A Randomized, Double-Blind, Placebo-controlled Study Evaluating the Efficacy and Safety of SAGE-217 in the Treatment of Adults With Severe Postpartum Depression
Phase: PHASE3
Conditions: Depression, Postpartum
Sponsor: Biogen

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 

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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 
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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 
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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. 
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