose through the follow-up period (Day 45). Initiation of new antidepressants or any other 
medications that may potentially have an impact on efficacy or safety endpoints is prohibited 
from at least the screening visit and through completion of the Day 45 assessments. 
Antidepressant medications are identified by ATC level 3 code of N06A.  A summary of 
antidepressant use at baseline and any change in these medications post-baseline (including 
the follow up period) will be provided.  
Concomitant procedures are recorded on a separate eCRF page; this will be presented in a 
listing by participant. The study day for the end date of the procedure will be provided when 
a complete end date is available.  
Prohibited medications are reviewed by the medical monitor in the study team on an ongoing 
basis in blinded fashion; any medication identified as prohibited medication intake is 
captured in the protocol deviations list.   
8.2.6. 
Investigational Product Exposure 
The following analyses will use the Safety Set. 
Total drug exposure (in mg) is defined as the total investigational product in mg for 
SAGE-217 that was taken during the study. Total drug exposure for participants randomized 
to placebo is zero, unless the participant has taken SAGE-217 by mistake due to being 
provided wrong investigational product kits, in which case the total exposure comes from 
SAGE-217 exposure. If the participant skips the dose on any of the days, the dose taken is 
0 mg.   


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The kit for 50 mg dose contains two capsules – one for 30 mg, the other for 20 mg.  For 
participants who took only 1 capsule inadvertently for a dosing day of 50 mg, it is assumed 
that the participant took the higher dose (ie, 30 mg capsule) for the day and will be calculated 
as such for the total drug exposure and percent of the planned exposure received. 
The kit for 40 mg dose contains two capsules, 20 mg each; therefore, taking one capsule will 
unambiguously be assigned to 20 mg. 
Total exposure duration to investigational product (in days) is defined as: Date of last dose – 
date of first dose + 1. Note that this does not exclude days when the dose has been missed. 
Percent of the planned exposure received is defined as the total drug exposure, divided by 
planned exposure, times 100.  For participants who complete the treatment period without 
dose reduction, planned exposure is 14 days of treatment planned, times 50 mg for 
participants randomized to SAGE-217. For participants who reduce dose to 40 mg, the 
planned exposure is the number of days (last date of 50 mg – first dose date + 1), times 50 
mg plus the number of days (date of study day 14 – first date of 40 mg + 1), times 40 mg for 
participants randomized to SAGE-217. For participants who discontinue the treatment early 
and reduce dose, the planned exposure is the number of days (last date of 50 mg – first dose 
date + 1), times 50 mg plus the number of days (last date of dose - first date of 40 mg + 1), 
times 40 mg for participants randomized to SAGE-217.  
For participants who discontinued the treatment early without dose reduction, the planned 
exposure is the number of days (last date of 50 mg – first dose date + 1), times 50 mg. 
For participants randomized to placebo, this measure is not applicable. 
Total drug exposure, total exposure duration and percent of the planned exposure received 
will be summarized descriptively.  Number and percentage of participants with less than 22 
capsules consumed will be provided.  
The number and percent of participants who had dose adjustment (ie, reduced, interrupted, 
withdrawn) and dose modification (ie, missed dose, took an extra day of dosing, took more 
than the planned dose for dosing day, partial dose, other) will also be summarized 
descriptively.  
A listing of IP administration & IP exposure will be provided. Whether the participant has 
eaten fat-containing food within the last 1 hour of the IP administration will be included in 
the IP exposure data listing. 
8.2.7. 
Investigational Product Adherence 
The following analyses will use the Full Analysis Set. Investigational product adherence (%) 
is defined as the number of capsules taken, divided by the number of capsules planned to be 
taken, times 100.   
The schedule of investigational product is two capsules per day.  The number of capsules 
planned to be taken is defined as follows: 
1. If the participant discontinues treatment within Day 1 and Day 14 (both inclusive), 
the number of capsules planned to be taken is the last dose day of investigational 
product × 2.  


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2. If the participant does not discontinue treatment, the number of capsules planned to 
be taken is 28.  
Investigational product adherence will be summarized descriptively and listed.  Number and 
percentage of participants with investigational product adherence in categories (<80%, 80-
100%, >100%) will be provided.  Investigational product accountability will be listed. 
8.3. 
Efficacy Analysis  
8.3.1. 
Definition of Efficacy Variables 
The efficacy variables are defined below: 
8.3.1.1. 
 Hamilton Rating Scale for Depression (HAM-D) 
The 17-item HAM-D will be used to rate the severity of depression in participants already 
diagnosed as depressed.  HAM-D is collected on screening  and the clinic visit on Days 1, 3, 
8, 15, 21, 28 and 45. The 17-item HAM-D comprises of individual ratings related to the 
following symptoms: depressed mood (sadness, hopeless, helpless, worthless), feelings of 
guilt, suicide, insomnia (early, middle, late), work and activities, retardation (slowness of 
thought and speech; impaired ability to concentrate; decreased motor activity), agitation, 
anxiety (psychic and somatic), somatic symptoms (gastrointestinal and general), genital 
symptoms, hypochondriasis, loss of weight, and insight.  Each item is scored in a range of 0 
to 2 or 0 to 4, with higher scores indicating a greater degree of depression.  The score for 
each item will be summed to compute a total score, which ranges from 0 to 52.   If more than 
3 individual items are missing a response, the HAM-D total score will not be calculated and 
will be left as missing.  If less than or equal to 3 individual item scores are missing, the 
missing item scores will be imputed by the mean of all other available item scores, or the 
maximum possible values for the missing responses, whichever is smaller, to calculate the 
HAM-D total score. 
Four HAM-D subscale scores will be calculated as the sum of the individual rating scores 
related to each subscale, divided by the total possible score within the subscale, multiplied by 
100, and rounded to a whole number.  If more than one item is missing or HAM-D total score 
is missing, the subscale score is left as missing; if one item on a particular subscale is missing 
but has been imputed for the calculation of total score, the imputed value from total score 
calculation will be used in subscale score calculation for that item.  Following Table 2  
describes the subscale score calculation: 
Table 2: 
HAM-D Subscale Calculation 
HAM-D Subscales 
Items 
Calculation 
Core 
Depressed mood 
Feeling of guilt 
Suicide 
Work and activities 
Retardation 
Sum of the 5-item responses/20 x 100.   
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 


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HAM-D Subscales 
Items 
Calculation 
calculate HAM-D total score to 
calculate the subscale.  
Anxiety 
Anxiety psychic 
Anxiety somatic 
Somatic symptoms gastrointestinal 
Somatic symptoms general 
Hypochondriasis 
Insight  
Sum of the 6-item responses/18 x 100.   
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale.  
Bech-6 
Depressed mood 
Feeling of guilt 
Work and activities 
Retardation 
Anxiety psychic 
Somatic symptoms general 
Sum of the 6-item responses/22 x 100.   
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale.  
Maier 
Depressed mood 
Feeling of guilt 
Work and activities 
Retardation 
Agitation 
Anxiety psychic 
Sum of the 6-item responses/24 x 100.   
If more than one item responses are 
missing or HAM-D total score is 
missing, leave as missing; otherwise, 
use the imputed item score used to 
calculate HAM-D total score to 
calculate the subscale.  
HAM-D response will be defined as having a 50% or greater reduction from baseline in 
HAM-D total score; only participants who have a non-missing total score of HAM-D at 
baseline as well as the visit will be considered in HAM-D response evaluations. 
HAM-D remission will be defined as having a HAM-D total score of ≤7; if HAM-D total 
score is missing, remission will not be defined.  
For a sensitivity analysis the worst-case scenario imputation will be used, ie, missing values 
for HAM-D response (remission) will be considered as “No response” (“No remission”). 
8.3.1.2. 
 Clinical Global Impression – Improvement (CGI-I) 
The Clinical Global Impression - Improvement (CGI-I) employs a 7-point Likert scale to 
measure the overall improvement in the participant’s condition post-treatment. The 
Investigator will rate the participant’s total improvement. Response choices include: 1=very 
much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally 
worse, 6=much worse, and 7=very much worse. The CGI-I is only rated at post-treatment 
assessments on Days 3, 8, 15, 21, 28 and 45. 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, ie, missing values for CGI-I response will be considered as “No response” 


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8.3.1.3. 
 Clinical Global Impression – Severity (CGI-S) 
The Clinical Global Impression - Severity (CGI-S) uses a 7-point Likert scale to rate the 
severity of the participant’s illness at the time of assessment, relative to the clinician’s past 
experience with participants who have the same diagnosis. Considering total clinical 
experience, a participant is assessed on severity of mental illness at the time of rating as 
1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly 
ill; 6=severely ill; and 7=extremely ill.  CGI-S is collected at Screening, Days 1, 3, 8, 15, 21, 
28 and 45. 
8.3.1.4. 
Hamilton Anxiety Rating Scale (HAM-A) 
The 14-item HAM-A will be used to rate the severity of symptoms of anxiety. HAM-A is 
collected during the clinic visit at Days 1, 3, 8, 15, 21, 28 and 45.  Each of the 14 items is 
defined by a series of symptoms, and measures both psychic anxiety (mental agitation and 
psychological distress) and somatic anxiety (physical complaints related to anxiety). Scoring 
for HAM-A is calculated by assigning scores of 0 (not present) to 4 (very severe), with a total 
score range of 0 to 56, where <17 indicates mild severity, 18 to 24, mild to moderate 
severity, and 25 to 30, moderate to severe severity. The HAM-A total score will be calculated 
as the sum of the 14 individual item scores. If more than 3 individual items are missing a 
response, the HAM-A total score will not be calculated and will be left as missing.  If less 
than or equal to 3 individual item scores are missing, the missing item scores will be imputed 
by the mean of all other available item scores to calculate the HAM-A total score.   
8.3.1.5. 
 Montgomery-Åsberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive 
episodes in participants with mood disorders.  MADRS is collected during the clinic visit on 
Days 1, 8, 15, 28 and 45. 
Each MADRS item range from 0 to 6; higher MADRS scores indicate more severe 
depression.  The MADRS total score will be calculated as the sum of the 10 individual item 
scores, which ranges from 0 to 60.  If more than 2 individual items are missing, the MADRS 
total score will not be calculated and will be left as missing.  If less than or equal to 2 
individual item scores are missing, the missing item scores will be imputed by the mean of 
all other available item scores to calculate the MADRS total score. 
MADRS response will be defined as having a 50% or greater reduction from baseline in 
MADRS total score; only participants who have a non-missing total score of MADRS at 
baseline as well as the visit will be considered in MADRS response evaluations.  MADRS 
remission will be defined as having a MADRS total score of ≤10; if MADRS total score is 
missing, remission will not be defined. 
For a sensitivity analysis the worst-case scenario imputation will be used, ie, missing values 
for MADRS response (remission) will be considered as “No response” (“No remission”). 
8.3.1.6. 
Edinburgh Postnatal Depression Scale (EPDS) 
 


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The EPDS is a patient-rated depressive symptom severity scale specific to the perinatal 
period (Cox 1987). The EPDS will be collected in the clinic at Screening and Days 1, 3, 8, 
15, 21, 28 and 45.  
The scale consists of 10 questions. Items 1, 2, and 4 are scored from 0 to 3. Items 3, 5, 6, 7, 
8, 9, and 10 are reverse scored from 3 to 0. After the reverse scoring is done, higher scores 
indicate more severe symptoms. The EPDS total score will be calculated as the sum of the 10 
individual item scores. If more than 2 individual items are missing, the EPDS total score will 
not be calculated and will be left as missing. If 1 or 2 individual item scores are missing, the 
missing item scores will be imputed by the mean of all other available item scores. Imputed 
individual scores will be rounded to the nearest integer.  
8.3.1.7. 
Patient Health Questionnaire (PHQ-9)  
The PHQ-9 is a 9-item participant-rated depressive symptom severity scale. It is collected 
during the clinic visit at Screening and Days 1, 3, 8, 15, 21, 28 and 45. 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: 1 to 4=minimal depression, 5 to 9=mild 
depression, 10 to 14=moderate depression, 15 to 19=moderately severe depression; and 20 to 
27=severe depression. 
8.3.2. 
Visit Windows 
The scheduled visits will not be windowed and will be used at nominal visit value for 
treatment period (Days 3, 8 and 15).  Post-treatment period visits (Days 21, 28 and 45) and 
unscheduled, end-of-treatment (EOT) and early termination (ET) visit will be mapped to a 
scheduled visit for analysis.   In order to accommodate as much data as possible into analysis, 
the windows in the table below have been widened compared to protocol-specified 
operational window, to have no gap between them; these windows are used for analysis 
purposes only.  Once analysis visit windows are assigned, all visits, including scheduled 
visits, and windowed visits will be eligible for being flagged as the “analyzed record” within 
the analysis window; a participant’s individual analysis visit window could potentially 
contain more than 1 visit.  In the event of multiple visits falling within an analysis window or 
in case of a tie, the following rules will be used in sequence to determine the “analyzed 
record” for the analysis visit window: 
For treatment period visits: 
  If the data from the scheduled visit is available, then the scheduled visit data will 
be used.  
  If there is no data from the scheduled visit available, the windowed visit data will 
be used. 


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For post-treatment period visits: 
 If more than one windowed visits available in the same window, the data closest 
to the targeted study day will be used.  
 If there is a tie with distance from   the targeted day, the later data will be used.  
Table 3  displays windows for efficacy analysis.  
Table 3: 
Visit Windows for Efficacy Analysis 
Scheduled Visit  
(+/1 window days) in protocol 
Target Study Day  
Study Day Window for Visit 
in Analysis 
Day 1 
Day 1 (predose) 
Day 1 (predose) or last non-
missing assessment before pre-
dose 
Day 3 (±1 day) 
Day 3 
Day 2 - Day 5  
Day 8 (+1 day) 
Day 8 
Day 6 - Day 11 
Day 15 (+1 day) 
Day 15 
Day 12 - Day 17 
Day 21 (±1 day) 
Day 21  
Day 18 - Day 23  
Day 28  (±3 day) 
Day 28 
Day 24 - Day 31  
Day 45 (±3 days) 
Day 45  
≥Day 32  
The summary by visit will use the “analyzed records” only – at most one per participant.  The 
data not flagged as the “analyzed record” will be included in listings. A windowed visit that 
does not fall under any analysis window will remain in the database and will be included in 
the listings.   
8.3.3. 
Analysis of Efficacy Variable(s) 
The FAS will be used for all efficacy summary tables. Participants will be analyzed 
according to randomized treatment. 
The following efficacy endpoints will be summarized descriptively by scheduled assessment 
time point:  
 HAM-D total score – observed, change from baseline, percent change from 
baseline 
 HAM-D subscale scores – observed, change from baseline, percent change from 
baseline 
 HAM-D individual item score – observed, change from baseline  
 HAM-D response – missing response not accounted 
 HAM-D response – missing response counted as No response 
 HAM-D remission – missing remission not accounted 


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 HAM-D remission – missing remission counted as No remission 
 CGI-I score -observed  
 CGI-I response - missing response not accounted 
 CGI-I response – missing response counted as No response 
 CGI-S score – observed and change from baseline 
 HAM-A total score – observed, change from baseline, percent change from 
baseline 
 HAM-A individual item score -– observed, change from baseline  
 MADRS total score – observed, change from baseline, percent change from 
baseline 
 MADRS individual item score – observed, change from baseline 
 MADRS response – missing response not accounted 
 MADRS remission – missing remission not accounted 
 MADRS response – missing response counted as No response 
     MADRS remission – missing remission counted as No remission 
 EPDS total score– observed, change from baseline, percent change from baseline 
 PHQ-9 score – observed (including categories), change from baseline  
The HAM-D change from baseline in total score will also be presented by the following 
subgroups: 
 Antidepressant use at baseline: yes, no 
 Age group: 18-24, 25-45 years 
 Race: White, Black or African American, Other 
 BMI (≤18.4, 18.5-24.9, 25-29.9, ≥30 kg/m2) 
 HAM-D total score at baseline: < median of baseline HAM-D total score, 
≥median of baseline HAM-D total score 
 Onset of PPD (3rd trimester vs. postpartum) 
 History of PPD (1st episode vs recurrent PPD episode) 
 Depression with elevated anxiety, by Baseline HAMA total score (>=20, <20) 
 Country (US vs. Rest of World) 
No model-based analysis will be performed for the subgroup of “Depression with elevated 
anxiety, by baseline HAM-D anxiety subscale” since over 95% of participants had 
depression with elevated anxiety categorized by baseline HAM-D anxiety subscale (>=7) or 
the subgroup of  COVID-19 history as majority of participants were ‘Not impacted’; 


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similarly for the subgroup of country as only handful of participants were enrolled outside 
the US.   
In addition, post-baseline percentage improvement in HAM-D total score will be presented in 
histogram over scheduled visits by treatment group under the following categories: < 0% 
(worsened), ≥0% but < 25%, ≥25% but < 50%, ≥50% but <75%, ≥75%. Post baseline HAM-
D total score will also be presented in histogram over time: ≤7, >7 but ≤15, >15 but ≤23, >23 
but <26, >=26.  Supporting data will be presented in summary tables. 
Bar charts over scheduled visits by treatment for HAM-D response, HAM-D remission and 
CGI-I response will be provided.  In addition, line plots for LS means for HAM-D total score 
and bar charts for HAM-D response and remission will be provided by antidepressant use at 
baseline. 
As part of supportive analyses, summary statistics and Model-based estimates for the HAM-
D total scores will be provided for Per Protocol Set.  
All above efficacy variables will be listed in a separate listing. 
8.3.3.1. 
Mixed Effects Model for Repeated Measures 
The estimand for the primary efficacy analysis is defined as follows: 
1. The treatment regimens for participants are: placebo or SAGE-217 for 14 days. 
2. The target population is adult participants with a diagnosis with severe PPD (baseline 
HAM-D total score ≥26). 
3. The variable of interest is the change from baseline in HAM-D total score at Day 15. 
4. The population summary level is the model-based estimate of the difference between 
SAGE-217 and placebo treatments in mean change from baseline in HAM-D total 
score or in CGI-S total score. 
a. The population summary level for the primary endpoint is the model-based 
estimate of the difference between SAGE-217 and placebo in change from 
baseline in HAM-D total score at Day 15 
b. The population summary level for the key secondary endpoints is the model-
based estimate of the difference between SAGE-217 and placebo in change from 
baseline in HAM-D total score at Day 3, Day 28, Day 45 and in change from 
baseline in CGI-S total score at Day 15 respectively  
5.    The intercurrent events could be: 
a. The premature discontinuation of treatment for any reason. Treatment policy 
strategy will be used.    
b. Certain medications including, but not limited to, new antidepressants or 
benzodiazepines are prohibited in the protocol until Day 45 follow-up; however, 
the treatment policy strategy requires that data following initiation of such 
prohibited medications are included in analysis.  The protocol does not specify 
any rescue process, hence there is no rescue medication.   
 


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Data from SAGE-217 group versus placebo group will be analyzed using a mixed effects 
model for repeated measures (MMRM); the model will include treatment (SAGE-217 or 
placebo), baseline HAM-D total score, antidepressant use at baseline (Yes or No), 
assessment time point, and time point-by-treatment interaction as explanatory variables. All 
explanatory variables will be treated as fixed effects. All post-baseline time points will be 
included in the model. The main comparison will be between SAGE-217 and placebo at Day 
15. Model-based point estimates ie, treatment difference in least squares [LS] mean is the 
estimate of the effect and will be reported where applicable along with 95% confidence 
intervals, and p-values. An unstructured (UN) covariance structure with the default Newton-
Raphson algorithm used by SAS PROC MIXED will be used to model the within-participant 
errors. If there is a convergence issue with the unstructured covariance model, the Fisher 
Scoring algorithm (via the SCORING option of the PROC MIXED statement), the no-
diagonal factor analytic structure (via the TYPE=FA0(T) option of the REPEATED 
statement, where T is the total number of time points), Toeplitz, Autoregressive (1) [AR (1)] 
covariance structure will be used, following this sequence until convergence is achieved. If 
the model still does not converge with AR (1) structure, no results will be reported. When the 
covariance structure is not UN, the sandwich estimator for the variance-covariance matrix 
will be derived, using the EMPIRICAL option in the PROC MIXED statement in SAS. 
Observed Margins (OM) option will be used in SAS with LSMEAN statement. The p-value 
will be interpreted at 5% 2-sided level of significance. 
 
If the comparison of SAGE-217 versus placebo is significant at 0.05 level, the hypotheses 
testing for the key secondary endpoints will proceed in the prespecified fixed sequence as 
described in Section 8.3.3.5 . 
Similar to the methods described above for the primary endpoint, MMRM will be used for 
the analysis of the change from baseline in other time points in HAM-D total score, all time 
points in HAM-D subscale scores (Core Subscale score, Anxiety Subscale score, Bech-6 
Subscale score and Maier Subscale score), HAM-D individual item scores, CGI-S score, 
HAM-A total score, HAM-D individual item scores, MADRS total score, MADRS 
individual item scores, EPDS total score, and PHQ-9 total score.  PHQ-9 total score category 
will be summarized. 
The MMRM analyses will also be used for change from baseline in HAM-D total score 
within each baseline subgroup level defined in Section 8.2.3 separately. If any treatment 
group for any level of subgroup has ≤15 participants, the subgroup level will not be used in 
the analysis. 
For each model, the comparison of interest will be between SAGE-217 and placebo at Day 
15. In addition, model-based point estimates (ie, LS means), 95% confidence intervals, and 
p-values will be reported for all time points. 
Line plot of model-based LS Mean and standard error (SE) over time will be prepared for 
change from baseline in HAM-D total score, CGI-S score, HAM-A total score, MADRS total 
score. Forest plot for subgroup analysis for change from baseline in HAM-D total score at 
Day 15 – LS mean, LS mean difference, 95% confidence interval, and P-value – will be 


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provided. In addition, a Forest plot for individual items in HAM-D and for subscales of 
HAM-D will also be provided.   
Summary of HAM-D total score along with model-based estimates will be provided for Per 
Protocol Set as a supportive analysis for the primary endpoint. 
8.3.3.2. 
Generalized Estimating Equation (GEE) Models 
Generalized estimating equation (GEE) methods will be used for the analysis of HAM-D 
response (missing response not accounted or missing response counted as No response 
respectively) and HAM-D remission (missing remission not accounted or missing remission 
counted No remission respectively). GEE models will include terms for treatment (SAGE-
217, or Placebo), baseline HAM-D score, antidepressant use at baseline (Yes or No), 
assessment time point, and time point-by-treatment as explanatory variables.  
An unstructured (UN) covariance structure will be used to model the within-participant 
errors. If there is a convergence issue with the unstructured covariance model, then 
exchangeable covariance structure will be used. If the model still does not converge with 
exchangeable structure, no results will be reported. 
Model-based point estimates (ie, odds ratios), 95% confidence intervals, and p-values will be 
reported.  
A GEE method will also be used for the analysis of MADRS response (missing response not 
accounted or missing response counted as No response respectively) and remission (missing 
remission not accounted or missing remission counted No remission respectively) including 
terms for treatment, baseline MADRS score, antidepressant use at baseline, assessment time 
point, and time point-by-treatment as explanatory variables. 
A GEE method will also be used for the analysis of CGI-I response (missing response not 
accounted or missing response counted as No response respectively) including terms for 
treatment, baseline CGI-S score, antidepressant use at baseline, assessment time point, and 
time point-by-treatment as explanatory variables.   
Model diagnostics to access the goodness of fit for the GEE models will be examined. In the 
event of poor goodness of fit, logistic regression will be performed separately for each visit, 
including baseline score and antidepressant use at baseline as explanatory variables. 
Bar charts over scheduled visits by treatment for HAM-D response/remission, MADRA 
response/remission and CGI-I response will be provided for FAS. 
8.3.3.3. 
Sensitivity Analysis 
8.3.3.3.1. Imputation Based on Study Withdrawal Reasons for Assessing MAR 
Assumption for Missing HAM-D Total Scores  
A sensitivity analysis will be used to investigate the impact of missing data if ≥ 5% of 
participants have missing HAM-D total score at timepoints (ie, HAM-D total score at Days 3, 
8, 15, 21, 28 or 45).   
Imputation based on study withdrawal reason will be used.  The missing HAM-D total scores 
will be imputed using multiple imputation methods. The MMRM model will use the imputed 


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dataset (all observed and imputed values included) to estimate the treatment difference.  The 
FAS will be used for sensitivity analyses. Sample SAS codes for MI imputation is provided 
in Section 11.2, Appendix B. 
Imputation distribution: 
The imputation distribution for the missing HAM-D total score at each timepoint will be 
assumed to have a normal distribution.  All randomized participants will be classified as non-
missing category, missing category 1, or missing category 2, based on the following rules: 
 Non-missing category: Participant with non-missing change from baseline in 
HAM-D total score at Day X 
 Missing category 1: Participant discontinued due to adverse events, physician 
decision, protocol deviation, non-compliance with investigational product, or 
other, and is missing change from baseline in HAM-D total score at Day X, lost to 
follow up, withdrawal by participant, or participant completed study but is 
missing change from baseline in HAM-D total score at Day X or participants 
discontinued due to sponsor decision, 
 Missing category 2: Participant discontinued due to pregnancy. 
Imputation algorithm: 
Missing values of HAM-D total score at all visits will be imputed using the fully conditional 
specification (FCS) models. Two different imputation models will be used based on reasons 
of missing:   
 Missing category 1: simulate missing values of HAM-D total score using an 
imputation model based on the non-missing HAM-D total scores for placebo group 
(Jump to Reference).  This represents a conservative approach as it tends to reduce 
the difference between treatment and placebo group since higher values of change 
from baseline represents worse outcome, and placebo is supposed to provide a higher 
value. 
 Missing category 2: simulate missing values of HAM-D total score using an 
imputation model based on the non-missing HAM-D total scores within the same 
treatment group. 
 
Analysis model: 
The complete MI method is described below: 
 Impute missing values using the normal distribution specified in the above 
algorithm to form a complete dataset (imputed dataset).  After imputation, all FAS 
participants will have non-missing change from baseline in HAM-D total score at 
all scheduled assessment time points. 
 Repeat the process K (K=100) times, using the procedure described above to form 
K imputed complete datasets with the same variance structure. 




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3. The 100 sets of MMRM results will be combined with SAS PROC MIANALYZE, which 
combines estimates as specified in step 2.  
4. Steps 1 to 3 will be repeated with different values of the shift parameter until the treatment 
effect is no longer significant at 0.05 level at each study visit. The range of shift may be 
adjusted at the time of the final analysis if it will not reach a tipping point properly at 
majority of study visits.  
The tipping point will be provided by study visit along with the main estimates in change 
from baseline by study visit from MMRM in Section 8.3.3.1 . Sample SAS code for MI is 
provided in Section 11.2 Appendix B. 
8.3.3.3.3. Weighted Generalized Estimating Equation  
The standard GEE method in Section 8.3.3.2 is valid if the data are missing completely at 
random (MCAR), but it can lead to biased results if the data are missing at random (MAR). 
The weighted GEE implements the inverse probability-weighted method to account for 
dropouts under the MAR assumption. This analysis will be performed using the binary 
secondary endpoints, ie. HAM-D response, HAM-D remission, MADRA response and 
MADRA remission and CGI-I response. This analysis will use FAS. 
A weighted GEE method does not apply for the data with intermittent missing from any of 
the participants and the procedure does not converge in SAS. A SAS procedure with MI 
Markov Chain Monte Carlo (MCMC) with 100 imputations will be used to fill out 
intermittent missing values so that the data will have monotone missing pattern. Therefore, a 
weighted GEE on each binary endpoint will be run as a sensitivity analysis. Since the 
endpoints are binary outcomes, the imputation to fill out intermittent missing will be 
performed based on the raw scores. The imputed values will be rounded and converted as 
each binary endpoint as defined in Section 8.3.1.1 and Section 8.3.1.2 . 
Therefore, a weighted GEE model including baseline HAM-D score, antidepressant use at 
baseline (Yes or No), assessment time point, and time point-by-treatment as explanatory 
variables will be used to estimate point estimates (ie, odds ratios), 95% confidence intervals, 
and p-values. The results from the 100 imputed datasets will be combined using the SAS 
procedure PROC MIANALYZE. 
Sample SAS code for weighted GEE is provided in Section 11.2  Appendix B. 
8.3.3.4. 
Analysis of Time to First HAM-D Response/Remission 
Using the FAS, Kaplan-Meier (KM) survival method will be provided for time to first HAM-
D response; the median time (Days) to first response, min, max, 25th and 75th percentiles will 
be estimated from KM analysis. A participant will be censored at the participant’s last day of 
HAM-D evaluation in the database if the participant did not have a response.  Similar 
analysis will be done for first HAM-D remission.  
These analyses will be provided on FAS for supportive purposes only. 


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8.3.3.5. 
Multiplicity Adjustment for Key Secondary Endpoints 
Multiplicity adjustment to statistical testing of hypotheses of the key secondary endpoints are 
conducted by using fixed sequence strategy. Only if the primary endpoint is statistically 
significant at 0.05 level, the key secondary endpoints will be tested sequentially, testing each 
endpoint at 5% level of significance only if the previous endpoint in the below sequence has 
been significant at 5% level. If an endpoint is not significant at 5% level, the next endpoint in 
the sequence will be interpreted only with nominal p-value.   
The sequence of testing key secondary endpoints is as follows: 
  Change from Baseline in HAM-D total score at Day 3 
  Change from Baseline in HAM-D total score at Day 28 
 Change from Baseline in HAM-D total score at Day 45 
 Change from Baseline in CGI-S at Day 15 
 
A secondary endpoint not included above is not adjusted for multiplicity, and hence will be 
interpreted with nominal p-value.   
8.3.4. 
Characterization of Durability of SAGE-217 Treatment Effect  
After completion of 14 days of treatment, the study participant is followed for 31 days, 
without any further treatment with study drug.  During this 31-day follow-up period, clinic 
visits are scheduled for Days 21, 28 and 45.  Day 45 change from baseline in HAM-D total 
score is pre-specified as a key secondary endpoint in this study. 
 
Demonstration of SAGE-217 durable effect will be characterized via 2 complementary 
approaches:  
1) clinically meaningful durable SAGE-217 treatment effect at Day 45 (see Section 8.3.4.1 
below), and  
2) statistically significant change from baseline at Day 45 in SAGE-217 versus placebo (for 
statistical demonstration of durable SAGE-217 treatment effect, see Section  8.3.4.2  below).  
8.3.4.1. 
Durability of Clinically Meaningful Treatment Effect for SAGE-217 
Durability of treatment effect is assessed over the post-treatment period in the SAGE-217 
group, based on the efficacy observed at Day 15.  The primary endpoint for clinically durable 
effect will be examined by the percent retention of the Day 15 reduction from baseline in 
HAM-D total score (referred to as “percent retention of D15 change from baseline (CFB)” 
going forward).   
Percent retention of D15 CFB is defined as follows: Let Xb be baseline HAM-D total score, 
X15 be Day 15 HAM-D total score, Xy be Day Y (Y>15) HAM-D total score.  Then percent 
retention (%) for Day Y is 
𝑋𝑦−𝑋𝑏
𝑋15−𝑋𝑏× 100.  It will be calculated for the scheduled visits after 
Day 15 for the participants by the randomized treatment groups.  For example, for a 


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participant with a baseline HAM-D of 27 (Xb) and a HAM-D score of 13 (X15) at Day 15, 
percent retention at Day 45 with HAM-D of 16 (Xy) would be 79%. If D45 HAM-D score is 
18, percent retention would be 64%. 
A summary of percent retention of D15 CFB will be presented for participants at Day 15 for 
post-Day 15 visits by treatment group, based on FAS.  This will serve as the primary 
approach for assessing clinically durable effect; mean percent retention of D15 CFB at Day 
45 is considered clinically meaningful durability if it is >=65%. The mean percent retention 
(±SE) over time by treatment group will be presented in a line plot.  In addition, the number 
and percent of participants with at least 65% retention of D15 CFB at each of post-Day 15 
visit will also be provided by treatment group.  
 
Following analysis will be presented by treatment group for supportive purposes to assist 
with further understanding of clinical durability of effect of SAGE-217.  These analyses will 
be conducted using FAS. 
A. A summary of percent retention of D15 CFB will be presented for HAM-D 
responders at Day 15 for post-Day 15 visits. The mean percent retention (±SD) over 
time will be presented in a line plot.  In addition, the number and percent of HAM-D 
responders at Day 15 with at least 65% retention of D15 CFB at each of post-Day 15 
visit will also be provided. 
B. The number and percent of HAM-D responders at post-Day 15 visits among HAM-D 
responders at Day 15 will be provided. A bar chart will be provided. 
C. The number and percent of HAM-D remitters (HAM-D total score <=7) at post-Day 
15 visits among the HAM-D remitters at Day 15 will be provided. A bar chart will be 
provided. 
D. Relapse: A relapse is defined for HAM-D responders at Day 15.  A relapse is defined 
as having at least 2 consecutive HAM-D total score >=20 after Day 15.  The number 
and percent of participants with relapse will be provided.    
E. Rebound: A rebound is defined for HAM-D responders at Day 15.  A rebound is any 
HAM-D total score (after Day 15) >=Baseline HAM-D total score.  The number and 
percent of participants with rebound will be provided.  
F. The number and percent of CGI-I responders (CGI-IR) at post-Day 15 visits among 
the CGI-I responders at Day 15 will be provided. A bar chart will be provided base. 
Post Day 15 HAM-D results supporting the above analyses will be listed separately for the 
participants based on FAS. 
8.3.4.2. 
Durability of Treatment Effect at Day 45 via Statistical Comparison of 
SAGE-217 Versus Placebo 
These analyses have been discussed in Section 8.3.3.1 and Section 8.3.3.2 as part of the 
efficacy analyses with Day 45 as one of key secondary efficacy endpoints: 


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A. MMRM analysis of change from baseline in HAM-D total score at Day 45 (key 
secondary efficacy endpoint), comparing SAGE-217 versus placebo (LS mean, p-
value and 95% CI) will be provided. 
B. GEE analysis of HAM-D response/remission rates comparing SAGE-217 versus 
placebo at Day 45 (Odds Ratio, p-value and 95% CI) will be provided.  
8.3.5. 
Anxious Subgroup Analysis 
Efficacy analysis will be repeated for the anxiety subgroup.    
 Depression with elevated anxiety, by Baseline HAMA total score (>=20, <20) 
HAM-D total score and CGI-S score observed, change from baseline, percent change from 
baseline - will be summarized descriptively by scheduled assessment time point for the 
subgroup, respectively.   
A MMRM analysis will be provided for the change from baseline in HAM-D total score and 
CGI-S score by scheduled assessment time point for each group, respectively. 
A GEE method will also be used for the analysis of HAM-D response, HAM-D remission, 
and CGI-I response by scheduled assessment time point for each subgroup, respectively.   
8.4. 
Safety Analysis 
A secondary objective is to evaluate the safety and tolerability of SAGE-217 as assessed by 
the incidence and severity of adverse events; 
 
 
 
. Safety analyses will be conducted using the Safety Set, unless specified otherwise. 
The data will be presented by the actual treatment received rather than the treatment to which 
the participant has been randomized; for definition of actual treatment assignment, please see 
Section 8.1   
 The safety endpoints evaluated at scheduled visits within treatment period 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.    If scheduled visit value is not available, a 
value from the specific visit window will be included in summary. For Post-treatment period 
visits, the choice of the visit will follow the same rule as described in Section 8.3.2. 
All parameters will be converted to consistent units according to the International System of 
Units (SI) before analysis. 
Any time during treatment, last value on treatment and last value on study will be included in 
the summaries whenever indicated in the relevant sections below.  Any time during treatment 
is defined as measurement on or after first dose, on or before last dose + 1 day. Last value on 
treatment is defined as the last post-baseline value between first dose of investigational 
product (exclusive) and up to last dose of investigational product + 1 days (inclusive).  Last 
value on study is defined as the last post-baseline value after the first dose of investigational 
product. 


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The safety endpoints and variables considered in the summary tables for this study are 
summarized in Table 4. 
Table 4: 
Safety Endpoints and Variables in the Summary Tables 
Safety 
Evaluation 
Incidence 
Observed 
Value 
Change 
from 
Baseline 
Abnormality/Clinical 
Significance (CS) 
Potentially 
Clinical 
Significance 
(PCS) 
AEs 
X 
 
 
 
 
Note: PCS criteria are outlined in sections 8.4.2-8.4.4 
X = to be summarized in tables 
Z = to be presented in listings only 
8.4.1. 
Adverse Events 
Adverse events (AEs) are collected starting at the time of informed consent and throughout 
the duration of the participant’s participation in the study.  A treatment-emergent adverse 
event (TEAE) is defined as an adverse event with onset on or after the start of investigational 
product. The TEAEs will be further categorized by the phase of occurrence as follows: 
Adverse events are assigned an AE period based on the onset date/time.  AE periods are 
defined as follows: 
 Pre-treatment AE: AE onset date before first investigational product dosing date 
 TEAE: AE onset date/time on or after first investigational product dose date/time 
(If an AE start date same as investigational product first dose date, but no time 
either in AE start or treatment start, then consider this AE to be in treatment 
period TEAE.)   
 On-treatment TEAE: AE onset date/time on or after first investigational product 
dose date/time and on or before investigational product last dose date + 1 day 
(Note that time does not matter for the end of this period.) 
 Post-treatment TEAE: AE onset date after investigational product last dose date 
+1 day (Typically, Day 16 through Day 45 – time does not matter) 
If the date of an adverse event is incomplete and an unambiguous determination could not be 
made with respect to its onset time versus the first dose of investigational product and/or last 
dose of investigational product, the adverse event will be assumed to be a TEAE and a 


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treatment period AE.  For imputation of missing AE dates, please refer to Appendix C, 
Section 11.3.  
All adverse events will be coded using MedDRA version 23.0 or higher.  
An overview summary table of TEAEs will present the number and percentage of 
participants as well as the number of events for the following: 
 TEAE  
  On-treatment TEAE 
  Post-treatment TEAE 
 TEAEs by maximum severity (severe>moderate>mild) 
 TEAE leading to investigational product dose reduction 
 TEAE leading to discontinuation of investigational product 
 TEAE leading to withdrawal from the study 
 Treatment-emergent Serious Adverse Event (SAE) 
 Death 
Incidence of TEAEs in following categories will be provided by SOC and PT.  A participant 
is counted only once under each SOC and PT in case of multiple occurrences of the same 
AE. These tables will be sorted by decreasing frequency of System Organ Class (SOC) in 
SAGE-217 group, then in placebo group, then alphabetically first within SOC then within 
preferred term.  
 TEAE 
 On-treatment TEAE 
 Post-treatment TEAE 
 TEAEs by maximum Severity 
 TEAEs by relationship  
 Serious TEAEs 
 TEAEs leading to discontinuation of investigational product 
 TEAEs leading to withdrawal from the study  
 TEAEs leading to investigational product dose reduction  
Listing of AEs with onset prior to first dose of investigational product will be provided.  All 
listings on TEAEs will provide the period designation for each AE.   
A summary of most common study period TEAE just by preferred term where the incidence 
is more than 2% in any treatment group will be provided, sorted by decreasing frequency of 
system organ class (SOC) first by SAGE-217 group, then by placebo, then alphabetically 
first within SOC then within preferred term.  


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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 investigational 
product, participant will be counted only once within each SOC and PT at the strongest 
relationship to investigational product in the following order: related > not related, an AE 
with relationship missing is treated as related. The incidences will be presented by 
descending frequency of SOC and then, within a SOC, by descending frequency of PT based 
on the participant count, and in alphabetical order of PT if the incidence within a PT is a tie.  
Adverse events with onset before the first dose of investigational product will be provided in 
a separate listing.  Separate data listing for deaths and SAEs will be provided.  A listing of all 
adverse events experienced by participants who had investigational product dose reduction 
due to adverse event will be generated as well. A listing of participants with COVID-19 
related AEs will be provided. 
In addition, TEAE summary by SOC/PT will also be presented by the following subgroups: 
 Antidepressant use at baseline: yes, no 
 Age group: 18-24, 25-45 years 
 Race: White, Black or African American, Other 
 BMI (≤18.4, 18.5-24.9, 25-29.9, ≥30 kg/m2) 
 Baseline HAM-D total score: < median of baseline HAM-D total score, ≥ median 
of baseline HAM-D total score  
 Country (US, Rest of World) 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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.     
 
 
 
 
 
 
. 
 
 
 
 
 
 
. 
 
  
8.4.5. 
Physical Examination  
Physical examination is scheduled on screening, Days 8 and 21. 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.  
 
 
 
 
 
.   


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.  
 
 
 
 
. 
 
 
 
. 
 
.   
9. 
SUMMARY OF INTERIM AND DMC ANALYSES 
Not applicable 
10. 
REFERENCES 
Clinical study protocol, version 2.0, 29 JAN 2021, Company: Sage Therapeutics Inc. 


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11. 
LIST OF APPENDICES 
11.1. 
Appendix A: Schedule of Assessments 
Study Procedure 
Study Period / Visit Day 
Screening 
Period 
Treatment Perioda 
Follow-up Period 
D-28 to -1 
D1 (assessments 
completed pre-
dose) 
D3 
(±1 d) 
D8  (+1 d) D15 (+1 d) 
 
D18 (±1 d) 
D21 
(±1 d) 
D28 (±3 d) 
D45/ET 
(±3 d) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Duplicate Participant Check b 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
SCID-5-CT 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical/Family History c 
X 
 
 
 
 
 
 
 
 
Participant training d 
X 
X 
 
 
 
 
 
 
 
Physical Examination e 
X 
 
 
X 
X 
 
X 
 
Xf  
Body Weight/Height 
X 
 
 
 
X 
(weight 
only) 
 
X 
(weight only) 
 
X (weight 
only) f 
Drug & Alcohol Screen h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test i 
X 
X 
 
 
X 
 
 
 
X 
Hormone Sample j 
O 
 
 
O 
O 
 
 
 
 
Genetic Sample k 
O 
 
 
 
 
 
 
 
 


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Study Procedure 
Study Period / Visit Day 
Screening 
Period 
Treatment Perioda 
Follow-up Period 
D-28 to -1 
D1 (assessments 
completed pre-
dose) 
D3 
(±1 d) 
D8  (+1 d) D15 (+1 d) 
 
D18 (±1 d) 
D21 
(±1 d) 
D28 (±3 d) 
D45/ET 
(±3 d) 
 CGI-I 
 
 
X 
X 
X 
 
X 
X 
X 
CGI-S 
X 
X 
X 
X 
X 
 
X 
X 
X 
HAM-A o 
 
X 
X 
X 
X 
 
X 
X 
X 
HAM-D o, p 
X 
X 
X 
X 
X 
 
X 
X 
X 
MADRS 
 
X 
 
X 
X 
 
 
X 
X 
EPDS 
X 
X 
X 
X 
X 
 
X 
X 
X 
PHQ-9 
X 
X 
X 
X 
X 
 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
Dispense IP 
 
X 
 
X 
 
 
 
 
 
IP Administration 
 
X 
 (once daily in the evening through Day 14 - inclusive) 
 
 
 
 
IP Adherence r 
 
X 
 
 
 
 
IP Accountability/Return 
 
 
 
X 
X 
 
 
 
X f 
Adverse Events c 
X (from time of ICF throughout the duration of participation) 
Prior/Concomitant Medications c, s 
X 
 
 
CGI-I = Clinical Global Impressions - Improvement; CGI-S = Clinical Global Impressions - Severity; 
 D = day; 
; EPDS = Edinburgh Postnatal Depression Scale; ET = early termination; HAM-A = Hamilton Anxiety Rating Scale; HAM-D = Hamilton Rating 


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Scale for Depression, 17-item; IP = investigational product; MADRS = Montgomery-Åsberg Depression Rating Scale; O = optional; PHQ-9 = Patient Health Questionnaire; 
  
Note: When 
, and/or blood draws are scheduled to occur at the same time, the order of assessments should be as follows: 
, blood draw. 
a An unscheduled visit may be needed if a dose adjustment is deemed necessary by the investigator. Any remaining current dose should be returned, and the adjusted dose 
should be dispensed at this visit.  
b Participants in the US only will be asked to authorize that their unique participant identifiers be entered into a registry with the intent of identifying participants who may 
meet exclusion criteria for participation in another clinical study. 
c  Information regarding diagnosis, isolation, and/or hospitalization due to COVID-19 will be documented as part of medical history, AE collection, and prior/concomitant 
medication/procedure collection at screening and throughout the study. 
d Participants will be trained on the use of software applications and devices necessary for the conduct of the study by site personnel. 
e A full physical examination will be conducted at screening and abbreviated physical examinations will be conducted thereafter. A full physical examination includes 
assessment of body systems (eg; head; eye; ear, nose, and throat; heart; lungs; abdomen; and extremities). An abbreviated physical examination includes a brief medical 
history followed by targeted physical examination. 
f   To be completed at ET only for participants who withdraw from the study/stop study participation before the Day 15 visit. 
 
   
h Urine toxicology for selected drugs of abuse and breath test for alcohol 
i Urine and serum pregnancy test to be conducted at screening; the urine test is recommended to precede other screening assessments. Qualifying criteria will be based on 
serum test results. Urine pregnancy test to be conducted at all other visits indicated. A urine pregnancy test will also be collected as part of the ET assessments for 
participants who discontinue the study early. 
j An optional blood sample for stress hormone levels, kynurenine biochemistry, and markers of inflammation, where consent is given.   
k An optional genetic sample for biomarker testing, where consent is given. 
 
 
 
. 
 
. 
 
 
o The assessment timeframe for HAM-D scales will refer to the past 7 days (1 week) at Screening and “Since Last Visit” for all other visits. The assessment timeframe for 
HAM-A scales will refer to the past 7 days (1 week) at all visits. 
p HAM-D is to be completed as early during the visit as possible. 
 
 
. 
r As local regulations permit, IP administration will be monitored via a medication adherence monitoring platform used on smartphones to visually confirm IP ingestion. IP 
adherence will not be captured after participants discontinue IP. Optional consent may be required in regions with restricted regulations. 
s Prior medications will be collected at screening and concomitant medications and/or procedures will be collected at each subsequent visit (see Section 9.2.1 from 
protoocol). 
 


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11.2. 
Appendix B: Details of Statistical Methodology 
Sample SAS code for Mixed Effects Model for Repeated Measures (MMRM): 
   If type=un: 
ods output lsmeans=estimates diffs=diffs; 
proc mixed data=&data; 
class trtpn avisitn usubjid antidep; 
model chg=base trtpn avisitn trtpn*avisitn antidep / ddfm=kr s; 
repeated avisitn / subject=usubjid type=un;  
lsmeans trtpn*avisitn /diff=all cl alpha=0.05 OM; 
** assuming trtpn= 1 for the Placebo, trtpn=2 for SAGE-217  
run;  
 
if above model doesn’t converge, use following model: 
 
ods output lsmeans=estimates diffs=diffs; 
proc mixed data=&data scoring=x; 
class trtpn avisitn usubjid antidep; 
model chg=base trtpn avisitn trtpn*avisitn antidep / ddfm=kr s; 
repeated avisitn / subject=usubjid type=un;  
lsmeans trtpn*avisitn /diff=all cl alpha=0.05 OM; 
** assuming trtpn= 1 for the Placebo, trtpn=2 for SAGE-217  
run;  
 
if above ‘scoring’ option doesn’t  converge, use following model: 
ods output lsmeans=estimates diffs=diffs; 
proc mixed data=&data empirical; 
class trtpn avisitn usubjid antidep; 
model chg=base trtpn avisitn trtpn*avisitn antidep / ddfm=kr s; 
repeated avisitn / subject=usubjid type=fa0(6);  
lsmeans trtpn*avisitn /diff=all cl alpha=0.05 OM; 
** assuming trtpn= 1 for the Placebo, trtpn=2 for SAGE-217  
run;  
 
 
 If type=un does not converge, use type=TOEP or AR(1); 
ods output lsmeans=estimates diffs=diffs; 
proc mixed data=&data empirical; 
class trtpn avisitn usubjid antidep; 
model chg=base trtpn avisitn trtpn*avisitn antidep / s; 


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repeated avisitn / subject=usubjid type=TOEP;  
**If type=TOEP does not converge, use type=AR(1); 
lsmeans trtpn*avisitn /diff=all cl alpha=0.05 OM; 
** assuming trtpn= 1 for the Placebo, trtpn=2 for SAGE-217  
run;  
 
Sample SAS code for Generalized Estimating Equation (GEE): 
ods output lsmeans=lsmeans diffs=diffs ObStats=dd; 
 
proc genmod data=&data desc  plots=all; 
class usubjid trtpn antidep avisitn; 
model aval=base trtpn avisitn trtpn*avisitn antidep /dist=bin link=logit OBSTATS; 
repeated subject=usubjid / within=avisitn type=un; * if convergence not met, use type=exch; 
lsmeans trtpn*avisitn / diff exp cl; 
run;  
 
Sample SAS code for Multiple Imputation (MI): 
** Missing category 1, trtp=A represent the PLACEBO group 
proc mi data=in seed=xxxx nimpute=20 round=. . . . 1 1 1 1 1 1 1 1 1 1 1 1 1 out= fcs_reg1; 
class trtp antidep; 
FCS reg; 
mnar model (base day3 day8 day15 day21 day28 day45/ modelobs= (trtp='A')); 
var antidep base day3 day8  day15 day21 day28  day45; 
run; 
** Missing category 2 
 
proc mi data=&data seed=xxxx nimpute=20 round=. . . . 1 1 1 1 1 1 1 1 1 1 1 1 1 out=fcs_reg2; 
class trtp antidep; 
fcs nbiter=20 reg (base day3 day8  day15  day21 day28  day45/details); 
var trtp antidep base day3 day8 day15 day21 day28  day45; 
run;  
 
A sample of the SAS code for sensitivity analysis using the tipping-point approach is provided as 
below: 
 
proc mi data=&data out=temp seed=xxxxxx nimpute=100; 
class trtpn antidep;  
var trtpn antidep base day3 day8 day15 day21 day28  day45 ; 
fcs reg;  
mnar adjust(day_xx/shift=xx adjustobs=(trtpn='2'))  
     adjust(day_xx/shift=xx adjustobs=(trtpn='2'))  
     adjust(day_xx/shift=xx adjustobs=(trtpn='2'))  
     adjust(day xx/shift=xx adjustobs=(trtpn='2'))  
     adjust(day_xx/shift=xx adjustobs=(trtpn='2')) 


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     adjust(day_xx/shift=xx adjustobs=(trtpn='2'))  
      
run; 
 
Sample SAS code for Weighted GEE analysis: 
*Chage the missing pattern from arbitrary to monotone; 
proc mi data=work1 out=im1 seed= 12345 nimpute=100;  
mcmc chain=multiple impute= monotone ;  
var base antidep day3  day8  day15 day21 day28  day42 ;  
run; 
 
proc gee data=cgiim desc ; 
by _imputation_; 
class usubjid trtpn antidep avisitn ; 
missmodel BASE trtpn avisitn trtpn*avisitn antidep / type=obslevel; 
model dep = BASE trtpn avisitn trtpn*avisitn antidep  /dist=bin link=logit ; 
repeated subject=usubjid / type=un ; * if convergence not met, use type=exch; 
lsmeans trtpn*avisitn / diff exp cl; 
run;  
ods output close; 
 
11.3. 
Appendix C: Handling of Missing Dates 
Dates missing the day, or both the day and month of the year will adhere to the following 
conventions in order to classify TEAEs and to classify prior and concomitant medications.  
In general, listings will present the actual partial or missing values rather than the imputed 
values that may be used in derivation. In instances where imputed values will be presented, 
imputed values will be flagged.  
Adverse Events 
If the AE start date is completely missing, do not impute a date but consider it as TEAE, 
unless the AE end date is before the initiation of treatment, in which case the AE will be 
considered prior. 
For partial AE start dates: 
 When the year is known, but the month and day is unknown, then: 
o If the year matches the year of first dose date and the end date (if present) is 
after first dose date, or AE is ongoing, then impute as the month and day of 
earlier date of (the first dose date + 1 day, last dose date). 
o If the year of AE onset < year of initiation of the treatment, then the month 
and day will be set to December 31st.  
o If the year of AE onset > the year of initiation of treatment, then the month 
and day will be set to January 1st. 
 If the year and month are known, but the day is unknown, then: 


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o If the year of AE onset = the year of initiation of the treatment and: 
 the month of AE onset = the month of initiation of the treatment, 
then the day will be set to the day of initiation of the treatment. 
 the month of AE onset < the month of initiation of the treatment, 
then the day will be set to the last day of month of the particular 
year. 
 if the month of AE onset > the month of initiation of the treatment, 
then the day will be set to the 1st day of month. 
o If the year of AE onset < the year of initiation of the treatment, then the 
day will be set to the last day of month of the particular year. 
o If the year of AE onset > the year of initiation of the treatment, then the 
day will be set to the 1st day of month. 
If the imputed AE onset date is after the AE stop date, then the onset date will be set to 
   the stop date. 
 When the year and day are present and the month is missing, treat it as if the day is 
missing, and only year is present.  Follow the imputation rules for “year is known, but 
the month and day is unknown”. 
 When the year is missing, but the month and/or day is known, treat this date as 
missing; do not impute. 
 
Dates in Disease History (Dates of diagnosis, current episode, first episode) 
o If the year is present and the month and day are missing, then the month and day 
will be set to January 1. 
o If the year and day are present and the month is missing, then the month will be 
set to January. 
o If the year and month are present and the day is missing, then the day will be set 
to the 1st day of month 
 
Prior and Concomitant Medications 
For the partial start date of medication: 
o If the year is present and the month and day are missing, then the month and day 
will be set to January 1. 
o If the year and day are present and the month is missing, then the month will be 
set to January. 
o If the year and month are present and the day is missing, then the day will be set 
to the 1st day of month. 
o If the imputed start date of medication is after the end date (imputed date if 
applicable) of medication, then the start date will be set to the end date of 
medication. 
For the partial end date of medication: 
o If the year is present and the month and day are missing, then the month and day 
will be set to either December 31 or date of death whichever is earlier. 


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o If the year and month are present and the day is missing, then the day will be set 
to the last day of the month or month of death. 
o If the year and day are present and the month is missing, then treat it as if the day 
is also missing.  Set the month and day to be either December 31 or date of death 
whichever is earlier.   
 
 
 
 


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11.4. 
Appendix D: List of Displays 
Tables  
Table Number 
Title 
Analysis Set 
Table 14.1.1.1 
Summary of Participant Disposition 
All Participants 
Table 14.1.1.2 
Summary of Analysis Sets 
All Participants 
Table 14.1.2.1 
Summary of Major Protocol Deviations 
Full Analysis Set 
Table 14.1.2.2 
Reasons for Exclusion from Analysis Sets 
Randomized Set 
Table 14.1.3.1.1 
Summary of Demographics and Baseline 
Characteristics 
Safety Set 
Table 14.1.3.1.2 
Summary of Demographics and Baseline 
Characteristics 
Full Analysis Set 
Table 14.1.3.1.3 
Summary of Baseline Subgroups 
Safety Set 
Table 14.1.3.1.4 
Summary of Baseline Subgroups 
Full Analysis Set 
Table 14.1.3.2.1 
Summary of Disease History 
Safety Set 
Table 14.1.3.3.1 
Summary of Medical and Surgical History 
Safety Set 
Table 14.1.3.3.2 
Summary of Medical and Surgical History ongoing at 
Screening 
Safety Set 
Table 14.1.3.3.3 
Summary of Participant History of Psychiatric 
Disorder 
Safety Set 
Table 14.1.3.3.4 
Summary of Family History of Postpartum 
Depression  
Safety Set 
Table 14.1.4.1 
Summary of Prior Non-Psychotropic Medications 
Safety Set 
Table 14.1.4.2 
Summary of Concomitant Non-Psychotropic 
Medications 
Safety Set 
Table 14.1.4.3 
Summary of On-treatment Concomitant Non-
Psychotropic Medications  
Safety Set 
Table 14.1.4.4 
Summary of Post-treatment Concomitant Non-
Psychotropic Medications 
Safety Set 
Table 14.1.4.5.1 
Summary of Prior Psychotropic Medications 
Safety Set 
Table 14.1.4.5.2 
Summary of Prior Psychotropic Medications by ATC 
Level 1 and Level 4 
Safety Set 
Table 14.1.4.6.1 
Summary of Concomitant Psychotropic Medications 
Safety Set 
Table 14.1.4.6.2 
Summary of Concomitant Psychotropic Medications 
by ATC Level 1 and Level 4 
Safety Set 
Table 14.1.4.7 
Summary of On-treatment Psychotropic Medications 
Safety Set 


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Table Number 
Title 
Analysis Set 
Table 14.1.4.8 
Summary of Post-treatment Psychotropic Medications 
Safety Set 
Table 14.1.4.9 
Summary of Use of Concomitant Antidepressant 
Medications 
Safety Set 
Table 14.1.4.10 
Summary of Investigational Product Exposure  
Safety Set 
Table 14.1.4.11 
Summary of Investigational Product Adherence 
Full Analysis Set 
Table 14.2.1.1.1 
Summary of Hamilton Rating Scale for Depression 
(HAM-D) Total Score by Study Visit 
Full Analysis Set 
Table 14.2.1.1.2 
Model-based Results on Change from Baseline in 
Hamilton Rating Scale for Depression (HAM-D) 
Total Score by Study Visit 
Full Analysis Set 
Table 14.2.1.1.3 
Model-based Sensitivity Analysis on Change from 
Baseline in Hamilton Rating Scale for Depression 
(HAM-D) Total Score at Day 15 (Missing Data 
Imputed Algorithmically Based on Reason of 
Missing) 
Full Analysis Set 
Table 14.2.1.1.4 
Summary of Hamilton Rating Scale for Depression 
(HAM-D) Total Score by Study Visit 
Per Protocol Set 
Table 14.2.1.1.5 
Model-based Results on Change from Baseline in 
Hamilton Rating Scale for Depression (HAM-D) 
Total Score by Study Visit 
Per Protocol Set 
Table 14.2.1.1.6 
Imputation Based on Study Withdrawal Reasons 
for Assessing MAR Assumption for Missing 
HAM-D Total Scores  
Full Analysis Set 
Table 14.2.1.1.7 
Tipping Point Analysis for Assessing Missing 
HAM-D total score 
Full Analysis Set 
Table 14.2.1.2.1 
Summary of Hamilton Rating Scale for Depression 
(HAM-D) Subscale Scores by Study Visit 
Full Analysis Set 
Table 14.2.1.2.2 
Model-based Results on Change from Baseline in 
Hamilton Rating Scale for Depression (HAM-D) 
Subscale Score by Study Visit 
Full Analysis Set 
Table 14.2.1.3.1 
Summary of Hamilton Rating Scale for Depression 
(HAM-D) Individual Item Score by Study Visit 
Full Analysis Set 
Table 14.2.1.3.2 
Model-based Results on Hamilton Rating Scale for 
Depression (HAM-D) Individual Item Score, Change 
from Baseline by Study Visit 
Full Analysis Set 
Table 14.2.1.4.1 
Summary of Hamilton Rating Scale for Depression 
(HAM-D) Response by Study Visit 
Full Analysis Set 
Table 14.2.1.4.2 
Model-based Results on Hamilton Rating Scale for 
Depression (HAM-D) Response by Study Visit 
Full Analysis Set 


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Table Number 
Title 
Analysis Set 
Table 14.2.1.4.3 
Sensitivity Analysis: Summary of Hamilton Rating 
Scale for Depression (HAM-D) Response by Study 
Visit  
Full Analysis Set 
Table 14.2.1.4.4 
Summary of Hamilton Rating Scale for Depression 
(HAM-D) Total Score - Percent Improvement - by 
Study Visit 
Full Analysis Set 
Table 14.2.1.4.5 
Summary of Time to First Hamilton Rating Scale for 
Depression (HAM-D) Response - Kaplan-Meier 
Analysis 
Full Analysis Set 
Table 14.2.1.5.1 
Summary of Hamilton Rating Scale for Depression 
(HAM-D) Remission by Study Visit 
Full Analysis Set 
Table 14.2.1.5.2 
Model-based Results on Hamilton Rating Scale for 
Depression (HAM-D) Remission by Study Visit 
Full Analysis Set 
Table 14.2.1.5.3 
Sensitivity Analysis: Summary of Hamilton Rating 
Scale for Depression (HAM-D) Remission by Study 
Visit 
Full Analysis Set 
Table 14.2.1.5.4 
Summary of Hamilton Rating Scale for Depression 
(HAM-D) Total Score in Categories, by Study Visit 
Full Analysis Set 
Table 14.2.1.5.5 
Summary of Time to First Hamilton Rating Scale for 
Depression (HAM-D) Remission - Kaplan-Meier 
Analysis 
Full Analysis Set 
Table 14.2.1.6.1 
Summary of Change from Baseline in HAM-D Total 
Score by Study Visit and Antidepressant Use at 
Baseline 
Full Analysis Set 
Table 14.2.1.6.2 
Model-based Results on Change from Baseline in 
Hamilton Rating Scale for Depression (HAM-D) 
Total Score by Study Visit and Antidepressant Use at 
Baseline 
Full Analysis Set 
Table 14.2.1.6.3 
Summary of Change from Baseline in HAM-D Total 
Score by Study Visit and Age Group 
Full Analysis Set 
Table 14.2.1.6.4 
Model-based Results on Change from Baseline in 
Hamilton Rating Scale for Depression (HAM-D) 
Total Score by Study Visit and Age Group 
Full Analysis Set 
Table 14.2.1.6.5 
Summary of Change from Baseline in HAM-D Total 
Score by Study Visit and Race 
Full Analysis Set 
Table 14.2.1.6.6 
Model-based Results on Change from Baseline in 
Hamilton Rating Scale for Depression (HAM-D) 
Total Score by Study Visit and Race  
Full Analysis Set 
Table 14.2.1.6.7 
Summary of Change from Baseline in HAM-D Total 
Score by Study Visit and BMI (kg/m2) Group 
Full Analysis Set 


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Table Number 
Title 
Analysis Set 
Table 14.2.1.6.8 
Model-based Results on Change from Baseline in 
Hamilton Rating Scale for Depression (HAM-D) 
Total Score by Study Visit and BMI (kg/m2)  Group 
Full Analysis Set 
Table 14.2.1.6.9 
Summary of Change from Baseline in HAM-D Total 
Score by Study Visit and Baseline HAM-D Total 
Score Category 
Full Analysis Set 
Table 14.2.1.6.10 
Model-based Results on Change from Baseline in 
Hamilton Rating Scale for Depression (HAM-D) 
Total Score by Study Visit and Baseline HAM-D 
Total Score Category 
Full Analysis Set 
Table 14.2.1.6.11 
Summary of Change from Baseline in HAM-D Total 
Score by Study Visit and Country 
Full Analysis Set 
Table 14.2.1.6.12 
Model-based Results on Change from Baseline in 
Hamilton Rating Scale for Depression (HAM-D) 
Total Score by Study Visit and Country 
Full Analysis Set 
Table 14.2.1.6.13 
Summary of Change from Baseline in HAM-D Total 
Score by Study Visit and Onset of PPD 
Full Analysis Set 
Table 14.2.1.6.14 
Model-based Results on Change from Baseline in 
Hamilton Rating Scale for Depression (HAM-D) 
Total Score by Study Visit and Onset of PPD 
Full Analysis Set 
Table 14.2.1.6.15 
Summary of Change from Baseline in HAM-D Total 
Score by Study Visit and History of PPD 
Full Analysis Set 
Table 14.2.1.6.16 
Model-based Results on Change from Baseline in 
Hamilton Rating Scale for Depression (HAM-D) 
Total Score by Study Visit and History of PPD 
Full Analysis Set 
Table 14.2.1.6.17 
Summary of Change from Baseline in HAM-D Total 
Score by Study Visit and Depression with elevated 
anxiety (by Baseline HAMA Total Score) 
Full Analysis Set 
Table 14.2.1.6.18 
Model-based Results on Change from Baseline in 
Hamilton Rating Scale for Depression (HAM-D) 
Total Score by Study Visit and Depression with 
elevated anxiety (by Baseline HAMA Total Score) 
Full Analysis Set 
Table 14.2.1.7.1 
Summary of HAM-D Response by Study Visit and 
Antidepressant Use at Baseline 
Full Analysis Set 
Table 14.2.1.7.2.1 
Model-based Results on Hamilton Rating Scale for 
Depression (HAM-D) Response by Study Visit and 
Antidepressant Use at Baseline 
Full Analysis Set 


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Table Number 
Title 
Analysis Set 
Table 14.2.1.7.2.2 
Sensitivity Analysis:  Model-based Results on 
Hamilton Rating Scale for Depression (HAM-D) 
Response by Study Visit and Antidepressant Use at 
Baseline 
Full Analysis Set 
Table 14.2.1.7.3 
Summary of Hamilton Rating Scale for Depression 
(HAM-D) Response by Study Visit and Depression 
with elevated anxiety (by Baseline HAMA Total 
Score) 
Full Analysis Set 
Table 14.2.1.7.4 
Model-based Results on Hamilton Rating Scale for 
Depression (HAM-D) Response by Study Visit and 
Depression with elevated anxiety (by Baseline HAMA 
Total Score) 
Full Analysis Set 
Table 14.2.1.7.5 
Weighted GEE Model-Based Results on Hamilton 
Rating Scale for Depression (HAM-D) Response by 
Study Visit 
Full Analysis Set 
Table 14.2.1.8.1 
Summary of HAM-D Remission by Study Visit and 
Antidepressant Use at Baseline 
Full Analysis Set 
Table 14.2.1.8.2.1 
Model-based Results on Hamilton Rating Scale for 
Depression (HAM-D) Remission by Study Visit and 
Antidepressant Use at Baseline 
Full Analysis Set 
Table 14.2.1.8.2.2 
Sensitivity Analysis: Model-based Results on 
Hamilton Rating Scale for Depression (HAM-D) 
Remission by Study Visit and Antidepressant Use at 
Baseline 
Full Analysis Set 
Table 14.2.1.8.3 
Summary of Hamilton Rating Scale for Depression 
(HAM-D) Remission by Study Visit and Depression 
with elevated anxiety (by Baseline HAMA Total 
Score) 
Full Analysis Set 
Table 14.2.1.8.4 
Model-based Results on Hamilton Rating Scale for 
Depression (HAM-D) Remission by Study Visit and 
Depression with elevated anxiety (by Baseline HAMA 
Total Score) 
Full Analysis Set 
Table 14.2.1.8.5 
Weighted GEE Model-Based Results on Hamilton 
Rating Scale for Depression (HAM-D) Remission by 
Study Visit 
Full Analysis Set 
Table 14.2.2.1.1 
Summary of Clinical Global Impression – 
Improvement (CGI-I) by Study Visit 
Full Analysis Set 
Table 14.2.2.1.2 
Summary of Clinical Global Impression – 
Improvement (CGI-I) by Study Visit – Categorical 
Results 
Full Analysis Set 


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Table Number 
Title 
Analysis Set 
Table 14.2.2.2.1 
Summary of Clinical Global Impression – 
Improvement (CGI-I) Response by Study Visit 
Full Analysis Set 
Table 14.2.2.2.2 
Model-based Results on Clinical Global Impression – 
Improvement (CGI-I) Response by Study Visit 
Full Analysis Set 
Table 14.2.2.2.3 
Sensitivity Analysis: Summary of Clinical Global 
Impression - Improvement (CGI-I) Response by Study 
Visit 
Full Analysis Set 
Table 14.2.2.2.4 
Weighted GEE Model-Based Results on Clinical 
Global Impression - Improvement (CGI-I) Response 
by Study Visit 
Full Analysis Set 
Table 14.2.2.2.5 
Summary of Clinical Global Impression - 
Improvement (CGI-I) Response by Study Visit and 
Depression with elevated anxiety (by Baseline HAMA 
Total Score) 
Full Analysis Set 
Table 14.2.2.2.6 
Model-based Results on Clinical Global Impression - 
Improvement (CGI-I) Response by Study Visit and 
Depression with Elevated Anxiety (by Baseline 
HAMA Total Score) 
Full Analysis Set 
Table 14.2.3.1.1 
Summary of Clinical Global Impression – Severity 
(CGI-S) Score by Study Visit 
Full Analysis Set 
Table 14.2.3.1.2 
Model-based Results on Change from Baseline in 
Clinical Global Impression - Severity (CGI-S) by 
Study Visit 
Full Analysis Set 
Table 14.2.3.1.3 
Summary of Clinical Global Impression – Severity 
(CGI-S) by Study Visit – Categorical Results 
Full Analysis Set 
Table 14.2.3.1.4 
Summary of Clinical Global Impression – Severity 
(CGI-S) Score by Study Visit and Depression with 
Elevated Anxiety (by Baseline HAMA Total Score) 
Full Analysis Set 
Table 14.2.3.1.5 
Model-based Results on Change from Baseline in 
Clinical Global Impression - Severity (CGI-S) by 
Study Visit and Depression with Elevated Anxiety (by 
Baseline HAMA Total Score) 
Full Analysis Set 
Table 14.2.4.1.1 
Summary of Hamilton Rating Scale for Anxiety 
(HAM-A) Total Score by Visit 
Full Analysis Set 
Table 14.2.4.1.2 
Model-based Results on Change from Baseline in 
Hamilton Rating Scale for Depression (HAM-A) 
Total Score by Study Visit 
Full Analysis Set 
Table 14.2.4.2.1 
Summary of Hamilton Rating Scale for Anxiety 
(HAM-A) Individual Item Score by Study Visit 
Full Analysis Set 


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Table Number 
Title 
Analysis Set 
Table 14.2.4.2.2 
Model-based on Results on Change from Baseline in 
Hamilton Rating Scale for Anxiety (HAM-A) 
Individual Item Score by Study Visit 
Full Analysis Set 
Table 14.2.5.1.1 
Summary of Montgomery-Asberg Depression Rating 
Scale (MADRS) Total Score by Study Visit 
Full Analysis Set 
Table 14.2.5.1.2 
Model-based Results on Change from Baseline in 
Montgomery-Asberg Depression Rating Scale 
(MADRS) Total Score by Study Visit 
Full Analysis Set 
Table 14.2.5.2.1 
Summary of Montgomery-Asberg Depression Rating 
Scale (MADRS) Individual Item Score by Study Visit 
Full Analysis Set 
Table 14.2.5.2.2 
Model-based Results on Change from Baseline in 
Montgomery-Asberg Depression Rating Scale 
(MADRS) Individual Item Score by Study Visit 
Full Analysis Set 
Table 14.2.5.3.1 
Summary of Montgomery-Asberg Depression Rating 
Scale (MADRS) Response by Study Visit 
Full Analysis Set 
Table 14.2.5.3.2 
Model-based Results on Montgomery-Asberg 
Depression Rating Scale (MADRS) Response by 
Study Visit 
Full Analysis Set 
Table 14.2.5.3.3 
Sensitivity Analysis: Montgomery-Asberg Depression 
Rating Scale (MADRS) Response by Study Visit 
Full Analysis Set 
Table 14.2.5.3.4 
Weighted GEE Model-Based Results on 
Montgomery-Asberg Depression Rating Scale 
(MADRS) Response by Study Visit 
Full Analysis Set 
Table 14.2.5.4.1 
Summary of Montgomery-Asberg Depression Rating 
Scale (MADRS) Remission by Study Visit 
Full Analysis Set 
Table 14.2.5.4.2 
Model-based Results on Montgomery-Asberg 
Depression Rating Scale (MADRS) Remission by 
Study Visit 
Full Analysis Set 
Table 14.2.5.4.3 
Sensitivity Analysis: Montgomery-Asberg Depression 
Rating Scale (MADRS) Remission by Study Visit 
Full Analysis Set 
Table 14.2.5.4.4 
Weighted GEE Model-Based Results on 
Montgomery-Asberg Depression Rating Scale 
(MADRS) Remission by Study Visit 
Full Analysis Set 
Table 14.2.6.1.1 
Summary of Patient Health Questionnaire (PHQ-9) 
Total Score by Study Visit 
Full Analysis Set 
Table 14.2.6.1.2 
Summary of Patient Health Questionnaire (PHQ-9) 
Total Score Category by Study Visit 
Full Analysis Set 


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Table Number 
Title 
Analysis Set 
Table 14.2.6.1.3 
Model-based Results on Change from Baseline in 
Patient Health Questionnaire (PHQ-9) Total Score by 
Study Visit 
Full Analysis Set 
Table 14.2.7.1.1 
Summary of Edinburgh Postpartum Depression Scale 
(EPDS) Total Score by Study Visit  
Full Analysis Set 
Table 14.2.7.1.2 
Model-based Results on Change from Baseline in 
Edinburgh Postpartum Depression Scale (EPDS) by 
Study Visit  
Full Analysis Set 
Table 14.2.8.1 
Summary of Hamilton Rating Scale for Depression 
(HAM-D) Percent Retention (%) of Day 15 Change 
from Baseline at Post-Day 15 Visits 
Full Analysis Set – 
Participants who 
Had HAM-D 
Improvement at 
Day 15  
Table 14.2.8.2 
Summary of Hamilton Rating Scale for Depression 
(HAM-D) Percent Retention (%) of Day 15 Change 
from Baseline at Post-Day 15 Visits 
Full Analysis Set - 
Day 15 HAM-D 
Responders Only 
Table 14.2.8.3 
Summary of Hamilton Rating Scale for Depression 
(HAM-D) Response at Post-Day 15 Visits, for HAM-
D Responders at Day 15 
Full Analysis Set - 
Day 15 HAM-D 
Responders Only 
Table 14.2.8.4 
Summary of Hamilton Rating Scale for Depression 
(HAM-D) Remission at Post-Day 15 Visits, for HAM-
D Remitters at Day 15 
Full Analysis Set - 
Day 15 HAM-D 
Remitters Only 
Table 14.2.8.5 
Summary of Hamilton Rating Scale for Depression 
(HAM-D) Relapse and Rebound Post-Day 15 Visits, 
for HAM-D Responders at Day 15 
Full Analysis Set - 
Day 15 HAM-D 
Responders Only 
Table 14.2.8.6 
Summary of Clinical Global Impression-Improvement 
(CGI-I) Response at Post-Day 15 Visits, for CGI 
Responders at Day 15 
Full Analysis Set – 
Day 15 CGI-I 
Responders Only 
Table 14.3.1.1 
Overview of Treatment-Emergent Adverse Events 
Safety Set 
Table 14.3.1.2 
Summary of Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.3.1 
Summary of On-Treatment Treatment Emergent 
Adverse Events by System Organ Class and Preferred 
Term 
Safety Set 
Table 14.3.1.3.2 
Summary of Post-Treatment-Emergent Adverse 
Events by System Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.4.1 
Summary of Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term, and Use of 
Antidepressant at Baseline 
Safety Set 


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Table Number 
Title 
Analysis Set 
Table 14.3.1.4.2 
Summary of Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term, and Age Group 
Safety Set 
Table 14.3.1.4.3 
Summary of Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term, and Race Group 
Safety Set 
Table 14.3.1.4.4 
Summary of Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term, and BMI at 
Baseline 
Safety Set 
Table 14.3.1.4.5 
Summary of Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term, and Baseline 
HAM-D Total Score 
Safety Set 
Table 14.3.1.4.6 
Summary of Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term, and Country 
Safety Set 
Table 14.3.1.5 
Summary of Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term, and Maximum 
Severity 
Safety Set 
Table 14.3.1.6 
Summary of Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term, and 
Relationship to Investigational Product 
Safety Set 
Table 14.3.1.7 
Summary of Treatment Period Treatment-Emergent 
Adverse Events Leading to Discontinuation of 
Investigational Product by System Organ Class and 
Preferred Term 
Safety Set 
Table 14.3.1.8 
Summary of Treatment-Emergent Adverse Events 
Leading to Withdrawal from the Study by System 
Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.9 
Summary of Treatment Emergent Adverse Events 
leading to Investigational Product Dose Reduction by 
System Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.9 
Summary of Treatment-Emergent Serious Adverse 
Events by System Organ Class and Preferred Term 
Safety Set 
Table 14.3.1.10 
Summary of Most Common (>2%) Treatment-
Emergent Adverse Events by Preferred Term 
Safety Set 


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Table Number 
Title 
Analysis Set 
 
Figures 


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Figure Number 
Title 
Analysis Set 
Figure 14.2.1.1 
 
Line Plot of LS Mean (±SE) Change from Baseline in 
Hamilton Rating Scale for Depression (HAM-D) 
Total Score Over Time by Treatment Group 
Full Analysis Set 
Figure 14.2.1.1.1 
 
Line Plot of LS Mean (±SE) Change from Baseline in 
Hamilton Rating Scale for Depression (HAM-D) 
Total Score over Time by Treatment Group and 
Antidepressant Use at Baseline 
Full Analysis Set 
Figure 14.2.1.2 
 
Forest Plot of LS Mean (95% CI) Change from 
Baseline in Hamilton Rating Scale for Depression 
(HAM-D) Total Score by Treatment Group and 
Subgroups on Day 15 
Full Analysis Set 
Figure 14.2.1.3.1 
 
Bar Chart of Hamilton Rating Scale for Depression 
(HAM-D) Response over Time 
Full Analysis Set 
Figure 14.2.1.3.2 
 
Sensitivity Analysis: Bar Chart of Hamilton Rating 
Scale for Depression (HAM-D) Response over Time 
Full Analysis Set 
Figure 14.2.1.3.3 
 
Bar Chart of Hamilton Rating Scale for Depression 
(HAM-D) Response over Time by Antidepressant Use 
at Baseline 
Full Analysis Set 
Figure 14.2.1.3.4 
 
Sensitivity Analysis: Bar Chart of Hamilton Rating 
Scale for Depression (HAM-D) Response over Time 
by Antidepressant Use at Baseline 
Full Analysis Set 
Figure 14.2.1.4 
 
Histogram of Hamilton Rating Scale for Depression 
(HAM-D) Percentage Improvement over Time 
Full Analysis Set 
Figure 14.2.1.5.1 
 
Bar Chart of Hamilton Rating Scale for Depression 
(HAM-D) Remission over Time 
Full Analysis Set 
Figure 14.2.1.5.2 
 
Sensitivity Analysis: Bar Chart of Hamilton Rating 
Scale for Depression (HAM-D) Remission over Time 
Full Analysis Set 
Figure 14.2.1.5.3 
 
Bar Chart of Hamilton Rating Scale for Depression 
(HAM-D) Remission over Time by Antidepressant 
Use at Baseline 
Full Analysis Set 
Figure 14.2.1.5.4 
 
Sensitivity Analysis: Bar Chart of Hamilton Rating 
Scale for Depression (HAM-D) Remission over Time 
by Antidepressant Use at Baseline 
Full Analysis Set 
Figure 14.2.1.6 
 
Histogram of Hamilton Rating Scale for Depression 
(HAM-D) Total Score in Categories over Time 
Per Protocol Set 
Figure 14.2.1.7 
 
Forest Plot of LS Mean (95% CI) Change from 
Baseline in Hamilton Rating Scale for Depression 
(HAM-D) Subscales on Day 15 by Treatment Group  
Full Analysis Set 


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Figure Number 
Title 
Analysis Set 
Figure 14.2.1.8 
 
Forest Plot of LS Mean (95% CI) Change from 
Baseline at Day 15 in Hamilton Rating Scale for 
Depression (HAM-D) for Individual Items by 
Treatment Group  
Full Analysis Set 
Figure 14.2.2 
 
Bar Chart of CGI-I Response over Time by Treatment 
Group 
Full Analysis Set 
Figure 14.2.3 
 
Line Plot of LS Mean (±SE) Change from Baseline in 
CGI-S over Time by Treatment Group 
 Full Analysis Set 
Figure 14.2.4 
 
Line Plot of LS Mean (±SE) Change from Baseline in 
Hamilton Rating Scale for Anxiety (HAM-A) Total 
Score over Time by Treatment Group 
Full Analysis Set 
Figure 14.2.5 
 
Line Plot of LS Mean (±SE) Change from Baseline in 
Montgomery-Åsberg Depression Rating Scale 
(MADRS) Total Score over Time by Treatment Group 
Full Analysis Set 
Figure 14.2.5.1.1 
Bar Chart of Montgomery-Åsberg Depression Rating 
Scale (MADRS) Response over Time 
Full Analysis Set 
Figure 14.2.5.1.2 
Sensitivity Analysis: Bar Chart of Montgomery-
Åsberg Depression Rating Scale (MADRS) Response 
over Time 
Full Analysis Set 
Figure 14.2.5.2.1 
Bar Chart of Montgomery-Åsberg Depression Rating 
Scale (MADRS) Remission over Time 
Full Analysis Set 
Figure 14.2.5.2.2 
Sensitivity Analysis: Bar Chart of Montgomery-
Åsberg Depression Rating Scale (MADRS) Remission 
over Time 
Full Analysis Set 
Figure 14.2.6 
 
Line Plot of Hamilton Rating Scale for Depression 
(HAM-D) Percent Retention (%) of Day 15 Change 
from Baseline over Time 
Full Analysis Set – 
Participants who 
Had HAM-D 
Improvement at 
Day 15  
Figure 14.2.7 
 
Line Plot of Hamilton Rating Scale for Depression 
(HAM-D) Percent Retention (%) of Day 15 Reduction 
from Baseline over Time, for HAM-D Responders at 
Day 15 
Full Analysis Set- 
Day 15 HAM-D 
Responders Only  
 
Figure 14.2.8 
 
Bar Chart of Hamilton Rating Scale for Depression 
(HAM-D) Response at Post-Day 15 Visits, for HAM-
D Responders at Day 15 
Full Analysis Set- 
Day 15 HAM-D 
Responders Only 
Figure 14.2.9 
 
Bar Chart of Hamilton Rating Scale for Depression 
(HAM-D) Remission at Post-Day 15 Visits, for HAM-
D Remitters at Day 15 
Full Analysis Set- 
Day 15 HAM-D 
Remitters Only 


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Figure Number 
Title 
Analysis Set 
Figure 14.2.10 
Bar Chart of Clinical Global Impression-Improvement 
(CGI-I) Response at Post-Day 15 Visits, for CGI-I 
Responders at Day 15 
Full Analysis Set- 
Day 15 CGI-I 
Responders Only 
Figure 14.2.11 
 
Line Plot of LS Mean (±SE) Change from 
Baseline in Edinburgh Postpartum Depression 
Scale (EPDS) 
Full Analysis Set 
 
 
Listings 
Listing Number 
Title 
Analysis Set 
Listing 16.1.7 
Participant Randomization 
Randomized Set 
Listing 16.2.1.1 
Participant Disposition 
Randomized Set 
Listing 16.2.1.2 
Premature Discontinuation from Investigational 
Product and/or Withdrawal from the Study 
Safety Set 
Listing 16.2.2.1.1 
Protocol Deviations 
Full Analysis Set 
Listing 16.2.2.1.2 
A Listing of All Participants Affected by the COVID-
19 Related Study Disruptions 
Full Analysis Set 
Listing 16.2.2.2 
Inappropriate Investigational Product Consumption 
Safety Set 
Listing 16.2.3.1 
Inclusion/Exclusion Criteria Violations 
Randomized Set 
Listing 16.2.4.1 
Demographics 
Safety Set 
Listing 16.2.4.2 
Baseline Characteristics 
Safety Set 
Listing 16.2.4.2.1 
Incorrect Stratification related to Antidepressant Use 
at Baseline 
Safety Set 
Listing 16.2.4.2.2 
Diagnostic Laboratory Results 
Safety Set 
Listing 16.2.4.3.1 
Disease History 
Safety Set 
Listing 16.2.4.3.2 
Medical and Surgical History 
Safety Set 
Listing 16.2.4.3.3 
Participant History of Psychiatric Disorder 
Safety Set 
Listing 16.2.4.3.4 
Family History of Postpartum Depression 
Safety Set 
Listing 16.2.4.4.1 
Prior and Concomitant Psychotropic Medications 
Safety Set 
Listing 16.2.4.4.2 
Prior and Concomitant Non-Psychotropic Medications 
Safety Set 
Listing 16.2.4.4.3 
Listing of Use of Antidepressant during the Study 
Safety Set 


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Listing Number 
Title 
Analysis Set 
Listing 16.2.4.4.4 
Concomitant Procedures 
Safety Set 
Listing 16.2.5.1 
Investigational Product Administration 
Safety Set 
Listing 16.2.5.2 
Investigational Product Exposure 
Safety Set 
Listing 16.2.5.3 
Investigational Product Adherence 
Full Analysis Set 
Listing 16.2.6.1 
Hamilton Rating Scale for Depression (HAM-D) 
Full Analysis Set 
Listing 16.2.6.2 
Clinical Global Impression (CGI) – Improvement 
Full Analysis Set 
Listing 16.2.6.3 
Clinical Global Impression (CGI) – Severity 
Full Analysis Set 
Listing 16.2.6.4 
Hamilton Anxiety Rating Scale (HAM-A) 
Full Analysis Set 
Listing 16.2.6.5 
Montgomery-Asberg Depression Rating Scale 
(MADRS) 
Full Analysis Set 
Listing 16.2.6.6 
Summary of Edinburgh Postpartum Depression Scale 
(EPDS) Individual Item Scores 
Full Analysis Set 
Listing 16.2.6.7 
Patient Health Questionnaire (PHQ-9) 
Full Analysis Set 
Listing 16.2.6.8 
Hamilton Rating Scale for Depression (HAM-D) with 
Response Retention (%), Response, Remission, 
Relapse and Rebound   
Full Analysis Set, 
SAGE-217 Only 
Listing 16.2.7.1 
Treatment-Emergent Adverse Events 
Safety Set 
Listing 16.2.7.2 
Non-fatal Serious Adverse Events 
Safety Set 
Listing 16.2.7.3 
Adverse Events Leading to Death 
Safety Set 
Listing 16.2.7.4 
Adverse Events with Onset Prior to First Dose of 
Investigational Product 
Safety Set 
Listing 16.2.7.5 
Adverse Events leading to Premature Discontinuation 
of Investigational Product 
Safety Set 
Listing 16.2.7.6 
Adverse Events leading to Premature Withdrawal 
from the Study 
Safety Set 
Listing 16.2.7.7 
Listing of Adverse Events Experienced by 
Participants with Investigational Product Dose 
Reduction due to Adverse Events 
Safety Set 
Listing 16.2.7.8 
Listing of Participants with COVID-19 Related 
Adverse Events  
Safety Set 


Statistical Analysis Plan Methods 11April 2022 Final Version 1.0 
Page 67 
Protocol Number: SAGE-217-PPD-301 
 
 
Sage Therapeutics Inc. 
Confidential Information 
 
Listing Number 
Title 
Analysis Set 
Listing 16.2.8.1.6 
Pregnancy Test 
Safety Set 
Listing 16.2.8.4 
Physical Examination 
Safety Set